Patent Publication Number: US-2006009633-A9

Title: Complementary DNAs encoding proteins with signal peptides

Description:
RELATED U.S. APPLICATION DATA  
      The present application is a continuation-in-part of:  
      U.S. CIP application Ser. No. 09/663,600, filed Sep. 15, 2000, and claims priority from U.S. application Ser. No. 09/191,997, filed Nov. 13, 1998; U.S. Provisional Application Serial No. 60/066,677, filed Nov. 13, 1997; U.S. Provisional Application Serial No. 60/069,957, filed Dec. 17, 1997; U.S. Provisional Application Serial No. 60/074,121, filed Feb. 9, 1998; U.S. Provisional Application Serial No. 60/081,563, filed Apr. 13, 1998; U.S. Provisional Application Serial No. 60/096,116, filed Aug. 10, 1998, and U.S. Provisional Application Serial No. 60/099,273, filed Sep. 4, 1998, the entireties of which are hereby incorporated by reference;  
      U.S. patent application Ser. No. 09/215,435 and PCT Application PCT/IB98/02122, filed Dec. 17, 1998, and claims priority from U.S. Provisional Patent Application Serial No. 60/069,957, filed Dec. 17, 1997; U.S. Provisional Patent Application Serial No. 60/074,121, filed Feb. 9, 1998; U.S. Provisional Patent Application Serial No. 60/081,563, filed Apr. 13, 1998; U.S. Provisional Patent Application Serial No. 60/096,116, filed Aug. 10, 1998; and U.S. Provisional Patent Application Serial No. 60/099,273, filed Sep. 4, 1998, the disclosures of which are incorporated herein by reference in their entirety;  
      U.S. patent application Ser. No. 09/247,155 and PCT Application PCT/IB99/00282 filed Feb. 9, 1999, and claims priority from U.S. Provisional Patent Application Serial No. 60/074,121, filed Feb. 9, 1998; U.S. Provisional Patent Application Serial No. 60/081,563, filed Apr. 13, 1998; U.S. Provisional Patent Application Serial No. 60/096,116, filed Aug. 10, 1998; and U.S. Provisional Patent Application Serial No. 60/099,273, filed Sep. 4, 1998, the disclosures of which are incorporated herein by reference in their entirety; and  
      U.S. CIP application Ser. No. 09/599,360 and PCT Application PCT/1B00/00951 filed Jun. 21, 2000, and claims priority from U.S. application Ser. No. 09/469,099, filed Dec. 21, 1999; U.S. Provisional Patent Application Serial No. 60/113,686, filed Dec. 22, 1998; and U.S. Provisional Patent Application Serial No. 60/141,032, filed Jun. 25, 1999, the disclosures of which are incorporated herein by reference in their entireties.  
    
    
     BACKGROUND OF THE INVENTION  
      The estimated 50,000-100,000 genes scattered along the human chromosomes offer tremendous promise for the understanding, diagnosis, and treatment of human diseases. In addition, probes capable of specifically hybridizing to loci distributed throughout the human genome find applications in the construction of high resolution chromosome maps and in the identification of individuals.  
      In the past, the characterization of even a single human gene was a painstaking process, requiring years of effort. Recent developments in the areas of cloning vectors, DNA sequencing, and computer technology have merged to greatly accelerate the rate at which human genes can be isolated, sequenced, mapped, and characterized.  
      Currently, two different approaches are being pursued for identifying and characterizing the genes distributed along the human genome. In one approach, large fragments of genomic DNA are isolated, cloned, and sequenced. Potential open reading frames in these genomic sequences are identified using bio-informatics software. However, this approach entails sequencing large stretches of human DNA which do not encode proteins in order to find the protein encoding sequences scattered throughout the genome. In addition to requiring extensive sequencing, the bio-informatics software may mischaracterize the genomic sequences obtained, i.e., labeling non-coding DNA as coding DNA and vice versa.  
      An alternative approach takes a more direct route to identifying and characterizing human genes. In this approach, complementary DNAs (cDNAs) are synthesized from isolated messenger RNAs (mRNAs) which encode human proteins. Using this approach, sequencing is only performed on DNA which is derived from protein coding fragments of the genome. Often, only short stretches of the cDNAs are sequenced to obtain sequences called expressed sequence tags (ESTs). The ESTs may then be used to isolate or purify cDNAs which include sequences adjacent to the EST sequences. The cDNAs may contain all of the sequence of the EST which was used to obtain them or only a fragment of the sequence of the EST which was used to obtain them. In addition, the cDNAs may contain the full coding sequence of the gene from which the EST was derived or, alternatively, the cDNAs may include fragments of the coding sequence of the gene from which the EST was derived. It will be appreciated that there may be several cDNAs which include the EST sequence as a result of alternate splicing or the activity of alternative promoters.  
      In the past, these short EST sequences were often obtained from oligo-dT primed cDNA libraries. Accordingly, they mainly corresponded to the 3′ untranslated region of the mRNA. In part, the prevalence of EST sequences derived from the 3′ end of the mRNA is a result of the fact that typical techniques for obtaining cDNAs, are not well suited for isolating cDNA sequences derived from the 5′ ends of mRNAs (Adams et al.,  Nature  377:3-174, 1996, Hillier et al.,  Genome Res.  6:807-828, 1996). In addition, in those reported instances where longer cDNA sequences have been obtained, the reported sequences typically correspond to coding sequences and do not include the full 5′ untranslated region (5′UTR) of the mRNA from which the cDNA is derived. Indeed, 5′UTRs have been shown to affect either the stability or translation of mRNAs. Thus, regulation of gene expression may be achieved through the use of alternative 5′UTRs as shown, for instance, for the translation of the tissue inhibitor of metalloprotease mRNA in mitogenically activated cells (Waterhouse et al.,  J Biol. Chem.  265:5585-9. 1990). Furthermore, modification of 5′UTR through mutation, insertion or translocation events may even be implied in pathogenesis. For instance, the fragile X syndrome, the most common cause of inherited mental retardation, is partly due to an insertion of multiple CGG trinucleotides in the 5′UTR of the fragile X mRNA resulting in the inhibition of protein synthesis via ribosome stalling (Feng et al.,  Science  268:731-4, 1995). An aberrant mutation in regions of the 5′UTR known to inhibit translation of the proto-oncogene c-myc was shown to result in upregulation of c-myc protein levels in cells derived from patients with multiple myelomas (Willis et al.,  Curr Top Microbiol Immunol  224:269-76, 1997). In addition, the use of oligo-dT primed cDNA libraries does not allow the isolation of complete 5′UTRs since such incomplete sequences obtained by this process may not include the first exon of the mRNA, particularly in situations where the first exon is short. Furthermore, they may not include some exons, often short ones, which are located upstream of splicing sites. Thus, there is a need to obtain sequences derived from the 5′ ends of mRNAs.  
      Moreover, despite the great amount of EST data that large-scale sequencing projects have yielded (Adams et al.,  Nature  377:174, 1996, Hillier et al.,  Genome Res.  6:807-828, 1996), information concerning the biological function of the mRNAs corresponding to such obtained cDNAs has revealed to be limited. Indeed, whereas the knowledge of the complete coding sequence is absolutely necessary to investigate the biological function of mRNAs, ESTs yield only partial coding sequences. So far, large-scale full-length cDNA cloning has been achieved only with limited success because of the poor efficiency of methods for constructing full-length cDNA libraries. Indeed, such methods require either a large amount of mRNA (Ederly et al., 1995), thus resulting in non representative full-length libraries when small amounts of tissue are available or require PCR amplification (Maruyama et al., 1994; CLONTECHniques, 1996) to obtain a reasonable number of clones, thus yielding strongly biased cDNA libraries where rare and long cDNAs are lost. Thus, there is a need to obtain full-length cDNAs, i.e. cDNAs containing the full coding sequence of their corresponding mRNAs.  
      While many sequences derived from human chromosomes have practical applications, approaches based on the identification and characterization of those chromosomal sequences which encode a protein product are particularly relevant to diagnostic and therapeutic uses. Of the 50,000-100,000 protein coding genes, those genes encoding proteins which are secreted from the cell in which they are synthesized, as well as the secreted proteins themselves, are particularly valuable as potential therapeutic agents. Such proteins are often involved in cell to cell communication and may be responsible for producing a clinically relevant response in their target cells. In fact, several secretory proteins, including tissue plasminogen activator, G-CSF, GM-CSF, erythropoietin, human growth hormone, insulin, interferon-α, interferon-β, interferon-γ, and interleukin-2, are currently in clinical use. These proteins are used to treat a wide range of conditions, including acute myocardial infarction, acute ischemic stroke, anemia, diabetes, growth hormone deficiency, hepatitis, kidney carcinoma, chemotherapy induced neutropenia and multiple sclerosis. For these reasons, cDNAs encoding secreted proteins or fragments thereof represent a particularly valuable source of therapeutic agents. Thus, there is a need for the identification and characterization of secreted proteins and the nucleic acids encoding them.  
      In addition to being therapeutically useful themselves, secretory proteins include short peptides, called signal peptides, at their amino termini which direct their secretion. These signal peptides are encoded by the signal sequences located at the 5′ ends of the coding sequences of genes encoding secreted proteins. Because these signal peptides will direct the extracellular secretion of any protein to which they are operably linked, the signal sequences may be exploited to direct the efficient secretion of any protein by operably linking the signal sequences to a gene encoding the protein for which secretion is desired. In addition, fragments of the signal peptides called membrane-translocating sequences, may also be used to direct the intracellular import of a peptide or protein of interest. This may prove beneficial in gene therapy strategies in which it is desired to deliver a particular gene product to cells other than the cells in which it is produced. Signal sequences encoding signal peptides also find application in simplifying protein purification techniques. In such applications, the extracellular secretion of the desired protein greatly facilitates purification by reducing the number of undesired proteins from which the desired protein must be selected. Thus, there exists a need to identify and characterize the 5′ fragments of the genes for secretory proteins which encode signal peptides.  
      Sequences coding for secreted proteins may also find application as therapeutics or diagnostics. In particular, such sequences may be used to determine whether an individual is likely to express a detectable phenotype, such as a disease, as a consequence of a mutation in the coding sequence for a secreted protein. In instances where the individual is at risk of suffering from a disease or other undesirable phenotype as a result of a mutation in such a coding sequence, the undesirable phenotype may be corrected by introducing a normal coding sequence using gene therapy. Alternatively, if the undesirable phenotype results from overexpression of the protein encoded by the coding sequence, expression of the protein may be reduced using antisense or triple helix based strategies.  
      The secreted human polypeptides encoded by the coding sequences may also be used as therapeutics by administering them directly to an individual having a condition, such as a disease, resulting from a mutation in the sequence encoding the polypeptide. In such an instance, the condition can be cured or ameliorated by administering the polypeptide to the individual.  
      In addition, the secreted human polypeptides or fragments thereof may be used to generate antibodies useful in determining the tissue type or species of origin of a biological sample. The antibodies may also be used to determine the cellular localization of the secreted human polypeptides or the cellular localization of polypeptides which have been fused to the human polypeptides. In addition, the antibodies may also be used in immunoaffinity chromatography techniques to isolate, purify, or enrich the human polypeptide or a target polypeptide which has been fused to the human polypeptide.  
      Public information on the number of human genes for which the promoters and upstream regulatory regions have been identified and characterized is quite limited. In part, this may be due to the difficulty of isolating such regulatory sequences. Upstream regulatory sequences such as transcription factor binding sites are typically too short to be utilized as probes for isolating promoters from human genomic libraries. Recently, some approaches have been developed to isolate human promoters. One of them consists of making a CpG island library (Cross et al.,  Nature Genetics  6: 236-244, 1994). The second consists of isolating human genomic DNA sequences containing SpeI binding sites by the use of SpeI binding protein. (Mortlock et al.,  Genome Res.  6:327-335, 1996). Both of these approaches have their limits due to a lack of specificity and of comprehensiveness. Thus, there exists a need to identify and systematically characterize the 5′ fragments of the genes.  
      cDNAs including the 5′ ends of their corresponding mRNA may be used to efficiently identify and isolate 5′UTRs and upstream regulatory regions which control the location, developmental stage, rate, and quantity of protein synthesis, as well as the stability of the mRNA (Theil et al.,  BioFactors  4:87-93, (1993). Once identified and characterized, these regulatory regions may be utilized in gene therapy or protein purification schemes to obtain the desired amount and locations of protein synthesis or to inhibit, reduce, or prevent the synthesis of undesirable gene products.  
      In addition, cDNAs containing the 5′ ends of secretory protein genes may include sequences useful as probes for chromosome mapping and the identification of individuals. Thus, there is a need to identify and characterize the sequences upstream of the 5′ coding sequences of genes encoding secretory proteins.  
     SUMMARY OF THE INVENTION  
      The present invention relates to purified, isolated, or recombinant cDNAs which encode secreted proteins or fragments thereof. Preferably, the purified, isolated or recombinant cDNAs contain the entire open reading frame of their corresponding mRNAs, including a start codon and a stop codon. For example, the cDNAs may include nucleic acids encoding the signal peptide as well as the mature protein. Such cDNAs will be referred herein as “full-length” cDNAs. Alternatively, the cDNAs may contain a fragment of the open reading frame. Such cDNAs will be referred herein as “ESTs” or “5′ESTs”. In some embodiments, the fragment may encode only the sequence of the mature protein. Alternatively, the fragment may encode only a fragment of the mature protein. A further aspect of the present invention is a nucleic acid which encodes the signal peptide of a secreted protein.  
      The term “corresponding mRNA” refers to the mRNA which was the template for the cDNA synthesis which produced the cDNA of the present invention.  
      As used herein, the term “purified” does not require absolute purity; rather, it is intended as a relative definition. Purification of starting material or natural material is at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. As an example, purification from 0.1% concentration to 10% concentration is two orders of magnitude.  
      To illustrate, individual cDNA clones isolated from a cDNA library have been conventionally purified to electrophoretic homogeneity. The sequences obtained from these clones could not be obtained directly either from the library or from total human DNA. The cDNA clones are not naturally occurring as such, but rather are obtained via manipulation of a partially purified naturally occurring substance (messenger RNA). The conversion of mRNA into a cDNA library involves the creation of a synthetic substance (cDNA) and pure individual cDNA clones can be isolated from the synthetic library by clonal selection. Thus, creating a cDNA library from messenger RNA and subsequently isolating individual clones from that library results in an approximately 10 4 - 10   6  fold purification of the native message.  
      The term “purified” is further used herein to describe a polypeptide or polynucleotide of the invention which has been separated from other compounds including, but not limited to, polypeptides or polynucleotides, carbohydrates, lipids, etc. The term “purified” may be used to specify the separation of monomeric polypeptides of the invention from oligomeric forms such as homo- or hetero-dimers, trimers, etc. The term “purified” may also be used to specify the separation of covalently closed polynucleotides from linear polynucleotides. A polynucleotide is substantially pure when at least about 50%, preferably 60 to 75% of a sample exhibits a single polynucleotide sequence and conformation (linear versus covalently close). A substantially pure polypeptide or polynucleotide typically comprises about 50%, preferably 60 to 90% weight/weight of a polypeptide or polynucleotide sample, respectively, more usually about 95%, and preferably is over about 99% pure. Polypeptide and polynucleotide purity, or homogeneity, is indicated by a number of means well known in the art, such as agarose or polyacrylamide gel electrophoresis of a sample, followed by visualizing a single band upon staining the gel. For certain purposes higher resolution can be provided by using HPLC or other means well known in the art. As an alternative embodiment, purification of the polypeptides and polynucleotides of the present invention may be expressed as “at least” a percent purity relative to heterologous polypeptides and polynucleotides (DNA, RNA or both). As a preferred embodiment, the polypeptides and polynucleotides of the present invention are at least; 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 96%, 98%, 99%, or 100% pure relative to heterologous polypeptides and polynucleotides, respectively. As a further preferred embodiment the polypeptides and polynucleotides have a purity ranging from any number, to the thousandth position, between 90% and 100% (e.g., a polypeptide or polynucleotide at least 99.995% pure) relative to either heterologous polypeptides or polynucleotides, respectively, or as a weight/weight ratio relative to all compounds and molecules other than those existing in the carrier. Each number representing a percent purity, to the thousandth position, may be claimed as individual species of purity.  
      As used herein, the term “recombinant polynucleotide” means that the cDNA is adjacent to “backbone” nucleic acid to which it is not adjacent in its natural environment. Additionally, to be “enriched” the cDNAs will represent 5% or more of the number of nucleic acid inserts in a population of nucleic acid backbone molecules. Backbone molecules according to the present invention include nucleic acids such as expression vectors, self-replicating nucleic acids, viruses, integrating nucleic acids, and other vectors or nucleic acids used to maintain or manipulate a nucleic acid insert of interest. Preferably, the enriched cDNAs represent 15% or more of the number of nucleic acid inserts in the population of recombinant backbone molecules. More preferably, the enriched cDNAs represent 50% or more of the number of nucleic acid inserts in the population of recombinant backbone molecules. In a highly preferred embodiment, the enriched cDNAs represent 90% or more (including any number between 90 and 100%, to the thousandth position, e.g., 99.5%) of the number of nucleic acid inserts in the population of recombinant backbone molecules.  
      Unless otherwise specified, nucleotides and amino acids of polynucleotide and polypeptide fragments (respectively) of the present invention are contiguous and not interrupted by heterologous sequences.  
      The term “isolated” requires that the material be removed from its original environment (e.g., the natural environment if it is naturally occurring). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or DNA or polypeptide, separated from some or all of the coexisting materials in the natural system, is isolated. Such polynucleotide could be part of a vector and/or such polynucleotide or polypeptide could be part of a composition, and still be isolated in that the vector or composition is not part of its natural environment. Specifically excluded from the definition of “isolated” are: naturally occurring chromosomes (such as chromosome spreads), artificial chromosome libraries, genomic libraries, and cDNA libraries that exist either as an in vitro nucleic acid preparation or as a transfected/transformed host cell preparation, wherein the host cells are either an in vitro heterogeneous preparation or plated as a heterogeneous population of single colonies, and/or further wherein the polynucleotide of the present invention makes up less than 5% (or alternatively 1%, 2%, 3%, 4%, 10%, 25%, 50%, 75%, or 90%, 95%, or 99%) of the number of nucleic acid inserts in the vector molecules. Further specifically excluded are whole cell genomic DNA or whole cell RNA preparations (including said whole cell preparations which are mechanically sheared or enzymaticly digested). Further specifically excluded are the above whole cell preparations as either an in vitro preparation or as a heterogeneous mixture separated by electrophoresis (including blot transfers of the same) wherein the polynucleotide of the invention have not been further separated from the heterologous polynucleotides in the electrophoresis medium (e.g., further separating by excising a single band from a heterogeneous band population in an agarose gel or nylon blot).  
      Thus, cDNAs encoding secreted polypeptides or fragments thereof which are present in cDNA libraries in which one or more cDNAs encoding secreted polypeptides or fragments thereof make up 5% or more of the number of nucleic acid inserts in the backbone molecules are “enriched recombinant cDNAs” as defined herein. Likewise, cDNAs encoding secreted polypeptides or fragments thereof which are in a population of plasmids in which one or more cDNAs of the present invention have been inserted such that they represent 5% or more of the number of inserts in the plasmid backbone are “enriched recombinant cDNAs” as defined herein. However, cDNAs encoding secreted polypeptides or fragments thereof which are in cDNA libraries in which the cDNAs encoding secreted polypeptides or fragments thereof constitute less than 5% of the number of nucleic acid inserts in the population of backbone molecules, such as libraries in which backbone molecules having a cDNA insert encoding a secreted polypeptide are extremely rare, are not “enriched recombinant cDNAs.” 
      The term “polypetide” refers to a polymer of amino acids without regard to the length of the polymer; thus, “peptides,” “oligopeptides”, and “proteins” are included within the definition of polypeptide and used interchangeably herein. This term also does not specify or exclude chemical or post-expression modifications of the polypeptides of the invention, although chemical or post-expression modifications of these polypeptides may be included or excluded as specific embodiments. Therefore, for example, modifications to polypeptides that include the covalent attachment of glycosyl groups, acetyl groups, phosphate groups, lipid groups and the like are expressly encompassed by the term polypeptide. Further, polypeptides with these modifications may be specified as individual species to be included or excluded from the present invention. The natural or other chemical modifications, such as those listed in examples above can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12, 1983; Seifter et al., Meth Enzymol 182:626-646, 1990; Rattan et al., Ann NY Acad Sci 663:48-62, 1992). Also included within the definition are polypeptides which contain one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.), polypeptides with substituted linkages, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. The term “polypeptide” may also be used interchangeably with the term “protein”.  
      As used interchangeably herein, the terms “nucleic acid molecule”, “oligonucleotides”, and “polynucleotides” include RNA or, DNA (either single or double stranded, coding, non-coding, complementary or antisense), or RNA/DNA hybrid sequences of more than one nucleotide in either single chain or duplex form (although each of the above species may be particularly specified). The term “nucleotide” as used herein as an adjective to describe molecules comprising RNA, DNA, or RNA/DNA hybrid sequences of any length in single-stranded or duplex form. The term “nucleotide” is also used herein as a noun to refer to individual nucleotides or varieties of nucleotides, meaning a molecule, or individual unit in a larger nucleic acid molecule, comprising a purine or pyrimidine, a ribose or deoxyribose sugar moiety, and a phosphate group, or phosphodiester linkage in the case of nucleotides within an oligonucleotide or polynucleotide. The term “nucleotide” is also used herein to encompass “modified nucleotides” which comprise at least one modifications (a) an alternative linking group, (b) an analogous form of purine, (c) an analogous form of pyrimidine, or (d) an analogous sugar; for examples of analogous linking groups, purine, pyrimidines, and sugars see for example PCT publication No. WO 95/04064. Preferred modifications of the present invention include, but are not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v) ybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, and 2,6-diaminopurine. Methylenemethylimino linked oligonucleosides as well as mixed backbone compounds having, may be prepared as described in U.S. Pat. Nos. 5,378,825; 5,386,023; 5,489,677; 5,602,240; and 5,610,289. Formacetal and thioformacetal linked oligonucleosides may be prepared as described in U.S. Pat. Nos. 5,264,562 and 5,264,564. Ethylene oxide linked oligonucleosides may be prepared as described in U.S. Pat. No. 5,223,618. Phosphinate oligonucleotides may be prepared as described in U.S. Pat. No. 5,508,270. Alkyl phosphonate oligonucleotides may be prepared as described in U.S. Pat. No. 4,469,863. 3′-Deoxy-3′-methylene phosphonate oligonucleotides may be prepared as described in U.S. Pat. Nos. 5,610,289 or 5,625,050. Phosphoramidite oligonucleotides may be prepared as described in U.S. Pat. No. 5,256,775 or U.S. Pat. No. 5,366,878. Alkylphosphonothioate oligonucleotides may be prepared as described in published PCT applications WO 94/17093 and WO 94/02499. 3′-Deoxy-3′-amino phosphoramidate oligonucleotides may be prepared as described in U.S. Pat. No. 5,476,925. Phosphotriester oligonucleotides may be prepared as described in U.S. Pat. No. 5,023,243. Borano phosphate oligonucleotides may be prepared as described in U.S. Pat. Nos. 5,130,302 and 5,177,198.  
      In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2 kb, 1.5 kb, or 1 kb in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5′ or 3′ to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 75, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).  
      The polynucleotide sequences of the invention may be prepared by any known method, including synthetic, recombinant, ex vivo generation, or a combination thereof, as well as utilizing any purification methods known in the art.  
      The terms “comprising”, “consisting of” and “consisting essentially of” may be interchanged for one another throughout the instant application”. The term “having” has the same meaning as “comprising” and may be replaced with either the term “consisting of” or “consisting essentially of”.  
      “Stringent”, “moderate,” and “low” hybridization conditions are as defined below.  
      A sequence which is “operably linked” to a regulatory sequence such as a promoter means that said regulatory element is in the correct location and orientation in relation to the nucleic acid to control RNA polymerase initiation and expression of the nucleic acid of interest. As used herein, the term “operably linked” refers to a linkage of polynucleotide elements in a functional relationship. For instance, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence.  
      The terms “base paired” and “Watson &amp; Crick base paired” are used interchangeably herein to refer to nucleotides which can be hydrogen bonded to one another be virtue of their sequence identities in a manner like that found in double-helical DNA with thymine or uracil residues linked to adenine residues by two hydrogen bonds and cytosine and guanine residues linked by three hydrogen bonds (See Stryer, L.,  Biochemistry,  4th edition, 1995).  
      The terms “complementary” or “complement thereof” are used herein to refer to the sequences of polynucleotides which are capable of forming Watson &amp; Crick base pairing with another specified polynucleotide throughout the entirety of the complementary region. For the purpose of the present invention, a first polynucleotide is deemed to be complementary to a second polynucleotide when each base in the first polynucleotide is paired with its complementary base. Complementary bases are, generally, A and T (or A and U), or C and G. “Complement” is used herein as a synonym from “complementary polynucleotide,” “complementary nucleic acid” and “complementary nucleotide sequence”. These terms are applied to pairs of polynucleotides based solely upon their sequences and not any particular set of conditions under which the two polynucleotides would actually bind. Preferably, a “complementary” sequence is a sequence which an A at each position where there is a T on the opposite strand, a T at each position where there is an A on the opposite strand, a G at each position where there is a C on the opposite strand and a C at each position where there is a G on the opposite strand.  
      The term “allele” is used herein to refer to variants of a nucleotide sequence. A biallelic polymorphism has two forms. Diploid organisms may be homozygous or heterozygous for an allelic form. Unless otherwise specified, the polynucleotides of the present invention encompass all allelic variants of the disclosed polynucleotides.  
      The term “upstream” is used herein to refer to a location that is toward the 5′ end of the polynucleotide from a specific reference point.  
      As used herein, the term “non-human animal” refers to any non-human vertebrate animal, including insects, birds, rodents and more usually mammals. Preferred non-human animals include: primates; farm animals such as swine, goats, sheep, donkeys, cattle, horses, chickens, rabbits; and rodents, more preferably rats or mice. As used herein, the term “animal” is used to refer to any species in the animal kingdom, preferably vertebrates, including birds and fish, and more preferable a mammal. Both the terms “animal” and “mammal” expressly embrace human subjects unless preceded with the term “non-human”.  
      The terms “vertebrate nucleic acid” and “vertebrate polpeptide” are used herein to refer to any nucleic acid or polypeptide respectively which are derived from a vertebrate species including birds and more usually mammals, preferably primates such as humans, farm animals such as swine, goats, sheep, donkeys, and horses, rabbits or rodents, more preferably rats or mice. As used herein, the term “vertebrate” is used to refer to any vertebrate, preferably a mammal. The term “vertebrate” expressly embraces human subjects unless preceded with the term “non-human” 
      “Stringent”, “moderate,” and “low” hybridization conditions are as defined below.  
      The term “capable of hybridizing to the polyA tail of said mRNA” refers to and embraces all primers containing stretches of thymidine residues, so-called oligo(dT) primers, that hybridize to the 3′ end of eukaryotic poly(A)+mRNAs to prime the synthesis of a first cDNA strand. Techniques for generating said oligo(dT) primers and hybridizing them to mRNA to subsequently prime the reverse transcription of said hybridized mRNA to generate a first cDNA strand are well known to those skilled in the art and are described in  Current Protocols in Molecular Biology,  John Wiley and Sons, Inc. 1997 and Sambrook et al.,  Molecular Cloning: A Laboratory Manual,  Second Edition, Cold Spring Harbor Laboratory Press, 1989, the entire disclosures of which are incorporated herein by reference. Preferably, said oligo(dT) primers are present in a large excess in order to allow the hybridization of all mRNA 3′ends to at least one oligo(dT) molecule. The priming and reverse transcription step are preferably performed between 37° C. and 55° C. depending on the type of reverse transcriptase used.  
      Preferred oligo(dT) primers for priming reverse transcription of mRNAs are oligonucleotides containing a stretch of thymidine residues of sufficient length to hybridize specifically to the polyA tail of mRNAs, preferably of 12 to 18 thymidine residues in length. More preferably, such oligo(T) primers comprise an additional sequence upstream of the poly(dT) stretch in order to allow the addition of a given sequence to the 5′end of all first cDNA strands which may then be used to facilitate subsequent manipulation of the cDNA. Preferably, this added sequence is 8 to 60 residues in length. For instance, the addition of a restriction site in 5′ of cDNAs facilitates subcloning of the obtained cDNA. Alternatively, such an added 5′end may also be used to design primers of PCR to specifically amplify cDNA clones of interest.  
      In particular, the present invention relates to cDNAs which were derived from genes encoding secreted proteins. As used herein, a “secreted” protein is one which, when expressed in a suitable host cell, is transported across or through a membrane, including transport as a result of signal peptides in its amino acid sequence. “Secreted” proteins include without limitation proteins secreted wholly (e.g. soluble proteins), or partially (e.g. receptors) from the cell in which they are expressed. “Secreted” proteins also include without limitation proteins which are transported across the membrane of the endoplasmic reticulum.  
      cDNAs encoding secreted proteins may include nucleic acid sequences, called signal sequences, which encode signal peptides which direct the extracellular secretion of the proteins encoded by the cDNAs. Generally, the signal peptides are located at the amino termini of secreted proteins. Polypeptides comprising these signal peptides (as delineated in the sequence  
      Secreted proteins are translated by ribosomes associated with the “rough” endoplasmic reticulum. Generally, secreted proteins are co-translationally transferred to the membrane of the endoplasmic reticulum. Association of the ribosome with the endoplasmic reticulum during translation of secreted proteins is mediated by the signal peptide. The signal peptide is typically cleaved following its co-translational entry into the endoplasmic reticulum. After delivery to the endoplasmic reticulum, secreted proteins may proceed through the Golgi apparatus. In the Golgi apparatus, the proteins may undergo post-translational modification before entering secretory vesicles which transport them across the cell membrane.  
      The cDNAs of the present invention have several important applications. For example, they may be used to express the entire secreted protein which they encode. Alternatively, they may be used to express fragments of the secreted protein. The fragments may comprise the signal peptides encoded by the cDNAs or the mature proteins encoded by the cDNAs (i.e. the proteins generated when the signal peptide is cleaved off). The cDNAs and fragments thereof also have important applications as polynucleotides. For example, the cDNAs of the sequence listing and fragments thereof, may be used to distinguish human tissues/cells from non-human tissues/cells and to distinguish between human tissues/cells that do and do not express the polynucleotides comprising the cDNAs. By knowing the tissue expression pattern of the cDNAs, either through routine experimentation or by using the instant disclosure, the polynucleotides of the present invention may be used in methods of determining the identity of an unknown tissue/cell sample. As part of determining the identity of an unknown tissue/cell sample, the polynucleotides of the present invention may be used to determine what the unknown tissue/cell sample is and what the unknown sample is not. For example, if a cDNA is expressed in a particular tissue/cell type, and the unknown tissue/cell sample does not express the cDNA, it may be inferred that the unknown tissue/cells are either not human or not the same human tissue/cell type as that which expresses the cDNA. These methods of determining tissue/cell identity are based on methods which detect the presence or absence of the mRNA (or corresponding cDNA) in a tissue/cell sample using methods well know in the art (e.g., hybridization or PCR based methods).  
      In other useful applications, fragments of the cDNAs encoding signal peptides as well as degenerate polynucleotides encoding the same, may be ligated to sequences encoding either the polypeptide from the same gene or to sequences encoding a heterologous polypeptide to facilitate secretion.  
      Antibodies which specifically recognize the entire secreted proteins encoded by the cDNAs or fragments thereof having at least 6 consecutive amino acids, 8 consecutive amino acids, 10 consecutive amino acids, at least 15 consecutive amino acids, at least 25 consecutive amino acids, or at least 40 consecutive amino acids may also be obtained as described below. Antibodies which specifically recognize the mature protein generated when the signal peptide is cleaved may also be obtained as described below. Similarly, antibodies which specifically recognize the signal peptides encoded by the cDNAs may also be obtained.  
      In some embodiments, the cDNAs include the signal sequence. In other embodiments, the cDNAs may include the full coding sequence for the mature protein (i.e. the protein generated when the signal polypeptide is cleaved off). In addition, the cDNAs may include regulatory regions upstream of the translation start site or downstream of the stop codon which control the amount, location, or developmental stage of gene expression. As discussed above, secreted proteins are therapeutically important. Thus, the proteins expressed from the cDNAs may be useful in treating or controlling a variety of human conditions. The cDNAs may also be used to obtain the corresponding genomic DNA. The term “corresponding genomic DNA” refers to the genomic DNA which encodes mRNA which includes the sequence of one of the strands of the cDNA in which thymidine residues in the sequence of the cDNA are replaced by uracil residues in the RNA.  
      The cDNAs or genomic DNAs obtained therefrom may be used in forensic procedures to identify individuals or in diagnostic procedures to identify individuals having genetic diseases resulting from abnormal expression of the genes corresponding to the cDNAs. In addition, the present invention is useful for constructing a high resolution map of the human chromosomes.  
      The present invention also relates to secretion vectors capable of directing the secretion of a protein of interest. Such vectors may be used in gene therapy strategies in which it is desired to produce a gene product in one cell which is to be delivered to another location in the body. Secretion vectors may also facilitate the purification of desired proteins.  
      The present invention also relates to expression vectors capable of directing the expression of an inserted gene in a desired spatial or temporal manner or at a desired level. Such vectors may include sequences upstream of the cDNAs such as promoters or upstream regulatory sequences.  
      In addition, the present invention may also be used for gene therapy to control or treat genetic diseases. Signal peptides may also be fused to heterologous proteins to direct their extracellular secretion.  
      One embodiment of the present invention is a purified or isolated nucleic acid comprising the sequence of one of SEQ ID NOs: 1-405 or a sequence complementary thereto, allelic variants thereof, and degenerate variants thereof. In one aspect of this embodiment, the nucleic acid is recombinant.  
      Another embodiment of the present invention is a purified or isolated nucleic acid comprising at least 8 consecutive bases of the sequence of one of SEQ ID NOs: 1-405 or one of the sequences complementary thereto, allelic variants thereof, and degenerate variants thereof. In one aspect of this embodiment, the nucleic acid comprises at least 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 consecutive bases of one of the sequences of SEQ ID NOs: 1-405 or one of the sequences complementary thereto, allelic variants thereof, and degenerate variants thereof. The nucleic acid may be a recombinant nucleic acid.  
      In addition to the above preferred nucleic acid sizes, further preferred sub-genuses of nucleic acids comprise at least 8 nucleotides, wherein “at least 8” is defined as any integer between 8 and the integer representing the 3′ most nucleotide position as set forth in the sequence listing or elsewhere herein. Further included as preferred polynucleotides of the present invention are nucleic acid fragments at least 8 nucleotides in length, as described above, that are further specified in terms of their 5′ and 3′ position. The 5′ and 3′ positions are represented by the position numbers set forth in the sequence listing below. For allelic and degenerate variants, position 1 is defined as the 5′ most nucleotide of the ORF, i.e., the nucleotide “A” of the start codon with the remaining nucleotides numbered consecutively. Therefore, every combination of a 5′ and 3′ nucleotide position that a polynucleotide fragment of the present invention, at least 8 contiguous nucleotides in length, could occupy is included in the invention as an individual species. The polynucleotide fragments specified by 5′ and 3′ positions can be immediately envisaged and are therefore not individually listed solely for the purpose of not unnecessarily lengthening the specifications.  
      It is noted that the above species of polynucleotide fragments of the present invention may alternatively be described by the formula “a to b”; where “x” equals the 5″ most nucleotide position and “y” equals the 3″ most nucleotide position of the polynucleotide; and further where “x” equals an integer between 1 and the number of nucleotides of the polynucleotide sequence of the present invention minus 8, and where “y” equals an integer between 9 and the number of nucleotides of the polynucleotide sequence of the present invention; and where “x” is an integer smaller then “y” by at least 8.  
      The present invention also provides for the exclusion of any species of polynucleotide fragments of the present invention specified by 5′ and 3′ positions or sub-genuses of polynucleotides specified by size in nucleotides as described above. Any number of fragments specified by 5′ and 3′ positions or by size in nucleotides, as described above, may be excluded.  
      Another embodiment of the present invention is a vertebrate purified or isolated nucleic acid of at least 15, 18, 20, 23, 25, 28, 30, 35, 40, 50, 75, 100, 200, 300, 500 or 1000 nucleotides in length which hybridizes under stringent conditions to the sequence of one of SEQ ID NOs: 1-405 or a sequence complementary to one of the sequences of SEQ ID NOs: 1-405. In one aspect of this embodiment, the nucleic acid is recombinant.  
      Another embodiment of the present invention is a purified or isolated nucleic acid comprising the full coding sequences of one of SEQ ID NOs: 1-405, or an allelic variant thereof, wherein the full coding sequence optionally comprises the sequence encoding signal peptide as well as the sequence encoding mature protein. In one aspect of this embodiment, the nucleic acid is recombinant.  
      A further embodiment of the present invention is a purified or isolated nucleic acid comprising the nucleotides of one of SEQ ID NOs: 1-405, or an allelic variant thereof which encode a mature protein. In one aspect of this embodiment, the nucleic acid is recombinant. In another aspect of this embodiment, the nucleic acid is an expression vector wherein said nucleotides of one of SEQ ID NOs: 1-405, or an allelic variant thereof which encode a mature protein, are operably linked to a promoter.  
      Yet another embodiment of the present invention is a purified or isolated nucleic acid comprising the nucleotides of one of SEQ ID NOs: 1-405, or an allelic variant thereof, which encode the signal peptide. In one aspect of this embodiment, the nucleic acid is recombinant. In another aspect of this embodiment, the nucleic acid is an fusion vector wherein said nucleotides of one of SEQ ID NOs: 1-405, or an allelic variant thereof which encode the signal peptide, are operably linked to a second nucleic acid encoding an heterologous polypeptide.  
      Another embodiment of the present invention is a purified or isolated nucleic acid encoding a polypeptide comprising the sequence of one of the sequences of SEQ ID NOs: 406-810, or allelic variant thereof. In one aspect of this embodiment, the nucleic acid is recombinant.  
      Another embodiment of the present invention is a purified or isolated nucleic acid encoding a polypeptide comprising the sequence of a mature protein included in one of the sequences of SEQ ID NOs: 406-810, or allelic variant thereof. In one aspect of this embodiment, the nucleic acid is recombinant.  
      Another embodiment of the present invention is a purified or isolated nucleic acid encoding a polypeptide comprising the sequence of a signal peptide included in one of the sequences of SEQ ID NOs: 406-810, or allelic variant thereof. In one aspect of this embodiment, the nucleic acid is recombinant. In another aspect it is present in a vector of the invention.  
      Further embodiments of the invention include isolated polynucleotides that comprise, a nucleotide sequence at least 70% identical, more preferably at least 75% identical, and still more preferably at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any of the polynucleotides of the present invention. Methods of determining identity include those well known in the art and described herein.  
      Yet another embodiment of the present invention is a purified or isolated protein comprising the sequence of one of SEQ ID NOs: 406-810, or allelic variant thereof.  
      Another embodiment of the present invention is a purified or isolated polypeptide comprising at least 5 or 8 consecutive amino acids of one of the sequences of SEQ ID NOs: 406-810. In one aspect of this embodiment, the purified or isolated polypeptide comprises at least 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 150 or 200 consecutive amino acids of one of the sequences of SEQ ID NOs: 406-810.  
      In addition to the above polypeptide fragments, further preferred sub-genuses of polypeptides comprise at least 8 amino acids, wherein “at least 8” is defined as any integer between 8 and the integer representing the C-terminal amino acid of the polypeptide of the present invention including the polypeptide sequences of the sequence listing below. Further included are species of polypeptide fragments at least 8 amino acids in length, as described above, that are further specified in terms of their N-terminal and C-terminal positions. Preferred species of polypeptide fragments specified by their N-terminal and C-terminal positions include the signal peptides delineated in the sequence listing below. However, included in the present invention as individual species are all polypeptide fragments, at least 8 amino acids in length, as described above, and may be particularly specified by a N-terminal and C-terminal position. That is, every combination of a N-terminal and C-terminal position that a fragment at least 8 contiguous amino acid residues in length could occupy, on any given amino acid sequence of the sequence listing or of the present invention is included in the present invention  
      The present invention also provides for the exclusion of any fragment species specified by N-terminal and C-terminal positions or of any fragment sub-genus specified by size in amino acid residues as described above. Any number of fragments specified by N-terminal and C-terminal positions or by size in amino acid residues as described above may be excluded as individual species.  
      The above polypeptide fragments of the present invention can be immediately envisaged using the above description and are therefore not individually listed solely for the purpose of not unnecessarily lengthening the specification. Moreover, the above fragments need not be active since they would be useful, for example, in immunoassays, in epitope mapping, epitope tagging, as vaccines, and as molecular weight markers. The above fragments may also be used to generate antibodies to a particular portion of the polypeptide. These antibodies can then be used in immunoassays well known in the art to distinguish between human and non-human cells and tissues or to determine whether cells or tissues in a biological sample are or are not of the same type which express the polypeptide of the present invention. Preferred polypeptide fragments of the present invention comprising a signal peptide may be used to facilitate secretion of either the polypeptide of the same gene or a heterologous polypeptide using methods well known in the art.  
      Another embodiment of the present invention is an isolated or purified polypeptide comprising a signal peptide of one of the polypeptides of SEQ ID NOs: 406-810.  
      Yet another embodiment of the present invention is an isolated or purified polypeptide comprising a mature protein of one of the polypeptides of SEQ ID NOs: 406-810.  
      Yet another embodiment of the present invention is an isolated or purified polypeptide comprising a fall length polypeptide, mature protein, or signal peptide encoded by an allelic variant of the polynucleotides of the present invention.  
      A further embodiment of the present invention are polypeptides having an amino acid sequence with at least 70% similarity, and more preferably at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% similarity to a polypeptide of the present invention, as well as polypeptides having an amino acid sequence at least 70% identical, more preferably at least 75% identical, and still more preferably 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a polypeptide of the present invention. Further included in the invention are isolated nucleic acid molecules encoding such polypeptides. Methods for determining identity include those well known in the art and described herein.  
      A further embodiment of the present invention is a method of making a protein comprising one of the sequences of SEQ ID NO: 406-810, comprising the steps of obtaining a cDNA comprising one of the sequences of sequence of SEQ ID NO: 1-405, inserting the cDNA in an expression vector such that the cDNA is operably linked to a promoter, and introducing the expression vector into a host cell whereby the host cell produces the protein encoded by said cDNA. In one aspect of this embodiment, the method further comprises the step of isolating the protein.  
      Another embodiment of the present invention is a protein obtainable by the method described in the preceding paragraph.  
      Another embodiment of the present invention is a method of making a protein comprising the amino acid sequence of the mature protein contained in one of the sequences of SEQ ID NO: 406-810, comprising the steps of obtaining a cDNA comprising one of the nucleotides sequence of sequence of SEQ ID NO: 1-405 which encode for the mature protein, inserting the cDNA in an expression vector such that the cDNA is operably linked to a promoter, and introducing the expression vector into a host cell whereby the host cell produces the mature protein encoded by the cDNA. In one aspect of this embodiment, the method further comprises the step of isolating the protein.  
      Another embodiment of the present invention is a mature protein obtainable by the method described in the preceding paragraph.  
      Another embodiment of the present invention is a host cell containing the purified or isolated nucleic acids comprising the sequence of one of SEQ ID NOs: 1-405 or a sequence complementary thereto described herein.  
      Another embodiment of the present invention is a host cell containing the purified or isolated nucleic acids comprising the full coding sequences of one of SEQ ID NOs: 1-405, wherein the full coding sequence comprises the sequence encoding the signal peptide and the sequence encoding the mature protein described herein.  
      Another embodiment of the present invention is a host cell containing the purified or isolated nucleic acids comprising the nucleotides of one of SEQ ID NOs: 1-405 which encode a mature protein which are described herein.  
      Another embodiment of the present invention is a host cell containing the purified or isolated nucleic acids comprising the nucleotides of one of SEQ ID NOs: 1-405 which encode the signal peptide which are described herein.  
      Another embodiment of the present invention is a purified or isolated antibody capable of specifically binding to a protein comprising the sequence of one of SEQ ID NOs: 406-810. In one aspect of this embodiment, the antibody is capable of binding to a polypeptide comprising at least 6 consecutive amino acids, at least 8 consecutive amino acids, or at least 10 consecutive amino acids of the sequence of one of SEQ ID NOs: 406-810.  
      Another embodiment of the present invention is an array of cDNAs or fragments thereof of at least 15 nucleotides in length which includes at least one of the sequences of SEQ ID NOs: 1-405, or one of the sequences complementary to the sequences of SEQ ID NOs: 1-405, or a fragment thereof of at least 15 consecutive nucleotides. In one aspect of this embodiment, the array includes at least two of the sequences of SEQ ID NOs: 1-405, the sequences complementary to the sequences of SEQ ID NOs: 1-405, or fragments thereof of at least 15 consecutive nucleotides. In another aspect of this embodiment, the array includes at least five of the sequences of SEQ ID NOs: 1-405, the sequences complementary to the sequences of SEQ ID NOs: 1-405, or fragments thereof of at least 15 consecutive nucleotides.  
      A further embodiment of the invention encompasses purified polynucleotides comprising an insert from a clone deposited in an ECACC deposit, which contains the sequences of SEQ ID NOs. 2-17 and 19-23, having an accession No. 99061735 and named SignalTag 15061999 or deposited in an ECACC deposit having an accession No. 98121805 and named SignalTag 166-191, which contains SEQ ID NOs.: 24-50, or a fragment of these nucleic acids comprising a contiguous span of at least 8, 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 nucleotides of said insert. In one aspect of this embodiment, the purified polynucleotide is recombinant.  
      An additional embodiment of the invention encompasses purified polypeptides which comprise, consist of, or consist essentially of an amino acid sequence encoded by the insert from a clone deposited in an ECACC deposit, which contains the sequences of SEQ ID NOs. 2-17 and 19-23, having an accession No. 99061735 and named SignalTag 15061999 or deposited in an ECACC deposit having an accession No. 98121805 and named SignalTag 166-191, which contains SEQ ID NOs.: 24-50, as well as polypeptides which comprise a fragment of said amino acid sequence consisting of a signal peptide, a mature protein, or a contiguous span of at least 5, 8, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 150 or 200 amino acids encoded by said insert.  
      An additional embodiment of the invention encompasses purified polypeptides which comprise a contiguous span of at least 5, 8, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 150 or 200 amino acids of SEQ ID NOs: 406-810, wherein said contiguous span comprises at least one of the amino acid positions which was not shown to be identical to a public sequence in the instant application. Also encompassed by the invention are purified polynucleotides encoding said polypeptides.  
      Another embodiment of the present invention is a computer readable medium having stored thereon a sequence selected from the group consisting of a cDNA code of SEQ ID NOs. 1-405 and a polypeptide code of SEQ ID NOs. 406-810.  
      Another embodiment of the present invention is a computer system comprising a processor and a data storage device wherein the data storage device has stored thereon a sequence selected from the group consisting of a cDNA code of SEQ ID NOs. 1-405 and a polypeptide code of SEQ ID NOs. 406-810. In some embodiments the computer system further comprises a sequence comparer and a data storage device having reference sequences stored thereon. For example, the sequence comparer may comprise a computer program which indicates polymorphisms. In other aspects of the computer system, the system further comprises an identifier which identifies features in said sequence.  
      Another embodiment of the present invention is a method for comparing a first sequence to a reference sequence wherein the first sequence is selected from the group consisting of a cDNA code of SEQ ID NOs. 1-405 and a polypeptide code of SEQ ID NOs. 406-810 comprising the steps of reading the first sequence and the reference sequence through use of a computer program which compares sequences and determining differences between the first sequence and the reference sequence with the computer program. In some aspects of this embodiment, said step of determining differences between the first sequence and the reference sequence comprises identifying polymorphisms.  
      Another aspect of the present invention is a method for determining the level of identity between a first sequence and a reference sequence, wherein the first sequence is selected from the group consisting of a cDNA code of SEQ ID NOs. 1-405 and a polypeptide code of SEQ ID NOs. 406-810, comprising the steps of reading the first sequence and the reference sequence through the use of a computer program which determines identity levels and determining identity between the first sequence and the reference sequence with the computer program.  
      Another embodiment of the present invention is a method for identifying a feature in a sequence selected from the group consisting of a cDNA code of SEQ ID NOs. 1-405 and a polypeptide code of SEQ ID NOs. 406-810 comprising the steps of reading the sequence through the use of a computer program which identifies features in sequences and identifying features in the sequence with said computer program. In one aspect of this embodiment, the computer program comprises a computer program which identifies open reading frames. In a further embodiment, the computer program comprises a program that identifies linear or structural motifs in a polypeptide sequence. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  is a table with all of the parameters that can be used for each step of cDNA analysis.  
       FIG. 2  is an analysis of the 43 amino terminal amino acids of all human SwissProt proteins to determine the frequency of false positives and false negatives using the techniques for signal peptide identification described herein.  
       FIG. 3  provides a diagram of a RT-PCR-based method to isolate cDNAs containing sequences adjacent to 5′ESTs used to obtain them  
       FIG. 4  is a block diagram of an exemplary computer system.  
       FIG. 5  is a flow diagram illustrating one embodiment of a process  200  for comparing a new nucleotide or protein sequence with a database of sequences in order to determine the identity levels between the new sequence and the sequences in the database.  
       FIG. 6  is a flow diagram illustrating one embodiment of a process  250  in a computer for determining whether two sequences are homologous.  
       FIG. 7  is a flow diagram illustrating one embodiment of an identifier process  300  for detecting the presence of a feature in a sequence. 
    
    
     BRIEF DESCRIPTION OF THE TABLES  
      Table I provides structural features of each cDNAs of SEQ ID NOs: 1-405, i.e., the locations of the full coding sequences, the locations of the nucleotides which encode the signal peptides, the locations of nucleotides which encode the mature proteins generated by cleavage of the signal peptides, the locations of stop codons, the locations of the polyA signals and the locations of polyA sites.  
      Table II provides structural features for each polypeptide of SEQ ID NOs: 406-810, i.e; the locations of the full length polypeptide, the locations of the signal peptides, and the locations of the mature polypeptide created by cleaving the signal peptide from the full length polypeptide.  
      Table III lists the positions of preferred fragments, defined as fragments not sharing more than 90% identity with any public sequence over at least 30 nucleotides in length, for some cDNAs of SEQ ID NOs: 1-405.  
      Table IVa provides the positions of fragments which are preferably included in the present invention while Table IVb provides the positions of fragments which are preferably excluded from the present invention. Tables IVa and IVb provides for the inclusion and exclusion of polynucleotides in addition to those described elsewhere in the specification and is therefore, not meant as limiting description.  
      Table V provides the applicant&#39;s internal designation number assigned to each sequence identification number and indicates whether the sequence is a nucleic acid sequence or a polypeptide sequence.  
      Table VI lists the Genset&#39;s libraries of tissues and cell types examined that express the polynucleotides of the present invention.  
      Table VII relates to the bias in spatial distribution of the polynucleotide sequences of the present invention.  
      Table VIII relates to the spatial distribution of the polynucleotide sequences of the sequence listing using information from public databases.  
      Table IX lists known biologically structural and functional domains for the cDNA of the present invention.  
      Table X lists antigenic peaks of predicted antigenic epitopes for cDNAs or the present invention.  
      Table XI lists the putative chromosomal location of the polynucleotides of the present invention.  
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
      I. Obtaining cDNA Libraries Including the 5′Ends of their Corresponding mRNAS  
      The cDNAs of the present invention may include the entire coding sequence of the protein encoded by the corresponding mRNA, including the authentic translation start site, the signal sequence, and the sequence encoding the mature protein remaining after cleavage of the signal peptide. Such cDNAs are referred to herein as “full length cDNAs.” Alternatively, the cDNAs may include only the sequence encoding the mature protein remaining after cleavage of the signal peptide, or only the sequence encoding the signal peptide.  
      The methods explained therein can also be used to obtain cDNAs which encode less than the entire coding sequence of the secreted proteins encoded by the genes corresponding to the cDNAs. In some embodiments, the cDNAs isolated using these methods encode at least 5 amino acids of one of the proteins encoded by the sequences of SEQ ID NOs: 1-405. In further embodiments, the cDNAs encode at least 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 150 or 200 consecutive amino acids of the proteins encoded by the sequences of SEQ ID NOs: 1-405. In a preferred embodiment, the cDNAs encode a full length protein sequence, which includes the protein coding sequences of SEQ ID NOs: 1-405.  
      The cDNAs of the present invention were obtained from cDNA libraries derived from mRNAs having intact 5′ ends as described in Examples 1 to 5 using either a chemical or enzymatic approach.  
     EXAMPLE 1  
      Preparation of mRNA  
      Total human RNAs or polyA+ RNAs derived from different tissues were respectively purchased from LABIMO and CLONTECH and used to generate cDNA libraries as described below. The purchased RNA had been isolated from cells or tissues using acid guanidium thiocyanate-phenol-chloroform extraction (Chomczyniski and Sacchi,  Analytical Biochemistry  162:156-159, 1987). PolyA+ RNA was isolated from total RNA (LABIMO) by two passes of oligo dT chromatography, as described by Aviv and Leder,  Proc. Natl. Acad. Sci. USA  69:1408-1412, 1972) in order to eliminate ribosomal RNA.  
      The quality and the integrity of the polyA+ RNAs were checked. Northern blots hybridized with a probe corresponding to an ubiquitous mRNA, such as elongation factor 1 or elongation factor 2, were used to confirm that the mRNAs were not degraded. Contamination of the polyA+ mRNAs by ribosomal sequences was checked using Northern blots and a probe derived from the sequence of the 28S rRNA. Preparations of mRNAs with less than 5% of rRNAs were used in library construction. To avoid constructing libraries with RNAs contaminated by exogenous sequences (prokaryotic or fungal), the presence of bacterial 16S ribosomal sequences or of two highly expressed fungal mRNAs was examined using PCR.  
     EXAMPLE 2  
      Methods for Obtaining mRNAs having Intact 5′ Ends  
      Following preparation of the mRNAs from various tissues as described above, selection of mRNA with intact 5′ ends and specific attachment of an oligonucleotide tag to the 5′ end of such mRNA is performed using either a chemical or enzymatic approach. Both techniques take advantage of the presence of the “cap” structure, which characterizes the 5′end of intact mRNAs and which comprises a guanosine generally methylated once, at the 7 position.  
      The chemical modification approach involves the optional elimination of the 2′,3′-cis diol of the 3′ terminal ribose, the oxidation of the 2′, 3′, -cis diol of the ribose linked to the cap of the 5′ ends of the mRNAs into a dialdehyde, and the coupling of the dialdehyde to a derivatized oligonucleotide tag. Further detail regarding the chemical approaches for obtaining mRNAs having intact 5′ ends are disclosed in International Application No. WO96/34981, published Nov. 7, 1996, the disclosure of which is incorporated herein by reference in its entirety.  
      The enzymatic approach for ligating the oligonucleotide tag to the 5′ ends of mRNAs with intact 5′ ends involves the removal of the phosphate groups present on the 5′ ends of uncapped incomplete mRNAs, the subsequent decapping of mRNAs with intact 5′ ends and the ligation of the phosphate present at the 5′ end of the decapped mRNA to an oligonucleotide tag. Further detail regarding the enzymatic approaches for obtaining mRNAs having intact 5′ ends are disclosed in Dumas Milne Edwards J. B. (Doctoral Thesis of Paris VI University, Le clonage des ADNc complets: difficultes et perspectives nouvelles. Apports pour l&#39;etude de la regulation de l&#39;expression de la tryptophane hydroxylase de rat, 20 Dec. 1993), EP0 625572 and Kato et al.,  Gene  150:243-250 (1994), the disclosures of which are incorporated herein by reference in their entireties.  
      In either the chemical or the enzymatic approach, the oligonucleotide tag has a restriction enzyme site (e.g. EcoRI sites) therein to facilitate later cloning procedures. Following attachment of the oligonucleotide tag to the mRNA, the integrity of the mRNA was then examined by performing a Northern blot using a probe complementary to the oligonucleotide tag.  
     EXAMPLE 3  
      cDNA Synthesis Using mRNA Templates having Intact 5′ Ends  
      For the mRNAs joined to oligonucleotide tags using either the chemical or the enzymatic method, first strand cDNA synthesis was performed using reverse transcriptase with an oligo-dT primer or random nonamer. In some instances, this oligo-dT primer contained an internal tag of at least 4 nucleotides which is different from one tissue to the other. In order to protect internal EcoRI sites in the cDNA from digestion at later steps in the procedure, methylated dCTP was used for first strand synthesis. After removal of RNA by an alkaline hydrolysis, the first strand of cDNA was precipitated using isopropanol in order to eliminate residual primers.  
      The second strand of the cDNA was then synthesized with a Klenow fragment using a primer corresponding to the 5′end of the ligated oligonucleotide. Preferably, the primer is 20-25 bases in length. Methylated dCTP was also used for second strand synthesis in order to protect internal EcoRI sites in the cDNA from digestion during the cloning process.  
     EXAMPLE 4  
      Cloning of cDNAs Derived from mRNA with Intact 5′ Ends into BlueScript  
      Following second strand synthesis, the cDNAs were cloned into the phagemid pBlueScript II SK− vector (Stratagene). The ends of the cDNAs were blunted with T4 DNA polymerase (Biolabs) and the cDNA was digested with EcoRI. Since methylated dCTP was used during cDNA synthesis, the EcoRI site present in the tag was the only hemi-methylated site, hence the only site susceptible to EcoRI digestion. In some instances, to facilitate subcloning, an Hind III adaptor was added to the 3′ end of cDNAs.  
      The cDNAs were then size fractionated using either exclusion chromatography (AcA, Biosepra) or electrophoretic separation which yields 3 or 6 different fractions. The cDNAs were then directionally cloned either into pBlueScript using either the EcoRI and SmaI restriction sites or the EcoRI and Hind III restriction sites when the Hind III adaptator was present in the cDNAs. The ligation mixture was electroporated into bacteria and propagated under appropriate antibiotic selection.  
     EXAMPLE 5  
      Selection of Clones having the Oligonucleotide Tag Attached Thereto  
      Clones containing the oligonucleotide tag attached to cDNAs were then selected as follows.  
      The plasmid DNAs containing cDNA libraries made as described above were purified (Qiagen). A positive selection of the tagged clones was performed as follows. Briefly, in this selection procedure, the plasmid DNA was converted to single stranded DNA using gene II endonuclease of the phage Fl in combination with an exonuclease (Chang et al.,  Gene  127:95-8, 1993) such as exonuclease III or T7 gene 6 exonuclease. The resulting single stranded DNA was then purified using paramagnetic beads as described by Fry et al.,  Biotechniques,  13: 124-131, 1992. In this procedure, the single stranded DNA was hybridized with a biotinylated oligonucleotide having a sequence corresponding to the 3′ end of the oligonucleotide tag described in example 2. Preferably, the primer has a length of 20-25 bases. Clones including a sequence complementary to the biotinylated oligonucleotide were captured by incubation with streptavidin coated magnetic beads followed by magnetic selection. After capture of the positive clones, the plasmid DNA was released from the magnetic beads and converted into double stranded DNA using a DNA polymerase such as the ThermoSequenase obtained from Amersham Pharmacia Biotech. Alternatively, protocols such as the Gene Trapper kit (Gibco BRL) may be used. The double stranded DNA was then electroporated into bacteria. The percentage of positive clones having the 5′ tag oligonucleotide was estimated to typically rank between 90 and 98% using dot blot analysis.  
      Following electroporation, the libraries were ordered in 384-microtiter plates (MTP). A copy of the MTP was stored for future needs. Then the libraries were transferred into 96 MTP.  
      II. Characterization of the 5′ Ends of Clones  
      In order to sequence only cDNAs which contain the 5′ ends of their corresponding MrRNA, a first round of sequencing was performed on the 5′ end of clones as described in example 6. In some instances, only a partial sequence of the clone, therein referred to as “5′EST” was obtained. In other instances, the complete sequence of the clone, herein referred to as a “cDNA” is obtained. A computer analysis was then performed on the 5′ ESTs or cDNAs as described in Examples 7 and 8 in order to evaluate the quality of the cDNA libraries and in order to select clones containing sequences of interest among cDNAs which contain the 5′ ends of their corresponding mRNA.  
     EXAMPLE 6  
      Sequencing of The 5′End of cDNA Clones  
      The 5′ ends of cloned cDNAs were then sequenced as follows. Plasmid inserts were first amplified by PCR on PE 9600 thermocyclers (Perkin-Elmer, Applied Biosystems Division, Foster City, Calif.) using standard SETA-A and SETA-B primers (Genset SA), AmpliTaqGold (Perkin-Elmer), dNTPs (Boehringer), buffer and cycling conditions as recommended by the Perkin-Elmer Corporation.  
      PCR products were then sequenced using automatic ABI Prism 377 sequencers (Perkin Elmer). Sequencing reactions were performed using PE 9600 thermocyclers with standard dye-primer chemistry and ThermoSequenase (Amersham Pharmacia Biotech). The primers used were either T7 or 21M13 (available from Genset SA) as appropriate. The primers were labeled with the JOE, FAM, ROX and TAMRA dyes. The dNTPs and ddNTPs used in the sequencing reactions were purchased from Boehringer. Sequencing buffer, reagent concentrations and cycling conditions were as recommended by Amersham.  
      Following the sequencing reaction, the samples were precipitated with ethanol, resuspended in formamide loading buffer, and loaded on a standard 4% acrylamide gel. Electrophoresis was performed for 2.5 hours at 3000V on an ABI 377 sequencer, and the sequence data were collected and analyzed using the ABI Prism DNA Sequencing Analysis Software, version 2.1.2.  
      The sequence data obtained from the sequencing of 5′ ends of all cDNA libraries made as described above were transferred to a proprietary database, where quality control and validation steps were performed. A proprietary base-caller, working using a Unix system automatically flagged suspect peaks, taking into account the shape of the peaks, the inter-peak resolution, and the noise level. The proprietary base-caller also performed an automatic trimming. Any stretch of 25 or fewer bases having more than 4 suspect peaks was considered unreliable and was discarded. Sequences corresponding to cloning vector or ligation oligonucleotides were automatically removed from the sequences. However, the resulting sequences may contain 1 to 5 nucleotides belonging to the above mentioned sequences at their 5′ end. If needed, these can easily be removed on a case by case basis.  
      Following sequencing as described above, the sequences of the cDNA clones were entered in a database for storage and manipulation as described below. Before searching the cDNA clones in the database for sequences of interest, cDNAs derived from mRNAs which were not of interest were identified and eliminated, namely, endogenous contaminants (ribosomal RNAs, transfert RNAs, mitochondrial RNAs) and exogenous contaminants (prokaryotic RNAs and fungal RNAs) using software and parameters described in  FIG. 1 . In addition, cDNA sequences showing showing identity to repeated sequences (Alu, L1, THE and MER repeats, SSTR sequences or satellite, micro-satellite, or telomeric repeats) were identified and masked in further processing.  
     EXAMPLE 7  
      Determination of Efficiency of 5′ End Selection  
      To determine the efficiency at which the above selection procedures isolated cDNAs which include the 5′ ends of their corresponding mRNAs, the sequences of 5′ESTs or cDNAs were aligned with a reference pool of complete mRNA/cDNA extracted from the EMBL release 57 using the FASTA algorithm. The reference mRNA/cDNA starting at the most 5′ transcription start site was obtained, and then compared to the 5′ transcription start site position of the 5′EST or cDNA. More than 75% of 5′ESTs or cDNAs had their 5′ ends close to the 5′ ends of the known sequence. As some of the mRNA sequences available in the EMBL database are deduced from genomic sequences, a 5′ end matching with these sequences will be counted as an internal match. Thus, the method used here underestimates the yield of 5′ESTs or cDNAs including the authentic 5′ ends of their corresponding mRNAs.  
     EXAMPLE 8  
      Identification of Open Reading Frames Coding for Potential Signal Peptides  
      The obtained nucleic acid sequences were then screened to identify those having uninterrupted open reading frames (ORF) with a good coding probability using proprietary software. When the full-length cDNA was obtained, only complete ORFs, namely nucleic acid sequences beginning with a start codon and ending with a stop codon, longer than 150 nucleotides were considered. When only 5′EST sequences were obtained, both complete ORFS longer than 150 nucleotides and incomplete ORFs, namely nucleic acid sequences beginning with a start codon and extending up to the end of the 5′EST, longer than 60 nucleotides were considered.  
      The retrieved ORFs were then searched to identify potential signal motifs using slight modifications of the procedures disclosed in Von Heijne,  Nucleic Acids Res.  14:46834690, 1986, the disclosure of which is incorporated herein by reference. Those 5′ESTs or cDNA sequences encoding a polypeptide with a score of at least 3.5 in the Von Heijne signal peptide identification matrix were considered to possess a signal sequence. Those 5′ESTs or cDNAs which matched a known human mRNA or EST sequence and had a 5′ end more than 30 nucleotides downstream of the known 5′ end were excluded from further analysis.  
     EXAMPLE 9  
      Confirmation of Accuracy of Identification of Potential Signal Sequences in 5′ ESTs  
      The accuracy of the above procedure for identifying signal sequences encoding signal peptides was evaluated by applying the method to the 43 amino acids located at the N terminus of all human SwissProt proteins. The computed Von Heijne score for each protein was compared with the known characterization of the protein as being a secreted protein or a non-secreted protein. In this manner, the number of non-secreted proteins having a score higher than 3.5 (false positives) and the number of secreted proteins having a score lower than 3.5 (false negatives) could be calculated.  
      Using the results of the above analysis, the probability that a peptide encoded by the 5′ region of the mRNA is in fact a genuine signal peptide based on its Von Heijne&#39;s score was calculated based on either the assumption that 10% of human proteins are secreted or the assumption that 20% of human proteins are secreted. The results of this analysis are shown in  FIG. 2 .  
      Using the above method of identification of secretory proteins, 5′ ESTs of the following polypeptides known to be secreted were obtained: human glucagon, gamma interferon induced monokine precursor, secreted cyclophilin-like protein, human pleiotropin, and human biotinidase precursor. Thus, the above method successfully identified those 5′ ESTs which encode a signal peptide.  
      To confirm that the signal peptide encoded by the 5′ ESTs or cDNAs actually functions as a signal peptide, the signal sequences from the 5′ ESTs or cDNAs may be cloned into a vector designed for the identification of signal peptides. Such vectors are designed to confer the ability to grow in selective medium only to host cells containing a vector with an operably linked signal sequence. For example, to confirm that a 5′ EST or cDNA encodes a genuine signal peptide, the signal sequence of the 5′ EST or cDNA may be inserted upstream and in frame with a non-secreted form of the yeast invertase gene in signal peptide selection vectors such as those described in U.S. Pat. No. 5,536,637, the disclosure of which is incorporated herein by reference. Growth of host cells containing signal sequence selection vectors with the correctly inserted 5′ EST or cDNA signal sequence confirms that the 5′ EST or cDNA encodes a genuine signal peptide.  
      Alternatively, the presence of a signal peptide may be confirmed by cloning the 5′ESTs or cDNAs into expression vectors such as pXT1 as described below, or by constructing promoter-signal sequence-reporter gene vectors which encode fusion proteins between the signal peptide and an assayable reporter protein. After introduction of these vectors into a suitable host cell, such as COS cells or NIH 3T3 cells, the growth medium may be harvested and analyzed for the presence of the secreted protein. The medium from these cells is compared to the medium 10 from control cells containing vectors lacking the signal sequence or cDNA insert to identify vectors which encode a functional signal peptide or an authentic secreted protein.  
     EXAMPLE 10  
      Evaluation of Expression Levels and Patterns of mRNAs Corresponding to 5′ ESTs or cDNAs  
      The spatial and temporal expression patterns of the mRNAs corresponding to the 5′ ESTs or cDNAs, as well as their expression levels, may be determined. Characterization of the spatial and temporal expression patterns and expression levels of these mRNAs is useful for constructing expression vectors capable of producing a desired level of gene product in a desired spatial or temporal manner, as will be discussed in more detail below.  
      In addition, cDNAs or 5′ ESTs whose corresponding mRNAs are associated with disease states may also be identified. For example, a particular disease may result from lack of expression, over expression, or under expression of an mRNA corresponding to a cDNA or 5′ EST. By comparing mRNA expression patterns and quantities in samples taken from healthy individuals with those from individuals suffering from a particular disease, cDNAs and 5′ ESTs responsible for the disease may be identified.  
      Expression levels and patterns of mRNAs corresponding to 5′ ESTs or cDNAs may be analyzed by solution hybridization with long probes as described in International Patent Application No. WO 97/05277, the entire contents of which are hereby incorporated by reference. Briefly, a 5′ EST, cDNA, or fragment thereof corresponding to the gene encoding the mRNA to be characterized is inserted at a cloning site immediately downstream of a bacteriophage (T3, T7 or SP6) RNA polymerase promoter to produce antisense RNA. Preferably, the 5′ EST or cDNA is 100 or more nucleotides in length. The plasmid is linearized and transcribed in the presence of ribonucleotides comprising modified ribonucleotides (i.e. biotin-UTP and DIG-UTP). An excess of this doubly labeled RNA is hybridized in solution with mRNA isolated from cells or tissues of interest. The hybridizations are performed under standard stringent conditions (40-50° C. for 16 hours in an 80% formamide, 0.4 M NaCl buffer, pH 7-8). The unhybridized probe is removed by digestion with ribonucleases specific for single-stranded RNA (i.e. RNases CL3, Ti, Phy M, U2 or A). The presence of the biotin-UTP modification enables capture of the hybrid on a microtitration plate coated with streptavidin. The presence of the DIG modification enables the hybrid to be detected and quantified by ELISA using an anti-DIG antibody coupled to alkaline phosphatase.  
      The 5′ ESTs, cDNAs, or fragments thereof may also be tagged with nucleotide sequences for the serial analysis of gene expression (SAGE) as disclosed in UK Patent Application No. 2 305 241 A, the entire contents of which are incorporated by reference. In this method, cDNAs are prepared from a cell, tissue, organism or other source of nucleic acid for which it is desired to determine gene expression patterns. The resulting cDNAs are separated into two pools. The cDNAs in each pool are cleaved with a first restriction endonuclease, called an “anchoring enzyme,” having a recognition site which is likely to be present at least once in most cDNAs. The fragments which contain the 5′ or 3′ most region of the cleaved cDNA are isolated by binding to a capture medium such as streptavidin coated beads. A first oligonucleotide linker having a first sequence for hybridization of an amplification primer and an internal restriction site for a “tagging endonuclease” is ligated to the digested cDNAs in the first pool. Digestion with the second endonuclease produces short “tag” fragments from the cDNAs.  
      A second oligonucleotide having a second sequence for hybridization of an amplification primer and an internal restriction site is ligated to the digested cDNAs in the second pool. The cDNA fragments in the second pool are also digested with the “tagging endonuclease” to generate short “tag” fragments derived from the cDNAs in the second pool. The “tags” resulting from digestion of the first and second pools with the anchoring enzyme and the tagging endonuclease are ligated to one another to produce “ditags.” In some embodiments, the ditags are concatamerized to produce ligation products containing from 2 to 200 ditags. The tag sequences are then determined and compared to the sequences of the 5′ ESTs or cDNAs to determine which 5′ ESTs or cDNAs are expressed in the cell, tissue, organism, or other source of nucleic acids from which the tags were derived. In this way, the expression pattern of the 5′ ESTs or cDNAs in the cell, tissue, organism, or other source of nucleic acids is obtained.  
      Quantitative analysis of gene expression may also be performed using arrays. As used herein, the term array means a one dimensional, two dimensional, or multidimensional arrangement of full length cDNAs (i.e. cDNAs which include the coding sequence for the signal peptide, the coding sequence for the mature protein, and a stop codon), cDNAs, 5′ ESTs or fragments of the full length cDNAs, cDNAs, or 5′ ESTs of sufficient length to permit specific detection of gene expression. Preferably, the fragments are at least 15 nucleotides in length. More preferably, the fragments are at least 100 nucleotides in length. More preferably, the fragments are more than 100 nucleotides in length. In some embodiments the fragments may be more than 500 nucleotides in length.  
      For example, quantitative analysis of gene expression may be performed with full length cDNAs, cDNAs, 5′ ESTs, or fragments thereof in a complementary DNA microarray as described by Schena et al. ( Science  270:467-470, 1995 ; Proc. Natl. Acad. Sci. U.S.A.  93:10614-10619, 1996). Full length cDNAs, cDNAs, 5′ ESTs or fragments thereof are amplified by PCR and arrayed from 96-well microtiter plates onto silylated microscope slides using high-speed robotics. Printed arrays are incubated in a humid chamber to allow rehydration of the array elements and rinsed, once in 0.2% SDS for 1 min, twice in water for 1 min and once for 5 min in sodium borohydride solution. The arrays are submerged in water for 2 min at 95° C., transferred into 0.2% SDS for 1 min, rinsed twice with water, air dried and stored in the dark at 25° C.  
      Cell or tissue mRNA is isolated or commercially obtained and probes are prepared by a single round of reverse transcription. Probes are hybridized to 1 cm 2  microarrays under a 14×14 mm glass coverslip for 6-12 hours at 60° C. Arrays are washed for 5 min at 25° C. in low stringency wash buffer (1×SSC/0.2% SDS), then for 10 min at room temperature in high stringency wash buffer (0.1×SSC/0.2% SDS). Arrays are scanned in 0.1×SSC using a fluorescence laser scanning device fitted with a custom filter set. Accurate differential expression measurements are obtained by taking the average of the ratios of two independent hybridizations.  
      Quantitative analysis of the expression of genes may also be performed with full length cDNAs, cDNAs, 5′ ESTs, or fragments thereof in complementary DNA arrays as described by Pietu et al. (Genome Research 6:492-503, 1996). The full length cDNAs, cDNAs, 5′ ESTs or fragments thereof are PCR amplified and spotted on membranes. Then, mRNAs originating from various tissues or cells are labeled with radioactive nucleotides. After hybridization and washing in controlled conditions, the hybridized mRNAs are detected by phospho-imaging or autoradiography. Duplicate experiments are performed and a quantitative analysis of differentially expressed mRNAs is then performed.  
      Alternatively, expression analysis of the 5′ ESTs or cDNAs can be done through high density nucleotide arrays as described by Lockhart et al. (Nature Biotechnology 14: 1675-1680, 1996) and Sosnowsky et al. (Proc. Natl. Acad. Sci. 94:1119-1123, 1997). Oligonucleotides of 15-50 nucleotides corresponding to sequences of the 5′ ESTs or cDNAs are synthesized directly on the chip (Lockhart et al., supra) or synthesized and then addressed to the chip (Sosnowski et al., supra). Preferably, the oligonucleotides are about 20 nucleotides in length.  
      cDNA probes labeled with an appropriate compound, such as biotin, digoxigenin or fluorescent dye, are synthesized from the appropriate mRNA population and then randomly fragmented to an average size of 50 to 100 nucleotides. The said probes are then hybridized to the chip. After washing as described in Lockhart et al., supra and application of different electric fields (Sosnowsky et al., Proc. Natl. Acad. Sci. 94:1119-1123)., the dyes or labeling compounds are detected and quantified. Duplicate hybridizations are performed. Comparative analysis of the intensity of the signal originating from cDNA probes on the same target oligonucleotide in different cDNA samples indicates a differential expression of the mRNA corresponding to the 5′ EST or cDNA from which the oligonucleotide sequence has been designed.  
      III. Characterization of cDNAs including the 5′End of their Corresponding mRNA  
     EXAMPLE 11  
      Characterization of the Complete Sequence of cDNA Clones  
      Clones which include the 5′end of their corresponding mRNA and which encode a new protein with a signal peptide as determined in the aforementioned procedure were then fully sequenced as follows.  
      First, both 5′ and 3′ ends of cloned cDNAs were sequenced twice in order to confirm the identity of the clone using a Die Terminator approach with the AmpliTaq DNA polymerase FS kit available from Perkin Elmer. Second, primer walking was performed if the full coding region had not been obtained yet using software such as OSP to choose primers and automated computer software such as ASMG (Sutton et al.,  Genome Science Technol.  1: 9-19, 1995) to construct contigs of walking sequences including the initial 5′ tag. Contigation was then performed using 5′ and 3′ sequences and eventually primer walking sequences. The sequence was considered complete when the resulting contigs included the full coding region as well as overlapping sequences with vector DNA on both ends. In addition, clones were entirely sequenced in order to obtain at least two sequences per clone. Preferably, the sequences were obtained from both sense and antisense strands. All the contigated sequences for each clone were then used to obtain a consensus sequence which was then submitted to the computer analysis described below.  
      Alternatively, clones which include the 5′end of their corresponding mRNA and which encode a new protein with a signal peptide, as determined in the aforementioned procedure, may be subcloned into an appropriate vector such as pED6dpc2 (DiscoverEase, Genetics Institute, Cambridge, Mass.) before full sequencing.  
     EXAMPLE 12  
      Determination of Structural and Functional Features  
      Following identification of contaminants and masking of repeats, structural features, e.g. polyA tail and polyadenylation signal, of the sequences of cDNAs were subsequently determined using the algorithm, parameters and criteria defined in  FIG. 1 . Briefly, a polyA tail was defined as a homopolymeric stretch of at least 11 A with at most one alternative base within it. The polyA tail search was restricted to the last 100 nt of the sequence and limited to stretches of 11 consecutive A&#39;s because sequencing reactions are often not readable after such a polyA stretch. To search for a polyadenylation signal, the polyA tail was clipped from the full-length sequence. The 50 bp preceding the polyA tail were searched for the canonic polyadenylation AAUAAA signal allowing one mismatch to account for possible sequencing errors as well as known variation in the canonical sequence of the polyadenylation signal.  
      Functional features, e.g. ORFs and signal sequences, of the sequences of cDNAs were subsequently determined as follows. The 3 upper strand frames of cDNAs were searched for ORFs defined as the maximum length fragments beginning with a translation initiation codon and ending with a stop codon. ORFs encoding at least 80 amino acids were preferred. Each found ORF was then scanned for the presence of a signal peptide using the matrix method described in example 10.  
      Sequences of cDNAs were then compared, on a nucleotidic or proteic basis, to public sequences available at the time of filing.  
     EXAMPLE 13  
      Selection of Full Length Sequences  
      cDNAs that had already been characterized by the aforementioned computer analysis were then submitted to an automatic procedure in order to preselect cDNAs containing sequences of interest.  
      a) Automatic Sequence Preselection  
      All cDNAs clipped for vector on both ends were considered. First, a negative selection was performed in order to eliminate sequences which resulted from either contaminants or artifacts as follows. Sequences matching contaminant sequences were discarded as well as those encoding ORF sequences exhibiting identity to repeats. Sequences lacking polyA tail were also discarded. Those cDNAs which matched a known human mRNA or EST sequence and had a 5′ end more than 30 nucleotides downstream of the known 5′ end were also excluded from further analysis. Only ORFs ending before the polyA tail were kept.  
      Then, for each remaining cDNA containing several ORFs, a preselection of ORFs was performed using the following criteria. The longest ORF was preferred. If the ORF sizes were similar, the chosen ORF was the one which signal peptide had the highest score according to Von Heijne method as defined in Example 10.  
      Sequences of cDNA clones were then compared pairwise with BLAST after masking of the repeat sequences. Sequences containing at least 90% identity over 30 nucleotides were clustered in the same class. Each cluster was then subjected to a clustal analysis that detects sequences resulting from internal priming or from alternative splicing, identical sequences or sequences with several frameshifts. This automatic analysis served as a basis for manual selection of the sequences.  
      b) Manual Sequence Selection  
      Manual selection was carried out using automatically generated reports for each sequenced cDNA clone. During the manual selection procedure, a selection was performed between clones belonging to the same class as follows. ORF sequences encoded by clones belonging to the same class were aligned and compared. If the identity between nucleotidic sequences of clones belonging to the same class was more than 90% over 30 nucleotide stretches or if the identity between amino acid sequences of clones belonging to the same class was more than 80% over 20 amino acid stretches, then the clones were considered as being identical. The chosen ORF was either the one exhibiting matches with known amino acid sequences or the best one according to the criteria mentioned in the automatic sequence preselection section. If the nucleotide and amino acid homologies were less than 90% and 80% respectively, the clones were said to encode distinct proteins which can be both selected if they contain sequences of interest.  
      Selection of full length cDNA clones encoding sequences of interest was performed using the following criteria. Structural parameters (initial tag, polyadenylation site and signal, eventually matches with public ESTs in 5′ or 3′ of the sequence) were first checked in order to confirm that the cDNA was complete in 5′ and in 3′. Then, homologies with known nucleic acids and proteins were examined in order to determine whether the clone sequence matched a known nucleic acid or protein sequence and, in the latter case, its covering rate and the date at which the sequence became public. If there was no extensive match with sequences other than ESTs or genomic DNA, or if the clone sequence included substantial new information, such as encoding a protein resulting from alternative splicing of an mRNA coding for an already known protein, the sequence was kept. Examples of such cloned full length cDNAs containing sequences of interest are described in Example 14. Sequences resulting from chimera or double inserts as assessed by identity to other sequences were discarded during this procedure.  
     EXAMPLE 14  
      Characterization of Full-Length cDNAs  
      The procedure described above was used to obtain full-length cDNAs of the invention comprising the sequences of SEQ ID NOs: 1-405 derived from a variety of tissues. The polypeptides encoded by the extended or full-length cDNAs may be screened for the presence of known structural or functional motifs or for the presence of signatures or small amino acid sequences which are well conserved amongst the members of a protein family. Some of the results obtained for the polypeptides encoded by full-length cDNAs that were screened for the presence of known protein signatures and motifs using the Proscan software from the GCG package and the Prosite database are provided below.  
      Bacterial clones containing plasmids containing the full-length cDNAs are presently stored in the inventor&#39;s laboratories under the internal identification numbers provided. The inserts may be recovered from the deposited materials by growing an aliquot of the appropriate bacterial clone in the appropriate medium. The plasmid DNA can then be isolated using plasmid isolation procedures familiar to those skilled in the art such as alkaline lysis minipreps or large scale alkaline lysis plasmid isolation procedures. If desired the plasmid DNA may be further enriched by centrifugation on a cesium chloride gradient, size exclusion chromatography, or anion exchange chromatography. The plasmid DNA obtained using these procedures may then be manipulated using standard cloning techniques familiar to those skilled in the art. Alternatively, a PCR can be done with primers designed at both ends of the cDNA insertion. The PCR product which corresponds to the cDNA can then be manipulated using standard cloning techniques familiar to those skilled in the art.  
      Table I provides the sequence identification numbers of the cDNAs of the present invention, the locations of the first and last nucleotides of the full coding sequences in SEQ ID NOs: 1-405 (i.e. the nucleotides encoding both the signal peptide and the mature protein, listed under the heading FCS location in Table I), the locations of the first and last nucleotides in SEQ ID NOs: 1-405 which encode the signal peptides (listed under the heading SigPep Location in Table 1), the locations of the first and last nucleotides in SEQ ID NOs: 1-405 which encode the mature proteins generated by cleavage of the signal peptides (listed under the heading Mature Polypeptide Location in Table I), the locations in SEQ ID NOs: 1-405 of stop codons (listed under the heading Stop Codon Location in Table I), the locations of the first and last nucleotides in SEQ ID NOs: 1-405 of the polyA signals (listed under the heading Poly A Signal Location in Table I) and the locations of the first and last nucleotides of the polyA sites (listed under the heading Poly A Site Location in Table I).  
      Table II lists the sequence identification numbers of the polypeptides of SEQ ID NOs: 406-810, the locations of the first and last amino acid residues of SEQ ID NOs: 406-810 in the full length polypeptide (second column), the locations of the first and last amino acid residues of SEQ ID NOs: 406-810 in the signal peptides (third column), and the locations of the first and last amino acid residues of SEQ ID NOs: 406-810 in the mature polypeptide created by cleaving the signal peptide from the full length polypeptide (fourth column).  
      The nucleotide sequences of the sequences of SEQ ID NOs: 1-405 and the amino acid sequences encoded by SEQ ID NOs: 1-405 (i.e. amino acid sequences of SEQ ID NOs: 406-810) are provided in the appended sequence listing. In some instances, the sequences are preliminary and may include some incorrect or ambiguous sequences or amino acids. All instances of the symbol “n” in the nucleic acid sequences mean that the nucleotide can be adenine, guanine, cytosine or thymine. For each amino acid sequence, Applicants have identified what they have determined to be the reading frame best identifiable with sequence information available at the time of filing. In some instances the polypeptide sequences in the Sequence Listing contain the symbol “Xaa.” These “Xaa” symbols indicate either (1) a residue which cannot be identified because of nucleotide sequence ambiguity or (2) a stop codon in the determined sequence where applicants believe one should not exist (if the sequence were determined more accurately). Thus, “Xaa” indicates that a residue may be any of the twenty amino acids. In some instances, several possible identities of the unknown amino acids may be suggested by the genetic code.  
      The sequences of SEQ ID NOs: 1-405 can readily be screened for any errors therein and any sequence ambiguities can be resolved by resequencing a fragment containing such errors or ambiguities on both strands. Nucleic acid fragments for resolving sequencing errors or ambiguities may be obtained from the deposited clones or can be isolated using the techniques described herein. Resolution of any such ambiguities or errors may be facilitated by using primers which hybridize to sequences located close to the ambiguous or erroneous sequences. For example, the primers may hybridize to sequences within 50-75 bases of the ambiguity or error. Upon resolution of an error or ambiguity, the corresponding corrections can be made in the protein sequences encoded by the DNA containing the error or ambiguity. The amino acid sequence of the protein encoded by a particular clone can also be determined by expression of the clone in a suitable host cell, collecting the protein, and determining its sequence.  
     EXAMPLE 15A  
      Categorization of cDNAs of the Present Invention  
      The nucleic acid sequences of the present invention (SEQ ID NOs. 1-405) were grouped based on their identity to known sequences as follows. All sequences were compared to public sequences available at the time of filing the priority applications.  
      In some instances, the cDNAs did not match any known vertebrate sequence nor any publicly available EST sequence, thus being completely new.  
      All sequences exhibiting more than 90% of identity to known sequences over at least 30 nucleotides were retrieved and further analyzed. For cDNAs referred to by their sequence identification numbers (first column), Table III gives the positions of preferred fragments within these sequences (second column entitled “Positions of preferred fragments”). Each fragment is represented by x-y where x and y are the start and end positions respectively of a given preferred fragment. Preferred fragments are separated from each other by a coma. As used herein the term “polynucleotide described in Table III” refers to the all of the preferred polynucleotide fragments defined in Table III in this manner.  
      For polynucleotides referred to by sequence identification numbers (first column), the second column of Table IVa provides the positions of fragments which are preferably included in the present invention (column 2) while the second column of IVb provides the positions of fragments which are preferably excluded from the present invention. Each fragment is represented by x-y where x and y are the start and end positions respectively of a given fragment. Fragments are separated from each other by a semi-column. Tables IVa and IVb provides for the inclusion and exclusion of polynucleotides in addition to those described elsewhere in the specification and is therefore, not meant as limiting description. As used herein the terms “polynucleotide described in Table IVa” and “polynucleotide described in Table UVb” refers to the all of the polynucleotide fragments defined in the second column of Tables IVa or IVb respectively in this manner.  
      The present invention encompasses isolated, purified, or recombinant nucleic acids which consist of, consist essentially of, or comprise a contiguous span of one of the sequences of SEQ ID Nos. 1-405 or a sequence complementary thereto, said contiguous span comprising at least 8, 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 nucleotides of the sequence of SEQ ID Nos. 1-405 or a sequence complementary thereto, to the extent that a contiguous span of these lengths is consistent with the lengths of the particular sequence, wherein the contiguous span comprises at least 1, 2, 3, 5, 10, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400 or 500 of a polynucleotide described in Table III or of a polynucleotide described in Table IVa, or a sequence complementary thereto. The present invention also encompasses isolated, purified, or recombinant nucleic acids comprising, consisting essentially of, or consisting of a contiguous span of at least 8, 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 nucleotides of a polynucleotide described in Table III or of a polynucleotide described in Table IVa or a sequence complementary thereto, to the extent that a contiguous span of these lengths is consistent with the length of the particular sequence described in Table III. The present invention also encompasses isolated, purified, or recombinant nucleic acids which comprise, consist of or consist essentially of a polynucleotide described in Table III or of a polynucleotide described in Table IVa, or a sequence complementary thereto. The present invention further encompasses any combination of the nucleic acids listed in this paragraph.  
      Cells containing the cDNAs (SEQ ID NOs: 1-405) of the present invention in the vector pBluescriptII SK− (Stratagene) are maintained in permanent deposit by the inventors at Genset, S. A., 24 Rue Royale, 75008 Paris, France.  
      Pool of cells containing the cDNAs of SEQ ID NOs: 1-405, from which the cells containing a particular polynucleotide is obtainable, were deposited with the European Collection of Cell Cultures (ECACC), Vaccine Research and Production Laboratory, Public Health Laboratory Service, Centre for Applied Microbiology and Reasearch, Porton Down, Salisbury, Wiltshire SP4 OJG, United Kingdom. Each cDNA clone has been transfected into separate bacterial cells (E-coli) for these composite deposits. In particular, cells containing the sequences of SEQ ID NOs: 2-17 and 19-23 were deposited on Jun. 17, 1999 in the pool having ECACC Accession No. 99061735 and designated SignalTag 15061999. In addition, cells containing the sequences of SEQ ID Nos: 24-50 were deposited on Dec. 18, 1998, in the pool having ECACC Accession No. 98121805 and designated SignalTag 166-191. Table IV provides the internal designation number assigned to each SEQ ID NO. and indicates whether the sequence is a nucleic acid sequence or a protein sequence.  
      Each cDNA can be removed from the Bluescript vector in which it was deposited by performing a BsH II double digestion to produce the appropriate fragment for each clone provided the cDNA clone sequence does not contain this restriction site. Alternatively, other restriction enzymes of the multicloning site of the vector may be used to recover the desired insert as indicated by the manufacturer.  
      Bacterial cells containing a particular clone can be obtained from the composite deposit as follows:  
      An oligonucleotide probe or probes should be designed to the sequence that is known for that particular clone. This sequence can be derived from the sequences provided herein, or from a combination of those sequences. The design of the oligonucleotide probe should preferably follow these parameters: 
          (a) It should be designed to an area of the sequence which has the fewest ambiguous bases (“N&#39;s”), if any;     (b) Preferably, the probe is designed to have a T m  of approx. 80° C. (assuming 2 degrees for each A or T and 4 degrees for each G or C). However, probes having melting temperatures between 40° C. and 80° C. may also be used provided that specificity is not lost.        

      The oligonucleotide should preferably be labeled with (−[ 32 P]ATP (specific activity 6000 Ci/mmole) and T4 polynucleotide kinase using commonly employed techniques for labeling oligonucleotides. Other labeling techniques can also be used. Unincorporated label should preferably be removed by gel filtration chromatography or other established methods. The amount of radioactivity incorporated into the probe should be quantified by measurement in a scintillation counter. Preferably, specific activity of the resulting probe should be approximately 4×10 6  dpm/pmole.  
      The bacterial culture containing the pool of full-length clones should preferably be thawed and 100 μl of the stock used to inoculate a sterile culture flask containing 25 ml of sterile L-broth containing ampicillin at 100 μg/ml. The culture should preferably be grown to saturation at 37° C., and the saturated culture should preferably be diluted in fresh L-broth. Aliquots of these dilutions should preferably be plated to determine the dilution and volume which will yield approximately 5000 distinct and well-separated colonies on solid bacteriological media containing L-broth containing ampicillin at 100 μg/ml and agar at 1.5% in a 150 mm petri dish when grown overnight at 37° C. Other known methods of obtaining distinct, well-separated colonies can also be employed.  
      Standard colony hybridization procedures should then be used to transfer the colonies to nitrocellulose filters and lyse, denature and bake them.  
      The filter is then preferably incubated at 65° C. for 1 hour with gentle agitation in 6×SSC (20× stock is 175.3 g NaCl/liter, 88.2 g Na citrate/liter, adjusted to pH 7.0 with NaOH) containing 0.5% SDS, 100 pg/ml of yeast RNA, and 10 mM EDTA (approximately 10 ml per 150 mm filter). Preferably, the probe is then added to the hybridization mix at a concentration greater than or equal to 1×10 6  dpm/ml. The filter is then preferably incubated at 65° C. with gentle agitation overnight. The filter is then preferably washed in 500 ml of 2×SSC/0.1% SDS at room temperature with gentle shaking for 15 minutes. A third wash with 0.1×SSC/0.5% SDS at 65° C. for 30 minutes to 1 hour is optional. The filter is then preferably dried and subjected to autoradiography for sufficient time to visualize the positives on the X-ray film. Other known hybridization methods can also be employed.  
      The positive colonies are picked, grown in culture, and plasmid DNA isolated using standard procedures. The clones can then be verified by restriction analysis, hybridization analysis, or DNA sequencing.  
      The plasmid DNA obtained using these procedures may then be manipulated using standard cloning techniques familiar to those skilled in the art. Alternatively, a PCR can be done with primers designed at both ends of the cDNA insertion. The PCR product which corresponds to the cDNA can then be manipulated using standard cloning techniques familiar to those skilled in the art.  
      Tissue expression of the cDNAs of the present invention was also examined. Table VI list the Genset&#39;s libraries of tissues and cell types examined that express the polynucleotides of the present invention. The tissues and cell types examined for polynucleotide expression were: brain, fetal brain, fetal kidney, fetal liver, pituitary gland, liver, placenta, prostate, salivary gland, stomach/intestine, and testis. For cDNAs referred to by sequence identification number (first column), the number of proprietary 5′ESTs expressed in a particular tissue referred to by its name is indicated in parentheses (second column). In addition, the bias in the spatial distribution of the polynucleotide sequences of the present invention is indicated in Table VII. The expression of these sequences were examined by comparing the relative proportions of the biological polynucleotides of a given tissue using the following statistical analysis. The under- or over-representation of a polynucleotide of a given cluster in a given tissue was performed using the normal approximation of the binomial distribution. When the observed proportion of a polynucleotide of a given tissue in a given consensus had less than 1% chance to occur randomly according to the chi2 test, the frequency bias was reported as “preferred”. The results are given in Table VII as follows. For some polynucleotides showing a bias in tissue distribution as referred to by sequence identification number in the first column, the list of tissues where the polynucleotides are over-represented is given in the second column entitled “preferential expression”.  
      In addition, the spatial distribution of the polynucleotide sequences of the present invention was investigated using information from public databases. The expression of the sequences of SEQ ID NOs:1-405 was examined by comparing them to the polynucleotide sequences in public databases. Table VIII lists tissues and cell types which express the polynucleotides of the sequence listing. Column one lists the sequence identification number and column two lists the corresponding tissues and cell types that were found to express the polynucleotide sequences using information from public databases. The number to the right of the tissue or cell type in column two represents the number of entries in the databases listing that tissue or cell type as expressing the sequence of column 1.  
      In one embodiment, polynucleotides of the invention selectively expressed in tissues may be used as markers to identify these tissues using any technique known to those skilled in the art those skilled in the art such as in situ PCR. Such tissue-specific markers may then be used to identify tissues of unknown origin, for example, forensic samples, differentiated tumor tissue that has metastasized to foreign bodily sites, or to differentiate different tissue types in a tissue cross-section using immunochemistry. For example, polynucleotides of the invention preferentially expressed in given tissues as indicated in Table VII may be used for this purpose. In addition, the polynucleotide of SEQ ID NO: 16 may be used to selectively identify liver tissue. The polynucleotide of SEQ ID NO:29 may be used to selectively identify prostate tissue. The polynucleotides of SEQ ID NO:21, 23 and 49 may be used to selectively identify normal or diseased brain tissue.  
     EXAMPLE 15B  
      Functional Analysis of Predicted Protein Sequences  
      Following double-sequencing, contigated sequences were assembled for each of the cDNAs of the present invention and further reanalyzed. The following databases were used in sequence analyses: Genbank (release 117), EMBL (release 62), TrEmbl (release 13.4) Genseq (release 0011) Swissprot (release 38), PIR (release 64). In some cases, more preferred open reading frames differing from the ones previously selected in priority applications are indicated.  
      The polypeptides (SEQ ID NOs: 406-810) encoded by the cDNAs were screened for the presence of known structural or functional motifs or for the presence of signatures, small amino acid sequences that are well conserved amongst the members of a protein family. The search was conducted on the Pfam 5.2 database using HMMER-2.1.1 (for info see Sonnhammer et Durbin, http:/www.sanger.ac.uk/Pfam/), on the BLOCKSPLUS v 11.0 database using emotif (for info see Nevill-Manning et al.,  PNAS,  95, 5865-5871, (1998), http://motif.stanford/edu/EMOTIF) and on the Prosite 15.0 database using bla (Tatusov, R. L. &amp; Koonin, E. V. CABIOS 10, No. 4) and pfscan (http://www.isrec.isb-sib.ch/cgi-bin/man.cgi?section=1 &amp;topic=pfscan).  
      It should be noted that, in the numbering of amino acids in the protein sequences discussed below, and in Table IX, the first methionine encountered is designated as amino acid number 1, i.e.; the leader sequence is not numbered negatively. In the appended sequence listing, the first amino acid of the mature protein resulting from cleavage of the signal peptide is designated as amino acid number 1 and the first amino acid of the signal peptide is designated with the appropriate negative number, in accordance with the regulations governing sequence listings. Each of the references cited in this example are hereby incorporated by reference in their entireties.  
      Table IX lists known biologically structural and functional domains for the cDNA of the present invention corresponding to the sequence identification number indicated in the first column. Column 2 lists the positions of the domains where each domain is represented by x-y where x and y are the start and end positions respectively of a given domain. Column 3 lists the domain designation. Column 4 lists the database from which the domain was identified.  
      Protein of SEQ ID NO: 425 (Internal Designation 117-007-2-0-C4-FLC)  
      The protein of SEQ ID NO: 425 encoded by the cDNA of SEQ ID NO:20 found in liver is homologous to a human protein thought to be transmembraneous (Genseq accession number W88491). In addition, this protein displays homology to alpha-2-HS glycoprotein precursors (fetuins) of human and pigs. The 382-amino-acid-long protein of SEQ ID NO: 425, which is similar in size to fetuins, displays pfam cystatin domains 1 and 2 from positions 37 to 104 and from positions 157 to 254. It also displays the 12 conserved cysteines of this family (positions 36, 93, 104, 117, 137, 151, 154, 216, 224, 237, 254 and 368) and a conserved region around the second cysteine (positions 89 to 96). In addition, the potential active site QxVxG is also present in the protein of the invention (positions 198 to 202).  
      Mammalian fetuins are secreted glycoproteins synthesized in liver and selectively concentrated in bone matrix. Their functions include control of endocytosis, cell proliferation and differentiation, immune response, bone formation and resorption, and apoptosis. More specifically, fetuin levels in human plasma are regulated in the manner of a negative acute phase reactant (Lebreton et al., J. Clin. Invest. 64:1118-29 (1979)) and serum levels decline in some cancer patients correlating with impaired cellular immune function (Baskies et al., Cancer 45:3050-58 (1980)). During mouse embryogenesis, fetuin mRNA is expressed in a number of developing organs and tissues including the heart, kidney, lung, nervous system and liver (Yang et al., Biochem. Biophysic. Acta 1130:149-56 (1992)). Mammalian fetuin present in sub-populations of neurons in the developing central and peripheral nervous system is associated to cell survival (Saunders et al., Anat. Embryol 186:477-86 (1992)); Kitchener et al., Int J. Dev. Neurosci. 15:717-27 (1997)). Fetuin is able to promote growth in tissue culture (Puck et al. Proc. Natl. Acad. Sci. U. S. A., 59:192-99 (1968)), to enhance bone resorption (Coclasure et al., J. Clin. Endocrinol. Metab. 66:187-192 (1988)) and to stimulate adipogenesis in cell culture models (Cayatte et al., J. Biol. Chem. 265:5883-8 (1990)). Abnormal serum levels of fetuin are associated with alteration in cellular and biochemical properties of bone, Paget&#39;s disease, reduced bone quality and osteogenesis imperfecta (for a review see Binkert et al, J. Biol. Chem. 274:28514-20 (1999)). Part of the fetuin activities has been shown to depend upon their ability to inhibit the activity of TGF-beta cytokines and bone morphogenetic proteins (BMPs) through direct binding (Demetriou et al., J. Biol. Chem. 271:12755-61 (1996); Binkert et al., J. Biol. Chem. 274:28514-20 (1999)). These ligands are members of the TGF-beta superfamily comprising proteins belonging to the TGF-beta, activin/inhibin, DPP/VG1, and Mullerian Inhibiting Substance Family families mediating a wide range of biological processes in vertebrates and invertebrates, including regulation of cell proliferation, differentiation, recognition, and death, and thus play a major role in developmental processes, tissue recycling, and repair (J. Wrana and L. Attisano, “Mad-related Proteins in TGF-beta Signaling,” TIG 12:493-496, 1996; U.S. Pat. No. 5,981,483). In addition, fetuins are members of the cystatin superfamily which contains evolutionarily related proteins with diverse functions such as cysteine protease inhibitors, stefins, fetuins and kininogens (see review by Brown and Dziegielewska,  Prot. Science,  6:5-12 (1997)).  
      It is believed that the protein of SEQ ID NO: 425 or part thereof is a member of the cystatin superfamily and, as such, plays a role in cellular proteolysis, endocytosis, cell proliferation and differentiation, immune response, bone formation and resorption, and/or apoptosis. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:425 from positions 37 to 104, 89 to 96, 157 to 254, 198 to 202, and 36 to 368. Other preferred polypeptides of the invention are fragments of SEQ ID NO:425 having any of the biological activity described herein.  
      An embodiment of the present invention relates to methods of using the protein of the invention or part thereof to identify and/or quantify cytokines of the TGF-beta superfamily, more preferably TGF-1beta, TGF-2beta and BMP-2, BMP-4 and BMP-6 in a biological sample, and thus used in assays and diagnostic kits for the quantification of such cytokines in bodily fluids, in tissue samples, and in mammalian cell cultures. The binding activity of the protein of the invention or part thereof may be assessed using the assay described in Demetriou et al., J. Biol. Chem. 271:12755-61 (1996) or any other method familiar to those skilled in the art. Preferably, a defined quantity of the protein of the invention or part thereof is added to the sample under conditions allowing the formation of a complex between the protein of the invention or part thereof and the cytokine to be identified and/or quantified. Then, the presence of the complex and/or or the free protein of the invention or part thereof is assayed and eventually compared to a control using any of the techniques known by those skilled in the art.  
      Another embodiment of the invention relates to compositions and methods using the protein of the invention or part thereof to modulate the activity of members of the TGF beta superfamily, preferably members of TGF beta family, members of actin/inhibin family, members of DPP/VG1 family, and members of Mullerian inhibiting substance family, more preferably TGF-1beta, TGF-2beta, BMP-2, BMP-4 and BMP-6, in contexts where the production of such proteins is undesirable.  
      In a preferred embodiment, the protein of the invention or part thereof is used to inhibit and/or attenuate the effects of cytokines belonging to the TGF beta family, such as TGF-1beta, TGF-2beta and BMP-2, BMP-4 and BMP-6, by blocking the binding of endogenous cytokines to its natural receptor, thereby blocking cell proliferative or inhibitory signals generated by the ligand-receptor binding event. The protein of the invention or part thereof would thereby stimulate immune responses and reduce the deposition of extracellular matrix. Accordingly, the protein of the invention or part thereof, would be particularly suitable for the treatment of conditions such as fibrosis including pulmonary fibrosis, fibrosis associated with chronic liver disease, hepatic veno-occlusive and idiopathic interstitial pneumonitis, kidney disease, and radiotherapy or radiation accidents; proliferative vitreoretinopathy; systemic sclerosis; autoimmune disorders such as rheumatoid arthritis, Graves disease, systemic lupus erythematosus, Wegener&#39;s granulomatosis, sarcoidosis, polyarthritis, pemphigus, pemphigoid, erythema multiform, Sjogren&#39;s syndrome, inflammatory bowel disease, multiple sclerosis, myasthenia gravis keratitis, scleritis, Type I diabetes, insulin-dependent diabetes mellitus, Lupus Nephritis, and allergic encephalomyelitis; proliferative disorders including various forms of cancer such as leukemias, lymphomas (Hodgkins and non-Hodgkins), sarcomas, melanomas, adenomas, carcinomas of solid tissue, hypoxic tumors, squamous cell carcinomas of the mouth, throat, larynx, and lung, genitourinary cancers such as cervical and bladder cancer, hematopoietic cancers, head and neck cancers, and nervous system cancers, benign lesions such as papillomas, atherosclerosis, angiogenesis, and viral infections, in particular HIV infections. The protein of the invention or part thereof may also be used, as an antagonist of cytokines of the TGF-beta family, to elevate blood pressure through the inhibition of hypotension induced by TGF-beta. Methods which lower and/or maintain the level of circulating TGF-beta in a subject may result in a similar pressor effect and may prevent excessive hypotensive signal generation and resulting hypotension.  
      In another preferred embodiment, the protein of the invention or part thereof is used to block the normal interaction between activin and its receptor. The protein of the invention or part thereof would thereby stimulate the release of FSH. Accordingly, the protein of the invention or part thereof can be applied to the control of fertility in humans, domesticated animals, and animals of commercial interest. The action of activin on erythropoiesis can also be modulated by administering a modulating effective amount of the protein of the invention or part thereof. Thus, the protein of the invention or part thereof may be used in the diagnosis and/or treatment of activin-dependent tumors or for enhancing the survival of brain neurons.  
      In still another preferred embodiment, the protein of the invention or part thereof is used to modulate bone formation and bone cell differentiation through binding to bone morphogenetic proteins and/or to TGF-beta proteins. Therefore, the protein of the invention or part thereof may be used to repair or heal fractures, treat osteoporosis, address dental problems, and with implants to encourage bone growth. In addition, the protein of the invention or part thereof may be used in disorders where there is too much bone formation (for example, achondroplasia, Paget&#39;s disease, and osteoporosis). The utility of the protein of the invention or part thereof may be further confirmed using binding assays and animal models described in Demetriou et al., J. Biol. Chem. 271:12755-61 (1996) and in U.S. Pat. No. 5,981,483.  
      In still another embodiment, the invention relates to methods and compositions containing the protein of the invention or part thereof to treat and/or prevent the ill-effects of bacterial infection during pregnancy in mammals, such as spontaneous abortion and maternal death. In a preferred embodiment, the protein of the invention may be used to counteract the effects of the bacterial endotoxin lipopolysaccharide (LPS). The method to use such compositions is described in Dziegielewska and Andersen, Biol. Neonate, 74:372-5 (1998).  
      In another series of embodiments, the protein of the invention, or part thereof may be used to inhibit proteases, preferably cysteine proteases. Examples of cysteine proteases that may be inhibited by the protein of the invention or part thereof include, but are not limited to, the plant cysteine proteases such as papain, ficin, aleurain, oryzain and actinidin; mammalian cysteine proteases such as cathepsins B, H, J, L, N, S, T, 0, 02 and C, (cathepsin C is also known as dipeptidyl peptidase I), interleukin converting enzyme (ICE), calcium-activated neutral proteases, calpain I and II; bleomycin hydrolase, viral cysteine proteases such as picomian 2A and 3C, aphthovirus endopeptidase, cardiovirus endopeptidase, comovirus endopeptidase, potyvirus endopeptidases I and II, adenovirus endopeptidase, the two endopeptidases from chestnut blight virus, togavirus cysteine endopeptidase, as well as cysteine proteases of the polio and rhinoviruses; and cysteine proteases known to be essential for parasite lifecycles, such as the proteases from species of Plasmodia, Entamoeba, Onchocera, Trypanosoma, Leishmania, Haemonchus, Dictyostelium, Therileria, and Schistosoma, such as those associated with malaria ( P. falciparum ), trypanosomes ( T. cruzi , the enzyme is also known as cruzain or cruzipain), murine  P. vinckei , and the  C. elegans  cysteine protease. For an extensive listing of cysteine proteases that may be inhibited by the protein or part thereof of the present invention, see Rawlings et al., Biochem. J. 290:205-218 (1993). Assays for testing the inhibitory activities of cysteine protease inhibitors are presented in the U.S. Pat. No. 5,973,110, using methods for determining inhibition constants well known to those skilled in the art (see Fersht, ENZYME STRUCTURE AND MECHANISM, 2nd ed., W.H. Freeman and Co., New York, (1985)).  
      Since proteases play an important role in the regulation of many biological processes in virtually all living organisms as well as a major role in diseases, the protein of the invention or part thereof are useful in a wide variety of applications, such as those described in U.S. Pat. No. 6,004,933.  
      An embodiment of the present invention further relates to methods of using the protein of the invention or part thereof to quantify the amount of a given protease in a biological sample, and thus used in assays and diagnostic kits for the quantification of proteases in bodily fluids or other tissue samples, in addition to bacterial, fungal, plant, yeast, viral or mammalian cell cultures. In a preferred embodiment, the sample is assayed using a standard protease substrate. A known concentration of protease inhibitor is added, and allowed to bind to a particular protease present. The protease assay is then rerun, and the loss of activity is correlated to the protease inhibitor activity using techniques well known to those skilled in the art.  
      In addition, the protein of the invention or part thereof may be useful to remove, identify or inhibit contaminating proteases in a sample. Compositions comprising the polypeptides of the present invention may be added to biological samples as a “cocktail” with other protease inhibitors to prevent degradation of protein samples. The advantage of using a cocktail of protease inhibitors is that one is able to inhibit a wide range of proteases without knowing the specificity of any of the proteases. Using a cocktail of protease inhibitors also protects a protein sample from a wide range of future unknown proteases which may contaminate a protein sample from a vast number of sources. Such protease inhibitor cocktails (see for example the ready to use cocktails sold by Sigma) are widely used in research laboratory assays to inhibit proteases susceptible of degrading a protein of interest for which the assay is to be performed. For example, the protein of the invention or part thereof is added to samples where proteolytic degradation by contaminating proteases is undesirable. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other protease inhibitors, using techniques well known in the art, to form an affinity chromatography column. A sample containing the undesirable protease is run through the column to remove the protease. Alternatively, the same methods may be used to identify new proteases.  
      In a preferred embodiment, the protein of the invention or part thereof may be used to inhibit proteases implicated in a number of diseases where cellular proteolysis occur. In particular, the protein of the invention or part thereof may be useful to inhibit lysosomal cysteine proteases, both in vivo or in vitro, implicated in a wide spectrum of diseases characterized by tissue degradation including but not limited to arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, parasite-borne infections, Alzheimer&#39;s disease, periodontal disease, and cancer metastasis.  
      In another preferred embodiment, the protein of the invention or part thereof may be used to inhibit exogenous proteases, both in vivo or in vitro, implicated in a number of infectious diseases including but not limited to gingivitis, malaria, leishmaniasis, filariasis, osteoporosis and osteoarthritis, and other bacterial, and parasite-borne or viral infections. In particular, the protein of the invention or part thereof may offer applications in viral diseases where the proteolysis of primary polypeptide precursors is essential to the replication of the virus, as for HIV and HCV.  
      In another preferred embodiment, the protein of the invention or part thereof is used to prevent cells to undergo apoptosis. In a preferred embodiment, the apoptosis active polypeptide is added to an in vitro culture of mammalian cells in an amount effective to reduce apoptosis. For example, inhibiting the activity of apopain, a cysteine protease member of the ICE/CED-3 subfamily involved in apoptosis, attenuates apoptosis in vitro (U.S. Pat. No. 5,798,442). Furthermore, the protein of the invention or part thereof may be useful in the diagnosis, the treatment and/or the prevention of disorders in which apoptosis is deleterious, including but not limited to immune deficiency syndromes (including AIDS), type I diabetes, pathogenic infections, cardiovascular and neurological injury, alopecia, aging, Parkinson&#39;s disease and Alzheimer&#39;s disease.  
      Additionally, the protein of the invention or part thereof offer application in the treatment of inflammation and immune based disorders of the lung, airways, central nervous system and surrounding membranes, eyes, ears, joints, bones, connective tissues, cardiovascular system including the pericardium, gastrointestinal and urogenital systems, the skin and the mucosal membranes. These conditions include infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complications of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, chalangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis. Bone and cartilage reabsorption as well as diseases resulting in excessive deposition of extracellular matrix such as interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, and keloid formation may also be treated with the protein of the invention or part thereof.  
      Furthermore, the protein of the present invention or part thereof find use in drug potentiation applications. For example, therapeutic agents such as antibiotics or antitumor drugs can be inactivated through proteolysis by endogenous proteases, thus rendering the administered drug less effective or inactive. Accordingly, the protein of the invention or part thereof may be administered to a patient in conjunction with a therapeutic agent in order to potentiate or increase the activity of the drug. This co-administration may be by simultaneous administration, such as a mixture of the protease inhibitor and the drug, or by separate simultaneous or sequential administration.  
      In addition, protease inhibitors have been shown to inhibit the growth of microorganisms including human pathogenic bacteria. For example, protease inhibitors are able to inhibit growth of all strains of group A streptococci, including antibiotic-resistant strains (Merigan, T. et al (1996) Ann Intern Med 124:1039-1050; Stoka, V. (1995) FEBS. Lett 370:101-104; Vonderfecht, S. et al (1988) J Clin Invest 82:2011-2016; Collins, A. et al (1991) Antimicrob Agents Chemother 35:2444-2446). Accordingly, the protein of the invention may or part thereof be used as antibacterial agents to retard or inhibit the growth of certain bacteria either in vitro or in vivo. Particularly, the polypeptides of the present invention may be used to inhibit the growth of group A streptococci on non-living matter such as instruments not conducive to other methods of preventing or removing contamination by group A streptococci, and in culture of living plant, fungi, and animal cells.  
      Protein of SEQ ID NO: 418 (Internal Designation 116-054-3-0-G12-FLC)  
      The protein of SEQ ID NO: 418 encoded by the cDNA of SEQ ID NO: 13 found in liver is homologous to the subunit 2 of NADH dehydrogenase (Genseq accession number Y14556) 35 and to the MLRQ subunit of NADH dehydrogenase (NADH-ubiquinone oxidoreductase, NADH-D or complex I) of bovine, murine and human species (Genbank accession numbers X64897, U59509 and EMBL accession number U94586 respectively). In addition, the 83-amino-acid-long protein of SEQ ID NO: 418 has a size similar to those of known MLRQ subunits as well as an hydrophobic N-terminal region of 25-30 amino acids.  
      Complex I is the first of 3 multienzyme complexes located in the mitochondrial membrane that make up the mitochondrial electron transport chain. Complex I accomplishes the first step in this process by accepting electrons from NADH and passing them through a flavin molecule to ubiquinone which then transfers electrons to the second enzyme complex in the chain.  
      Complex I contains approximately 40 polypeptide subunits of widely varying size and composition and is highly conserved in a variety of mammalian species including rat, rabbit, cow, and human (Cleeter, M. W. J. and Ragan, C. I. (1985) Biochem. J. 230: 739-46). The best characterized complex I is from bovine heart mitochondria and is composed of 41 polypeptides (Walker, J. E. et al. (1992) J. Mol. Biol. 226: 1051-72). Seven of these polypeptides are encoded by mitochondrial DNA, while the remaining 34 are nuclear gene products that are imported into the mitochondria. Six of these imported polypeptides are characterized by N-terminal signal peptide sequences which target these polypeptides to the mitochondria and are then cleaved from the mature proteins. A second group of polypeptides lack N-terminal targeting sequences and appear to contain import signals which lie within the mature protein (Walker et al., supra). The functions of many of the individual subunits in NADH-D are largely unknown. The 24-, 51-, and 75-kDa subunits have been identified as being catalytically important in electron transport, with the 51-kDa subunit forming part of the NADH binding site and containing the flavin moiety that is the initial electron acceptor (Ali, S. T. et al. (1993) Genomics 18:435-39). The location of other functionally important groups, such as the electron-carrying iron-sulfate centers, remains to be determined. Many of the smaller subunits (&lt;30 kDa) contain hydrophobic sequences that may be folded into membrane spanning alpha-helices. These subunits presumably are anchored into the inner membrane of the mitochondria and interact via more hydrophilic parts of their sequence with globular proteins in the large extrinsic domain of NADH-D. The remaining proteins are likely to be globular and form part of a domain outside the lipid bilayer. The MLRQ subunit is one of the small (9 kDa) subunits that is nuclear encoded and contains no N-terminal extension to direct the protein into the mitochondrion, thus implying that the import signal should lie into the mature protein (Walker et al. supra). A potential membrane-spanning alpha-helix presumably anchors the MLRQ subunit to the inner membrane of the mitochondria, but the precise function of the subunit is unknown.  
      Mitochondriocytopathies due to complex I deficiency are frequently encountered and affect tissues with a high-energy demand such as brain (mental retardation, convulsions, movement disorders), heart (cardiomyopathy, conduction disorders), kidney (Fanconi syndrome), skeletal muscle (exercise intolerance, muscle weakness, hypotonia) and/or eye (opthmaloplegia, ptosis, cataract and retinopathy). Complex I is also thought to play a role in the regulation of apoptosis and necrosis. For a review on complex I, see Smeitink et al.,  Hum. Mol. Gent.,  7: 1573-1579 (1998); Lenaz et al., Acta Biochem Pol 46:1-21 (1999); Lee and Wei, J Biomed Sci 7:2-15 (2000). In addition, defects and altered expression of complex I are associated with a variety of disease conditions in man, including neurodegenerative diseases, myopathies, and cancer (Singer, T. P. et al. (1995) Biochim. Biophys. Acta 1271:211-19; Selvanayagam, P. and Rajaraman, S. (1996) Lab. Invest. 74:592-99). Moreover, NADH-D reduction of the quinone moiety in chemotherapeutic agents such as doxorubicin is believed to contribute to the antitumor activity and/or mutagenicity of these drugs (Akman, S. A. et al. (1992) Biochemistry 31:3500-6).  
      It is believed that the protein of SEQ ID NO: 418 is a NADH-ubiquinone oxidoreductase MLRQ-like protein and/or plays a role in mitochondria electron transport. Preferred polypeptides of the invention are fragments of SEQ ID NO: 443 having any of the biological activities described herein  
      An object of the present invention are compositions and methods of targeting heterologous compounds, either polypeptides or polynucleotides to mitochondria by recombinantly or chemically fusing a fragment of the protein of the invention to an heterologous polypeptide or polynucleotide. Preferred fragments are signal peptide, amphiphilic alpha helices and/or any other fragments of the protein of the invention, or part thereof, that may contain targeting signals for mitochondria including but not limited to matrix targeting signals as defined in Herrman and Neupert, Curr. Opinion Microbiol. 3:210-4 (2000); Bhagwat et al. J. Biol. Chem. 274:24014-22 (1999), Murphy Trends Biotechnol. 15:326-30 (1997); Glaser et al. Plant Mol Biol 38:311-38 (1998); Ciminale et al. Oncogene 18:4505-14 (1999). Such heterologous compounds may be used to modulate mitochondria&#39;s activities. For example, they may be used to induce and/or prevent mitochondrial-induced apoptosis or necrosis. In addition, heterologous polynucleotides may be used for mitochondrial gene therapy to replace a defective mitochondrial gene and/or to inhibit the deleterious expression of a mitochondrial gene.  
      In another embodiment, the protein of the invention or part thereof is used to prevent cells to undergo apoptosis. In a preferred embodiment, the apoptosis active polypeptide is added to an in vitro culture of mammalian cells in an amount effective to reduce apoptosis. Furthermore, the protein of the invention or part thereof may be useful in the diagnosis, the treatment and/or the prevention of disorders in which apoptosis is deleterious, including but not limited to immune deficiency syndromes (including AIDS), type I diabetes, pathogenic infections, cardiovascular and neurological injury, alopecia, aging, degenerative diseases such as Alzheimer&#39;s Disease, Parkinson&#39;s Disease, Huntington&#39;s disease, dystonia, Leber&#39;s hereditary optic neuropathy, schizophrenia, and myodegenerative disorders such as “mitochondrial encephalopathy, lactic acidosis, and stroke” (MELAS), and “myoclonic epilepsy ragged red fiber syndrome” (MERRF).  
      The invention further relates to methods and compositions using the protein of the invention or part thereof to diagnose, prevent and/or treat several disorders in which mitochondrial respiratory electron transport chain is impaired, or needs to be impaired, including but not limited to mitochondriocytopathies, necrosis, aging, neurodegenerative diseases, myopathies, and cancer. For diagnostic purposes, the expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals. For prevention and/or treatment purposes, the protein of the invention may be used to enhance electron transport and increase energy delivery using any of the gene therapy methods described herein or known to those skilled in the art.  
      Moreover, antibodies to the protein of the invention or part thereof may be used for detection of mitochondria organelles and/or mitochondrial membranes using any techniques known to those skilled in the art.  
      Protein of SEQ ID NO: 443 (Internal Designation 108-013-5-0-H9-FL)  
      The protein of SEQ ID NO: 443 encoded by the extended cDNA SEQ ID NO:38 is homologous to the human IHLP lysophospholipase (Genseq accession number W88457) and to a family of lysophospholipases conserved among eukaryotes (yeast, rabbit, rodents and human). In addition, some members of this family (rat:Genbank accession number U97146, rabbit: Genbank accession number U97147) exhibit a calcium-independent phospholipase A2 activity (Portilla et al,  J. Am. Soc. Nephro.,  9:1178-1186 (1998)). All members of this family exhibit the active site consensus GXSXG motif of carboxylesterases that is also found in the protein of the invention (position 54 to 58). The protein of the invention also exhibits an emotif alpha/beta hydrolase fold signature from positions 52 to 66. In addition, this protein may be a membrane protein with one transmembrane domain as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)).  
      Lysophospholipids are found in very low concentrations in biological membranes. Higher concentrations of lysophospholipids have been shown to disturb membrane conformation, affect the activities of many membrane-bound enzymes and may even lead to cell lysis. In addition, increased lysophospholipid levels were observed in atherosclerosis, inflammation, hyperlipidemia, lethal dysrhythmias in myocardial ischemia and segmental demyelination of peripheral nerves. Some lysophospholipids, such as lysophosphatidylcholine, may act as lipid second messengers, transducing signals eliciting from membrane receptors. They may also potentiate immune responses and exhibit anti-tumor effects as bactericidal activities (for a review see Wang and Dennis, Biochim Biophys Acta; 1439:1-16 (1999)).  
      Lysophospholipase is a widely distributed enzyme which regulates the level of lysophospholipids and occurs in numerous isoforms. These isoforms vary in molecular mass, substrate metabolized, and optimum pH required for activity. Small isoforms, approximately 15-30 kDa, function as hydrolases; large isoforms, those exceeding 60 kDa function both as transacylases and hydrolases. Lysophospholipases are regulated by lipid factors such as acylcamitine, arachidonic acid and phosphatidic acid. The expression of IHLP is associated with proliferation and differentiation of cells of the immune system.  
      The role of lysophospholipases in human tissues has been investigated in various research studies. Selle, H. et al. (1993; Eur. J. Biochem. 212:411-16) characterized the role of lysophopholipase in the hydrolysis of lysophosphatidylcholine which causes lysis in erythrocyte membranes. Similarly, Endresen, M. J. et al. (1993) Scand. J. Clin. Invest. 53:733-9 reported that the increased hydrolysis of lysophosphatidylcholine by lysophopholipase in pre-eclamptic women causes release of free fatty acids into the sera. In renal studies, lysophopholipase was shown to protect NA+,K+-ATPase from the cytotoxic and cytolytic effects of cyclosporin A (Anderson, R. et al. (1994) Toxicol. Appl. Pharmacol. 125:176-83).  
      It is believed that the protein of SEQ ID NO:443 or part thereof plays a role in fatty acid metabolism, probably as a phospholipase. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:443 from positions 54 to 58, and 52 to 66. Other preferred polypeptides of the invention are fragments of SEQ ID NO:443 having any of the biological activities described herein. The hydrolytic activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in Portilla et al., J Am Soc Nephrol; 9:1178-1186 (1998) and in the U.S. Pat. No. 6,004,792.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to hydrolyze one or several substrates, alone or in combination with other substances. Such substrates are glycerophospholipids, preferably containing an acyl ester bond at the sn-2 position, more preferably lysophosphatidylcholine, lysophosphatidylinositol, lysophosphatidylserine, 1-oleoyl-2-acetyl-sn-glycero-3-phosphocholine, lecithin and lysolecithin. For example, the protein of the invention or part thereof is added to a sample containing the substrate(s) in conditions allowing hydrolysis, and allowed to catalyze the hydrolysis of the substrate(s). In a preferred embodiment, the hydrolysis is carried out using a standard assay such as those described by Portilla et al., supra and in the U.S. Pat. No. 6,004,792.  
      In a preferred embodiment, the protein of the invention or part thereof may be used to hydrolyze undesirable phospholipids, both in vitro or in vivo. In particular, the protein of the invention or part thereof may be used as a food additive to improve fat digestibility and to promote growth in animals using methods described in U.S. Pat. No. 6,017,530. In another preferred embodiment, the protein of the invention or part thereof may be used to improve the filtration of starch syrup by hydrolyzing the turbidity consisting mainly from phospholipids and resulting from the production of highly concentrated solutions of glucose isomers using methods described in U.S. Pat. No. 5,965,422. In addition, the protein of the invention or part thereof may be used in an enzymatic degumming process to free vegetable oils from phospholipids in order to allow their refining using methods described in U.S. Pat. No. 6,001,640. In another preferred embodiment, compositions comprising the protein of the present invention or part thereof are added to samples as a “cocktail” with other hydrolytic enzymes, such as other phospholipases for example to improve feed utilization in animals (see U.S. Pat. No. 6,017,530). The advantage of using a cocktail of hydrolytic enzymes is that one is able to hydrolyze a wide range of substrates without knowing the specificity of any of the enzymes. Using a cocktail of hydrolytic enzymes also protects a sample from a wide range of future unknown contaminants from a vast number of sources. For example, the protein of the invention or part thereof is added to samples where contaminating substrates is undesirable. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other hydrolytic enzymes, using techniques well known in the art, to form an affinity chromatography column. A sample containing the undesirable substrate is run through the column to remove the substrate. Immobilizing the protein of the invention or part thereof on a support is particularly advantageous for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the enzyme from the batch of product and subsequent reuse of the enzyme. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by replacing the transmembrane region by a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature. Alternatively, the same methods may be used to identify new substrates.  
      In another embodiment, the protein of the invention or part thereof may be used to identify or quantify the amount of a given substrate in a biological sample. In a preferred embodiment, the protein of the invention or part thereof is used in assays and diagnostic kits for the identification and quantification of substrates in a biological sample.  
      In still another embodiment, the protein of the invention or part thereof may be used to diagnose, treat and/or prevent disorders where the presence of substrates is undesirable or deleterious. Such disorders include but are not limited to, cancer, neurodegenerative disorders such as Parkinson&#39;s and Alzheimer&#39;s diseases, diabetes. In a preferred embodiment, the protein of the invention or part thereof may be administered to a subject to reduce immune response. Although the inventors do not wish to be limited to a particular mechanism of action, it is thought that reduction would at least protect against lysophospholipid toxicity, deacylate platelet activating factor, and hydrolyze lytic lysophospholipids such as lysophosphatidylcholine which contribute to immune response, and in particular hypersensitivity reactions and immune cell mediated injuries. Such injuries include, but are not limited to, adult respiratory distress syndrome, allergies, asthma, arteriosclerosis, bronchitis, emphysema, hypereosinophilia, myocardial or pericardial inflammation, rheumatoid arthritis, complications of heart attack, stroke, cancer, hemodialysis, infections, and trauma.  
      In addition, the protein of the invention or part thereof may be used to identify inhibitors for mechanistic and clinical applications. Such inhibitors may then be used to identify or quantify the protein of the invention in a sample, and to diagnose, treat or prevent any of the disorders where the protein&#39;s activity is undesirable and/or deleterious including but not limited to inflammation, disorders associated with cell proliferation, immune and inflammatory disorders. Disorders associated with cell proliferation include adenocarcinoma, sarcoma, lymphoma, leukemia, melanoma, myeloma, teratocarcinoma, and in particular, cancers of the adrenal gland, bladder, bone, brain, breast, gastrointestinal tract, heart, kidney, liver, lung, ovary, pancreas, paraganglia, parathyroid, prostate, salivary glands, skin, spleen, testis, thyroid, and uterus. Immune and inflammatory disorders include Addison&#39;s disease, AIDS, adult respiratory distress syndrome, allergies, anemia, asthma, atherosclerosis, bronchitis, cholecystitus, Crohn&#39;s disease, ulcerative colitis, atopic dermatitis, dernatomyositis, diabetes mellitus, emphysema, atrophic gastritis, glomerulonephritis, gout, Graves&#39; disease, hypereosinophilia, irritable bowel syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polycystic kidney disease, polymyositis, rheumatoid arthritis, scleroderma, Sjogren&#39;s syndrome, autoimmune thyroiditis.  
      Moreover, antibodies to the protein of the invention or part thereof may be used for detection of the Golgi apparatus using any techniques known to those skilled in the art.  
      Protein of SEQ ID NO: 408 (Internal Designation 105-095-1-0-D10-FLC)  
      The protein of SEQ ID NO:408 encoded by the cDNA of SEQ ID NO:3 is homologous to the human parotid secretory protein HPSP (Genseq accession number W60682). PSPs are leucine-rich glycoproteins well conserved among the murine, rat, bovine and human species which belongs to the PSP multigenic family with gland specific members which common traits are early and abundant expression. Because it is extremely abundant in saliva, PSP has been proposed as a marker for tissue-specific protein production of salivary glands and appears coordinately regulated with salivary amylase. PSP is also expressed although to a lesser extent in murine lacrimal glands. Although its function remains unknown, it was shown to bind to bacteria in exocrine secretions and was proposed to have antibacterial activity (Robinson et al.,  Am J Physiol  272:G863-G871 (1997)). Antagonists of this protein may be used to treat cancer and autoimmune diseases particularly of secretory or gastrointestinal tissue.  
      It is believed that the protein of SEQ ID NO:408 or part thereof plays a role in the defense against pathogens, preferably pathogens present in the oral and gastrointestinal tracts. Preferred polypeptides of the invention are fragments of SEQ ID NO:408 having any of the biological activity described herein. The activity of the protein of the invention or part thereof on pathogens may be assessed using techniques well known to those skilled in the art including those described in Robinson et al, supra.  
      In one embodiment, the present invention relates to methods and compositions using the protein of the invention or part thereof to detect bacteria in biological fluids, foods, water, air, solutions and the like. For example, the protein of the invention or part thereof is added to a sample containing bacteria and allowed to bind to such bacteria using any method known to those skilled in the art including those described in Robinson et al, supra. Then, the protein may be detected using any method known to those skilled including using an antibody able to bind to the protein of the invention or part thereof, or using another polypeptide fused to the protein of the invention or part thereof that may be detected directly, such as the green fluorescent protein, or though binding to a specific antibody. In a preferred embodiment, the protein of the invention or part thereof is used in assays and diagnostic kits for the detection of exogenous pathogens in bodily fluids, tissue samples or cell cultures. In another preferred embodiment, the protein of the invention or part thereof may be used to decontaminate samples. For example, the protein of the invention or part thereof may be bound to a chromatographic support using techniques well known in the art, to form an affinity chromatography column. A sample containing the undesirable contaminant is ran through the column in order to be removed. Immobilizing the protein of the invention or part thereof on a support advantageous is particularly for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the protein of the invention from the batch of product and its subsequent reuse. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature.  
      In another embodiment, the invention related to methods and compositions using the protein of the invention or part thereof to retard and/or inhibit the growth of pathogens, preferably bacteria, more preferably Listeria and Streptococci, and Actinobacilli, either in vitro or in vivo using any methods and techniques known to those skilled in the art, alone or in combination with other antimicrobial substances. For example, the protein of the invention or part thereof may be used to disinfect aqueous samples or materials, or as a food preservative. In a preferred embodiment, compositions comprising the protein of the present invention or part thereof are added to samples or materials as a “cocktail” with other antimicrobial substances to decontaminate samples. The advantage of using such a cocktail is that one is able to decontaminate samples without knowing the specificity of any of the antimicrobial substances. Using such a cocktail also protects a sample or material from a wide range of future unknown contaminants from a vast number of sources.  
      In another embodiment, the invention relates to methods and compositions using the protein of the invention or part thereof as a marker protein to selectively identify tissues, preferably salivary glands and lacrimal glands. For example, the protein of the invention or part may be used to synthesize specific antibodies using any techniques known to those skilled in the art including those described therein. Such tissue-specific antibodies may then be used to identify tissues of unknown origin, for example, forensic samples, differentiated tumor tissue that has metastasized to foreign bodily sites, or to differentiate different tissue types in a tissue cross-section using immunochemistry.  
      Protein of SEQ ID NO: 452 (Internal Designation 108-019-5-0-F5-FLC)  
      The protein of SEQ ID NO:452 encoded by the cDNA of SEQ ID NO:47 is homologous to human proteins either thought to be a transmembrane proteolipid protein down regulated upon cell differentiation induced by sodium butyrate (Genbank accession number AF057306) or described as the alternatively spliced chemokine-like factor 2 (Genbank accession number AF135380).  
      Proteolipids are a class of hydrophobic membrane proteins characterized in part by their capacity to assume conformations compatible with solubility in organic solvents and in water (Sapirstein V. S. et al (1983) Biochemistry 22:3330-3335). This amphipathic character of proteolipids explains their participation in transmembrane ion movement. Proteolipids are components of ion channel and transport systems, such as H +  channels (Arai H. et al (1987) J Biol Chem 262:11006-11011), Ca 2+  channels (Eytan G. D. et al (1977) J Biol Chem 252: 3208-3213) and the C (membrane channel) subunit of the vacuolar H + -ATPase (Nelson H. et al (1990) J Biol Chem 265: 20390-20393).  
      The latter proteolipid, also known as ductin, is also associated with gap junctions. Gap junctions are the relatively large pores which allow free diffusion of ions across biological membranes (Finbow M. E. et al (1995) Bioessays 17:247-255). Altered gap-junction intercellular communication (GJIC) may play an essential role in cancer development. A lack of GJIC has been observed between transformed and neighboring normal cells (Trosko et al (1990) Radiation Res 123:241-251). A decrease in GJIC has also been observed within tumor cells (Krutovskikh et al (1991) Carcinogenesis 12:1701-1706).  
      Proteolipids are also involved in membrane vesicular trafficking. Due to their lipid-like properties, proteolipids destabilize lipid bilayers and promote membrane vesicle fusion. Such proteolipid-assisted events may include the fusions and fissions of the nuclear membrane, endoplasmic reticulum, Golgi apparatus, and various inclusion bodies (peroxisomes, lysosomes, etc).  
      Human T-lymphocyte maturation-associated protein (MAL), a 153 amino acid proteolipid, has been localized to the endoplasmic reticulum (ER) of T-lymphocytes, where it mediates the fusion of ER-derived vesicles and Golgi cisterna (Rancano C. et al (1994) J Biol Chem 269:8159-8164). A canine MAL homologue, VIP17, is involved in the sorting and targeting of proteins between the Golgi complex and the apical plasma membrane (Zacchetti D. et al (1995) FEBS Left 377:465-469). A rat MAL homologue, rMAL, is expressed in the myelinating cells of the nervous system including oligodendrocytes and Schwann cells. The rMAL protein serves as a gap junction component and plays a role in myelin compaction (Schaeren-Wiemers N. et al (1995) J. Neurosci 5753-5764).  
      Plasmolipin from rat is a proteolipid localized to plasma membranes in kidney and brain. It has 157 amino acids and, based on hydropathy plots and secondary structure predictions, consists of four alpha-helical transmembrane domains (I through IV) of 20-22 amino acids in length. Transmembrane domains III and IV contain hydroxyl groups which may contribute to an aqueous channel. Domains I through III are connected by short hydrophilic segments of 9-11 amino acids in length, and domains III and IV are connected by a longer hydrophilic segment of 20 amino acids. The small size and high hydrophobicity of plasmolipin constrains the distribution of its transmembrane regions such that the four transmembrane alpha-helices form an antiparallel bundle, and both the amino- and carboxy-termini face the cytoplasm. This structural model defines the growing class of small hydrophobic transport-related proteolipids containing four-helix transmembrane segments, such as the MAL homologues (Rancano et al, supra), and the vacuolar H + -ATPase C subunit (Nelson et al, supra).  
      In rat brain, plasmolipin is localized to myelinated nerve tracts, and its expression increases markedly with the onset of myelination (Fischer I. et al (1991) Neurochem Res 28:81-89). The distribution of plasmolipin within myelin appears to include regions active in membrane recycling. Endocytotic coated vesicles isolated from myelinated tracts are enriched with plasmolipin (Sapirstein V. S. (1994) J Neurosci Res 37:348-358). Incorporation of the purified rat plasmolipin protein into lipid bilayers induces voltage-dependent K +  channel formation, suggesting it may function in vivo as a pore or channel (Tosteson M. T. et al (1981) J Membr Biol 63:77-84). Channel formation involved the trimerization of the plasmolipin molecule. The oligomerization model of the plasmolipin molecule portrays transmembrane domains III and IV as walls of the channel, consistent with the presence of hydroxyl groups in these domains (Sapirstein et al (1983) supra). The putative role of rat plasmolipin in transport suggests its function may be in the fluid volume regulation of the myelin complex (Fischer et al (1994), supra).  
      Proteolipids are involved in membrane trafficking, gap junction formation, ion transport and cellular fluid volume regulation. The selective modulation of their expression may provide a means for the regulation of vesicle trafficking or the formation of channels or gap junctions in normal as well as acute and chronic disease situations.  
      It is believed that the protein of SEQ ID NO: 452 or part thereof plays a role membrane trafficking, gap junction formation, ion transport and/or cellular fluid volume regulation. Preferred polypeptides of the invention are fragments of SEQ ID NO:452 having any of the biological activity described herein. The ability of the protein of the invention or part thereof to form pore and/or to destabilize lipid bilayers may be assessed using techniques well known to those skilled in the art including those described in U.S. Pat. No. 5,843,714.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to promote membrane vesicle fusion both in vitro and in vivo.  
      In an embodiment, the protein of the invention or part thereof is used to facilitate exocytosis. For example, the protein of the invention or part thereof may be used to increase the release of chemokines involved in cell migration, proteases which are active in inflammation or other similar activities involving endothelial cells, fibroblasts, lymphocytes, etc. Accordingly, the protein of the invention or part thereof may be used to diagnose, treat and/or prevent disorders associated with abnormal membrane trafficking including but not limited to viral or other infections, traumatic tissue damage, hereditary diseases such as arthritis or asthma, invasive leukemias and lymphomas.  
      In another embodiment, the protein of the invention or part thereof may be used to promote vesicle fusion for drug delivery. The protein of the invention or part thereof may be incorporated into liposomes or artificial vesicles with a drug of interest and then used to promote vesicle fusion for drug delivery. [0252] In another embodiment, antibodies to the protein of the invention or part thereof may be used for detection of membranes and/or gap junctions using any techniques known to those skilled in the art. In a preferred embodiment, the protein of the invention or part thereof may be used to diagnose disorders associated with altered intercellular communication, more preferably altered gap junction communication, including but not limited to cardiac arrhythmia.  
      Protein of SEQ ID NO:406 (Internal Designation 105-016-3-0-E3-FLC)  
      The 325-amino-acid-long protein of SEQ ID NO:406 encoded by the cDNA of SEQ ID NO:1 shows homology over the whole length of the 332-amino-acid-long murine neural proliferation differentiation and control 1 protein or NPDC-1 (Genbank accession number 35×67209) which is thought to play an important role in the control of neural cell proliferation and differentiation as well as in cell survival by interacting with cell cycle regulators such as E2F-1 (Galiana et al.,  Proc. Natl. Acad. Sci. USA  92:1560-1564 (1995); Dupont et al.,  J. Neurosci. Res.  51:257-267 (1998)).  
      It is believed that the protein of SEQ ID NO:406 or part thereof plays a role in cell proliferation and differentiation. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:406 from positions 1 to 81, and 129 to 308. Other preferred polypeptides of the invention are fragments of SEQ ID NO:406 having any of the biological activity described herein. The activity of the protein of the invention or part thereof on cellular proliferation and differentiation may be assessed using techniques well known to those skilled in the art including those described in Galiana et al, supra.  
      In one embodiment, the invention related to methods and compositions using the protein of the invention or part thereof to inhibit cellular proliferation, preferably neuronal cell proliferation, using any methods and techniques known to those skilled in the art including those described in Galiana et al, supra.  
      In another embodiment, the protein of the invention or part thereof, may be used to diagnose, treat and/or prevent several disorders linked to cell proliferation and differentiation including, but not limited to cancer and neurodegenerative disorders such as Parkinson&#39;s or Alzheimer&#39;s diseases. For diagnostic purposes, the expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals.  
      Protein of SEQ ID NO:407 (Internal Designation 105-031-3-O-D6-FLC)  
      The protein of SEQ ID NO:407 encoded by the cDNA of SEQ ID. NO:2 exhibits homology to a murine putative sialyltransferase protein (TREMBL accession number 088725). Although sialyltransferases have virtually no sequence homology, they display the features of type II transmembrane proteins with a short N-terminal cytoplasmic tail, a 16-20 amino acid signal-anchor domain, and an extended stem region which is followed by the large C-terminal catalytic domain (Weinstein, J. et al., J. Biol. Chem. 262, 17735-17743, 1987; Paulson, J. C. et al., J. Biol. Chem. 264,17615-17618, 1989).  
      The protein of SEQ ID NO:407 displays the two conserved motifs of the sialyltransferase protein family, namely the centrally located sialylmotifL (positions 73 to 120) thought to be involved in the recognition of the sugar nucleotide donor common to all sialyltransferases and the sialylmotifS (positions 211 to 233) thought to be the catalytic site and located in the C-terminus of the protein. Furthermore, the 302-amino-acid long protein of SEQ ID NO:407 has a size similar to the one of the members of the sialyltransferase family. In addition, the protein of the invention has a predicted transmembrane structure. Indeed, it contains 2 potential transmembrane segments (positions 7 to 27 and 206 to 226, underlined in  FIG. 12 ) as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)).  
      Sialyltransferases are glycosyl transferases found primarily in the Golgi apparatus and also in body fluids such as breast milk, colustrum and blood. They are responsible for the terminal sialylation of carbohydrate groups of glycoproteins, glycolipids and oligosaccharides widely distributed in animal tissues. Sialic acids play important roles in the biological functions of carbohydrate structures because of their terminal position. Sialyltransferases are indeed involved in a large variety of biological processes such as cell-cell communication, cell-matrix interactions, maintenance of serum glycoproteins in the circulation, and so on (Sjoberg et al., J. Biol. Chem. 271:7450-7459 (1996); Tsuji, J. Biochem. 120:1-13 (1996)). A variety of biological phenomena are associated with recognition of sialosides, including viral replication, escape of immune detection, and cell adhesion (Schauer, R. Trends Biochem. Sci. 1985, 10, 357-360; Biology of the Sialic Acids ed. A. Rosenberg, Plenum Press, New York, 1995). For example, suppressed antibody production was observed in alpha-2,6-sialyltransferase knockout mice (Muramatsu, J. Biochem. 127:171-6 (2000). In addition, carbohydrate structures have been shown to influence proteins&#39; stability, rate of in vivo clearance from blood stream, rate of proteolysis, thermal stability and solubility. Changes in the oligosaccharide portion of cell surface carbohydrates have been noted in cells which have become cancerous.  
      It is believed that the protein of SEQ ID NO:407 or part thereof plays a role in the biosynthesis of sialyl-glycoconjugates, probably as a sialyltransferase. Thus, the protein of the invention or part thereof is thought to be involved in cell-cell communication, cell-matrix interactions, maintenance of serum glycoproteins in the circulation, viral replication, escape of immune detection, and cell adhesion. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:407 from positions 73 to 120, and from position 211 to 233. Other preferred polypeptides of the invention are fragments of SEQ ID NO:407 having any of the biological activity described herein. The sialyltransferase activity of the protein of the invention or part thereof may be assayed using any other technique known to those skilled in the art including those described in Sadler et al., J. Biol. Chem., 254:4434-4443 (1979) or U.S. Pat. Nos. 5,827,714 and 6,017,743.  
      One object of the present invention are compositions and methods of targeting heterologous polypeptides to the Golgi apparatus by recombinantly or chemically fusing a fragment of the protein of the invention to an heterologous polypeptide. Preferred fragments are signal peptide, transmembrane domains, the proline-rich region comprised between positions 31 and 67, tyrosine containing regions and/or any other fragments of the protein of the invention, or part thereof, that may contain targeting signals for the Golgi apparatus including but not limited to proline-rich regions (Ugur and Jones, Mol Cell Biol 11:1432-32 (2000), Picetti and Borrelli, Exp Cell Res 255:258-69 (2000)), tyrosine-based Golgi targeting signal region (Zhan et al., Cancer Immunol Immunother 46:55-60 (1998); Watson and Pessin J. Biol. Chem. 275:1261-8 (2000); Ward and Moss, J. Virol. 74:3771-80 (2000) or any other region as defined in Munro, Trends Cell Biol. 8:11-15 (1998); Luetterforst et al., J. Cell. Biol. 145:1443-59 (1999); Essl et al., FEBS Lett. 453:169-73 (1999).  
      Sialylated compounds have considerable potential both as therapeutics and as reagents for clinical assays. However, synthesis of glycosylated compounds of potential commercial and/or therapeutic interest is difficult because of the very nature of the saccharide subunits. A multitude of positional isomers in which different substituent groups on the sugars become involved in bond formation, along with the potential formation of different anomeric forms, are possible. As a result of these problems, large scale chemical synthesis of most carbohydrates is not possible due to economic considerations arising from the poor yields of desired products. Enzymatic synthesis using glycosyl transferases such as sialyltransferases provides an alternative to chemical synthesis of carbohydrates. Enzymatic synthesis using glycosidases, glycosyl transferases, or combinations thereof, have been considered as a possible approach to the synthesis of carbohydrates. As a matter of fact, enzyme-mediated catalytic synthesis would offer dramatic advantages over the classical synthetic organic pathways, producing very high yields of carbohydrates economically, under mild conditions in aqueous solutions, and without generating notable amounts of undesired side products. To date, such enzymes are however difficult to isolate, especially from eukaryotic, e.g., mammalian sources, because these proteins are only found in low concentrations, and tend to be membrane-bound. In addition to being difficult to isolate, the acceptor (peptide) specificity of glycosyl transferases is poorly understood. Thus, there is a need for obtaining recombinant glycosyl transferase, including sialyltransferases, that could be produced in very large amounts.  
      Thus, the invention related to methods and compositions using the protein of the invention or part thereof to synthesize glycosylated compounds, either glycoproteins, glycoplipids, or oligosaccharides, more particularly sialylated compounds. If necessary, the protein of the invention or part thereof may be produced in a soluble form by removing its transmembrane domains and/or its Golgi retention signal using any of the methods skilled in the art including those described in U.S. Pat. No. 5,776,772. For example, the protein of the invention or part thereof is added to a sample containing sialic acid and a substrate compound in conditions allowing glycosylation, more particularly sialylation and allowed to catalyze the glycosylation of this compound. In a preferred embodiment, the enzymatic reaction carried out by the protein of the invention is part of a series of other chemical and/or enzymatic reactions aiming at the synthesis of complex glycosylated compounds, such as the ones described in U.S. Pat. Nos. 5,409,817 and 5,374,541. In another preferred embodiment where the method is to be practiced on a commercial scale, it may be advantageous to immobilize the glycosyl transferase on a support. This immobilization facilitates the removal of the enzyme from the batch of product and subsequent reuse of the enzyme. Immobilization of glycosyl transferases can be accomplished, for example, by removing from the transferase its membrane-binding domain, and attaching in its place a cellulose-binding domain. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature.  
      In another embodiment, the present invention relates to processes and compositions for producing glycosylated compounds, preferably sialylated compounds, wherein a cell is genetically engineered to produce the protein of the invention or part thereof and used in combination with one or several other cells able to produce the donor substrate for the protein of the invention. Preferably, a bacteria is engineered to express the protein of the invention and used with recombinant bacteria expressing enzymes able to synthesize cytidine 5′-monophospho-N-acetyl neuramininc acid (CMP-NeuAc). The methods for performing the above bacterial coupling process and making the above compositions are carried using the methods known in the art and described in Endo et al., Appl. Microbiol. Biotechnol. 53:257-61, (2000).  
      Another embodiment of the present invention relates to a process and compositions for controlling the glycosylation of proteins in a cell wherein an insect, plant, or animal cell is genetically engineered to produce one or more enzymes which provide internal control of the cell&#39;s glycosylation mechanism. Preferably, the invention relates to a Chinese hamster ovary (CHO) cell line that is genetically engineered to produce a sialyltransferase of the present invention either alone or in combination with other sialyltransferases. This supplemental sialyltransferase modifies the CHO glycosylation machinery to produce glycoproteins having carbohydrate structures which more closely resemble naturally occurring human glycoproteins. The methods for performing the above process and making the above compositions are carried using the methods known in the art and described in U.S. Pat. No. 5,047,335.  
      The invention further relates to glycosylated compounds, preferably sialylated compounds, obtained using any of the processes described herein using the protein of the invention or part thereof. Such compounds may be used in the diagnosing, prevention and/or treating of disorders in which the recognition of such compounds is impaired or needs to be impaired. These disorders include, but are not limited to, cancer, cystic fibrosis, ulcer, inflammation and immune based disorders, including autoimmune disorders such as arthritis, fertility disorders, and hypothyroidism. These conditions include infectious diseases where active infection exists at any body site, such as meningitis and salpingitis; complications of infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, chalangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis. In a preferred embodiment, these glycosylated compounds or derivatives thereof may be used as pharmacological agents to trap pathogens or endogenous ligands thus reducing the binding of pathogens or endogenous ligands to the endogenous glycosylated compounds. For example, such compounds may be used to prevent and/or inhibit the adhesion of cancer cells to inner wall of blood vessel or aggregation between cancer cells and platelets, thus reducing cancer metastasis, to prevent and/or inhibit the adhesion of neutrophils to blood vessels endothelial cells, thus reducing inflammation. Other disorders include infections in which recognition of a glycosylated product is essential to the development of the infection. Such infections include, but are not limited to, those caused by  Vibrio cholerae, Escherichia Coli , Salmonella, and the influenza virus. In a preferred embodiment, such compounds, preferably sialyl lactose, are used as neutralizers for enterotoxins from bacteria such as  Vibrio cholerae, Escherichia Coli , and Salmonella as described in U.S. Pat. No. 5,330,975. In another preferred embodiment, such compounds, preferably galactose oligosaccharides, are used to diagnose, identify and inhibit the adherence of uropathogenic bacteria to red blood cells (U.S. Pat. No. 4,657,849). In another preferred embodiment, such compound, preferably oligosaccharides, are used as gram positive antibiotics and disinfectants (U.S. Pat. Nos. 4,851,338 and 4,665,060). In another embodiment, such compounds, preferably sialyl lactose, may be used for the treatment of arthritis and related autoimmune diseases (see, U.S. Pat. No. 5,164,374). In another embodiment, such compounds, preferably sialylalpha (2,3) galactosides, sialyl lactose and sialyl lactosamine, may be used for the treatment of ulcers. Phase I clinical trials have began for the use of the former compound in this capacity. (Balkonen, et al., FEMS Immunology and Medical Microbiology 7:29 (1993) and BioWorld Today, p. 5, Apr. 4, 1995). In addition, such compounds, preferably sialyl lactose, may be used as food supplement, for instance in baby formula.  
      In addition, the protein of the invention or part thereof may be used in the development of inhibitors of glycosyl transferase, more particularly inhibitors of sialyltransferases and sialidases, for mechanistic and clinical applications (Taylor, G. Curr. Opin. Struc. Biol. 1996, 6, 830-837; Colman, P. M., Pure Appl. Chem. 1995, 67, 1683-1688; Bamford, M. J. J Enz. Inhib. 1995, 10, 1-16; Khan, S. H. &amp; Matta, K. L. In Glycoconjugates, Composition, Structure, and Function. pp361-378. ed., Allen, H. J. &amp; Kisailus, E. C. Marcel Dekker, Inc. New York, 1992, Thome-Tjomsland et al., Transplantation 69:806-8, (2000); Basset et al, Scand. J. Immunol. 51:307-11 (2000)).  
      The invention further relates to methods and compositions using the protein of the invention or part thereof to diagnose, prevent and/or treat several disorders in which recognition of glycosylated compounds, preferably of sialylated compounds, is impaired or needs to be impaired. For diagnostic purposes, the expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals. For prevention and/or treatment purposes, inhibiting the endogenous expression of the protein of the invention using any of the antisense or triple helix methods described herein may be used to reduce the production of glycosylated compounds detrimental to the organism in any of the disorders described above.  
      Protein of SEQ ID NOs:436 (Internal Designation 108-008-5-0-C5-FL)  
      The protein of SEQ ID NO:436 encoded by the cDNA of SEQ ID NO:31 exhibits homology over the whole length to the murine recombination activating gene 1 inducing protein found in stromal cell (Genbank accession number X96618). The amino acid residues are identical except for the positions 6, 7, 10-13, 17, 25, 34-35, 42, 51, 56, 62, 68, 71, 74, 78, 91, 93, 95-96, 106, 121-122, 151-152, 159, 162-163, 170-171, 176-177, 188, 190, 192, 196, 199, 202-203, 206, 210, 215 and 217 of the 221 amino acid long matched protein. This protein with 4 potential transmembrane segments facilitates gene activation of RAG-1 which is involved in the recombination of V(D)J segments in T cells (Tagoh et al.,  Biochem Biophysic Res Comm  221:744-749 (1996); Muraguchi et al,  Leuk Lymphoma,  30:73-85 (1998)).  
      It is believed that the protein of SEQ ID NO:436 may play a role in lymphocyte repertoire formation. Preferred polypeptides of the invention are fragments of SEQ ID NO:406 having any of the biological activity described herein. The activity of the protein of the invention or part thereof on the induction of RAG expression may be assessed using techniques well known to those skilled in the art including those described in Tagoh et al, supra.  
      In an embodiment, antibodies to the protein of the invention or part thereof may be used as markers for haematopoietic precursors, preferably precursors for B and T cells.  
      In another embodiment, the protein of the invention or part thereof, may be used to diagnose, treat and/or prevent immunological disorders including, but not limited to Ommen&#39;syndrome, acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis, lymphoid neoplasia including non Hodgkins&#39; lymphoma, ALL and CLL. For diagnostic purposes, the expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals. In another embodiment, the protein of the invention or part thereof may also be used to modulate the immune response to pathogens.  
      Protein of SEQ ID NO:419 (Internal Designation 116-073-4-0-C8-FLC)  
      The protein of SEQ ID NO:419 encoded by the cDNA of SEQ ID NO:14 shows homology over the whole length of the widely conserved family of lysozyme C precursors (fish, bird, and mammals). In particular, the protein of the invention displays 17 out of the 20 amino acids conserved among all known lysozyme C proteins at positions 115, 117, 123, 137, 141, 144, 146, 150, 151, 162, 166, 180, 181, 194, 197, 201 and 213 (Prager and Jollès, Lysozymes: model enzymes in biochemistry and biology, ed. Jollès, 9-321 (1996)). In addition, this protein displays the characteristic signature of the family 22 of glysosyl hydrolases (PROSITE signature from positions 162 to 185, eMotif signatures from positions 183 to 202 and from positions 111 to 120), which contain the evolutionary related alpha-lactalbumin, the regulatory subunit of lactose synthetase, and the bacteriolytic defensive enzymes lysozyme C (Qasba and Kumar,  Crit. Rev. Biochem. Mol. Biol.  32:255-306 (1997)). Furthermore, the cDNA of SEQ ID NO:14 seems to be preferentially expressed in testis (Table VII) and in germ cells tumors (Table VIII).  
      Lysozyme, an ubiquitous protein secreted in most body secretions, is defined as 1,4-beta-N-acetylmuramidases which cleave the glycoside bond between the C-1 of N-acetyl-muramic acid and the C-4 of N-acetylglucosamine in the peptidoglycan of bacteria. It has various therapeutic properties, such as antiviral, antibacterial, anti-inflammatory and antihistaminic effects. The activity of the lysozyme as an anti-bacterial agent appears to be based on both its direct bacteriolytic activity and also on stimulatory effects in connection with phagocytosis of polymorphonuclear leucocytes and macrophages (Biggar and Sturgess, J. M. Infect Immunol. 16: 974-982 (1977); Thacore and Willet, Am. Rev. Resp. Dis. 93: 786-790 (1966); Klockars and Roberts, P. Acta Haematol 55: 289-292 (1976)). Lysozyme has proven to be not only a selective factor but also an effective factor against microorganisms of the mouth (Iacono et al, J. J. Infect. Immunol. 29: 623-632 (1980)). Lysozyme can also kill pathogens by acting synergistically with other proteins such as complement or antibody to lyse pathogenic cells. Lysozyme, also inhibits chemotaxis of polymorphonuclear leukocytes and limits the production of oxygen free radicals following an infection. This limits the degree of inflammation, while at the same time enhances phagocytosis by these cells. Other postulated functions of lysozyme include immune stimulation (Jolles, P. Biomedicine 25: 275-276 (1976) Ossermann, E. F. Adv. Pathobiol 4: 98-102 (1976)) and immunological and non-immunological monitoring of host membranes for any neoplastic transformation (Jolles, P. Biomedicine 25: 275-276 (1976); Ossermann, E. F. Adv. Pathobiol 4: 98-102 (1976)). Lysozyme may thus be used in a wide spectrum of applications (see U.S. Pat. No. 5,618,712). Determination of the lysozymes from serum and/or urine is used to diagnose various diseases or as an indicator for their development. In acute lymphoblastic leukaemia the lysozyme serum level is significantly reduced, whereas in chronic myelotic leukaemia and in acute monoblastic and myelomonocytic leukaemia the lysozyme concentration in the serum is greatly increased. The therapeutically effective use of lysozyme is possible in the treatment of various bacterial and virus infections (Zona, Herpes zoster), in colitis, various types of pain, in allergies, inflammation and in pediatrics (the conversion of cows milk into a form suitable for infants by the addition of lysozyme).  
      It is believed that the protein of SEQ ID NO:419 or part thereof plays a role in glycoprotein and/or peptidoglycan metabolism, probably as a glycosyl hydrolase of family 22. Thus, the protein of the invention or part thereof may be involved in immune and inflammatory responses and may have antiviral, antibacterial, anti-inflammatory and/or anti-histaminic functions. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:419 from positions 70 to 215, 111 to 120, 183 to 202, and 162 to 185. Other preferred polypeptides of the invention are fragments of SEQ ID NO:419 having any of the biological activities described herein. The glycolytic activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in Gold and Schweiger, M. Methods in Enzymology, Vol. XX, Part C pp. 537-542, Ed. Moldave, Academic Press,New York and London, 1971 and in the U.S. Pat. No. 4,255,517.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to hydrolyze one or several substrates, alone or in combination with other substances, preferably antiviral, antifungal and/or antibacterial substances including but not limited to immunoglobulins, lactoferrin, betalysin, fibronectin, and complement components. Such substrates are glycosylated compounds, preferably containing beta-1-4-glycoside bonds, more preferably containing beta-1-4-glycoside bonds between n-acetylomuraminic acid and n-acetyloglucosamine. For example, the protein of the invention or part thereof is added to a sample containing the substrate(s) in conditions allowing hydrolysis, and allowed to catalyze the hydrolysis of the substrate(s). In a preferred embodiment, the hydrolysis is carried out using a standard assay such as those described by Gold and Schweiger, supra, and U.S. Pat. Nos. 5,871,477 and 4,255,517. In a preferred embodiment, the protein of the invention or part thereof may be used to lyze recombinant bacteria in order to recover the recombinant DNA, the recombinant protein of interest, or both using, for example, any of the assays described in Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989).  
      In an embodiment, the protein of the invention or part thereof is used to hydrolyze contaminating substrates in an aqueous sample or onto a material, preferably glassware and plasticware. In particular, the protein of the invention or part thereof may be used as a disinfectant in dental rinse, in protection of aqueous systems or in preparing material for medical applications using any of the methods and compositions described in U.S. Pat. Nos. 5,069,717, 4,355,022 and 5,001,062. In a preferred embodiment, the protein of the invention is used as a host resistance factor in infants&#39; formulas to convert cow&#39;s milk into a form more suitable for infants as described in U.S. Pat. No. 6,020,015. In another preferred embodiment, the protein of the invention or part thereof may be used as a food preservative (see Hayashi et al., Agric. Biol. Chem. (European Edition of Japanese Journal of Agriculture, Biochemistry and Chemistry), Vol. 53, pp. 3173-3177, 1989). In addition, the protein of the invention or part thereof may be used to clarify xanthan gum fermented broth for applications in food and in cosmetic industries using the method described in U.S. Pat. No. 5,994,107. In another preferred embodiment, compositions comprising the protein of the present invention or part thereof are added to samples or materials as a “cocktail” with other antimicrobial substances, preferably antibiotics or hydrolytic enzymes such as those described in U.S. Pat. Nos. 5,458,876 and 5,041,326 to decontaminate the samples. For example, the protein of the invention or part thereof may be used in place or in combination with antibiotics in cell cultures. The advantage of using a cocktail of hydrolytic enzymes is that one is able to hydrolyze a wide range of substrates without knowing the specificity of any of the enzymes. Using a cocktail of hydrolytic enzymes also protects a sample or material from a wide range of future unknown contaminants from a vast number of sources. For example, the protein of the invention or part thereof is added to samples where contaminating substrates is undesirable. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other hydrolytic enzymes, using techniques well known in the art, to form an affinity chromatography column. A sample containing the undesirable substrate is run through the column to remove the substrate. Immobilizing the protein of the invention or part thereof on a support advantageous is particularly for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the enzyme from the batch of product and subsequent reuse of the enzyme. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature. Alternatively, the same methods may be used to identify new substrates.  
      In addition, the protein of the invention or part thereof may be useful to identify or quantify the amount of a given substrate in biological fluids, foods, water, air, solutions and the like. In a preferred embodiment, the protein of the invention or part thereof is used in assays and diagnostic kits for the identification and quantification of exogenous substrates in bodily fluids including blood, lymph, saliva or other tissue samples, in addition to bacterial, fungal, plant, yeast, viral or mammalian cell cultures. In a preferred embodiment, the protein of the invention or part thereof is used to detect, identify, and or quantify eubacteria using reagents and assays described in U.S. Pat. No. 5,935,804. Briefly, the protein of the invention of part thereof is catalytically inactived, i.e. capable of binding but not cleaving a peptidoglycan comprising NAc-muramic acid in the eubacteria, using any of the methods known to those skilled in the art including those which produce a mutant enzyme, a recombinant-enzyme, or a chemically inactivated enzyme. The catalytically inactive protein of the invention is then incubated with an aliquot of a biological sample under conditions suitable for binding of the inactive enzyme to the peptidoglycan substrate. Then, the bound enzyme is detected to assess the presence or amount of the eubacteria in the biological sample.  
      In another embodiment, the nucleic acid of the invention or part thereof may be used to increase disease resistance of plants to bacterial, fungal and/or viral infections. A polynucleotide containing the nucleic acid of the invention or part thereof is introduced into the plant genome in conditions allowing correct expression of the transgenic protein using any methods known to those skilled in the art including those disclosed in U.S. Pat. Nos. 5,349,122 and 5,850,025.  
      In another preferred embodiment, the protein of the invention or part thereof may be useful to treat and/or prevent bacterial, fungal and viral infections in humans or in animals caused by various agents including but not limited to Streptococcus,  Veillonella alcalescens , Actinomyces, Herpes simplex,  Candida albicans, Micrococcus lysodeikticus  and HIV by hydrolyzing the glycosylated compounds contained in such micro-organisms. In still a preferred embodiment, the protein of the invention or part thereof is used to prevent and/or treat bacterial, fungal and viral infections in immunocompromised individuals who lack fully functional immune systems, such as neonates or geriatric patients or HIV-infected individuals, or who suffer from a disease affecting the respiratory tract such as cystic fibrosis or the gastrointestinal tract such as ulcerative colitis or sprue.  
      In still another embodiment, the protein of the invention or part thereof may be used as a growth factor for in vitro cell culture, preferably for T cells and T cell lines, as described in U.S. Pat. No. 5,468,635.  
      In addition, the protein of the invention or part thereof may be used to identify inhibitors for mechanistic and clinical applications. Such inhibitors may then be used to identify or quantify the protein of the invention in a sample, and to diagnose, treat or prevent any of the disorders where the protein&#39;s hydrolytic, immunostimulatory and/or inflammatory activities is/are undesirable and/or deleterious including but not limited to amyloidosis, colitis, lysosomal diseases, inflammatory and immune disorders including allergies and leukaemia. The protein of the invention may also be used to monitor host cell membranes for neoplastic transformation.  
      In still another embodiment, the invention relates to methods and compositions using the protein of the invention or part thereof as a marker protein to selectively identify tissues, preferably germ cells, more preferably testis. For example, the protein of the invention or part may be used to synthesize specific antibodies using any techniques known to those skilled in the art including those described therein. Such tissue-specific antibodies may then be used to identify tissues of unknown origin, for example, forensic samples, differentiated tumor tissue that has metastasized to foreign bodily sites, or to differentiate different tissue types in a tissue cross-section using immunochemistry.  
      Protein of SEQ ID NO:433 (Internal Designation 108-005-5-0-F9-FL)  
      The protein of SEQ ID NO:433 encoded by the extended cDNA SEQ ID NO:28 shows homology with the Drosophila rhythmically expressed gene 2 protein (Genbank accession number U65492) and with a 2-haloalkanoic acid dehalogenase (Embl accession number AJ248288). In addition, the protein of SEQ ID NO:433 exhibits the pfam signature for haloacid dehalogenase-like hydrolase family from positions 7 to 214.  
      Expression of the mRNA coding for Dreg-2 is dependent on the interplay between light-dark cycle, feeding conditions and expression of the per gene which is essential to the function of the endogenous circadian pacemaker (Van Gelder et al., Curr. Biol., 5:1424-1436 (1995)). The matched pfam hydrolase family include proteins which are structurally different from the alpha/beta hydrolase family and which include L-2-haloacid dehalogenase, epoxide hydrolases and phosphatases (see Pfam accession number PF00702).  
      Organohalogen compounds are by-products in several industrial processes that are considered as environmental pollutants. The detection of trihalomethanes, halogenated acetic acids, halogenated acetonitriles and halogenated ketones in city water has become a great problem because of their liver toxicity and mutagenicity. Halogenated organic acids, for example halogenated acetic acids such as chloroacetic acid, dichloroacetic acid, trichloroacetic acid and bromoacetic acid have been designated as environment surveillance items in Japan since 1993. Increasing environmental concerns have created a demand for products that are free from such environmentally unsound byproducts. Physical methods of decontaminating aqueous reaction products containing unwanted nitrogen-free organohalogen byproducts are known, such as solvent extraction with a water-immiscible solvent, or adsorption on a solid adsorbent, such as charcoal. However, such known methods can result in depletion of the reaction product, as well as requiring costly measures to recover and purify the solvent or adsorbent. Furthermore, such methods still leave the problem of how to ultimately dispose of the contaminants such as undesired halogenated oxyalkylene compounds. As one of the countermeasures, for example, biodegradation treatment such as a bioreactor is very useful because treatment can be conducted under mild conditions and is relatively low in cost. The conversion of nitrogen-free organohalogen compounds with microorganisms containing a dehalogenase is also known. For example, C. E. Castro, et al. (“Biological Cleavage of Carbon-Halogen Bonds Metabolism of 3-Bromopropanol by Pseudomonas sp.”, Biochimica et Biophysica Acta, 100, 384-392, 1965) describe the use of Pseudomonas sp. isolated from soil that metabolizes 3-bromopropanol in sequence to 3-bromopropionic acid, 3-hydroxypropionic acid and CO 2 . Various U.S. Patents also describe the use of microorganisms for dehalogenating halohydrins, e.g. U.S. Pat. Nos. 4,452,894; 4,477,570; and 4,493,895.  
      Epoxide hydrolases are a family of enzymes which hydrolyze a variety of exogenous and endogenous epoxides to their corresponding diols. Compounds containing the epoxide functionality have become common environmental contaminants because of their wide use as pesticides, sterilants, and industrial precursors. Such compounds also occur as products, by-products, or intermediates in normal metabolism and as the result of spontaneous oxidation of membrane lipids (i.e. see, Brash, et al., Proc. Natl. Acad. Sci., 85:3382-3386 (1988), and Sevanian, A., et al., Molecular Basis of Environmental Toxicology (Bhatnager, R. S., ed.) pp. 213-228, Ann Algor Science, Michigan (1980)). As three-membered cyclic ethers, epoxides are often very reactive and have been found to be cytotoxic, mutagenic and carcinogenic (i.e. see Sugiyama, S., et al., Life Sci. 40:225-231 (1987)). Cleavage of the ether bond in the presence of electrophiles often results in adduct formation. As a result, epoxides have been implicated as the proximate toxin or mutagen for a large number of xenobiotics. Reactions of detoxification using epoxide hydrolases typically decrease the hydrophobicity of a compound, resulting in a more polar and thereby excretable substance. In addition to degradation of potential toxic epoxides, dehalogenases are believed to play a role in the formation or degradation of endogenous chemical mediators (see U.S. Pat. No. 5,445,956).  
      Many eukaryotic cell functions, including signal transduction, cell adhesion, gene transcription, RNA splicing, apoptosis and cell proliferation, are controlled by protein phosphorylation which is in turn regulated by the dynamic relationship between kinases and phosphatases (see U.S. Pat. No. 6,040,323 for a short review). Thus, the protein phosphatases represent unique and attractive targets for small-molecule inhibition and pharmacological intervention. In addition, hydrolytic enzymes such as alkaline phosphatase are frequently used as markers or labels in enzyme-linked assays for biological molecules and other analytes of interest such as drugs, hormones, steroids and cancer markers.  
      It is believed that the protein of SEQ ID NO:433 or part thereof is an hydrolase, preferably a phosphatase, an ether hydrolase or an hydrolase acting on C-halide bonds. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:433 from positions 7 to 214. Other preferred polypeptides of the invention are fragments of SEQ ID NO:433 having any of the biological activity described herein. The hydrolytic activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in U.S. Pat. Nos. 5,445,942; 5,445,956, 6,017,746 and 5,871,616.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to hydrolyze one or several substrates, alone or in combination with other substances, either in vitro or in vivo. Such substrates are compounds containing phosphoric ester bonds, ether bonds or C-halide bonds. For example, the protein of the invention or part thereof is added to a sample containing the substrate(s) in conditions allowing hydrolysis, and allowed to catalyze the hydrolysis of the substrate(s). In a preferred embodiment, the hydrolysis is carried out using any assay known to those skilled in the art including those described by the U.S. Pat. Nos. 5,445,942; 5,445,956, 6,017,746 and 5,871,616. In a preferred embodiment, the protein of the invention is used to hydrolyze environmental pollutants, preferably organohalogen compounds and epoxide, such as those cited below using any of the methods and techniques described in U.S. Pat. Nos. 6,017,746 and 5,871,616.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to diagnose, prevent and/or treat several disorders of the circadian rhythm including, but not limited to, insomnia, depression, stress, night work or jet lag. For diagnostic purposes, the overexpression or the improper temporal expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals.  
      Protein of SEQ ID NO:427 (Internal Designation 122-005-2-0-F11-FLC)  
      The protein of SEQ ID NO:427 encoded by the cDNA of SEQ ID NO:22 exhibits homology with a fragment of NADH-cytochrome b5 reductases of rat, bovine and human species which are part of the mitochondrial electron transport chain (Genbank accession numbers J03867, M83104 and Y09501, respectively). This homology includes the flavin-adenine dinucleotide (FAD)-binding domain of this family of proteins from positions 118 to 148, and 157 to 192. Moreover, the 3 lysine residues shown to be implicated in the formation of charged ion pairs with carboxyl groups on NADH-cytochrome b5 reductase during interactions between the active sites of cytochrome b5 and NADH-cytochrome b5 reductase are conserved in the protein of the invention at positions 46, 112 and 150 (Strittmatter, P. et al. (1990) J. Biol. Chem. 265: 21709-13). In addition, the protein of the invention exhibits emotif signatures for cytochrome b5 reductase from positions 123 to 138, 163 to 180, and 256 to 265, emotif signatures for eukaryotic molybdopterin oxidoreductases from positions 256 to 266 and 256 to 268, and emotif signatures for flavoprotein pyridine nucleotide cytochrome reductases from positions 110 to 120, 163 to 177, and 163 to 179.  
      NADH-cytochrome b5 reductase proteins belong to a flavoenzyme family sharing common structural features and whose members (ferrodoxin-NADP+reductase, NADPH-cytochrome P450 reductase, NADPH-sulfite reductase, NADH-cytochrome b5 reductase and NADH-nitrate reductase) are involved in photosynthesis, in the assimilation of nitrogen and sulfur, in fatty-acid oxidation, in the reduction of methemoglobin and in the metabolism of many pesticides, drugs and carcinogens (Karplus et al., Science, 251:60-6 (1991)). In addition, cytochrome b5 reductase is thought to play a role in the prevention of apoptosis following oxidative stress (see review by Villalba et al., Mol Aspects Med 18 Suppl1:S7-13 (1997)).  
      It is believed that the protein of SEQ ID NO:427 may be an oxidoreductase. Thus it may play a role in electron transport and general aerobic metabolism and may be associated with mitochondrial membranes. In addition, the protein of the invention may be able to use FAD and/or molybdopterin as cofactors. It may be involved in photosynthesis, in the assimilation of nitrogen and sulfur, in fatty-acid oxidation, in the reduction of methemoglobin and in the metabolism of many pesticides, drugs and carcinogens. Preferred polypeptides of the SEQ ID NO:427 from positions 118 to 148, 157 to 192, 123 to 138, 163 to 180, 256 to 265, 256 to 266, 256 to 268, 110 to 120, 163 to 177, and 163 to 179. Other preferred polypeptides of the invention are fragments of SEQ ID NO:427 having any of the biological activity described herein. The oxidoreductase activity of the protein of the invention may be assayed using any technique known to those skilled in the art. The ability to bind a cofactor may also be assayed using any techniques well known to those skilled in the art including, for example, the assay for binding NAD described in U.S. Pat. No. 5,986,172.  
      An object of the present invention are compositions and methods of targeting heterologous compounds, either polypeptides or polynucleotides to mitochondria by recombinantly or chemically fusing a fragment of the protein of the invention to an heterologous polypeptide or polynucleotide. Preferred fragments are signal peptide, amphiphilic alpha helices and/or any other fragments of the protein of the invention, or part thereof, that may contain targeting signals for mitochondria including but not limited to matrix targeting signals as defined in Herrman and Neupert, Curr. Opinion Microbiol. 3:210-4 (2000); Bhagwat et al. J. Biol. Chem. 274:24014-22 (1999), Murphy Trends Biotechnol. 15:326-30 (1997); Glaser et al. Plant Mol Biol 38:311-38 (1998); Ciminale et al. Oncogene 18:4505-14 (1999). Such heterologous compounds may be used to modulate mitochondria&#39;s activities. For example, they may be used to induce and/or prevent mitochondrial-induced apoptosis or necrosis. In addition, heterologous polynucleotides may be used for mitochondrial gene therapy to replace a defective mitochondrial gene and/or to inhibit the deleterious expression of a mitochondrial gene.  
      In another embodiment, the protein of the invention or part thereof is used to prevent cells to undergo apoptosis. In a preferred embodiment, the apoptosis active polypeptide is added to an in vitro culture of mammalian cells in an amount effective to reduce apoptosis. Furthermore, the protein of the invention or part thereof may be useful in the diagnosis, the treatment and/or the prevention of disorders in which apoptosis is deleterious, including but not limited to immune deficiency syndromes (including AIDS), type I diabetes, pathogenic infections, cardiovascular and neurological injury, alopecia, aging, degenerative diseases such as Alzheimer&#39;s Disease, Parkinson&#39;s Disease, Huntington&#39;s disease, dystonia, Leber&#39;s hereditary optic neuropathy, schizophrenia, and myodegenerative disorders such as “mitochondrial encephalopathy, lactic acidosis, and stroke” (MELAS), and “myoclonic epilepsy ragged red fiber syndrome” (MERRF).  
      The invention further relates to methods and compositions using the protein of the invention or part thereof to diagnose, prevent and/or treat several disorders in which energy metabolism is impaired, or needs to be impaired, including but not limited to mitochondriocytopathies, necrosis, aging, neurodegenerative diseases, myopathies, methemoglobinemia, hyperlipidemia, obesity, cardiovascular disorders and cancer. For diagnostic purposes, the expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals. For prevention and/or treatment purposes, the protein of the invention may be used to enhance electron transport and increase energy delivery using any of the gene therapy methods described herein.  
      Protein of SEQ ID NO:445 (Internal Designation 108-014-5-0-C7-FLC)  
      The protein of SEQ ID NO:445 encoded by the extended cDNA SEQ ID NO:40 shows homology with a fragment of a cold active protease isolated from  Flavobacterium balustinum  (Genseq accession number W23332) which degrades casein, gelatin, haemoglobin and albumin. This protease is able to degrade proteins at low temperatures or in presence of organic solvents that are volatile at normal processing temperature.  
      These data suggest that the protein of SEQ ID NO:445 or part thereof is an hydrolase, preferably a protease. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:445 from positions 1 to 44. Other preferred polypeptides of the invention are fragments of SEQ ID NO:445 having any of the biological activity described herein. The hydrolytic activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in U.S. Pat. No. 6,069,229.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to hydrolyze one or several substrates, alone or in combination with other substances. Such substrates are compounds containing peptide bonds. For example, the protein of the invention or part thereof is added to a sample containing the substrate(s) in conditions allowing hydrolysis, and allowed to catalyze the hydrolysis of the substrate(s). In a preferred embodiment, the hydrolysis is carried out using a standard assay such as those described by the U.S. Pat. No. 6,069,229.  
      In a preferred embodiment, compositions comprising the protein of the present invention or part thereof are added to samples as a “cocktail” with other hydrolytic enzymes such as those described in U.S. Pat. Nos. 5,458,876 and 5,041,326. The advantage of using a cocktail of hydrolytic enzymes is that one is able to hydrolyze a wide range of substrates without knowing the specificity of any of the enzymes. Using a cocktail of hydrolytic enzymes also protects a sample from a wide range of future unknown protein contaminants from a vast number of sources. For example, the protein of the invention or part thereof is added to samples where contaminating substrates is undesirable. For example, the protein of the invention or part thereof may be used to remove protein contaminants from nucleic acid preparations, to remove cells from cultureware. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other hydrolytic enzymes, using techniques well known in the art, to form an affinity chromatography column. A sample containing the undesirable substrate is run through the column to remove the substrate. Immobilizing the protein of the invention or part thereof on a support is particularly advantageous for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the enzyme from the batch of product and subsequent reuse of the enzyme. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature. Alternatively, the same methods may be used to identify new substrates.  
      The protease of the invention may be used in many industrial processes, including in detergents and cleaning products, e.g., to degrade protein materials such as blood and stains or to clean contact lenses, in leather production, e.g., to remove hair, in baking, e.g., to break down glutens, in flavorings, e.g., soy sauce, in meat tenderizing, e.g., to break down collagen, in gelatin or food supplement production, in the textile industry, in waste treatment, and in the photographic industry. See, e.g., Gusek (1991) Inform 1:14-18; Zamost, et al. (1996) J. Industrial Microbiol. 8:71-82; James and Simpson (1996) CRC Critical Reviews in Food Science and Nutrition 36:437-463; Teichgraeber, et al. (1993) Trends in Food Science and Technology 4:145-149; Tjwan, et al. (1993) J. Dairy Research 60:269-286; Haard (1992) J. Aquatic Food Product Technology 1:17-35; van Dijk (1995) Laundry and Cleaning News 21:32-33; Nolte, et al. (1996) J. Textile Institute 87:212-226; Chikkodi, et al. (1995) Textile Res. J. 65:564-569; and Shih (1993) Poultry Science 72:1617-1620; PCT publication WO9925 848-Al.  
      In addition, the protein of the invention or part thereof may be used to identify inhibitors for mechanistic and clinical applications. Such inhibitors may then be used to identify or quantify the protein of the invention in a sample, and to diagnose, treat or prevent any of the disorders where the protein&#39;s hydrolytic activity is undesirable and/or deleterious such as disorders characterized by tissue degradation including but not limited to amyloidosis, colitis, lysosomal diseases, arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, parasite-borne infections, Alzheimer&#39;s disease, periodontal disease, and cancer metastasis.  
      Protein of SEQ ID NO:413 (Internal Designation 116-047-3-0-B1-FLC)  
      The protein of SEQ ID NO:413 encoded by the extended cDNA SEQ ID NO:8 shows homology with the ribokinase rbsk (Embl accession number Q9X4M5) which is part of the pfkb family of kinases. In addition, the protein of the invention exhibits the pfam signature for this family of carbohydrate and purine kinases from positions 28 to 94.  
      The pfkb family of carbohydrate kinase is composed of evolutionary related kinases including fructokinases, ribokinase, adenosine kinase, inosine-guanosine kinase, and phosphotagatokinase (for a short review see Prosite entry N° PD0C00504).  
      It is believed that the protein of SEQ ID NO:413 or part thereof is a carbohydrate or purine kinase. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:413 from positions 28 to 94, and from 1 to 94. Other preferred polypeptides of the invention are fragments of SEQ ID NO:413 having any of the biological activity described herein. The kinase activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described by the U.S. Pat. Nos. 5,756,315 and 5,861,294.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to phosphorylate substrates, preferably carbohydrate or purine substrates. For example, the protein of the invention or part thereof is added to a sample containing the substrate(s) as well as a phosphate donor group in conditions allowing the transfer of the phosphorus group, and allowed to transfer the phosphorus group to the substrate(s). In a preferred embodiment, the kination is carried out using a standard assay including those described by the U.S. Pat. Nos. 5,756,315 and 5,861,294. Such phosphorylated purine substrates, such as 5′-IMP and 5′-GMP, have an enhanced flavor activity and may be used as seasoning agents.  
      In another embodiment, the present invention relates to processes and compositions for controlling the production of phosphorylated substrates, preferably carbohydrate and purine substrates, more preferably glucose, fructose, inosine, guanosine, adenosine, wherein a cell or an organism is an organism is genetically engineered either to produce the protein of the invention or part thereof or to inhibit the endogenous expression of the protein of the invention or part thereof using methods and techniques known to those skilled in the art including those described in U.S. Pat. No. 6,031,154. For example, a plant may be genetically engineered to express the protein of the invention or part thereof, thereby increasing the amount of phosphorylated carbohydrate substrates to be imported into plastids and ultimately enhancing starch biosynthesis. On the contrary, a fruit may also be genetically engineered to inhibit the endogenous expression of the protein of the invention in order to increase the concentration of non phosphorylated carbohydrates, ultimately leading to fruits with enhanced sweetness.  
      The invention further relates to methods and composition using the protein of the invention or part thereof to diagnose, prevent and/or treat disorders in which the availability of phosphorylated substrates, preferably carbohydrate and purine substrates, is impaired or needs to be impaired. In a preferred embodiment, the protein of the invention or part thereof may be used to activate pharmacologically active nucleosides including but not limited to tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto) purine riboside which are antimetabolites with cytotoxic, anticancer and antiviral properties. In another preferred embodiment, the protein of the invention or part thereof may be used to compensate alterations observed in endogenous adenosine kinase activity observed in certain disorders including but not limited to hepatoma, hepatectomy, gout, and HIV infection. In still another preferred embodiment, the protein of the invention or part thereof may be used to modulate the concentration of adenosine which was shown to play important physiological roles. In the central nervous system, adenosine inhibits the release of certain neurotransmitters (Corradetti et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes membrane potential (Rudolphi et al., Cerebrovasc. Brain Metab. Rev. 1992, 4: 346-360), functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci. 1986, 7:128-130) and may have a role as an endogenous neuroprotective agent (Rudolphi et al., Trends Pharmacol. Sci. 1992, 13: 439-445). Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok et al., Br. J. Pharmacol. 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney et al., J. Pharmacol. Exp. Ther. 1987, 243: 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, impairment of atrioventricular conduction and endogenous cardioprotection in myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and Adenosine Receptors 1990 (Williams, ed) Humana Press, New Jersey, pp. 289-334). The widespread actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes. Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions are therefore highly localized. The inhibition of adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby minimizing systemic toxicities. Pharmacological compounds directed towards adenosine kinase inhibition provide potential effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine.  
      Protein of SEQ ID NO:439 (Internal Designation 108-011-5-0-C7-FLC)  
      The protein of SEQ ID NO:439 encoded by the extended cDNA SEQ ID NO:34 shows homology with the chicken ribonuclease A (Embl accession number X61192) which is part of the pancreatic ribonuclease family. In addition, the protein of the invention exhibits the pfam signature for this family of pancreatic ribonucleases from positions 17 to 67.  
      Ribonucleases are proteins which catalyze the hydrolysis of phosphodiester bonds in RNA chains. Pancreatic ribonucleases are pyrimidic-specific ribonucleases present in high quantity in the pancreas of a number of mammalia taxa and of a few reptiles. In addition to their function in hydrolysis of RNA, ribonucleases have evolved to support a variety of other physiological activities. Such activities include anti-parasite, anti-bacterium, anti-virus, anti-neoplastic activities, neurotoxicity, and angiogenesis. For example, bovine seminal ribonuclease is anti-neoplastic (Laceetti, P. et al. (1992) Cancer Res. 52: 4582-4586). Some frog ribonucleases display both anti-viral and anti-neoplastic activity (Youle, R. J. et al. (1994) Proc. Natl. Acad. Sci. USA 91: 6012-6016; Mikulski, S. M. et al. (1990) J. Natl. Cancer Inst. 82: 151-152; and Wu, Y.-N. et al. (1993) J. Biol. Chem. 268: 10686-10693). Angiogenin is a tRNA-specific ribonuclease which binds actin on the surface of endothelial cells for endocytosis. Endocytosed angiogenin is translocated to the nucleus where it promotes endothelial invasiveness required for blood vessel formation (Moroianu, J. and Riordan, J. F. (1994) Proc. Natl. Acad. Sci. USA 91: 1217-1221). Eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are related ribonucleases which possess neurotoxicity (Beintema, J. J. et al. (1988) Biochemistry 27: 4530-4538; Ackerman, S. J. (1993) In Makino, S. and Fukuda, T., Eosinophils: Biological and Clinical Aspects. CRC Press, Boca Raton, Fla., pp 33-74). In addition, ECP exhibits cytotoxic, anti-parasitic, and anti-bacterial activities. A EDN-related ribonuclease, named RNase k6, is shown to express in normal human monocytes and neutrophils, suggesting a role for this ribonuclease in host defense (Rosenberg, H. F. and Dyer, K. D. (1996) Nuc. Acid. Res. 24: 3507-3513).  
      It is believed that the protein of SEQ ID NO:439 or part thereof is a ribonuclease. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:439 from positions 17 to 67. Other preferred polypeptides of the invention are fragments of SEQ ID NO:439 having any of the biological activity described herein. The ribonuclease activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in U.S. Pat. No. 5,866,119.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to hydrolyze one or several substrates, preferably nucleic acids, more preferably RNA, alone or in combination with other substances. For example, the protein of the invention or part thereof is added to a sample containing the substrate(s) in conditions allowing hydrolysis, and allowed to catalyze the hydrolysis of the substrate(s).  
      In a preferred embodiment, the protein of the invention or part thereof may be used to remove contaminating RNA in a biological sample, alone or in combination with other nucleases. In a more preferred embodiment, the protein of the invention or part thereof may be used to purify DNA preparations from contaminating RNA, to remove RNA templates prior to second strand synthesis and prior to analysis of in vitro translation products. Compositions comprising the protein of the present invention or part thereof are added to biological samples as a “cocktail” with other nucleases. The advantage of using a cocktail of hydrolytic enzymes is that one is able to hydrolyze a wide range of substrates without knowing the specificity of any of the enzymes. Such cocktails of nucleases are commonly used in molecular biology assays, for example to remove unbound RNA in RNAse protection assays. Using a cocktail of hydrolytic enzymes also protects a sample from a wide range of future unknown RNA contaminants from a vast number of sources. For example, the protein of the invention or part thereof is added to samples where contaminating substrates is undesirable. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other hydrolytic enzymes, using techniques well known in the art, to form an affinity chromatography column. A sample containing the undesirable substrate is run through the column to remove the substrate. Immobilizing the protein of the invention or part thereof on a support is particularly advantageous for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the enzyme from the batch of product and subsequent reuse of the enzyme. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature. Alternatively, the same methods may be used to identify new substrates.  
      In another embodiment, the protein of the invention or part thereof may be used to decontaminate or disinfect samples infected by undesirable parasite, bacteria and/or viruses using any of the methods known to those skilled in the art including those described in Youle et al, (1994), supra; Mikulski et al (1990) supra, Wu et al (1993) supra.  
      In another embodiment, the present invention relates to compositions and methods using the protein of the invention or part thereof to selectively kill cells. The protein of the invention or part thereof is linked to a recognition moiety capable of binding to a chosen cell, such as lectins, receptors or antibodies thus generating cytotoxic reagents using methods and techniques described in U.S. Pat. No. 5,955,073.  
      In another embodiment, the protein of the invention or part thereof may be used in the diagnosis, prevention and/or treatment of disorders associated with excessive cell proliferation such as cancer.  
      Protein of SEQ ID NO:409 (Internal Designation 105-118-4-0-E6-FLC)  
      The protein of SEQ ID NO:409 encoded by the extended cDNA SEQ ID NO:4 is homologous to a hepatocellular carcinoma associated ring finger protein (Embl accession number AF247565) and homology with a putative anaphase-promoting complex subunit from Drosophila (Embl accession number AJ251510). In addition, the protein of the invention exhibits the pfam PHD zinc finger signature from positions 33 to 79.  
      Zinc finger domains are found in numerous zinc binding proteins which are involved in protein-nucleic acid interactions. They are independently folded zinc-containing mini-domains which are used in a modular repeating fashion to achieve sequence-specific recognition of DNA (Klug 1993 Gene 135, 83-92). Such zinc binding proteins are commonly involved in the regulation of gene expression, and usually serve as transcription factors (see U.S. Pat. Nos. 5,866,325; 6,013,453 and 5,861,495). PHD fingers are C 4 HC 3  zinc fingers spanning approximately 50-80 residues and distinct from RING fingers or LIM domains. They are thought to be mostly DNA or RNA binding domain but may also be involved in protein-protein interactions (for a review see Aasland et al, Trends Biochem Sci 20:56-59 (1995)).  
      It is believed that the protein of SEQ ID NO:409 or part thereof is a zinc binding protein, preferably able to bind nucleic acids, more preferably a transcription factor. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:409 from positions 33 to 79. Other preferred polypeptides of the invention are fragments of SEQ ID NO:409 having any of the biological activity described herein. The nucleic acid binding activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in U.S. Pat. No. 6,013,453.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to bind to nucleic acids, preferably DNA, alone or in combination with other substances. For example, the protein of the invention or part thereof is added to a sample containing nucleic acid in conditions allowing binding, and allowed to bind to nucleic acids. In a preferred embodiment, the protein of the invention or part thereof may be used to purify nucleic acids such as restriction fragments. In another preferred embodiment, the protein of the invention or part thereof may be used to visualize nucleic acids when the polypeptide is linked to an appropriate fusion partner, or is detected by probing with an antibody. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other DNA binding proteins, using techniques well known in the art, to form an affinity chromatography column. A sample containing nucleic acids to purify is run through the column. Immobilizing the protein of the invention or part thereof on a support advantageous is particularly for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the protein from the batch of product and subsequent reuse of the protein. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature.  
      In another embodiment, the present invention relates to compositions and methods using the protein of the invention or part thereof, especially the zinc binding domain, to alter the expression of genes of interest in a target cells. Such genes of interest may be disease related genes, such as oncogenes or exogenous genes from pathogens, such as bacteria or viruses using any techniques known to those skilled in the art including those described in U.S. Pat. Nos. 5,861,495; 5,866,325 and 6,013,453.  
      In still another embodiment, the protein of the invention or part thereof may be used to diagnose, treat and/or prevent disorders linked to dysregulation of gene transcription such as cancer and other disorders relating to abnormal cellular differentiation, proliferation, or degeneration, including hyperaldosteronism, hypocortisolism (Addison&#39;s disease), hyperthyroidism (Grave&#39;s disease), hypothyroidism, colorectal polyps, gastritis, gastric and duodenal ulcers, ulcerative colitis, and Crohn&#39;s disease.  
      Protein of SEQ ID NO:446 (Internal Designation 108-014-5-0-D12-FLC)  
      The protein of SEQ ID NO:446 encoded by the extended cDNA SEQ ID NO:41 shows homology with zinc binding proteins (Embl accession number Q9QZQ6 and Genseq accession number W69602). In addition, the protein of the invention exhibits the pfam RING zinc finger signature from positions 258 to 298.  
      Zinc binding (ZB) domains are found in numerous proteins which are involved in protein-nucleic acid or protein-protein interactions. ZB proteins are commonly involved in the regulation of gene expression, and may serve as transcription factors and signal transduction molecules. A ZB domain is generally composed of 25 to 30 amino acid residues which form one or more tetrahedral ion binding sites. The binding sites contain four ligands consisting of the sidechains of cysteine, histidine and occasionally aspartate or glutamate. The binding of zinc allows the relatively short stretches of polypeptide to fold into defined structural units which are well-suited to participate in macromolecular interactions (Berg, J. M. et al. (1996) Science 271:1081-1085). Zinc binding domains which contain a C 3 HC 4  sequence motif are known as RING domains (Lovering, R. et al. (1993) Proc. Natl. Acad. Sci. USA 90:2112-2116). The RING domain consists of eight metal binding residues, and the sequences that bind the two metal ions overlap (Barlow, P. N. et al. (1994) J. Mol. Biol. 237:201-211). Functions of RING finger proteins are mediated through DNA binding and include the regulation of gene expression, DNA recombination, and DNA repair (see Borden and Freemont, Curr Opin Struct Biol 6:395-401 (1996) and U.S. Pat. No. 5,861,495).  
      It is believed that the protein of SEQ ID NO:446 or part thereof is a zinc binding protein, preferably able to bind nucleic acids or proteins, more preferably a transcription factor. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:446 from positions 258 to 298. Other preferred polypeptides of the invention are fragments of SEQ ID NO:446 having any of the biological activity described herein. The nucleic acid binding activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in U.S. Pat. No. 6,013,453.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to bind to nucleic acids, preferably DNA, alone or in combination with other substances. For example, the protein of the invention or part thereof is added to a sample containing nucleic acid in conditions allowing binding, and allowed to bind to nucleic acids. In a preferred embodiment, the protein of the invention or part thereof may be used to purify nucleic acids such as restriction fragments. In another preferred embodiment, the protein of the invention or part thereof may be used to visualize nucleic acids when the polypeptide is linked to an appropriate fusion partner, or is detected by probing with an antibody. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other DNA binding proteins, using techniques well known in the art, to form an affinity chromatography column. A sample containing nucleic acids to purify is run through the column. Immobilizing the protein of the invention or part thereof on a support advantageous is particularly for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the protein from the batch of product and subsequent reuse of the protein. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature.  
      In another embodiment, the present invention relates to compositions and methods using the protein of the invention or part thereof, especially the zinc binding domain, to alter the expression of genes of interest in a target cells. Such genes of interest may be disease related genes, such as oncogenes or exogenous genes from pathogens, such as bacteria or viruses using any techniques known to those skilled in the art including those described in U.S. Pat. Nos. 5,861,495; 5,866,325 and 6,013,453.  
      In still another embodiment, the protein of the invention or part thereof may be used to diagnose, treat and/or prevent disorders linked to dysregulation of gene transcription such as cancer and other disorders relating to abnormal cellular differentiation, proliferation, or degeneration, including hyperaldosteronism, hypocortisolism (Addison&#39;s disease), hyperthyroidism (Grave&#39;s disease), hypothyroidism, colorectal polyps, gastritis, gastric and duodenal ulcers, ulcerative colitis, and Crohn&#39;s disease.  
      Protein of SEQ ID NO:437 (Internal Designation 108-008-5-0-G5-FLC)  
      The protein of SEQ ID NO:437 encoded by the extended cDNA SEQ ID NO:32 shows homology with zinc binding proteins (Embl accession number Q9VZJ9). In addition, the protein of the invention exhibits the pfam RING zinc finger signature from positions 302 to 339.— 
      Zinc binding (ZB) domains are found in numerous proteins which are involved in protein-nucleic acid or protein-protein interactions. ZB proteins are commonly involved in the regulation of gene expression, and may serve as transcription factors and signal transduction molecules. A ZB domain is generally composed of 25 to 30 amino acid residues which form one or more tetrahedral ion binding sites. The binding sites contain four ligands consisting of the sidechains of cysteine, histidine and occasionally aspartate or glutamate. The binding of zinc allows the relatively short stretches of polypeptide to fold into defined structural units which are well-suited to participate in macromolecular interactions (Berg, J. M. et al. (1996) Science 271:1081-1085). Zinc binding domains which contain a C 3 HC 4  sequence motif are known as RING domains (Lovering, R. et al. (1993) Proc. Natl. Acad. Sci. USA 90:2112-2116). The RING domain consists of eight metal binding residues, and the sequences that bind the two metal ions overlap (Barlow, P. N. et al. (1994) J. Mol. Biol. 237:201-211). Functions of RING finger proteins are mediated through DNA binding and include the regulation of gene expression, DNA recombination, and DNA repair (see Borden and Freemont, Curr Opin Struct Biol 6:395-401 (1996) and U.S. Pat. No. 5,861,495).  
      It is believed that the protein of SEQ ID NO:437 or part thereof is a zinc binding protein, preferably able to bind nucleic acids or proteins, more preferably a transcription factor. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:437 from positions 302 to 339. Other preferred polypeptides of the invention are fragments of SEQ ID NO:437 having any of the biological activity described herein. The nucleic acid binding activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in U.S. Pat. No. 6,013,453.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to bind to nucleic acids, preferably DNA, alone or in combination with other substances. For example, the protein of the invention or part thereof is added to a sample containing nucleic acid in conditions allowing binding, and allowed to bind to nucleic acids. In a preferred embodiment, the protein of the invention or part thereof may be used to purify nucleic acids such as restriction fragments. In another preferred embodiment, the protein of the invention or part thereof may be used to visualize nucleic acids when the polypeptide is linked to an appropriate fusion partner, or is detected by probing with an antibody. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other DNA binding proteins, using techniques well known in the art, to form an affinity chromatography column. A sample containing nucleic acids to purify is run through the column. Immobilizing the protein of the invention or part thereof on a support advantageous is particularly for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the protein from the batch of product and subsequent reuse of the protein. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature.  
      In another embodiment, the present invention relates to compositions and methods using the protein of the invention or part thereof, especially the zinc binding domain, to alter the expression of genes of interest in a target cells. Such genes of interest may be disease related genes, such as oncogenes or exogenous genes from pathogens, such as bacteria or viruses using any techniques known to those skilled in the art including those described in U.S. Pat. Nos. 5,861,495; 5,866,325 and 6,013,453.  
      In still another embodiment, the protein of the invention or part thereof may be used to diagnose, treat and/or prevent disorders linked to dysregulation of gene transcription such as cancer and other disorders relating to abnormal cellular differentiation, proliferation, or degeneration, including hyperaldosteronism, hypocortisolism (Addison&#39;s disease), hyperthyroidism (Grave&#39;s disease), hypothyroidism, colorectal polyps, gastritis, gastric and duodenal ulcers, ulcerative colitis, and Crohn&#39;s disease.  
      Protein of SEQ ID NO:438 (Internal Designation 108-011-5-0-B12-FL)  
      The protein of SEQ ID NO:438 encoded by the extended cDNA SEQ ID NO:33 shows homology to the predicted extracellular domain and part of transmembrane domain of interleukin-17 receptor of both human and murine species (Genbank accession numbers WO4185 and WO4184). These IL-17R proteins are thought to belong to a new family of receptors for cytokines which induce T cell proliferation, I-CAM expression and preferential maturation of haematopoietic precursors into neutrophils (Yao et al.,  Cytokine.,  9:794-8001 (1997)). It is also thought to play a proinflammatory role and to induce nitric oxide. The protein of the invention has a 21 amino acid transmembrane domain (positions 172 to 192) as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)) matching the 21 amino acid putative transmembrane domain of human interleukin-17 receptor.  
      It is believed that the protein of SEQ ID NO:438 plays a role in regulating immune and/or inflammatory responses. Preferred polypeptides of the invention are fragments of SEQ ID NO:438 having any of the biological activities described herein.  
      The present invention relates to methods and compositions using the protein of the invention or part thereof to inhibit the proliferation and/or the differentiation of lymphocytes or lymphocytic cell lines, both in vitro and in vivo. For example, soluble forms of the protein of the invention or part thereof may be added to cell culture medium in an amount effective to inhibit the proliferation and/or the differentiation of lymphocytes and/or lymphocytic cell lines.  
      Another embodiment relates to methods and compositions using the protein of the invention or part thereof to diagnose, treat and/or prevent several disorders including, but not limited to, cancer, inflammatory and immune disorders, septic shock and impotence. Immune and inflammatory disorders include Addison&#39;s disease, AIDS, acute or chronic inflammation due to antigen, antibody and/or complement deposition, acute and delayed hypersensitivity, adult respiratory distress syndrome, allergies, anemia, arthritis, asthma, atherosclerosis, bronchitis, chalangitis, cholecystitus, Crohn&#39;s disease, ulcerative colitis, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, encephalitis, endocarditis, atrophic gastritis, glomerulonephritis, gout, graft rejection, graft-versus-host disease, Graves&#39; disease, hepatitis, hypereosinophilia, irritable bowel syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polycystic kidney disease, polymyositis, reperfusion injury, rheumatoid arthritis, scleroderma, Sjogren&#39;s syndrome, and autoimmune thyroiditis.  
      In addition, this protein may also be useful to modulate immune and/or inflammatory responses to infectious responses and/or to suppress graft rejection. For example, soluble forms of the protein of the invention or blocking antibodies, or antagonists may be used to inhibit and/or reduce immune and/or inflammatory responses.  
      Protein of SEQ ID NO:429 (Internal Designation 108-004-5-0-B12-FLC)  
      The protein of SEQ ID NO:429 encoded by the extended cDNA SEQ ID NO:24 is homologous to a human protein either described as a maid-like gene (Embl accession number 35 AF132000) or a human secreted protein (Geneseq accession number Y41330).  
      Maid is a maternally transcribed gene encoding a putative regulator of basic helix-loop-helix transcription factor in the mouse egg and zygote. In vitro, maid is able to bind to DNA. When transfected, maid reduces the transcription of a CAT-reporter regulated by an E12/MyoD enhancer (Hwang et al, Dev Dyn, 209:217-26 (1997)).  
      It is believed that the protein of SEQ ID NO:429 or part thereof is involved in the regulation of gene transcription, probably through direct binding to DNA. Preferred polypeptides of the invention are fragments of SEQ ID NO:429 having any of the biological activity described herein. The nucleic acid binding activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in U.S. Pat. No. 6,013,453.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to bind to nucleic acids, preferably DNA, alone or in combination with other substances. For example, the protein of the invention or part thereof is added to a sample containing nucleic acid in conditions allowing binding, and allowed to bind to nucleic acids. In a preferred embodiment, the protein of the invention or part thereof may be used to purify nucleic acids such as restriction fragments. In another preferred embodiment, the protein of the invention or part thereof may be used to visualize nucleic acids when the polypeptide is linked to an appropriate fusion partner, or is detected by probing with an antibody. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other DNA binding proteins, using techniques well known in the art, to form an affinity chromatography column. A sample containing nucleic acids to purify is run through the column. Immobilizing the protein of the invention or part thereof on a support advantageous is particularly for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the protein from the batch of product and subsequent reuse of the protein. Immobilizing the protein of the invention or part thereof on a support advantageous is particularly for those embodiments in which the method is to be practiced on a commercial scale. This immobilization facilitates the removal of the protein from the batch of product and subsequent reuse of the protein. Immobilization of the protein of the invention or part thereof can be accomplished, for example, by inserting a cellulose-binding domain in the protein. One of skill in the art will understand that other methods of immobilization could also be used and are described in the available literature.  
      In another embodiment, the present invention relates to compositions and methods using the protein of the invention or part thereof to alter the expression of genes of interest in a target cell. Such genes of interest may be disease related genes, such as oncogenes or exogenous genes from pathogens, such as bacteria or viruses using any techniques known to those skilled in the art including those described in U.S. Pat. Nos. 5,861,495; 5,866,325 and 6,013,453.  
      In still another embodiment, the protein of the invention or part thereof may be used to diagnose, treat and/or prevent disorders linked to dysregulation of gene transcription such as cancer and other disorders relating to abnormal cellular differentiation, proliferation, or degeneration, including hyperaldosteronism, hypocortisolism (Addison&#39;s disease), hyperthyroidism (Grave&#39;s disease), hypothyroidism, colorectal polyps, gastritis, gastric and duodenal ulcers, ulcerative colitis, and Crohn&#39;s disease.  
      Protein of SEQ ID NO:454 (Internal Designation 108-020-5-O-D4-FLC)  
      The protein of SEQ ID NO:454 encoded by the extended cDNA SEQ ID NO:49 shows homology to a murine transmembrane protein (Genbank accession number BAA92746). When expressed in  E. Coli , the matched which suppresses bacterial growth (Inoue et al, Biochem Biophys Res Commun 268:553-61 (2000)). In addition, a transmembrane domain is predicted for the protein of SEQ ID NO:454 from positions 36 to 56 by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994).  
      It is believed that the protein of SEQ ID NO:454 or part thereof is able to suppress bacterial growth. Preferred polypeptides of the invention are fragments of SEQ ID NO:429 having any of the biological activity described herein. The growth inhibiting activity of the protein of the invention or part thereof may be assayed using any of the assays known to those skilled in the art including those described in Inoue et al, supra.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to suppress bacterial growth. For example, the protein of the invention may be expressed in a bacteria, preferably  E. coli , using recombinant DNA technology methods known to those skilled in the art. The bacterial growth may then be assessed using any methods or techniques known to those skilled in the art.  
      Protein of SEQ ID NO:428 (Internal Designation 122-007-3-0-D10-FLC)  
      The protein of SEQ ID NO:428 encoded by the extended cDNA SEQ ID NO:23 shows homology to a human secreted protein highly expressed in testis (Genseq accession number Y06940). In addition, it exhibits an emotif signature for the flagellar biosynthetic protein fliR 30 family from positions 7 to 27.  
      FliR is an integral membrane protein located in the flagellar basal body and thought to be a component of the type III export apparatus (Fan et al, Mol Microbiol 26:1035-46 (1997)).  
      It is believed that the protein of SEQ ID NO:428 or part thereof plays a role in gametogenesis, maybe as a component of spermatozoids. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:428 from positions 7 to 27. Other preferred polypeptides of the invention are fragments of SEQ ID NO:428 having any of the biological activity described herein.  
      The invention relates to methods and compositions using the protein of the invention or part thereof to diagnose, treat and/or prevent fertility disorders. For diagnostic purposes, the expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals. For prevention and/or treatment purposes, the protein of the invention may be used to enhance gametogenesis using any of the gene therapy methods described herein or known to those skilled in the art.  
      Moreover, antibodies to the protein of the invention or part thereof may be used for detection of gametes using any techniques known to those skilled in the art.  
      Protein of SEQ ID NO:442 (Internal Designation 108-013-5-0-G5-FLC)  
      The protein of SEQ ID NO:442 encoded by the extended cDNA SEQ ID NO:37 displays the pfam signature for the N-terminus of the alpha-macroglobulin A2M family from positions 17 to 40. A2M-like proteins are able to inhibit all four classes of proteinases by a “trapping mechanism” (see Prosite entry PS00477 for a short review).  
      It is believed that the protein of SEQ ID NO:442 or part thereof is a member of the alpha-2-macroglobulin family, more preferably a protease inhibitor. Preferred polypeptides of the invention are polypeptides comprising the amino acids of SEQ ID NO:442 from positions 17 to 40. Other preferred polypeptides of the invention are fragments of SEQ ID NO:425 having any of the biological activity described herein. The protease inhibitor activity of the protein of the invention or part thereof may be assessed using any techniques known to those skilled in the art.  
      The invention relates to compositions and methods using the protein of the invention or part thereof to inhibit proteases, both in vitro or in vivo. Since proteases play an important role in the regulation of many biological processes in virtually all living organisms as well as a major role in diseases, inhibitors of proteases are useful in a wide variety of applications.  
      In one embodiment, the protein of the invention or part thereof may be useful to quantify the amount of a given protease in a biological sample, and thus used in assays and diagnostic kits for the quantification of proteases in bodily fluids or other tissue samples, in addition to bacterial, fungal, plant, yeast, viral or mammalian cell cultures. In a preferred embodiment, the sample is assayed using a standard protease substrate. A known concentration of protease inhibitor is added, and allowed to bind to a particular protease present. The protease assay is then rerun, and the loss of activity is correlated to the protease inhibitor activity using techniques well known to those skilled in the art.  
      In addition, the protein of the invention or part thereof may be used to remove, identify or inhibit contaminating proteases in a sample. Compositions comprising the polypeptides of the present invention may be added to biological samples as a “cocktail” with other protease inhibitors to prevent degradation of protein samples. The advantage of using a cocktail of protease inhibitors is that one is able to inhibit a wide range of proteases without knowing the specificity of any of the proteases. Using a cocktail of protease inhibitors also protects a protein sample from a wide range of future unknown proteases which may contaminate a protein sample from a vast number of sources. For example, the protein of the invention or part thereof are added to samples where proteolytic degradation by contaminating proteases is undesirable. Such protease inhibitor cocktails (see for example the ready to use cocktails sold by Sigma) are widely used in research laboratory assays to inhibit proteases susceptible of degrading a protein of interest for which the assay is to be performed. Alternatively, the protein of the invention or part thereof may be bound to a chromatographic support, either alone or in combination with other protease inhibitor, using techniques well known in the art, to form an affinity chromatography column. A sample containing the undesirable protease is run through the column to remove the protease. Alternatively, the same methods may be used to identify new proteases.  
      In a preferred embodiment, the protein of the invention or part thereof may be used to inhibit proteases implicated in a number of diseases where cellular proteolysis occur such as diseases characterized by tissue degradation including but not limited to arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, parasite-borne infections, Alzheimer&#39;s disease, periodontal disease, and cancer metastasis.  
      In another preferred embodiment, the protein of the invention or part thereof may be useful to inhibit exogenous proteases, both in vivo and in vitro, implicated in a number of infectious diseases including but not limited to gingivitis, malaria, leishmaniasis, filariasis, osteoporosis and osteoarthritis, and other bacterial, and parasite-borne or viral infections. In particular, the protein of the invention or part thereof may offer applications in viral diseases where the proteolysis of primary polypeptide precursors is essential to the replication of the virus, as for HIV and HCV.  
      Furthermore, the protease inhibitors of the present invention find use in drug potentiation applications. For example, therapeutic agents such as antibiotics or antitumor drugs can be inactivated through proteolysis by endogenous proteases, thus rendering the administered drug less effective or inactive. Accordingly, the protease inhibitors of the invention may be administered to a patient in conjunction with a therapeutic agent in order to potentiate or increase the activity of the drug. This co-administration may be by simultaneous administration, such as a mixture of the protease inhibitor and the drug, or by separate simultaneous or sequential administration.  
      In addition, protease inhibitors have been shown to inhibit the growth of microorganisms including human pathogenic bacteria. For example, protease inhibitors are able to inhibit growth of all strains of group A streptococci, including antibiotic-resistant strains (Merigan, T. et al (1996) Ann Intern Med 124:1039-1050; Stoka, V. (1995) FEBS. Lett 370:101-104; Vonderfecht, S. et al (1988) J Clin Invest 82:2011-2016; Collins, A. et al (1991) Antimicrob Agents Chemother 35:2444-2446). Accordingly, the protease inhibitors of the present invention may be used as antibacterial agents to retard or inhibit the growth of certain bacteria either in vitro or in vivo. Particularly, the polypeptides of the present invention may be used to inhibit the growth of group A streptococci on non-living matter such as instruments not conducive to other methods of preventing or removing contamination by group A streptococci, and in culture of living plant, fungi, and animal cells.  
      Protein of SEQ ID NO:693  
      The protein of SEQ ID NO: 693 is encoded by the extended cDNA SEQ ID NO: 51. The protein of SEQ ID NO: 693 is human strictosidine synthase. Strictodine synthase is a key enzyme in the production of, and therefore useful in making, the pharmaceutically important monoterpene indole alkaloids. Pathways for the production of monoterpene indole alkaloids can be reconstructed in various cell types, for example, insect cell cultures as described in Kutchan, T. M. et al. (1994) Phyochemistry 35(2):353-360. Strictodine synthase can also be produced  E. coli  and its activity measuring using methods described in, for example, Roessner, C. A. et al. (1992) Protein Expr. Purif. 3(4):295-300; Kutchan, T. M. (1989) FEBS Lett. 257(1):127-130; Pennings, E. J. et al. (1989) Anal. Biochem. 176(2):412-415; Walton, N. J. (1987) Anal. Biochem. 163(2):482-488. Preferred fragments of SEQ ID NO: 693 and the mature polypeptide encoded by the corresponding human cDNA of the deposited clone are those with strictodine synthase activity. Further preferred are fragments with not less then 100 fold less activity, not less than 10 fold activity, and not less than 5 fold activity when compared to mature protein.  
      Protein of SEQ ID NO: 695  
      The protein of SEQ ID NO: 695, encoded by the extended cDNA SEQ ID NO: 53, is human inositol hexakisphophate kinase-2. Inositol hexakisphophate kinase-2 phosphorylates inositol hexakisphosphate (InsP(6)) to diphosphoinositol pentakisphosphate/inositol heptakisphosphate (InsP(7)), a high energy regulator of cellular trafficking. Human inositol hexakisphophate kinase-2 also stimulates the uptake of inorganic phosphate and its products act as energy reserves. Therefore, hexakisphosphate kinase-2 is an ATP synthase, and its product, diphosphoinositol pentakisphosphate, acts as a high-energy phosphate donor. The human inositol hexakisphophate kinase-2 gene may be transfected into eukaryotic cells (preferably mammalian, yeast, and insect cells) and expressed to increase their growth, viability, and for more efficient secretions of polypeptides, including recombinant polypeptides. Preferred fragments of SEQ ID NO: 695 and the corresponding mature polypeptide encoded by the human cDNA of the deposited clone are those with inositol hexakisphophate kinase-2 activity. Further preferred are fragments with not less then 100 fold less activity, not less than 10 fold activity, and not less than 5 fold activity when compared to mature protein.  
      Proteins of SEQ ID NOs: 697 and 727:  
      The proteins of SEQ ID NOs: 697 and 727 encoded by the extended cDNA SEQ ID NOs: 55 and 85, respectively, are MEK binding partners. These proteins enhance enzymatic activation of mitogen-activated protein (MAP) kinase cascade. The MAP kinase pathway is one of the important enzymatic cascade that is conserved among all eukaryotes from yeast to human. This kind of pathway is involved in vital functions such as the regulation of growth, differentiation and apoptosis. These proteins are believed to act by facilitating the interaction of the two sequentially acting kinases MEKI and ERKI (Schaffer et al., Science, 281:1668-1671 (1998)).  
      Thus, the proteins of SEQ ID NO: 697 and 727 are involved in regulating protein-protein interaction in the signal transduction pathways. These proteins may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases, cardiovascular disorders, hypertension, renal injury and repair and septic shock. More specifically, over expression and mutant forms of this gene can serve as markers for cancer, such as ovarian cancer, using the nucleic acid as a probe or by using antibodies directed to the protein. Cells transfected with this gene have increased growth rate.  
      Protein of SEQ ID NO: 698  
      The protein of SEQ ID NO: 698, encoded by the extended cDNA SEQ ID NO: 56, is a new claudin named Claudin-50.  
      Cell adhesion is a complex process that is important for maintaining tissue integrity and generating physical and permeability barriers within the body. All tissues are divided into discrete compartments, each of which is composed of a specific cell type that adheres to similar cell types. Such adhesion triggers the formation of intercellular junctions (i.e., readily definable contact sites on the surfaces of adjacent cells that are adhering to one another), also known as tight junctions, gap junctions, spot desmosomes and belt desmosomes. The formation of such junctions gives rise to physical and permeability barriers that restrict the free passage of cells and other biological substances from one tissue compartment to another. For example, the blood vessels of all tissues are composed of endothelial cells. In order for components in the blood to enter a given tissue compartment, they must first pass from the lumen of a blood vessel through the barrier formed by the endothelial cells of that vessel. Similarly, in order for substances to enter the body via the gut, the substances must first pass through a barrier formed by the epithelial cells of that tissue. To enter the blood via the skin, both epithelial and endothelial cell layers must be crossed.  
      The transmembrane component of tight junctions that has been the most studied is occluding. Occludin is believed to be directly involved in cell adhesion and the formation of tight junctions (Furuse et al., J. Cell Sci. 109:429-435, 1996; Chen et al., J. 5 Cell Biol. 138:891-899, 1997). It has been proposed that occludin promotes cell adhesion through homophilic interactions (an occludin on the surface of one cell binds to an identical occludin on the surface of another cell). A detailed discussion of occludin structure and function is provided by Lampugnani and Dejana, Curr. Opin Cell Biol. 9:674-682, 1997.  
      More recently, a second family of tight junction components has been identified. Claudins are transmembrane proteins that appear to be directly involved in cell adhesion and the formation of tight junctions (Furuse et al., J. Cell Biology 141:1539-1550, 1998; Morita et al., Proc. Natl. Acad. Sci. USA 96:511-516, 1999). Other previously described proteins that appear to be members of the claudin family include RVP-1 (Briehl and Miesfeld, Molecular Endocrinology 5:1381-1388, 1991; Katahira et al., J. Biological Chemistry 272:26652-26656, 1997), the  Clostridium perfringens  enterotoxin receptor (CPE-R; see Katahira et al., J. Cell Biology 136:1239-1247, 1997; Katahira et al., J. Biological Chemistry 272:26652-26656, 1997) and TMVCF (transmembrane protein deleted in Velo-cardio-facial syndrome; Sirotkin et al., Genomics 42:245-51, 1997).  
      Based on hydrophobicity analysis, all claudins appear to be approximately 22 kD and contain four hydrophobic domains that transverse the plasma membrane. It has been proposed that claudins promote cell adhesion through homophilic interactions (a claudin on the surface of one cell binds to an identical claudin on the surface of another cell) or heterophilic interactions, possibly with occludin.  
      Although cell adhesion is required for certain normal physiological functions, there are situations in which the level of cell adhesion is undesirable. For example, many pathologies (such as autoimmune diseases and inflammatory diseases) involve abnormal cellular adhesion. Cell adhesion may also play a role in graft rejection. In such circumstances, modulation of cell adhesion may be desirable.  
      In addition, permeability barriers arising from cell adhesion create difficulties for the delivery of drugs to specific tissues and tumors within the body. For example, skin patches are a convenient tool for administering drugs through the skin. However, the use of skin patches has been limited to small, hydrophobic molecules because of the epithelial and endothelial cell barriers. Similarly, endothelial cells render the blood capillaries largely impermeable to drugs, and the blood/brain barrier has hampered the targeting of drugs to the central nervous system. In addition, many solid tumors develop internal barriers that limit the delivery of anti-tumor drugs and antibodies to inner cells.  
      Attempts to facilitate the passage of drugs across such barriers generally rely on specific receptors or carrier proteins that transport molecules across barriers in vivo. However, such methods are often inefficient, due to low endogenous transport rates or to the poor functioning of a carrier protein with drugs. While improved efficiency has been achieved using a variety of chemical agents that disrupt cell adhesion, such agents are typically associated with undesirable side-effects, may require invasive procedures for administration and may result in irreversible effects.  
      Accordingly, there is a need in the art for compounds that modulate cell adhesion and improve drug delivery across permeability barriers without such disadvantages. The present invention fulfills this need and further provides other related advantages.  
      The present invention provides compounds and methods for modulating claudin-mediated cell adhesion and the formation of permeability barriers. Within certain aspects, the present invention provides cell adhesion modulating agents that inhibit or enhance claudin-mediated cell adhesion. Certain modulating agents comprise the claudin CAR sequence WKTSSTVG. Other modulating agents comprise at least five or seven consecutive amino acid residues of a claudin CAR sequence: Comprising the sequence TSSY, wherein each permutation is an individual specie of the present invention.  
      The present invention further provides for polypeptides comprising amino acid residues 32 to 35 of SEQ. ID NO: 698, wherein said sequence comprises an additional 1 to 31 consecutive residues of N-terminal sequence of SEQ. ID NO: 698 and an additional 1 to 193 consecutive C-terminal residues of SEQ. ID NO: 698. Further included are polypeptides comprising additional consecutive residues at both the N-terminal, C-terminal. Each permutation of the above polypeptides comprising additional N-terminal, C-terminal &amp; N— and C terminal residues are included in the present invention as individual species.  
      The present invention further provides, within other aspects, polynucleotides encoding a modulating agent as provided above, expression vectors comprising such a polynucleotide, and host cells transformed or transfected with such an expression vector.  
      Within further aspects, the present invention provides modulating agents that comprise an antibody or antigen-binding fragment thereof that specifically binds to a claudin CAR sequence and modulates a claudin-mediated function.  
      The present invention further provides modulating agents comprising a mimetic of a claudin CAR sequence that comprises at least three or five consecutive amino acid residues of the claudin CAR sequence WKTSSYVG.  
      Within other aspects, modulating agents as described above may be linked to one or more of a drug, a detectable marker, a targeting agent and/or a support material. Alternatively, or in addition, modulating agents as described above may further comprise one or more of: (a) a cell adhesion recognition sequence that is bound by an adhesion molecule other than a claudin, wherein the cell adhesion recognition sequence is separated from any claudin CAR sequence(s) by a linker; and/or (b) an antibody or antigen-binding fragment thereof that specifically binds to a cell adhesion recognition sequence bound by an adhesion molecule other than a claudin. Such adhesion molecules may be selected from the group consisting of integrins, cadherins, occludin, N-CAM, JAM, PE-CAM, desmogleins, desmocollins, fibronectin, lammin and other extracellular matrix proteins.  
      Within other aspects, a modulating agent may comprise an antibody or antigen-binding fragment thereof that specifically binds to the claudin-50 CAR sequence WKTSSYVG.  
      The present invention further provides pharmaceutical compositions comprising a cell adhesion modulating agent as described above, in combination with a pharmaceutically acceptable carrier. Such compositions may further comprise a drug. In addition, or alternatively, such compositions may further comprise one or more of: (a) a peptide comprising a cell adhesion recognition sequence that is bound by an adhesion molecule other than a claudin; and/or (b) an antibody or antigen-binding fragment thereof that specifically binds to a cell adhesion recognition sequence bound by an adhesion molecule other than a claudin.  
      Within further aspects, methods are provided for modulating cell adhesion, comprising contacting a claudin-expressing cell with a cell adhesion modulating agent as described above.  
      Within one such aspect, the present invention provides methods for increasing vasopermeability in a mammal, comprising administering to a mammal a cell adhesion modulating agent as provided above, wherein the modulating agent inhibits claudin-mediated cell adhesion.  
      Within another aspect, methods are provided for reducing unwanted cellular adhesion in a mammal, comprising administering to a mammal a cell adhesion modulating agent as provided above, wherein the modulating agent inhibits claudin-mediated cell adhesion.  
      In yet another aspect, the present invention provides methods for enhancing the delivery of a drug through the skin of a mammal, comprising contacting epithelial cells of a mammal with a cell adhesion modulating agent as provided above and a drug, wherein the modulating agent inhibits claudin-mediated cell adhesion, and wherein the step of contacting is performed under conditions and for a time sufficient to allow passage of the drug across the epithelial cells.  
      The present invention further provides methods for enhancing the delivery of a drug to a tumor in a mammal, comprising administering to a mammal a cell adhesion modulating agent as provided above and a drug, wherein the modulating agent inhibits claudin-mediated cell adhesion.  
      Within further aspects, the present invention provides methods for treating cancer in a mammal, comprising administering to a mammal a cell adhesion modulating agent as provided above, wherein the modulating agent inhibits claudin-mediated cell adhesion.  
      The present invention further provides methods for inhibiting angiogenesis in a mammal, comprising administering to a mammal a cell adhesion modulating agent as provided above, wherein the modulating agent inhibits claudin mediated cell adhesion.  
      Within further aspects, the present invention provides methods for enhancing drug delivery to the central nervous system of a mammal, comprising administering to a mammal a cell adhesion modulating agent as provided above, wherein the modulating agent inhibits claudin-mediated cell adhesion.  
      The present invention further provides methods for enhancing wound healing in a mammal, comprising contacting a wound in a mammal with a cell adhesion modulating agent as provided above, wherein the modulating agent enhances claudin mediated cell adhesion.  
      Within a related aspect, the present invention provides methods for enhancing adhesion of foreign tissue implanted within a mammal, comprising contacting a site of implantation of foreign tissue in a mammal with a cell adhesion modulating agent as provided above, wherein the modulating agent enhances claudin mediated cell adhesion.  
      The present invention further provides methods for inducing apoptosis in a claudin-expressing cell, comprising contacting a claudin-expressing cell with a cell adhesion modulating agent as provided above, wherein the modulating agent inhibits claudin-mediated cell adhesion.  
      The present invention further provides methods for identifying an agent capable of modulating claudin-mediated cell adhesion. One such method comprises the steps of (a) culturing cells that express a claudin in the presence and absence of a candidate agent, under conditions and for a time sufficient to allow cell adhesion; and (b) visually evaluating the extent of cell adhesion among the cells.  
      Within another embodiment, such methods may comprise the steps of: (a) culturing normal rat kidney cells in the presence and absence of a candidate agent, under conditions and for a time sufficient to allow cell adhesion; and (b) comparing the level of cell surface claudin and E-cadherin for cells cultured in the presence of candidate agent to the level for cells cultured in the absence of candidate agent.  
      Within a further embodiment, such methods may comprise the steps of: (a) culturing human aortic endothelial cells in the presence and absence of a candidate agent, under conditions and for a time sufficient to allow cell adhesion; and (b) comparing the level of cell surface claudin and N-cadherin for cells cultured in the presence of candidate agent to the level for cells cultured in the absence of candidate agent.  
      Within yet another embodiment, such methods comprise the steps of: (a) contacting an antibody that binds to a modulating agent comprising a claudin CAR sequence with a test compound; and (b) detecting the level of antibody that binds to the test compound.  
      The present invention further provides methods for detecting the presence of claudin-expressing cells in a sample, comprising: (a) contacting a sample with an antibody that binds to a claudin comprising a claudin CAR sequence under conditions and for a time sufficient to allow formation of an antibody-claudin complex; and (b) detecting the level of antibody-claudin complex, and there from detecting the presence of claudin-expressing cells in the sample.  
      Within further aspects, the present invention provides kits for detecting the presence of claudin-expressing cells in a sample, comprising: (a) an antibody that binds to a modulating agent comprising a claudin CAR sequence; and (b) a detection reagent.  
      The present invention further provides, within other aspects, kits for enhancing transdermal drug delivery, comprising: (a) a skin patch; and (b) a cell adhesion modulating agent, wherein the modulating agent comprises a claudin CAR sequence, and wherein the modulating agent inhibits claudin-mediated cell adhesion.  
      A detailed description of the above methods are described in PCT application WO 00/26360 (Blaschuck, O. W., et al.), incorporated herein in its entirety.  
      Further included in the present invention are methods of treating  Clostridium perfringens  or  Clostridium difficile  or  Clostridium botulinum  infections by targeting the enterotoxin, preferably  Clostridium perfringens  enterotoxin.  Clostridium enterotoxin  (CE) binds to Claudin-50. Purified Claudin-50 polypeptides can be used to absorb CE to prevent CE&#39;s cytotoxic effects on cells. Preferred CE binding Claudin-50 polypeptides include the full length and mature Claudin-50 polypeptide and fragments comprising the extracellular domains, amino acid residues 29 to 81 and 103 to 116. Further preferred CE binding Claudin-50 polypeptides include the extracellular domain 29 to 81 and fragments comprising the CAR sequence. CE binding Claudin-50 polypeptides may further be recombinantly fused or chemically coupled (covalently or non-covalently) to a heterologous polypeptide, molecule, or support. Means of administering CE binding Claudin-50 polypeptide compositions are those well known for administering biologically active polypeptides. Preferably, CE binding Claudin-50 polypeptide compositions are administered in at least equamolar concentration compared with CE. More preferably, CE binding Claudin-50 polypeptide compositions are administered in at least a 10 to 100 fold molar excess concentration compared with CE.  
      The above CE binding Claudin-50 polypeptides are also useful for affinity purification CE. For example, CE binding Claudin-50 polypeptides can be fixed or coupled to a solid support in a column and used to bind CE in a biological sample. CE can be released from the column for example, by using a salt gradient.  
      CE binding Claudin-50 polypeptide compositions are also useful in detecting and diagnosing  Clostridium perfringens  infection. The presence of CE indicates  Clostridium perfringens  infection. The level of CE is proportional to the level or degree of the disease or infection. Moreover, the degree of cellular disruption at tight junctions is also proportional to the level of CE. CE binding Claudin-50 polypeptides will preferentially bind endogenous claudins at the sites of tight junction disruptions. CE binding Claudin-50 polypeptides can therefore be used to detect or diagnose  Clostridium perfringens  infection by either binding CE or by binding sites of tight junction disruption. Biological samples including fluids and tissue samples can be assayed using methods well known in the art.  Clostridium perfringens  infections can further be localized in vivo using CE binding Claudin-50 polypeptides in in vivo imaging.  
      Protein of SEQ ID NO: 703  
      The protein of SEQ ID NO: 703 encoded by the extended cDNA SEQ ID NO: 61 and expressed in lymphocytes exhibits an extensive homology to a stretch of 91 amino acid of a human secreted protein expressed in peripheral blood mononucleocytes (Genpep accession number W36955 and Genseq accession number V00433). The amino acid residues are identical except for the substitution of asparagine to isoleucine at positions 94, and the conservative substitutions at positions 108, 109 and 110 of the 110 amino acids long matched protein.  
      Protein of SEQ ID NO: 704  
      The protein of SEQ ID NO: 704 encoded by the extended cDNA SEQ ID NO: 62 exhibits extensive homologies to stretches of proteins encoding vacuolar proton-ATPase subunits 9.2 of either human (Genbank accession number Y15286) or bovine species (Genbank accession umber Y15285). These two highly conserved proteins are extremely hydrophobic membrane roteins with two membrane-spanning helices and a potential metal-binding domain conserved in mammalian protein homologues (Ludwig et al., J. Biol. Chem., 273:10939-10947 (1998)). The amino acid residues are completely identical, the protein of SEQ ID NO: 704 is missing amino acids 1 to 92 from the Genbank sequences. The protein of SEQ ID NO: 704 contains the second putative transmembrane domain as well as the potential metal-binding site.  
      Taken together, these data suggest that the protein of SEQ ID NO: 704 may play a role in energy conservation, secondary active transport, acidification of intracellular compartments and/or cellular pH homeostasis. Preferred fragments of SEQ ID NO: 704 and the corresponding mature polypeptide encoded by the human cDNA of the deposited clone are those with inositol ATPase activity. Further preferred are fragments with not less then 100 fold less activity, not less than 10 fold activity, and not less than 5 fold activity when compared to mature protein.  
      Protein of SEQ ID NO: 705  
      The protein of SEQ ID NO: 705 encoded by the extended cDNA SEQ ID NO: 63 shows homology to short stretches of Drosophila,  C. elegans  and chloroplast proteins similar to  E. coli  ribosomal protein L16.  
      Taken together, these data suggest that the protein of SEQ ID NO: 705 may be a ribosomal protein.  
      Protein of SEQ ID NO: 706  
      The protein of SEQ ID NO: 706, encoded by the cDNA of SEQ ID NO:64, is a chemokine. The protein can be used to attract and activate monocytes and lymphocytes, especially to a site of infection or tumor. The protein can also be used in in vivo imaging to identify/locate/diagnose sites of infection or tumors. Preferred fragments of SEQ ID NO: 706 and the corresponding mature polypeptide encoded by the human cDNA of the deposited clone are those with the above activities. Further preferred are fragments with not less then 100 fold less activity, not less than 10 fold activity, and not less than 5 fold activity when compared to mature protein.  
      Protein of SEQ ID NO: 709  
      The protein of SEQ ID NO: 709, encoded by the extended cDNA SEQ ID NO: 67, is human Connexin 31.1. Connexins are a family of integral membrane proteins that oligomerize into clusters of intercellular channels called gap junctions, which join cells in virtually all metazoans. These channels permit exchange of ions between neurons and between neurons and excitable cells such as myocardiocytes (for review, see Goodenough et al., Ann. Rev. Biochem., 65:475-502 (1996)).  
      Human connexin 31.1 is expressed only in the skin, with Connexin 31.1 mRNA being 15-30 times more abundant in mature skin than in fetal skin. Within the skin layers, human Connexin 31.1 expression is localized to the keratinocyte layer. Human Connexin 31.1. is therefore useful as a marker for skin, particularly the keratinocyte layer, as well as keratinocytes, using either human Connexin 31.1 polynucleotides or antibodies made to human Connexin 31.1 polypeptides. Moreover, human Connexin 31.1 is useful as a marker for skin tumors because, whereas hyperplasia express Connexin 31.1, skin tumors at all stages do not. Hence, Connexin 31.1 polynucleotides and polupeptides are useful for differentiating between a skin hyperplasia and a tumor.  
      Human Connexin 31.1 is also useful in the methods for treating cancer, perferrably skin tumors, more preferably skin tumors involving keratinocytes. Preferred methods of using Human Connexin 31.1 for treating cancer includes the methods described in PCT application WO 97/28179 (Fick, J. R. et al.) incorporated herein in its entirety. Preferred fragments of SEQ ID NO: 709 and the corresponding mature polypeptide encoded by the human cDNA of the deposited clone are those with useful in the above methods, e.g., antigenic fragments and those fragments which form gap junctions.  
      Protein of SEQ ID NO: 710  
      The protein of SEQ ID NO: 710 encoded by the extended cDNA SEQ ID NO: 68 shows homologies with different DNA or RNA binding proteins such as the human Staf50 transcription factor (Genbank accession number X82200), the human Ro/SS-A ribonucleoprotein autoantigen (Swissprot accession number P19474) or the murine RPT1 transcription factor (Swissprot accession number P15533). The protein of SEQ ID NO: 710 exhibits a putative signal peptide and also a PROSITE signature for a RING type zinc finger domain located from positions 15 to 59. Secreted proteins may have nucleic acid binding domain as shown by a nematode protein thought to regulate gene expression which exhibits zinc fingers as well as a functional signal peptide (Holst and Zipfel, J. Biol. Chem., 271:16275-16733 (1996)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 710 may play a role in protein-protein interaction in intracellular signaling and eventually may directly or indirectly bind to DNA and/or RNA, hence regulating gene expression.  
      Protein of SEQ ID NO: 712  
      The protein of SEQ ID NO: 712 encoded by the extended cDNA SEQ ID NO: 70 exhibits extensive homologies to proteins encoding RING zinc finger proteins of the human, chicken and rodent species, as well as an EGF-like domain. Two stretches of 341 and of 13 amino acids of the human RING zinc finger protein which might bind DNA (Genbank accession number AF037204). The amino acid residues are identical except for conservative substitutions at positions 18, 29, 156 and 282 of the 381 amino acid long human RING zinc finger. Such RING zinc finger proteins are thought to be involved in protein-protein interaction and are especially found in nucleic acid binding proteins. Secreted proteins may have nucleic acid binding domain as shown by a nematode protein thought to regulate gene expression which exhibits zinc fingers as well as a functional signal peptide (Holst and Zipfel, J. Biol. Chem., 271:16275-16733 (1996)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 712 may play a role in protein-protein interaction or be a nucleic acid binding protein.  
      Proteins of SEQ ID NOs: 713 and 739  
      The proteins of SEQ ID NOs: 713 and 739 encoded by the extended cDNA SEQ ID NOs: 70 and 96, respectively, belong to the stomatin or band 7 family. The human stomatin is an integral membrane phosphoprotein thought to be involved to regulate the cation conductance by interacting with other proteins of the junctional complex of the membrane skeleton (Gallagher and Forget, J. Biol. Chem., 270:26358-26363 (1995)). The proteins of SEQ ID NOs: 713 and 739 exhibit the PROSITE signature typical for the band 7 family signature.  
      The proteins of SEQ ID NOs: 713 and 739 play a role in the regulation of ion transport, hence in the control of cellular volume. These proteins are useful in diagnosing and/or treating stomatocytosis and/or cryohydrocytosis by detecting a decreased level or absence of the proteins or alternatively by detecting a mutation or deletion affecting tertiary structure of the proteins.  
      Protein of SEQ ID NO: 725 and 740  
      The proteins of SEQ ID NO: 213 and 229, encoded by the cDNA of SEQ ID NO: 83 and 98, respectively, is human Glia Maturation Factor-gamma 2 (GMF-gamma 2). SEQ ID NO: 740 differs from SEQ ID NO: 725 in that SEQ ID NO: 740 has additional amino acids at the N-terminus. The following description applies equally to both SEQ ID NO: 725 and 740. A preferred use of GMF-gamma 2 is to stimulate neurite outgrowth or neurite re-sprouting. These methods include both in vitro and in vivo uses, but preferred uses are those for treating neural injuries and cancer as disclosed in WO9739133 and WO9632959, incorporated herein in their entireties.  
      GMF-gamma 2 may also be used as a neurotrophic and as a neuroprotective agent against toxic insults, such as ethonal and other neurotoxic agents. GMF-gamma2 may be used as a neurotrophic or neuroprotective agent either in vitro or in vivo. A preferred target of GMF-gamma 2 as a neurotrophic or neuroprotective agent are primary neurons.  
      GMF-gamma 2 may further be used to stimulate the expression and secretion of NGF and BDNF in glial cells both in vitro and in vivo. Conditioned media from cells treated with GMF-gamma 2 is useful as a source of NGF and BDNF. GMF-gamma 2 may further be used to target cells directly or by recombinantly fusing GMF-gamma 2 to a heterologous protein, such as a ligand or antibody specific to the target cell (e.g., glial cells). Alternatively, GMF-gamma 2 may be fused or covalently or non-covalently coupled to a heterologous protein or other biological or non-biological molecule wherein the heterologous protein or molecule is used as this targeting reagent.  
      Preferred fragments of SEQ ID NOs: 725 and 740 and the corresponding polypeptide encoded by the human cDNAs of the deposited clones are those with the above activities. Further preferred are fragments with not less then 100 fold less activity, not less than 10 fold activity, and not less than 5 fold activity when compared to the protein of SEQ ID NO: 740 or the protein encoded by the corresponding human cDNA of the deposited clone.  
      Protein of SEQ ID NO: 726:  
      The protein of SEQ ID NO: 726 encoded by the extended cDNA SEQ ID NO: 84 isolated from brain shows extensive homology to a human SH3 binding domain glutamic acid-rich like protein or SH3BGRL (Egeo et al, Biochem. Biophys. Res. Commun., 247:302-306 (1998)) with Genbank accession number is AF042081. The amino acid residues are identical to SH3BGRL except for positions 63 and 101 in the 114 amino acid long matched sequence. This SH3BRGL protein is itself homologous to the middle proline-rich region of a protein containing an SH3 binding domain, the SH3BGR protein (Scartezzini et al., Hum. Genet., 99:387-392 (1997)). This proline-rich region is also highly conserved in mice. Both SH3BGR and SH3BGRL proteins are thought to be involved in the Down syndrome pathogenesis. The protein SEQ ID NO: 726 also contains the proline-rich SH3 binding domain (bold) and a potential RGD cell attachment sequence (underlined).  
      SH3 domains are small important functional modules found in several proteins from all eukaryotic organisms that are involved in a whole range of regulation of protein-protein interaction, e.g. in regulating enzymatic activities, recruiting specific substrates to the enzyme in signal transduction pathways, in interacting with viral proteins and they are also thought to play a role in determining the localization of proteins to the plasma membrane or the cytoskeleton (for a review, see Cohen et al, Cell, 80:237-248 (1995)).  
      The Arg-Gly-Asp (RGD) attachment site promote cell adhesion of a large number of adhesive extracellular matrix, blood and cell surface proteins to their integrin receptors which have been shown to regulate cell migration, growth, differentiation and apoptosis. This cell adhesion activity is also maintained in short RGD containing synthetic peptides which were shown to exhibit anti-thrombolytic and anti-metastatic activities and to inhibit bone degradation in vivo (for review, see Ruoslahti, Annu. Rev. Cell Dev. Biol., 12:697-715 (1996)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 726 may be important in regulating protein-protein interaction in signal transduction pathways, and/or may play a role of localization of proteins to the plasma membrane or cytoskeleton, and/or may play a role in cell adhesion. Moreover, this protein or part therein, especially peptides containing the RGD motif, may be useful in diagnosing and treating cancer, thrombosis, osteoporosis and/or in diagnosing and treating disorders associated with the Down syndrome.  
      Protein of SEQ ID NO: 728  
      The protein of SEQ ID NO: 728 found in testis encoded by the extended cDNA SEQ ID NO: 86 shows homologies to protein domains with a 4-disulfide core signature found in either an extracellular proteinase inhibitor named chelonianin (Swissprot accession number P00993) or in rabbit and human proteins specifically expressed in epididymes (Genbank accession numbers U26725 and R13329). The matched domain in red sea turtle chelonianin is known to inhibit subtilisin, a serine protease (Kato and Tominaga, Fed. Proc., 38:832 (1979)). All cysteines of the 4 disulfide core signature thought to be crucial for biological activity are present in the protein of SEQ ID NO: 728. The 4 disulfide core signature is present except for a conservative substitution of asparagine to glutamine.  
      Taken together, these data suggest that the protein of SEQ ID NO: 728 may play a role in protein-protein interaction, act as a protease inhibitor and/or may also be related to male fertility.  
      Protein of SEQ ID NO: 735  
      The protein of SEQ ID NO: 735 encoded by the extended cDNA SEQ ID NO: 93 shows homology to short stretches of a human protein called Tspan-1 (Genbank accession number AF054838) which belongs to the 4 transmembrane superfamily of molecular facilitators called tetraspanin (Meakers et al., FASEB J., 11:428-442 (1997)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 735 may play a role in cell activation and proliferation, and/or adhesion and motility and/or differentiation and cancer.  
      Protein of SEQ ID NO: 532  
      The protein of SEQ ID NO: 532 encoded by the extended cDNA SEQ ID NO: 175 isolated from lymphocyte shows complete identity to a human protein TFAR19 that may play a role in apoptosis (Genbank accession number AF014955) as shown by the alignment in  FIG. 10 .  
      Taken together, these data suggest that the protein of SEQ ID NO: 532 may be involved in the control of development and homeostasis. Thus, this protein may be useful in diagnosis and/or treating several types of disorders including, but not limited to, cancer, autoimmune disorders, viral infections such as AIDS, neurodegenerative disorders, osteoporosis.  
      Proteins of SEQ ID NOs: 489, 490 and 547  
      The proteins of SEQ ID NOs: 174, 175 and 232 encoded by the extended cDNAs SEQ ID NOs:. 132, 133 and 190 respectively and isolated from lymphocytes shows complete extensive homologies to a human secreted protein (Genseq accession number W36955). As shown by the alignments of  FIG. 11 , the amino acid residues are identical to those of the 110 amino acid long matched protein except for positions 51 and 108-110 of the matched protein for the protein of SEQ ID NOs: 489, for positions 48, 94 and 108-110 of the matched protein of SEQ ID NOs:490 and for positions 94, and 108-110 of the matched protein for the protein of SEQ ID NOs: 547. Proteins of SEQ ID NOs: 489 and 547 may represent alternative forms issued from alternative use of polyadenylation signals.  
      Taken together, these data suggest that the proteins of SEQ ID NOs: 489, 490 and 547 may play a role in cell proliferation and/or differentiation, in immune responses and/or in haematopoeisis. Thus, this protein or part therein, may be useful in diagnosing and treating several disorders including, but not limited to, cancer, immunological, haematological and/or inflammatory disorders. It may also be useful in modulating the immune and inflammatory responses to infectious agents and/or to suppress graft rejection.  
      Proteins of SEQ ID NO: 546  
      The protein of SEQ ID NO: 546 encoded by the extended cDNA SEQ ID NO: 189 shows extensive homology with the human E25 protein (Genbank accession number AF038953). As shown by the alignments in  FIG. 12 , the amino acid residues are identical except for position 159 in the 263 amino acid long matched sequence. The matched protein might be involved in the development and differentiation of haematopoietic stem/progenitor cells. In addition, it is the human homologue of a murine protein thought to be involved in chondro-osteogenic differentiation and belonging to a novel multigene family of integral membrane proteins (Deleersnijder et al,  J. Biol. Chem.,  271: 19475-19482 (1996)).  
      The protein of invention contains two short segments from positions 1 to 21 and from 100 to 120 as predicted by the software TopPred II (Claros and von Heijne, CABIOS applic. Notes, 10: 685-686 (1994)). The first transmembrane domains matches exactly those predicted for the murine E25 protein.  
      Taken together, these data suggest that the protein of SEQ ID NO: 546 may be involved in cellular proliferation and differentiation. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer and embryogenesis disorders.  
      Protein of SEQ ID NO: 511  
      The protein of SEQ ID NO: 511 encoded by the extended cDNA SEQ ID NO: 154 shows extensive homology with the human seventransmembrane protein (Genbank accession number Y11395) and its murine homologue (Genbank accession number Y11550). As shown by the alignments in  FIG. 13 , the amino acid residues are identical except for position 174 in the 399 amino acid long human matched sequence. The matched protein potentially associated to stomatin may act as a G-protein coupled receptor and is likely to be important for the signal transduction in neurons and haematopoietic cells (Mayer et al, Biochem. Biophys. Acta., 1395: 301-308 (1998)).  
      Taken together, these data suggest that the protein of SEQ ID NOs: 511 may be involved in signal transduction. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases cardiovascular disorders, hypertension, renal injury and repair and septic shock.  
      Protein of SEQ ID NO: 473  
      The protein of SEQ ID NOs: 473 encoded by the extended cDNA SEQ ID NO: 116 shows homology with the murine subunit 7a of the COP9 complex (Genbank accession number AF071316). As shown by the alignments in  FIG. 14 , the amino acid residues are identical except for positions 90, 172 and 247 in the 275 amino acid long matched sequence. This complex is highly conserved between mammals and higher plants where it has been shown to act as a repressor of photomorphogenesis All the components of the mammalian COP9 complex contain structural features also present in components of the proteasome regulatory complex and the translation initiation complex eIF3 complex, suggesting that the mammalian COP9 complex is an important cellular regulator modulating multiple signaling pathways (Wei et al,  Curr. Biol.,  8 919-922 (1998)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 473 may be involved in cellular signaling, probably as a subunit of the human COP9 complex. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases, cardiovascular disorders, hypertension, renal injury and repair and septic shock.  
      Protein of SEQ ID NO: 541  
      The protein of SEQ ID NO:541 encoded by the extended cDNA SEQ ID NO: 184 shows homology with the bovine subunit B14.5B of the NADH-ubiquinone oxidureductase complex (Arizmendi et al,  FEBS Lett.,  313: 80-84 (1992) and Swissprot accession-number Q02827, SEQ ID NO: 514). As shown by the alignments in  FIG. 15 , the amino acid residues are identical except for positions 3-4,6-12, 32-34, 47, 53-55, 67 and 69-74 in the 120 amino acid long matched sequence. This complex is the first of four complexes located in the inner mitochondrial membrane and composing the mitochondrial electron transport chain. Complex I is involved in the dehydrogenation of NADH and the transportation of electrons to coenzyme Q. It is composed of 7 subunits encoded by the mitochondrial genome and 34 subunits encoded by the nuclear genome. It is also thought to play a role in the regulation of apoptosis and necrosis. Mitochondriocytopathies due to complex I deficiency are frequently encountered and affect tissues with a high energy demand such as brain (mental retardation, convulsions, movement disorders), heart (cardiomyopathy, conduction disorders), kidney (Fanconi syndrome), skeletal muscle (exercise intolerance, muscle weakness, hypotonia) and/or eye (opthmaloplegia, ptosis, cataract and retinopathy). For a review on complex I see Smeitink et al.,  Hum. Mol. Gent.,  7: 1573-1579 (1998).  
      Taken together, these data suggest that the protein of SEQ ID NO:541 may be part of the mitochondrial energy-generating system, probably as a subunit of the NADH-ubiquinone oxidoreductase complex. Thus, this protein or part therein, may be useful in diagnosing and/or treating several disorders including, but not limited to, brain disorders (mental retardation, convulsions, movement disorders), ‘heart disorders (cardiomyopathy, conduction disorders), kidney disorders (Fanconi syndrome), skeletal muscle disorders (exercise intolerance, muscle weakness, hypotonia) and/or eye disorders opthmalmoplegia, ptosis, cataract and retinopathy).  
      Proteins of SEQ ID NOs: 464, 465 and 526  
      The proteins of SEQ ID NOs: 464, 465 and 526 encoded by the extended cDNAs SEQ ID NOs: 107, 108 and 169 respectively and found in, skeletal muscle shows homologies with T1/ST2 ligand polypeptide of either human (Genbank accession number U41804 and Genseq accession number WO9639) or rodent species (Genbank accession number U41805 and Genseq accession number WO9640). These polypeptides are thought to be cytokines that bind to the ST2 receptor, a member of the immunoglobulin family homologous to the interleukin-1 receptor and present on some lymphoma cells. They are predicted to be cell-surface proteins containing a short transmembrane domain. (Gayle et al,  J. Biol. Chem.,  271: 5784-5789 (1996)). Proteins of SEQ ID NOs: 464, 465 and 526 may represent alternative forms issued from alternative use of polyadenylation signals.  
      The protein of invention contains two short transmembrane segments from positions 5 to 25 and from 195 to 215 as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)). The second transmembrane domain matches exactly those of the matched cell-surface protein.  
      Taken together, these data suggest that the protein of SEQ ID NOs: 464, 465 and 526 may act as a cytokine, thus may play a role in the regulation of cell growth and differentiation and/or in the regulation of the immune response. Thus, this protein or part therein, may be useful in diagnosing and treating several disorders including, but not limited to, cancer, immunological, haematological and/or inflammatory disorders. It may also be useful in modulating the immune and inflammatory responses to infectious agents such as HIV and/or to suppress graft rejection.  
      Protein of SEQ ID NO: 492  
      The protein SEQ ID NO: 492 found in testis encoded by the extended cDNA SEQ ID NO: 135 shows homologies to serine protease inhibitor proteins belonging to the pancreatic trypsin inhibitor family (Kunitz) such as the extracellular proteinase inhibitor named chelonianin (Swissprot accession number P00993). The characteristic PROSITE signature of this family is conserved in the protein of the invention (positions 69 to 87) except for a drastic change of the last cysteine residue into an arginine residue.  
      Taken together, these data suggest that the protein of SEQ ID NO: 492 may be a protease inhibitor, probably of the Kunitz family. Thus, this protein or part therein, may be useful in diagnosing and treating several disorders including but not limited to, cancer and neurodegenerative disorders such as Alzheimer&#39;s disease.  
      Protein of SEQ ID NO: 461  
      The protein SEQ ID NO: 461 encoded by the extended cDNA SEQ ID NO: 104 shows homology to human apolipoprotein L (Genbank accession number AF019225). The matched protein is a secreted high density lipoprotein associated with apoA-1-containing lipoproteins which play a key role in reverse cholesterol transport.  
      Taken together, these data suggest that the protein of SEQ ID NO. 461 may play a role in lipid metabolism. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, hyperlipidemia, hypercholesterolemia, atherosclerosis, cardiovascular disorders such as, coronary heart disease, and neurodegenerative disorders such as Alzheimer&#39;s disease or dementia.  
      Protein of SEQ ID NO: 478  
      The protein SEQ ID NO: 478 encoded by the extended cDNA SEQ ID NO: 121 shows homology to the yeast autophagocytosis protein AUT1 (SwissProt accession number P40344). The matched protein is required for starvation-induced non-specific bulk transport of cytoplasmic proteins to the vacuole.  
      Taken together, these data suggest that the protein of SEQ ID NO: 478 may play a role in protein transport. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, autoimmune disorders and immune disorders due to dysfunction of antigen presentation.  
      Protein of SEQ ID NO: 529  
      The protein of SEQ ID NO: 529 encoded by the extended cDNA SEQ ID NO: 172 and expressed in adult brain shows extensive homology to part of the murine SHYC protein (Genbank accession number AF072697) which is expressed in the developing and embryonic nervous system as well as along the olfactory pathway in adult brains (Koster et al.,  Neuroscience Letters.,  252: 69-71 (1998)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 529 may play a role in nervous system development and function. Thus, this protein may be useful in diagnosing and/or treating cancer and/or brain disorders, including neurodegenerative disorders such as Alzheimer&#39;s and Parkinson&#39;s diseases.  
      Protein of SEQ ID NO: 540  
      The protein of SEQ ID NO: 540 encoded by the extended cDNA SEQ ID NO: 183 and expressed in adult prostate belong to the phosphatidylethanolainin-binding protein from which it exhibits the characteristic PROSITE signature from positions 90 to 112 (see table VIII). Proteins from this widespread family, from nematodes to fly, yeast, rodent and primate species, bind hydrophobic ligands such as phospholipids and nucleotides. They are mostly expressed in brain and in testis and are thought to play a role in cell growth and/or maturation, in regulation of the sperm maturation, motility and ‘in membrane remodeling. They may act either through signal transduction or through oxidoreduction reactions (for a review see Schoentgen and Jollès,  FEBS Letters,  369: 22-26 (1995)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 540 may play a role in cell. Thus, these growth, maturation and in membrane remodeling and/or may be related to male fertility. Thus, this protein may be useful in diagnosing and/or treating cancer, neurodegenerative diseases, and/of, disorders related to male fertility and sterility.  
      Protein of SEQ ID NO: 468  
      The protein of SEQ ID NO: 468 encoded by the extended cDNA SEQ ID NO. 111 and expressed in brain exhibits homology to different integral membrane proteins. These membrane proteins include the nematode protein SRE-2 (Swissprot accession number Q09273) that belongs to the multigene SRE family of  C. elegans  receptor-like proteins and a family of tricarboxylate carriers conserved between flies and mammals. One member of this matched family is the rat tricarboxylate carrier (Genbank accession number S70011), an anion transporter localized in the inner membrane of mitochondria and involved in the biosynthesis of fatty acids and cholesterol. The protein of the invention contains a short transmembrane segments from positions 5 to 25 as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 468 may play a role in signal transduction and/or in molecule transport. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases, immune disorders, cardiovascular disorders, hypertension, renal injury and repair and septic shock.  
      Protein of SEQ ID NO: 528  
      The protein of SEQ ID NO: 528 encoded by the extended cDNA SEQ ID NO: 171 and expressed in brain exhibits homology with part of the tRNA pseudouridine 55 synthase found in  Escherichia Coli  (Swissprot accession number P09171). This bacterial protein belongs to the NAP57/CBF5/TRUB family of nuclieolar proteins found in bacteria, yeasts and mammals involved in rRNA or tRNA biosynthesis, ribosomal subunit assembly and/or centromere/mircotubule binding.  
      Taken together, these data suggest that the protein of SEQ ID NO:528 may play a role in rRNA or tRNA biogensis and function. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, hearing loss or disorders linked to chromosomal instability such as dyskeratosis.  
      Protein of SEQ ID NO: 555  
      The protein of SEQ ID NO: 555 encoded by the extended cDNA SEQ ID NO: 198 and expressed in brain exhibits homology with a family of eukaryotic cell surface antigens containing 4 transmembrane domains. The PROSITE signature for this family is conserved in the protein of the invention except for a substitution of an alanine residue in place of any of the following hydrophic residues: leucine, valine, isoleucine or methionine (positions 21 to 36).  
      The protein of the invention contains three short transmembrane segments from positions 6 to 26, 32 to 52 and from 56 to 76 as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10: 685-686 (1994)). These transmembrane domains match the last three transmembrane domains of the matched protein family.  
      Taken together, these data suggest that the protein of SEQ ID NO: 555 may play a role in immunological and/or inflammatory responses, probably as a cell surface antigen. Thus, this protein or part therein, may be useful in diagnosing and treating several disorders including, but not limited to, cancer, immunological, haematological and/or inflammatory disorders. It may also be useful in modulating the immune and inflammatory responses to infectious agents and/or to suppress graft rejection.  
      Protein of SEQ ID NO: 554  
      The protein of SEQ ID NO: 554 encoded by the extended cDNA SEQ ID NO: 197 exhibits homology with a conserved region in a family of NA+/H+ exchanger conserved in yeast, nematode and mammals. These cation/proton exchangers are integral membrane proteins with 5 transmembrane segments involved in intracellular pH regulation, maintenance of cell volume, reabsorption of sodium across specialized epithelia, vectorial transport and are also thought to play a role in signal transduction and especially in the induction of cell proliferation and in the induction of apoptosis.  
      The protein of invention contains four short transmembrane segments from positions 21 to 41, 48 to 68 and from 131 to 151 as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10: 685-686 (1994)). The third and fourth transmembrane domains match the fourth and fifth transmembrane segments of the matched family of proteins.  
      Taken together, these data suggest that the protein of SEQ ID NO: 554 may play a role in membrane permeability and/or in signal transduction. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases, cardiovascular disorders, hypertension, renal injury and repair, septic shock as well as disorders of membrane permeability such as diarrhea.  
      Protein of SEQ ID NO: 515  
      The protein of SEQ ID NO:515 encoded by the extended cDNA SEQ ID NO: 158 and expressed in brain exhibits extensive homology to the N-terminus of cell division cycle protein 23 (Genbank accession number AF053977) and also to a lesser extent to its homologue in  Saccharomyces cerevisiae . The matched protein is required for chromosome segregation and is part of the anaphae-promoting complex necessary for cell cycle progression to mitosis.  
      Taken together, these data suggest that the protein of SEQ ID NO: 515 may play a role in cellular mitosis. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer and leukemia.  
      Protein of SEQ ID NO: 545  
      The protein of SEQ ID NO: 545 encoded by the extended cDNA SEQ ID NO: 188 exhibits extensive homology to the C-terminus of the eta subunit of T-complex polypeptide 1 conserved from yeasts to mammals, and even complete identity with the last 54 amino acid residues of the human protein (Genbank accession number AF026292). The matched protein is a chaperonin which assists the folding of actins and tubulins in eukaryotic cells upon ATP hydrolysis.  
      Taken together, these data suggest that the protein of SEQ ID NO:545 may play a role in the folding, transport, assembly and degradation of proteins. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, cardiovascular disorders, immune disorders, neurodegenerative disorders, osteoporosis and arthritis.  
      Protein of SEQ ID NO: 482  
      The protein of SEQ ID NO: 482 encoded by the extended cDNA SEQ ID NO: 125 exhibits homology to a monkey pepsinogen A-4 precursor (Swissprot accession number P27678) and to related members of the aspartyl protease family. The matched protein belongs to a family of widely distributed proteolytic enzymes known to exist in vertebrate, fungi, plants, retroviruses and some plant viruses.  
      Taken together, these data suggest that the protein of SEQ ID NO: 482 may play a role in the degradation of proteins. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, autoimmune disorders and immune disorders due to dysfunction of antigen presentation.  
      Protein of SEQ ID NO: 494  
      The protein of SEQ ID NO: 494 encoded by the extended cDNA SEQ ID NO: 137 found in testis exhibits homology to part of mammalian colipase precursors. Colipases are secreted cofactors for pancreatic lipases that allow the lipase to anchor at the water-lipid interface. Colipase plays a crucial role in the intestinal digestion and absorption of dietary fats. The 5 cysteines characteristic for this protein family are conserved in the protein of the invention although the colipase PROSITE signature is not.  
      Taken together, these data suggest that the protein of SEQ ID NO: 494 may play a role in the lipid metabolism and/or in male fertility. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, hyperlipidemia, hypercholesterolemia, atherosclerosis, cardiovascular disorders such as coronary heart disease, and neurodegenerative disorders such as Alzheimer&#39;s disease or dementia, and disorders linked to male fertility.  
      Protein of SEQ ID NO: 542  
      The protein of SEQ ID NO: 542 encoded by the extended cDNA SEQ ID NO: 185 exhibits extensive homology to the ATP binding region of a whole family of serine/threonine protein kinases belonging to the CDC2/CDC28 subfamily. The PROSITE signature characteristic for this domain is present in the protein of the invention from positions 10 to 34.  
      Taken together, these data suggest that the protein of SEQ ID NO: 542 may bind ATP, and even be a protein kinase. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases, cardiovascular disorders, hypertension, renal injury and repair and septic shock.  
      Protein of SEQ ID NO: 776 (Internal Designation 26-44-1-B5-CL31)  
      The protein of SEQ ID NO: 776 encoded by the extended cDNA SEQ ID NO: 371 isolated from ovary shows extensive homology to a human protein called phospholemman or PLM and its homologues in rodent and canine species. PLM is encoded by the nucleic acid sequence of Genbank accession number U72245. Phospholemman is a prominent plasma membrane protein whose phosphorylation correlates with an increase in contractility of myocardium and skeletal muscle. Initially described as a simple chloride channel, it has recently been shown to be a channel for taurine that acts as an osmolyte in the regulation of cell volume (Moorman et al,  Adv Exp. Med. Biol.,  442:219-228 (1998)).  
      As shown by the alignment in  FIG. 10  between tha protein of SEQ ID NO:776 and PLM, the amino acid residues are identical except for positions 3 and 5 in the 92 amino acid long matched protein. The substitution of a proline residue at position 3 par another neutral residue, serine, is conservative. In addition, the protein of the invention also exhibits the typical ATP1G/PLM/MAT8 PROSITE signature (position 27 to 40 in bold in  FIG. 10 ) for a family containing mostly proteins known to be either chloride channels or chloride channel regulators In addition, the protein of invention contains 2 short transmembrane segments from positions 1 to 21 and from 37 to 57 as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)). The first segment (in italic) corresponds to the signal peptide of PLM and the second transmembrane domains (underlined) matches the transmembrane region (double-underlined) shown to be the chloride channel itself (Chen et al.,  Circ. Res.,  82:367-374 (1998)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 776 may be involved in the regulation of cell volume and in tissue contractility. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, diarrhea, fertility disorders, and in contractility disorders including muscle disorders, pulmonary disorders and myocardial disorders.  
      Proteins of SEQ ID NOs: 777 (Internal Designation 47-4-4-C6-CL23)  
      The protein of SEQ ID NO: 777 encoded by the extended cDNA SEQ ID NO: 372 found in substantia nigra shows extensive homology with the human E25 protein. The E25 protein 35 is encoded by the nucleic acid sequence of Genbank accession number AF038953. The matched protein might be involved in the development and differentiation of haematopoietic stem/progenitor cells. In addition, it is the human homologue of a murine protein thought to be involved in chondro-osteogenic differentiation and belonging to a novel multigene family of integral membrane proteins (Deleersnijder et al,  J. Biol. Chem.,  271:19475-19482 (1996)).  
      As shown by the alignments in  FIG. 11  between the protein of SEQ ID NO:777 and E25, the amino acid residues are identical except for positions 9, 24 and 121 in the 263 amino acid long matched sequence. All these substitutions are conservative. In addition, the protein of invention contains one short transmembrane segment from positions 1 to 21 (underlined in  FIG. 11 ) matching the one predicted for the murine E25 protein as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)).  
      Taken together, these data suggest that the protein of SEQ ID NO:777 may be involved in cellular proliferation and differentiation, and/or in haematopoiesis. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, hematological, chondro-osteogenic and embryogenetic disorders.  
      Proteins of SEQ ID NO: 784 (internal designation 58-34-2-H8-CL1 — 3)  
      The protein of SEQ ID NO: 784 encoded by the extended cDNA SEQ ID NO: 379 isolated from kidney shows extensive homology to the murine WW-domain binding protein 1 or WWBP-1. WWBP-1 is encoded by the nucleic acid sequence of Genbank accession number U40825. This protein is expressed in placenta, lung, liver and kidney is thought to play a role in intracellular signaling by binding to the WW domain of the Yes protooncogene-associated protein via its so-called PY domain (Chen and Sudol,  Proc. Natl. Acad. Sci.,  92:7819-7823 (1995)). The WW—PY domains are thought to represent a new set of modular protein-binding sequences just like the SH3—PXXP domains (Sudol et al.,  FEBS Lett.,  369:67-71 (1995)).  
      As shown by the alignments of  FIG. 12  between the protein of SEQ ID NO:784 and WWBP-1, the amino acid residues are identical to those of the 305 amino acid long matched protein except for positions 53, 66, 78, 89, 92, 94, 96, 100, 102, 106, 110, 113, 124, 128, 136, 139, 140, 142-144, 166, 168, 173, 176, 178, 181, 182, 188, 196, 199, 201, 202, 207 and 210 of the matched protein. 68% of these substitutions are conservative. Indeed the histidine-rich PY domain is present in the protein of the invention (positions 82-86 in bold in  FIG. 12 ).  
      Taken together, these data suggest that the protein of SEQ ID NO: 784 may play a role in intracellular signaling. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases, cardiovascular disorders, hypertension, renal injury and repair and septic shock.  
      Protein of SEQ ID NO: 753 (Internal Designation 108-004-5-0-G6-FL)  
      The protein SEQ ID NO: 753 found in liver encoded by the extended cDNA SEQ ID NO:348 shows homology to a lectin-like oxidized LDL receptor (LOX-1) found in human, bovine and murine species. Such type II proteins with a C-lectin-like domain, expressed in vascular endothelium and vascular-rich organs, bind and internalize oxidatively modified low-density lipoproteins (Sawamura et al,  Nature,  386:73-77, (1997)). The oxidized lipoproteins have been implicated in the pathogenesis of atherosclerosis, a leading cause of death in industrialized countries (see review by Parthasarathy et al,  Biochem. Pharmacol.  56:279-284 (1998)). In addition, type II membrane proteins with a C-terminus C-type lectin domain, also known as carbohydrate-recognition domains, also include proteins involved in target-cell recognition and cell activation.  
      The protein of invention has the typical structure of a type II protein belonging to the C-type lectin family. Indeed, it contains a short 31-amino-acid-long N-terminal tail, a transmembrane segment from positions 32 to 52 matching the one predicted for human LOX-I and a large 177-amino-acid-long C-terminal tail as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)). All six cysteines of LOX-1 C-type lectin domain are also conserved in the protein of the invention (positions 102, 113, 130, 195, 208 and 216) although the characteristic PROSITE signature of this family is not. The LOX-1 protein is encoded by the nucleic acid sequence of Genbank accession number: AB010710.  
      Taken together, these data suggest that the protein of SEQ ID NO:753 may be involved in the metabolism of lipids and/or in cell-cell or cell-matrix interactions and/or in cell activation. Thus, this protein or part therein, may be useful in diagnosing and treating several disorders including, but not limited to, cancer, hyperlipidaemia, cardiovascular disorders and neurodegenerative disorders.  
      Protein of SEQ ID NO: 767 (Internal Designation 108-008-5-O-G12-FL)  
      The protein SEQ ID NO: 767 encoded by the extended cDNA SEQ ID NO:362 shows homology to a mitochondrial protein found in  Saccharomyces Cerevisiae  (PIR:S72254) which is similar to  E. Coli  ribosomal protein L36. The typical PROSITE signature for ribosomal L36 is present in the protein of the invention (positions 76-102) except for a substitution of a tryptophane residue instead of a valine, leucine, isoleucine, methionine or asparagine residue.  
      Taken together, these data suggest that the protein of SEQ ID NO:767 may be involved in protein biosynthesis. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer.  
      Protein of SEQ ID NO: 750 (Internal Designation 108-004-5-0-D10-FL)  
      The protein SEQ ID NO: 750 encoded by the extended cDNA SEQ ID NO: 345 shows remote homology to a subfamily of beta4-galactosyltransferases widely conserved in animals (human, rodents, cow and chicken). Such enzymes, usually type II membrane proteins located in the endoplasmic reticulum or in the Golgi apparatus, catalyzes the biosynthesis of glycoproteins, glycolipid glycans and lactose. Their characteristic features defined as those of subfamily A in Breton et al,  J. Biochem.,  123:1000-1009 (1998) are pretty well conserved in the protein of the invention, especially the region I containing the DVD motif (positions 163-165) thought to be involved either in UDP binding or in the catalytic process itself.  
      In addition, the protein of invention has the typical structure of a type II protein. Indeed, it contains a short 28-amino-acid-long N-terminal tail, a transmembrane segment from positions 29 to 49 and a large 278-amino-acid-long C-terminal tail as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 750 may play a role in the biosynthesis of polysaccharides, and of the carbohydrate moieties of glycoproteins and glycolipids and/or in cell-cell recognition. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, atherosclerosis, cardiovascular disorders, autoimmune disorders and rheumatic diseases including rheumatoid arthritis.  
      Protein of SEQ ID NO: 760 (Internal Designation 108-006-5-0-G2-FL)  
      The protein of SEQ ID NO: 760 encoded by the extended cDNA SEQ ID NO: 355 shows homology to a neuronal murine protein NP15.6 whose expression is developmentally regulated. NP15.6 protein is encoded by the nucleic acid sequence of Genbank accession number Y08702.  
      Taken together, these data suggest that the protein of SEQ ID NO: 760 may be involved in cellular proliferation and differentiation. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative disorders and embryogenetic disorders.  
      Protein of SEQ ID NO: 769 (Internal Designation 108-009-5-0-A2-FL)  
      The protein of SEQ ID NO: 769 encoded by the extended cDNA SEQ ID NO: 364 shows extensive homology to the bZIP family of transcription factors, and especially to the human luman protein. (Lu et al.,  Mol. Cell. Biol.,  17:5117-5126 (1997)). The human luman protein is encoded by the nucleic acid sequence of Genbank accession number: AF009368. The match include the whole bZIP domain composed of a basic DNA-binding domain and of a leucine zipper allowing protein dimerization. The basic domain is conserved in the protein of the invention as shown by the characteristic PROSITE signature (positions 224-237) except for a conservative substitution of a glutamic acid with an aspartic acid in position 233. The typical PROSITE signature for leucine zipper is also present (positions 259 to 280). Secreted proteins may have nucleic acid binding domain as shown by a nematode protein thought to regulate gene expression which exhibits zinc fingers as well as a functional signal peptide (Holst and Zipfel,  J. Biol. Chem.,  271:16275-16733, 1996).  
      Taken together, these data suggest that the protein of SEQ ID NO: 113 may bind to DNA, hence regulating gene expression as a transcription factor. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer.  
      Proteins of SEQ ID NO:785 (Internal Designation 76-13-3-A9-CL1 — 1)  
      The protein of SEQ ID NO: 785 encoded by the extended cDNA SEQ ID NO:380 shows homology with part of a human seven transmembrane protein. The human seven transmembrane protein is encoded by the nucleic acid sequence of Genbank accession number Y11395. The matched protein potentially associated to stomatin may act as a G-protein coupled receptor and is likely to be important for the signal transduction in neurons and haematopoietic cells (Mayer et al,  Biochem. Biophys. Acta.,  1395:301-308 (1998)).  
      Taken together, these data suggest that the protein of SEQ ID NO:785 may be involved in signal transduction. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, neurodegenerative diseases, cardiovascular disorders, hypertension, renal injury and repair and septic shock.  
      Proteins of SEQ ID NO: 751 (Internal Designation 108-004-5-0-E8-FL)  
      The protein of SEQ ID NO: 751 encoded by the extended cDNA SEQ ID NO: 346 exhibit the typical PROSITE signature for amino acid permeases (positions 5 to 66) which are integral membrane proteins involved in the transport of amino acids into the cell. In addition, the protein of invention has a transmembrane segment from positions 9 to 29 as predicted by the software TopPred II (Claros and von Heijne,  CABIOS applic. Notes,  10:685-686 (1994)).  
      Taken together, these data suggest that the protein of SEQ ID NO: 751 may be involved in amino acid transport. Thus, this protein may be useful in diagnosing and/or treating several types of disorders including, but not limited to, cancer, aminoacidurias, neurodegenerative diseases, anorexia, chronic fatigue, coronary vascular disease, diphtheria, hypoglycemia, male infertility, muscular and myopathies.  
      As discussed above, the extended cDNAs of the present invention or portions thereof can be used for various purposes. The polynucleotides can be used to express recombinant protein for use for therapeutic use or research (not limited to research on the gene itself); as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on Southern gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; for selecting and making oligomers for attachment to a “gene chip” or other support (e.g., microarrays), including for examination for expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.  
      The proteins or polypeptides provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Where the protein binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.  
      Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.  
      Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include without limitation Molecular Cloning; A Laboratory Manual, 2d ed., Cole Spring Harbor Laboratory Press, Sambrook J., E. F. Fritsch and T. Maniatis eds., (1989), and Methods in Enzymology; Guide to Molecular Cloning Techniques, Academic Press, Berger, S. L. and A. R. Kimmel eds., (1987).  
      Polynucleotides and proteins of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the protein or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the protein or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.  
      Although this invention has been described in terms of certain preferred embodiments, other embodiments which will be apparent to those of ordinary skill in the art in view of the disclosure herein are also within the scope of this invention. Accordingly, the scope of the invention is intended to be defined only by reference to the appended claims. Throughout this application, various publications, patents, and published patent applications are cited.  
      Some of the disclosures of the publications, patents, and published patent specifications referenced in this application may not have been incorporated into the present disclosure at the point of reference. Regardless of this, all of the disclosures of the publications, patents, and published patent specifications referenced in this application are hereby incorporated by reference in their entireties into the present disclosure to more fully describe the state of the art to which this invention pertains.  
      The nucleic acid sequences of SEQ ID NOs: 1-405 or fragments thereof may also be used to construct fusion proteins in which the polypeptide sequences of SEQ ID NOs: 406-810 or fragments thereof are fused to heterologous polypeptides. For example, the fragments of the polypeptides of SEQ ID NOs. 406-810 which are included in the fusion proteins may comprise at least 5, 10, 15, 20, 25, 30, 35, 40, 50, 75, 100, or 150 consecutive amino acids of the polypeptides of SEQ ID NOs.406-810 or may be of any length suitable for the intended purpose of the fusion protein. Nucleic acids encoding the desired fusion protein are produced by cloning a nucleic acid of SEQ ID NOs. 1-405 in frame with a nucleic acid encoding the heterologous polypeptide. The nucleic acid encoding the desired fusion protein is operably linked to a promoter in an appropriate vector, such as any of the vectors described above, and introduced into a host capable of expressing the fusion protein.  
      Antibodies against the polypeptides of SEQ ID NOs. 406-810 or fragments thereof may be used in immunoaffinity chromatography to isolate the polypeptides of SEQ ID NOs. 406-810 or fragments thereof or to isolate fusion proteins containing the polypeptides of SEQ ID NOs. 406-810 or fragments thereof.  
      The invention further relates to methods and compositions using the protein of the invention or part thereof to diagnose, prevent and/or treat several disorders in which the activity of the protein of the invention is deleterious. For diagnostic purposes, the expression of the protein of the invention could be investigated using any of the Northern blotting, RT-PCR or immunoblotting methods described herein and compared to the expression in control individuals. For prevention and/or treatment purposes, inhibiting the endogenous expression of the protein of the invention using any of the antisense or triple helix methods described herein may be used. Alternatively, inhibitors for the protein&#39;s activity may be developed and use to inhibit and/or reduce its activity using any methods known to those skilled in the art.  
      Chromosomal localization of the cDNA of the present invention were also determined using information from public and proprietary databases. Table XI lists the putative chromosomal location of the polynucleotides of the present invention. Column 1 lists the sequence identification number with the corresponding chromosomal location listed in column two.  
      The present invention also relates to methods and compositions using the chromosomal location of the polynucleotides of the invention to construct a human high resolution map or to identify a given chromosome in a sample using any techniques to those skilled in the art including those disclosed in Example 43.  
      Alternatively, the cDNA clone obtained by the process described in Examples 1 through 13 may not include the entire coding sequence of the protein encoded by the corresponding mRNA, although they do include sequences derived from the 5′ends of their corresponding mRNA. Such 5′EST can be used to isolate extended cDNAs which contain sequences adjacent to the 5′ ESTs. Such obtained extended cDNAs may include the entire coding sequence of the protein encoded by the corresponding mRNA, including the authentic translation start site. Examples 16 and 17 below describe methods for obtaining extended cDNAs using 5′ ESTs. Example 17 also describes methods to obtain cDNA, mRNA or genomic DNA homologous to cDNA, 5′ESTs, or fragment thereof.  
      The methods of Examples 16 and 17 can also be used to obtain cDNAs which encode less than the entire coding sequence of proteins encoded by the genes corresponding to the 5′ ESTs. In some embodiments, the cDNAs isolated using these methods encode at least 5, 8, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 150 or 200 consecutive amino acids of one of the proteins encoded by the sequences of SEQ ID NOs. 406-810.  
     EXAMPLE 16  
      General Method for using 5′ ESTs to Clone and Sequence cDNAs which Include the Entire Coding Region and the Authentic 5′End of the Corresponding mRNA  
      The following general method may be used to quickly and efficiently isolate cDNAs including sequence adjacent to the sequences of the 5′ ESTs used to obtain them. This method, ilustrated in  FIG. 3 , may be applied to obtain cDNAs for any 5′ EST.  
      The method takes advantage of the known 5′ sequence of the mRNA. A reverse transcription reaction is conducted on purified mRNA with a poly dT primer containing a nucleotide sequence at its 5′ end allowing the addition of a known sequence at the end of the cDNA which corresponds to the 3′ end of the mRNA. Such a primer and a commercially-available reverse transcriptase enzyme are added to a buffered mRNA sample yielding a reverse transcript anchored at the 3′ polyA site of the RNAs. Nucleotide monomers are then added to complete the first strand synthesis. After removal of the mRNA hybridized to the first cDNA strand by alkaline hydrolysis, the products of the alkaline hydrolysis and the residual poly dT primer can be eliminated with an exclusion column.  
      Subsequently, a pair of nested primers on each end is designed based on the known 5′ sequence from the 5′ EST and the known 3′ end added by the poly dT primer used in the first strand synthesis. Software used to design primers is either based on GC content and melting temperatures of oligonucleotides, such as OSP (Illier and Green,  PCR Meth. Appl.  1:124-128, 1991), or based on the octamer frequency disparity method (Griffais et al.,  Nucleic Acids Res.  19: 3887-3891, 1991) such as PC-Rare (http://bioinformatics.weizmann.ac.il/software/PC-Rare/doc/manuel.html). Preferably, the nested primers at the 5′ end and the nested primers at the 3′ end are separated from one another by four to nine bases. These primer sequences may be selected to have melting temperatures and specificities suitable for use in PCR.  
      A first PCR run is performed using the outer primer from each of the nested pairs. A second PCR run using the inner primer from each of the nested pairs is then performed on a small aliquot of the first PCR product. Thereafter, the primers and remaining nucleotide monomers are removed.  
      Due to the lack of position constraints on the design of 5′ nested primers compatible for PCR use using the OSP software, amplicons of two types are obtained. Preferably, the second 5′ primer is located upstream of the translation initiation codon thus yielding a nested PCR product containing the entire coding sequence. Such a cDNA may be used in a direct cloning procedure such as the one described in example 4.  
      However, in some cases, the second 5′ primer is located downstream of the translation initiation codon, thereby yielding a PCR product containing only part of the ORF. For such amplicons which do not contain the complete coding sequence, intermediate steps are necessary to obtain both the complete coding sequence and a PCR product containing the full coding sequence. The complete coding sequence can be assembled from several partial sequences determined directly from different PCR products. Once the full coding sequence has been completely determined, new primers compatible for PCR use are then designed to obtain amplicons containing the whole coding region. However, in such cases, 3′ primers compatible for PCR use are located inside the 3′ UTR of the corresponding mRNA, thus yielding amplicons which lack part of this region, i.e. the polyA tract and sometimes the polyadenylation signal, as illustrated in  FIG. 3 . Such obtained cDNAs are then cloned into an appropriate vector using a procedure essentially similar to the one described in example 4.  
      Full-length PCR products are then sequenced using a procedure similar to the one described in example 11. Completion of the sequencing of a given cDNA fragment may be assessed by comparing the sequence length to the size of the corresponding nested PCR product. When Northern blot data are available, the size of the mRNA detected for a given PCR product may also be used to finally assess that the sequence is complete. Sequences which do not fulfill these criteria are discarded and will undergo a new isolation procedure.  
      Full-length PCR products are then cloned in an appropriate vector. For example, the cDNAs can be cloned into a vector using a procedure similar to the one described in example 4. Such full-length cDNA clones are then double-sequenced and submitted to computer analyses using procedure essentially similar to the ones described in Examples 11 through 13. However, it will be appreciated that full-length cDNA clones obtained from amplicons lacking part of the 3′UTR may lack polyadenylations sites and signals.  
     EXAMPLE 17  
      25 Methods for Obtaining cDNAs or Nucleic Acids Homologous to cDNAs or Fragments Thereof  
      In addition to PCR based methods for obtaining cDNAs, traditional hybridization based methods may also be employed. These methods may also be used to obtain the genomic DNAs which encode the mRNAs from which the cDNA is derived, mRNAs corresponding to the cDNAs, or nucleic acids which are homologous to cDNAs or fragments thereof. Indeed, cDNAs of the present invention or fragments thereof, including 5′ESTs, may also be used to isolate cDNAs or nucleic acids homologous to cDNAs from a cDNA library or a genomic DNA library as follows. Such cDNA libraries or genomic DNA libraries may be obtained from a commercial source or made using techniques familiar to those skilled in the art such as the one described in Examples 1 through 5. An example of such hybridization-based methods is provided below.  
      Techniques for identifying cDNA clones in a cDNA library which hybridize to a given probe sequence are disclosed in Sambrook et al.,  Molecular Cloning: A Laboratory Manual  2d Ed., Cold Spring Harbor Laboratory Press, 1989, the disclosure of which is incorporated herein by reference. The same techniques may be used to isolate genomic DNAs.  
      Briefly, cDNA or genomic DNA clones which hybridize to the detectable probe are identified and isolated for further manipulation as follows. A probe comprising at least 10 consecutive nucleotides from the cDNA or fragment thereof is labeled with a detectable label such as a radioisotope or a fluorescent molecule. Preferably, the probe comprises at least 12, 15, or 17 consecutive nucleotides from the cDNA or fragment thereof. More preferably, the probe comprises 20 to 30 consecutive nucleotides from the cDNA or fragment thereof. In some embodiments, the probe comprises more than 30 nucleotides from the cDNA or fragment thereof.  
      Techniques for labeling the probe are well known and include phosphorylation with polynucleotide kinase, nick translation, in vitro transcription, and non radioactive techniques. The cDNAs or genomic DNAs in the library are transferred to a nitrocellulose or nylon filter and denatured. After blocking of non specific sites, the filter is incubated with the labeled probe for an amount of time sufficient to allow binding of the probe to cDNAs or genomic DNAs containing a sequence capable of hybridizing thereto.  
      By varying the stringency of the hybridization conditions used to identify cDNAs or genomic DNAs which hybridize to the detectable probe, cDNAs or genomic DNAs having different levels of identity to the probe can be identified and isolated as described below.  
      1. Isolation of cDNA or Genomic DNA Sequences Having a High Degree of Identity to the Labeled Probe  
      To identify cDNAs or genomic DNAs having a high degree of identity to the probe sequence, the melting temperature of the probe may be calculated using the following formulas:  
      For probes between 14 and 70 nucleotides in length the melting temperature (Tm) is calculated using the formula: Tm=81.5+16.6(log (Na+))+0.41(fraction G+C)−(600/N) where N is the length of the probe.  
      If the hybridization is carried out in a solution containing formamide, the melting temperature may be calculated using the equation T=81.5+16.6(log (Na+))+0.41(fraction G+C)−(0.63% formamide)−(600/N) where N is the length of the probe.  
      Prehybridization may be carried out in 6×SSC, 5× Denhardt&#39;s reagent, 0.5% SDS, 100 μg denatured fragmented salmon sperm DNA or 6×SSC, 5× Denhardt&#39;s reagent, 0.5% SDS, 100 μg denatured fragmented salmon sperm DNA, 50% formamide. The formulas for SSC and Denhardt&#39;s solutions are listed in Sambrook et al., supra.  
      Hybridization is conducted by adding the detectable probe to the prehybridization solutions listed above. Where the probe comprises double stranded DNA, it is denatured before addition to the hybridization solution. The filter is contacted with the hybridization solution for a sufficient period of time to allow the probe to hybridize to cDNAs or genomic DNAs containing sequences complementary thereto or homologous thereto. For probes over 200 nucleotides in length, the hybridization may be carried out at 15-25° C. below the Tm. For shorter probes, such as oligonucleotide probes, the hybridization may be conducted at 15-25° C. below the Tm. Preferably, for hybridizations in 6×SSC, the hybridization is conducted at approximately 68° C. Preferably, for hybridizations in 50% formamide containing solutions, the hybridization is conducted at approximately 42° C.  
      All of the foregoing hybridizations would be considered to be under “stringent” conditions.  
      Following hybridization, the filter is washed in 2×SSC, 0.1% SDS at room temperature for 15 minutes. The filter is then washed with 0.1×SSC, 0.5% SDS at room temperature for 30 minutes to 1 hour. Thereafter, the solution is washed at the hybridization temperature in 0.1×SSC, 0.5% SDS. A final wash is conducted in 0.1×SSC at room temperature.  
      cDNAs or genomic DNAs which have hybridized to the probe are identified by autoradiography or other conventional techniques.  
      2. Isolation of cDNA or Genomic DNA Sequences Having Lower Degrees of Identity to the Labeled Probe  
      The above procedure may be modified to identify cDNAs or genomic DNAs having decreasing levels of identity to the probe sequence. For example, to obtain cDNAs or genomic DNAs of decreasing identity to the detectable probe, less stringent conditions may be used. For example, the hybridization temperature may be decreased in increments of 5° C. from 68° C. to 42° C. in a hybridization buffer having a sodium concentration of approximately 1M. Following hybridization, the filter may be washed with 2×SSC, 0.5% SDS at the temperature of hybridization. These conditions are considered to be “moderate” conditions above 50° C. and “low” conditions below 50° C.  
      Alternatively, the hybridization may be carried out in buffers, such as 6×SSC, containing formamide at a temperature of 42° C. In this case, the concentration of formamide in the hybridization buffer may be reduced in 5% increments from 50% to 0% to identify clones having decreasing levels of identity to the probe. Following hybridization, the filter may be washed with 6×SSC, 0.5% SDS at 50° C. These conditions are considered to be “moderate” conditions above 25% formamide and “low” conditions below 25% formamide. cDNAs or genomic DNAs which have hybridized to the probe are identified by autoradiography or other conventional techniques.  
      3. Determination of the Degree of Identity between the Obtained cDNAs or Genomic DNAs and cDNAs or Fragments thereof used as the Labeled Probe or Between the Polypeptides Encoded by the Obtained cDNAs or Genomic DNAs and the Polypeptides Encoded by the cDNAs or Fragment Thereof Used as the Labeled Probe  
      To determine the level of identity between the hybridized cDNA or genomic DNA and the cDNA or fragment thereof from which the probe was derived, the nucleotide sequences of the hybridized nucleic acid and the cDNA or fragment thereof from which the probe was derived are compared. The sequences of the cDNA or fragment thereof from which the probe was derived and the sequences of the cDNA or genomic DNA which hybridized to the detectable probe may be stored on a computer readable medium as described below and compared to one another using any of a variety of algorithms familiar to those skilled in the art such as those described below.  
      To determine the level of identity between the polypeptide encoded by the hybridizing cDNA or genomic DNA and the polypeptide encoded by the cDNA or fragment thereof from which the probe was derived, the polypeptide sequence encoded by the hybridized nucleic acid and the polypeptide sequence encoded by the cDNA or fragment thereof from which the probe was derived are compared. The sequences of the polypeptide encoded by the cDNA or fragment thereof from which the probe was derived and the polypeptide sequence encoded by the cDNA or genomic DNA which hybridized to the detectable probe may be stored on a computer readable medium as described below and compared to one another using any of a variety of algorithms familiar to those skilled in the art such as those described below.  
      Protein and/or nucleic acid sequence homologies may be evaluated using any of the variety of sequence comparison algorithms and programs known in the art. Such algorithms and programs include, but are by no means limited to, TBLASTN, BLASTP, FASTA, TFASTA, and CLUSTALW (Pearson and Lipman, 1988 , Proc. Natl. Acad. Sci. USA  85(8):2444-2448; Altschul et al., 1990 , J. Mol. Biol.  215(3):403-410; Thompson et al., 1994 , Nucleic Acids Res.  22(2):4673-4680; Higgins et al., 1996 , Methods Enzymol.  266:383-402; Altschul et al., 1990 , J. Mol. Biol.  215(3):403-410; Altschul et al., 1993 , Nature Genetics  3:266-272).  
      In a particularly preferred embodiment, protein and nucleic acid sequence homologies are evaluated using the Basic Local Alignment Search Tool (“BLAST”) which is well known in the art (see, e.g., Karlin and Altschul, 1990 , Proc. Natl. Acad. Sci. USA  87:2267-2268; Altschul et al., 1990 , J. Mol. Biol.  215:403-410; Altschul et al., 1993 , Nature Genetics  3:266-272; Altschul et al., 1997 , Nuc. Acids Res.  25:3389-3402). In particular, five specific BLAST programs are used to perform the following task: 
          (1) BLASTP and BLAST3 compare an amino acid query sequence against a protein sequence database;     (2) BLASTN compares a nucleotide query sequence against a nucleotide sequence database;     (3) BLASTX compares the six-frame conceptual translation products of a query nucleotide sequence (both strands) against a protein sequence database;     (4) TBLASTN compares a query protein sequence against a nucleotide sequence database translated in all six reading frames (both strands); and     (5) TBLASTX compares the six-frame translations of a nucleotide query sequence against the six-frame translations of a nucleotide sequence database.        

      The BLAST programs identify homologous sequences by identifying similar segments, which are referred to herein as “high-scoring segment pairs,” between a query amino or nucleic acid sequence and a test sequence which is preferably obtained from a protein or nucleic acid sequence database. High-scoring segment pairs are preferably identified (i.e., aligned) by means of a scoring matrix, many of which are known in the art. Preferably, the scoring matrix used is the BLOSUM62 matrix (Gonnet et al., 1992 , Science  256:1443-1445; Henikoff and Henikoff, 1993, Proteins 17:49-61). Less preferably, the PAM or PAM250 matrices may also be used (see, e.g., Schwartz and Dayhoff, eds., 1978 , Matrices for Detecting Distance Relationships: Atlas of Protein Sequence and Structure , Washington: National Biomedical Research Foundation)  
      The BLAST programs evaluate the statistical significance of all high-scoring segment pairs identified, and preferably selects those segments which satisfy a user-specified threshold of significance, such as a user-specified percent identity. Preferably, the statistical significance of a high-scoring segment pair is evaluated using the statistical significance formula of Karlin (see, e.g., Karlin and Altschul, 1990 , Proc. Natl. Acad. Sci. USA  87:2267-2268).  
      The parameters used with the above algorithms may be adapted depending on the sequence length and degree of identity studied. In some embodiments, the parameters may be the default parameters used by the algorithms in the absence of instructions from the user.  
      In some embodiments, the level of identity between the hybridized nucleic acid and the cDNA or fragment thereof from which the probe was derived may be determined using the FASTDB algorithm described in Brutlag et al. Comp. App. Biosci. 6:237-245, 1990. In such analyses the parameters may be selected as follows: Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the sequence which hybridizes to the probe, whichever is shorter. Because the FASTDB program does not consider 5′ or 3′ truncations when calculating identity levels, if the sequence which hybridizes to the probe is truncated relative to the sequence of the cDNA or fragment thereof from which the probe was derived the identity level is manually adjusted by calculating the number of nucleotides of the cDNA or fragment thereof which are not matched or aligned with the hybridizing sequence, determining the percentage of total nucleotides of the hybridizing sequence which the non-matched or non-aligned nucleotides represent, and subtracting this percentage from the identity level. For example, if the hybridizing sequence is 700 nucleotides in length and the cDNA or fragment thereof sequence is 1000 nucleotides in length wherein the first 300 bases at the 5′end of the cDNA or fragment thereof are absent from the hybridizing sequence, and wherein the overlapping 700 nucleotides are identical, the identity level would be adjusted as follows. The non-matched, non-aligned 300 bases represent 30% of the length of the cDNA or fragment thereof. If the overlapping 700 nucleotides are 100% identical, the adjusted identity level would be 100−30=70% identity. It should be noted that the preceding adjustments are only made when the non-matched or non-aligned nucleotides are at the 5′ or 3′ends. No adjustments are made if the non-matched or non-aligned sequences are internal or under any other conditions.  
      For example, using the above methods, nucleic acids having at least 95% nucleic acid identity, at least 96% nucleic acid identity, at least 97% nucleic acid identity, at least 98% nucleic acid identity, at least 99% nucleic acid identity, or more than 99% nucleic acid identity to the cDNA or fragment thereof from which the probe was derived may be obtained and identified. Such nucleic acids may be allelic variants or related nucleic acids from other species. Similarly, by using progressively less stringent hybridization conditions one can obtain and identify nucleic acids having at least 90%, at least 85%, at least 80% or at least 75% identity to the cDNA or fragment thereof from which the probe was derived.  
      Using the above methods and algorithms such as FASTA with parameters depending on the sequence length and degree of identity studied, for example the default parameters used by the algorithms in the absence of instructions from the user, one can obtain nucleic acids encoding proteins having at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 90%, at least 85%, at least 80% or at least 75% identity to the protein encoded by the cDNA or fragment thereof from which the probe was derived. In some embodiments, the identity levels can be determined using the “default” opening penalty and the “default” gap penalty, and a scoring matrix such as PAM 250 (a standard scoring matrix; see Dayhoff et al., in: Atlas of Protein Sequence and Structure, Vol. 5, Supp. 3 (1978)).  
      Alternatively, the level of polypeptide identity may be determined using the FASTDB algorithm described by Brutlag et al. Comp. App. Biosci. 6:237-245, 1990. In such analyses the parameters may be selected as follows: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty-20, Randomization Group Length=0, Cutoff Score=1, Window Size=Sequence Length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the homologous sequence, whichever is shorter. If the homologous amino acid sequence is shorter than the amino acid sequence encoded by the cDNA or fragment thereof as a result of an N terminal and/or C terminal deletion the results may be manually corrected as follows. First, the number of amino acid residues of the amino acid sequence encoded by the cDNA or fragment thereof which are not matched or aligned with the homologous sequence is determined. Then, the percentage of the length of the sequence encoded by the cDNA or fragment thereof which the non-matched or non-aligned amino acids represent is calculated. This percentage is subtracted from the identity level. For example wherein the amino acid sequence encoded by the cDNA or fragment thereof is 100 amino acids in length and the length of the homologous sequence is 80 amino acids and wherein the amino acid sequence encoded by the cDNA or fragment thereof is truncated at the N terminal end with respect to the homologous sequence, the identity level is calculated as follows. In the preceding scenario there are 20 non-matched, non-aligned amino acids in the sequence encoded by the cDNA or fragment thereof. This represents 20% of the length of the amino acid sequence encoded by the cDNA or fragment thereof. If the remaining amino acids are 100% identical between the two sequences, the identity level would be 100%-20%=80% identity. No adjustments are made if the non-matched or non-aligned sequences are internal or under any other conditions.  
      In addition to the above described methods, other protocols are available to obtain homologous cDNAs using cDNA of the present invention or fragment thereof as outlined in the following paragraphs. 
          cDNAs may be prepared by obtaining mRNA from the tissue, cell, or organism of interest using mRNA preparation procedures utilizing polyA selection procedures or other techniques known to those skilled in the art. A first primer capable of hybridizing to the polyA tail of the mRNA is hybridized to the mRNA and a reverse transcription reaction is performed to generate a first cDNA strand.        

      The first cDNA strand is hybridized to a second primer containing at least 10 consecutive nucleotides of the sequences of SEQ ID NOs 1-405. Preferably, the primer comprises at least 10, 12, 15, 17, 18, 20, 23, 25, or 28 consecutive nucleotides from the sequences of SEQ ID NOs 1-405. In some embodiments, the primer comprises more than 30 nucleotides from the sequences of SEQ ID NOs 1-405. If it is desired to obtain cDNAs containing the full protein coding sequence, including the authentic translation initiation site, the second primer used contains sequences located upstream of the translation initiation site. The second primer is extended to generate a second cDNA strand complementary to the first cDNA strand. Alternatively, RT-PCR may be performed as described above using primers from both ends of the cDNA to be obtained.  
      cDNAs containing 5′ fragments of the mRNA may be prepared by hybridizing an mRNA comprising the sequences of SEQ ID NOs. 1-405 with a primer comprising a complementary to a fragment of the known cDNA, genomic DNA or fragment thereof hybridizing the primer to the mRNAs, and reverse transcribing the hybridized primer to make a first cDNA strand from the mRNAs. Preferably, the primer comprises at least 10, 12, 15, 17, 18, 20, 23, 25, or 28 consecutive nucleotides of the sequences complementary to SEQ ID NOs. 1-405.  
      Thereafter, a second cDNA strand complementary to the first cDNA strand is synthesized. The second cDNA strand may be made by hybridizing a primer complementary to sequences in the first cDNA strand to the first cDNA strand and extending the primer to generate the second cDNA strand.  
      The double stranded cDNAs made using the methods described above are isolated and cloned. The cDNAs may be cloned into vectors such as plasmids or viral vectors capable of replicating in an appropriate host cell. For example, the host cell may be a bacterial, mammalian, avian, or insect cell.  
      Techniques for isolating mRNA, reverse transcribing a primer hybridized to mRNA to generate a first cDNA strand, extending a primer to make a second cDNA strand complementary to the first cDNA strand, isolating the double stranded cDNA and cloning the double stranded cDNA are well known to those skilled in the art and are described in  Current Protocols in Molecular Biology , John Wiley &amp; Sons, Inc. 1997 and Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, 1989.  
      Alternatively, other procedures may be used for obtaining full-length cDNAs or homologous cDNAs. In one approach, cDNAs are prepared from mRNA and cloned into double stranded phagemids as follows. The cDNA library in the double stranded phagemids is then rendered single stranded by treatment with an endonuclease, such as the Gene II product of the phage Fl and an exonuclease (Chang et al., Gene 127:95-8, 1993). A biotinylated oligonucleotide comprising the sequence of a fragment of a known cDNA, genomic DNA or fragment thereof is hybridized to the single stranded phagemids. Preferably, the fragment comprises at least 10, 12, 15, 17, 18, 20, 23, 25, or 28 consecutive nucleotides of the sequences of SEQ ID NOs. 1-405.  
      Hybrids between the biotinylated oligonucleotide and phagemids are isolated by incubating the hybrids with streptavidin coated paramagnetic beads and retrieving the beads with a magnet (Fry et al.,  Biotechniques,  13: 124-131, 1992). Thereafter, the resulting phagemids are released from the beads and converted into double stranded DNA using a primer specific for the cDNA or fragment thereof used to design the biotinylated oligonucleotide. Alternatively, protocols such as the Gene Trapper kit (Gibco BRL) may be used. The resulting double stranded DNA is transformed into bacteria. Homologous cDNAs or full length cDNAs containing the cDNA or fragment thereof sequence are identified by colony PCR or colony hybridization.  
      Using any of the above described methods, a plurality of cDNAs containing full-length protein coding sequences or fragments of the protein coding sequences may be provided as cDNA libraries for subsequent evaluation of the encoded proteins or use in diagnostic assays as described below.  
      cDNAs prepared by any method described therein may be subsequently engineered to obtain nucleic acids which include desired fragments of the cDNA using conventional techniques such as subcloning, PCR, or in vitro oligonucleotide synthesis. For example, nucleic acids which include only the full coding sequences (i.e. the sequences encoding the signal peptide and the mature protein remaining after the signal peptide peptide is cleaved off) may be obtained using techniques known to those skilled in the art. Alternatively, conventional techniques may be applied to obtain nucleic acids which contain only the coding sequence for the mature protein remaining after the signal peptide is cleaved off or nucleic acids which contain only the coding sequences for the signal peptides.  
      Similarly, nucleic acids containing any other desired fragment of the coding sequences for the encoded protein may be obtained. For example, the nucleic acid may contain at least 8, 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 consecutive bases of a cDNA.  
      Once a cDNA has been obtained, it can be sequenced to determine the amino acid sequence it encodes. Once the encoded amino acid sequence has been determined, one can create and identify any of the many conceivable cDNAs that will encode that protein by simply using the degeneracy of the genetic code. For example, allelic variants or other homologous nucleic acids can be identified as described below. Alternatively, nucleic acids encoding the desired amino acid sequence can be synthesized in vitro.  
      In a preferred embodiment, the coding sequence may be selected using the known codon or codon pair preferences for the host organism in which the cDNA is to be expressed.  
      IV. Use of cDNA or Fragments thereof to Express Proteins and uses of those Expressed Proteins  
      Using any of the above described methods, cDNAs containing the full protein coding sequences of their corresponding mRNAs or portions thereof, such as cDNAs encoding the mature protein, may be used to express the secreted proteins or portions thereof which they encode as described below. If desired, the cDNAs may contain the sequences encoding the signal peptide to facilitate secretion of the expressed protein. It will be appreciated that a plurality of extended cDNAs containing the full protein coding sequences or portions thereof may be simultaneously cloned into expression vectors to create an expression library for analysis of the encoded proteins as described below.  
     EXAMPLE 18  
      Expression of the Proteins Encoded by cDNAs or Fragments thereof  
      To express the proteins encoded by the cDNAs or fragments thereof, nucleic acids containing the coding sequence for the proteins or fragments thereof to be expressed are obtained as described above and cloned into a suitable expression vector. If desired, the nucleic acids may contain the sequences encoding the signal peptide to facilitate secretion of the expressed protein. For example, the nucleic acid may comprise the sequence of one of SEQ ID NOs: 1-405 listed in Table I and in the accompanying sequence listing. Alternatively, the nucleic acid may comprise those nucleotides which make up the full coding sequence of one of the sequences of SEQ ID NOs: 1-405 as defined in Table I above.  
      It will be appreciated that should the extent of the full coding sequence (i.e. the sequence encoding the signal peptide and the mature protein resulting from cleavage of the signal peptide) differ from that listed in Table I as a result of a sequencing error, reverse transcription or amplification error, mRNA splicing, post-translational modification of the encoded protein, enzymatic cleavage of the encoded protein, or other biological factors, one skilled in the art would be readily able to identify the extent of the full coding sequences in the sequences of SEQ ID NOs. 1-405. Accordingly, the scope of any claims herein relating to nucleic acids containing the full coding sequence of one of SEQ ID NOs. 1-405 is not to be construed as excluding any readily identifiable variations from or equivalents to the full coding sequences listed in Table I. Similarly, should the extent of the fall length polypeptides differ from those indicated in Table II as a result of any of the preceding factors, the scope of claims relating to polypeptides comprising the amino acid sequence of the full length polypeptides is not to be construed as excluding any readily identifiable variations from or equivalents to the sequences listed in Table II.  
      Alternatively, the nucleic acid used to express the protein or fragment thereof may comprise those nucleotides which encode the mature protein (i.e. the protein created by cleaving the signal peptide off) encoded by one of the sequences of SEQ ID NOs: 1-405 as defined in Table I above.  
      It will be appreciated that should the extent of the sequence encoding the mature protein differ from that listed in Table I as a result of a sequencing error, reverse transcription or amplification error, mRNA splicing, post-translational modification of the encoded protein, enzymatic cleavage of the encoded protein, or other biological factors, one skilled in the art would be readily able to identify the extent of the sequence encoding the mature protein in the sequences of SEQ ID NOs. 1405. Accordingly, the scope of any claims herein relating to nucleic acids containing the sequence encoding the mature protein encoded by one of SEQ ID NOs. 1-405 is not to be construed as excluding any readily identifiable variations from or equivalents to the sequences listed in Table I. Thus, claims relating to nucleic acids containing the sequence encoding the mature protein encompass equivalents to the sequences listed in Table I, such as sequences encoding biologically active proteins resulting from post-translational modification, enzymatic cleavage, or other readily identifiable variations from or equivalents to the secreted proteins in addition to cleavage of the signal peptide. Similarly, should the extent of the mature polypeptides differ from those indicated in Table II as a result of any of the preceding factors, the scope of claims relating to polypeptides comprising the sequence of a mature protein included in the sequence of one of SEQ ID NOs. 406-810 is not to be construed as excluding any readily identifiable variations from or equivalents to the sequences listed in Table II. Thus, claims relating to polypeptides comprising the sequence of the mature protein encompass equivalents to the sequences listed in Table II, such as biologically active proteins resulting from post-translational modification, enzymatic cleavage, or other readily identifiable variations from or equivalents to the secreted proteins in addition to cleavage of the signal peptide. It will also be appreciated that should the biologically active form of the polypeptides included in the sequence of one of SEQ ID NOs. 406-810 or the nucleic acids encoding the biologically active form of the polypeptides differ from those identified as the mature polypeptide in Table II or the nucleotides encoding the mature polypeptide in Table I as a result of a sequencing error, reverse transcription or amplification error, mRNA splicing, post-translational modification of the encoded protein, enzymatic cleavage of the encoded protein, or other biological factors, one skilled in the art would be readily able to identify the amino acids in the biologically active form of the polypeptides and the nucleic acids encoding the biologically active form of the polypeptides. In such instances, the claims relating to polypetides comprising the mature protein included in one of SEQ ID NOs. 406-810 or nucleic acids comprising the nucleotides of one of SEQ ID NOs. 1405 encoding the mature protein shall not be construed to exclude any readily identifiable variations from the sequences listed in Table I and Table II.  
      In some embodiments, the nucleic acid used to express the protein or fragment thereof may comprise those nucleotides which encode the signal peptide encoded by one of the sequences of SEQ ID NOs: 1-405 as defined in Table I above.  
      It will be appreciated that should the extent of the sequence encoding the signal peptide differ from that listed in Table I as a result of a sequencing error, reverse transcription or amplification error, mRNA splicing, post-translational modification of the encoded protein, enzymatic cleavage of the encoded protein, or other biological factors, one skilled in the art would be readily able to identify the extent of the sequence encoding the signal peptide in the sequences of SEQ ID NOs. 1-405. Accordingly, the scope of any claims herein relating to nucleic acids containing the sequence encoding the signal peptide encoded by one of SEQ ID NOs.1-405 is not to be construed as excluding any readily identifiable variations from the sequences listed in Table I. Similarly, should the extent of the signal peptides differ from those indicated in Table II as a result of any of the preceding factors, the scope of claims relating to polypeptides comprising the sequence of a signal peptide included in the sequence of one of SEQ ID NOs. 406-810 is not to be construed as excluding any readily identifiable variations from the sequences listed in Table II.  
      Alternatively, the nucleic acid may encode a polypeptide comprising at least 5 consecutive amino acids of one of the sequences of SEQ ID NOs: 406-810. In some embodiments, the nucleic acid may encode a polypeptide comprising at least 8, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 150 or 200 consecutive amino acids of one of the sequences of SEQ ID NOs: 406-810.  
      The nucleic acids inserted into the expression vectors may also contain sequences upstream of the sequences encoding the signal peptide, such as sequences which regulate expression levels or sequences which confer tissue specific expression.  
      The nucleic acid encoding the protein or polypeptide to be expressed is operably linked to a promoter in an expression vector using conventional cloning technology. The expression vector may be any of the mammalian, yeast, insect or bacterial expression systems known in the art. Commercially available vectors and expression systems are available from a variety of suppliers including Genetics Institute (Cambridge, Mass.), Stratagene (La Jolla, Calif.), Promega (Madison, Wis.), and Invitrogen (San Diego, Calif.). If desired, to enhance expression and facilitate proper protein folding, the codon context and codon pairing of the sequence may be optimized for the particular expression organism in which the expression vector is introduced, as explained by Hatfield, et al., U.S. Pat. No. 5,082,767, incorporated herein by this reference.  
      The following is provided as one exemplary method to express the proteins encoded by the cDNAs or the nucleic acids described above. First, the methionine initiation codon for the gene and the poly A signal of the gene are identified. If the nucleic acid encoding the polypeptide to be expressed lacks a methionine to serve as the initiation site, an initiating methionine can be introduced next to the first codon of the nucleic acid using conventional techniques. Similarly, if the cDNA lacks a poly A signal, this sequence can be added to the construct by, for example, splicing out the Poly A signal from pSG5 (Stratagene) using BglI and SalI restriction endonuclease enzymes and incorporating it into the mammalian expression vector pXT1 (Stratagene). pXT1 contains the LTRs and a fragment of the gag gene from Moloney Murine Leukemia Virus. The position of the LTRs in the construct allow efficient stable transfection. The vector includes the Herpes Simplex Thymidine Kinase promoter and the selectable neomycin gene. The cDNA or fragment thereof encoding the polypeptide to be expressed is obtained by PCR from the bacterial vector using oligonucleotide primers complementary to the cDNA or fragment thereof and containing restriction endonuclease sequences for Pst I incorporated into the 5′primer and BglII at the 5′ end of the corresponding cDNA 3′ primer, taking care to ensure that the cDNA is positioned in frame with the poly A signal. The purified fragment obtained from the resulting PCR reaction is digested with PstI, blunt ended with an exonuclease, digested with Bgl II, purified and ligated to pXT1, now containing a poly A signal and digested with BglII.  
      The ligated product is transfected into mouse NIH 3T3 cells using Lipofectin (Life Technologies, Inc., Grand Island, N.Y.) under conditions outlined in the product specification. Positive transfectants are selected after growing the transfected cells in 600 ug/ml G418 (Sigma, St. Louis, Mo.). Preferably the expressed protein is released into the culture medium, thereby facilitating purification.  
      Alternatively, the cDNAs may be cloned into pED6dpc2 (DiscoverEase, Genetics Institute, Cambridge, Mass.). The resulting pED6dpc2 constructs may be transfected into a suitable host cell, such as COS 1 cells. Methotrexate resistant cells are selected and expanded. Preferably, the protein expressed from the cDNA is released into the culture medium thereby facilitating purification.  
      Proteins in the culture medium are separated by gel electrophoresis. If desired, the proteins may be ammonium sulfate precipitated or separated based on size or charge prior to electrophoresis.  
      As a control, the expression vector lacking a cDNA insert is introduced into host cells or organisms and the proteins in the medium are harvested. The secreted proteins present in the medium are detected using techniques such as Coomassie or silver staining or using antibodies against the protein encoded by the cDNA. Coomassie and silver staining techniques are familiar to those skilled in the art.  
      Antibodies capable of specifically recognizing the protein of interest may be generated using synthetic 15-mer peptides having a sequence encoded by the appropriate 5′ EST, cDNA, or fragment thereof. The synthetic peptides are injected into mice to generate antibody to the polypeptide encoded by the 5′ EST, cDNA, or fragment thereof.  
      Secreted proteins from the host cells or organisms containing an expression vector which contains the cDNA or a fragment thereof are compared to those from the control cells or organism. The presence of a band in the medium from the cells containing the expression vector which is absent in the medium from the control cells indicates that the cDNA encodes a secreted protein. Generally, the band corresponding to the protein encoded by the cDNA will have a mobility near that expected based on the number of amino acids in the open reading frame of the cDNA. However, the band may have a mobility different than that expected as a result of modifications such as glycosylation, ubiquitination, or enzymatic cleavage.  
      Alternatively, if the protein expressed from the above expression vectors does not contain sequences directing its secretion, the proteins expressed from host cells containing an expression vector containing an insert encoding a secreted protein or fragment thereof can be compared to the proteins expressed in host cells containing the expression vector without an insert. The presence of a band in samples from cells containing the expression vector with an insert which is absent in samples from cells containing the expression vector without an insert indicates that the desired protein or fragment thereof is being expressed. Generally, the band will have the mobility expected for the secreted protein or fragment thereof. However, the band may have a mobility different than that expected as a result of modifications such as glycosylation, ubiquitination, or enzymatic cleavage.  
      The protein encoded by the cDNA may be purified using standard immunochromatography techniques. In such procedures, a solution containing the secreted protein, such as the culture medium or a cell extract, is applied to a column having antibodies against the secreted protein attached to the chromatography matrix. The secreted protein is allowed to bind the immunochromatography column. Thereafter, the column is washed to remove non-specifically bound proteins. The specifically bound secreted protein is then released from the column and recovered using standard techniques.  
      If antibody production is not possible, the cDNA sequence or fragment thereof may be incorporated into expression vectors designed for use in purification schemes employing chimeric polypeptides. In such strategies the coding sequence of the cDNA or fragment thereof is inserted in frame with the gene encoding the other half of the chimera. The other half of the chimera may be β-globin or a nickel binding polypeptide encoding sequence. A chromatography matrix having antibody to β-globin or nickel attached thereto is then used to purify the chimeric protein. Protease cleavage sites may be engineered between the β-globin gene or the nickel binding polypeptide and the cDNA or fragment thereof. Thus, the two polypeptides of the chimera may be separated from one another by protease digestion.  
      One useful expression vector for generating β-globin chimerics is pSG5 (Stratagene), which encodes rabbit β-globin. Intron II of the rabbit β-globin gene facilitates splicing of the expressed transcript, and the polyadenylation signal incorporated into the construct increases the level of expression. These techniques as described are well known to those skilled in the art of molecular biology. Standard methods are published in methods texts such as Davis et al., ( Basic Methods in Molecular Biology , L. G. Davis, M. D. Dibner, and J. F. Battey, ed., Elsevier Press, NY, 1986) and many of the methods are available from Stratagene, Life Technologies, Inc., or Promega. Polypeptide may additionally be produced from the construct using in vitro translation systems such as the In vitro Express™ Translation Kit (Stratagene).  
      Following expression and purification of the secreted proteins encoded by the 5′ ESTs, cDNAs, or fragments thereof, the purified proteins may be tested for the ability to bind to the surface of various cell types as described below. It will be appreciated that a plurality of proteins expressed from these cDNAs may be included in a panel of proteins to be simultaneously evaluated for the activities specifically described below, as well as other biological roles for which assays for determining activity are available.  
      Alternatively, the polypeptide to be expressed may also be a product of transgenic animals, i.e., as a component of the milk of transgenic cows, goats, pigs or sheeps which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein of interest.  
     EXAMPLE 19  
      Analysis of Secreted Proteins to Determine Whether they Bind to the Cell Surface  
      The proteins encoded by the cDNAs, or fragments thereof are cloned into expression vectors such as those described in the previous example. The proteins are purified by size, charge, immunochromatography or other techniques familiar to those skilled in the art. Following purification, the proteins are labeled using techniques known to those skilled in the art. The labeled proteins are incubated with cells or cell lines derived from a variety of organs or tissues to allow the proteins to bind to any receptor present on the cell surface. Following the incubation, the cells are washed to remove non-specifically bound protein. The labeled proteins are detected by autoradiography. Alternatively, unlabeled proteins may be incubated with the cells and detected with antibodies having a detectable label, such as a fluorescent molecule, attached thereto.  
      Specificity of cell surface binding may be analyzed by conducting a competition analysis in which various amounts of unlabeled protein are incubated along with the labeled protein. The amount of labeled protein bound to the cell surface decreases as the amount of competitive unlabeled protein increases. As a control, various amounts of an unlabeled protein unrelated to the labeled protein is included in some binding reactions. The amount of labeled protein bound to the cell surface does not decrease in binding reactions containing increasing amounts of unrelated unlabeled protein, indicating that the protein encoded by the cDNA binds specifically to the cell surface.  
      As discussed above, secreted proteins have been shown to have a number of important physiological effects and, consequently, represent a valuable therapeutic resource. The secreted proteins encoded by the cDNAs or fragments thereof made using any of the methods described therein may be evaluated to determine their physiological activities as described below.  
     EXAMPLE 20  
      Assaying the Proteins Expressed from cDNAs or Fragments Thereof for Cytokine, Cell Proliferation or Cell Differentiation Activity  
      As discussed above, secreted proteins may act as cytokines or may affect cellular proliferation or differentiation. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of a protein of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+(preB M+), 2E8, RB5, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7c and CMK. The proteins encoded by the above cDNAs or fragments thereof may be evaluated for their ability to regulate T cell or thymocyte proliferation in assays such as those described above or in the following references, which are incorporated herein by reference:  Current Protocols in Immunology , Ed. by J. E. Coligan et al., Greene Publishing Associates and Wiley-Interscience; Takai et al.  J. Immunol.  137:3494-3500, 1986. Bertagnolli et al.  J. Immunol.  145:1706-1712, 1990. Bertagnolli et al.,  Cellular Immunology  133:327-341, 1991. Bertagnolli, et al.  J. Immunol.  149:3778-3783, 1992; Bowman et al.,  J. Immunol.  152:1756-1761, 1994.  
      In addition, numerous assays for cytokine production and/or the proliferation of spleen cells, lymph node cells and thymocytes are known. These include the techniques disclosed in  Current Protocols in Immunology . J. E. Coligan et al. Eds., Vol 1 pp. 3.12.1-3.12.14 John Wiley and Sons, Toronto. 1994; and Schreiber, R. D.  Current Protocols in Immunology , supra Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994.  
      The proteins encoded by the cDNAs may also be assayed for the ability to regulate the proliferation and differentiation of hematopoietic or lymphopoietic cells. Many assays for such activity are familiar to those skilled in the art, including the assays in the following references, which are incorporated herein by reference: Bottomly, K., Davis, L. S. and Lipsky, P. E., Measurement of Human and Murine Interleukin 2 and Interleukin 4 , Current Protocols in Immunology ., J. E. Coligan et al. Eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al.,  J. Exp. Med.  173:1205-1211, 1991; Moreau et al.,  Nature  36:690-692, 1988; Greenberger et al.,  Proc. Natl. Acad. Sci. U.S.A.  80:2931-2938, 1983; Nordan, R., Measurement of Mouse and Human Interleukin 6  Current Protocols in Immunology . J. E. Coligan et al. Eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al.,  Proc. Natl. Acad. Sci. U.S.A.  83:1857-1861, 1986; Bennett, F., Giannotti, J., Clark, S. C. and Turner, K. J., Measurement of Human Interleukin 11  Current Protocols in Immunology . J. E. Coligan et al. Eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991; Ciarlefta, A., Giannotti, J., Clark, S. C. and Turner, K. J., measurement of Mouse and Human Interleukin 9  Current Protocols in Immunology. J. E. Coligan et al., Eds. Vol  1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991.  
      The proteins encoded by the cDNAs may also be assayed for their ability to regulate T-cell responses to antigens. Many assays for such activity are familiar to those skilled in the art, including the assays described in the following references, which are incorporated herein by reference: Chapter 3 (In vitro Assays for Mouse Lymphocyte Function), Chapter 6 (Cytokines and Their Cellular Receptors) and Chapter 7, (Immunologic Studies in Humans) in  Current Protocols in Immunology , J. E. Coligan et al. Eds. Greene Publishing Associates and Wiley-Interscienc; Weinberger et al.,  Proc. Natl. Acad. Sci. USA  77:6091-6095, 1980; Weinberger et al.,  Eur. J. Immun.  11:405-411, 1981; Takai et al.,  J. Immunol.  137:3494-3500, 1986; Takai et al.,  J. Immunol.  140:508-512, 1988.  
      Those proteins which exhibit cytokine, cell proliferation, or cell differentiation activity may then be formulated as pharmaceuticals and used to treat clinical conditions in which induction of cell proliferation or differentiation is beneficial. Alternatively, as described in more detail below, genes encoding these proteins or nucleic acids regulating the expression of these proteins may be introduced into appropriate host cells to increase or decrease the expression of the proteins as desired.  
     EXAMPLE 21  
      Assaying the Proteins Expressed from cDNAs or Fragments Thereof for Activity as Immune System Regulators  
      The proteins encoded by the cDNAs may also be evaluated for their effects as immune regulators. For example, the proteins may be evaluated for their activity to influence thymocyte or splenocyte cytotoxicity. Numerous assays for such activity are familiar to those skilled in the art including the assays described in the following references, which are incorporated herein by reference: Chapter 3 (In vitro Assays for Mouse Lymphocyte Function 3.1-3.19) and Chapter 7 (Immunologic studies in Humans) in  Current Protocols in Immunology , J. E. Coligan et al. Eds, Greene Publishing Associates and Wiley-Interscience; Herrmann et al.,  Proc. Natl. Acad. Sci. USA  78:2488-2492, 1981; Herrmann et al.,  J. Immunol.  128:1968-1974, 1982; Handa et al.,  J. Immunol.  135:1564-1572, 1985; Takai et al.,  J. Immunol.  137:3494-3500, 1986; Takai et al.,  J. Immunol.  140:508-512, 1988; Herrmann et al.,  Proc. Natl. Acad. Sci. USA  78:2488-2492, 1981; Herrmann et al.,  J. Immunol.  128:1968-1974, 1982; Handa et al.,  J. Immunol.  135:1564-1572, 1985; Takai et al.,  J. Immunol.  137:3494-3500, 1986; Bowman et al.,  J. Virology  61:1992-1998; akai et al.,  J. Immunol.  140:508-512, 1988; Bertagnolli et al.,  Cellular Immunology  133:327-341, 1991; Brown et al.,  J. Immunol.  153:3079-3092, 1994.  
      The proteins encoded by the cDNAs may also be evaluated for their effects on T-cell dependent immunoglobulin responses and isotype switching. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following eferences, which are incorporated herein by reference: Maliszewski,  J. Immunol.  144:3028-3033, 1990; Mond, J. J. and Brunswick, M Assays for B Cell Function: In vitro Antibody Production, Vol 1 pp. 3.8.1-3.8.16 in  Current Protocols in Immunology . J. E. Coligan et al Eds., John Wiley and Sons, Toronto. 1994.  
      The proteins encoded by the cDNAs may also be evaluated for their effect on immune effector cells, including their effect on Th1 cells and cytotoxic lymphocytes. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Chapter 3 (In vitro Assays for Mouse Lymphocyte Function 3.1-3.19) and Chapter 7 (Immunologic Studies in Humans) in  Current Protocols in Immunology , J. E. Coligan et al. Eds., Greene Publishing Associates and Wiley-Interscience; Takai et al.,  J. Immunol.  137:3494-3500, 1986; Takai et al.;  J. Immunol.  140:508-512, 1988; Bertagnolli et al.,  J. Immunol.  149:3778-3783, 1992.  
      The proteins encoded by the cDNAs may also be evaluated for their effect on dendritic cell mediated activation of naive T-cells. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Guery et al.,  J. Immunol.  134:536-544, 1995; Inaba et al.,  Journal of Experimental Medicine  173:549-559, 1991; Macatonia et al.,  Journal of Immunology  154:5071-5079, 1995; Porgador et al.,  Journal of Experimental Medicine  182:255-260, 1995; Nair et al.,  Journal of Virology  67:40624069, 1993; Huang et al.,  Science  264:961-965, 1994; Macatonia et al.,  Journal of Experimental Medicine  169:1255-1264, 1989; Bhardwaj et al.,  Journal of Clinical Investigation  94:797-807, 1994; and Inaba et al.,  Journal of Experimental Medicine  172:631-640, 1990.  
      The proteins encoded by the cDNAs may also be evaluated for their influence on the lifetime of lymphocytes. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Darzynkiewicz et al.,  Cytometry  13:795-808, 1992; Gorczyca et al.,  Leukemia  7:659-670, 1993; Gorczyca et al.,  Cancer Research  53:1945-1951, 1993; Itoh et al.,  Cell  66:233-243, 1991; Zacharchuk,  Journal oflmmunology  145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al.,  International Journal of Oncology  1:639-648, 1992.  
      Assays for proteins that influence early steps of T-cell commitment and evelopment include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki et al., Proc. Nat. Acad. Sci. USA 88:7548-7551, 1991.  
      Those proteins which exhibit activity as immune system regulators activity may hen be formulated as pharmaceuticals and used to treat clinical conditions in which regulation of mmune activity is beneficial. For example, the protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in egulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations. These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders. More specifically, infectious diseases caused by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpesviruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis. Of course, in this regard, a protein of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.  
      Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease. Such a protein of the present invention may also to be useful in the treatment of allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems. Other conditions, in which immune suppression is desired (including, for example, organ transplantation), may also be treatable using a protein of the present invention.  
      Using the proteins of the invention it may also be possible to regulate immune responses, in a number of ways. Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response. The functions of activated T-cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both. Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent. Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.  
      Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as, for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD). For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation. Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant. The administration of a molecule which inhibits or blocks interaction of a B7 lymphocyte antigen with its natural ligand(s) on immune cells (such as a soluble, monomeric form of a peptide having B7-2 activity alone or in conjunction with a monomeric form of a peptide having an activity of another B lymphocyte antigen (e.g., B7-1, B7-3) or blocking antibody), prior to transplantation can lead to the binding of the molecule to the natural ligand(s) on the immune cells without transmitting the corresponding costimulatory signal. Blocking B lymphocyte antigen function in this matter prevents cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant. Moreover, the lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject. Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens.  
      The efficacy of particular blocking reagents in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al, Proc. Natl. Acad. Sci USA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of blocking B lymphocyte antigen function in vivo on the development of that disease.  
      Blocking antigen function may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms. Administration of reagents which block costimulation of T cells by disrupting receptor ligand interactions of B lymphocyte antigens can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease. The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/pr/pr mice or NZB hybrid mice, murine autoimmuno collagen arthritis, diabetes mellitus in OD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856).  
      Upregulation of an antigen function (preferably a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy. Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response. For example, enhancing an immune response through stimulating B lymphocyte antigen function may be useful in cases of viral infection. In addition, systemic viral diseases such as influenza, the common cold, and encephalitis might be alleviated by the administration of stimulatory form of B lymphocyte antigens systemically.  
      Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to T cells in vivo, thereby activating the T cells.  
      In another application, up regulation or enhancement of antigen function (preferably B lymphocyte antigen function) may be useful in the induction of tumor immunity. Tumor cells (e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma) transfected with a nucleic acid encoding at least one peptide of the present invention can be administered to a subject to overcome tumor-specific tolerance in the subject. If desired, the tumor cell can be transfected to express a combination of peptides. For example, tumor cells obtained from a patient can be transfected ex vivo with an expression vector directing the expression of a peptide having B7-2-like activity alone, or in conjunction with a peptide having B7-1-like activity and/or B7-3-like activity. The transfected tumor cells are returned to the patient to result in expression of the peptides on the surface of the transfected cell. Alternatively, gene therapy techniques can be used to target a tumor cell for transfection in vivo.  
      The presence of the peptide of the present invention having the activity of a B lymphocyte antigen(s) on the surface of the tumor cell provides the necessary costimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells. In addition, tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient amounts of MHC class I or MHC class II molecules, can be transfected with nucleic acids encoding all or a fragment of (e.g., a cytoplasmic-domain truncated fragment) of an MHC class I α chain protein and P2 microglobulin protein or an MHC class II α chain protein and an MHC class II β chain protein to thereby express MHC class I or MHC class II proteins on the cell surface. Expression of the appropriate class II or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell. Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity. Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject. Alternatively, as described in more detail below, genes encoding these proteins or nucleic acids regulating the expression of these proteins may be introduced into appropriate host cells to increase or decrease the expression of the proteins as desired.  
     EXAMPLE 22  
      Assaying the Proteins Expressed from cDNAs or Fragments thereof for Hematopoiesis Regulating Activity  
      The proteins encoded by the cDNAs or fragments thereof may also be evaluated for their hematopoiesis regulating activity. For example, the effect of the proteins on embryonic stem cell differentiation may be evaluated. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Johansson et al.  Cellular Biology  15:141-151, 1995; Keller et al.,  Molecular and Cellular Biology  13:473-486, 1993; McClanahan et al.,  Blood  81:2903-2915, 1993.  
      The proteins encoded by the cDNAs or fragments thereof may also be evaluated for their influence on the lifetime of stem cells and stem cell differentiation. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Freshney, M. G. Methylcellulose Colony Forming Assays, in  Culture of Hematopoietic Cells . R. I. Freshney, et al. Eds. pp. 265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al.,  Proc. Natl. Acad. Sci. USA  89:5907-5911, 1992; McNiece, I. K. and Briddell, R. A. Primitive Hematopoietic Colony Forming Cells with High Proliferative Potential, in  Culture of Hematopoietic Cells . R. I. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, N.Y. 1994; Neben et al.,  Experimental Hematology  22:353-359, 1994; Ploemacher, R. E. Cobblestone Area Forming Cell Assay, In  Culture of Hematopoietic Cells . R. I. Freshney, et al. Eds. pp. 1-21, Wiley-Liss, Inc., New York, N.Y. 1994; Spooncer, E., Dexter, M. and Allen, T. Long Term Bone Marrow Cultures in the Presence of Stromal Cells, in  Culture of Hematopoietic Cells . R. I. Freshney, et al. Eds. pp. 163-179, Wiley-Liss, Inc., New York, N.Y. 1994; and Sutherland, H. J. Long Term Culture Initiating Cell Assay, in  Culture of Hematopoietic Cells . R. I. Freshney, et al. Eds. pp. 139-162, Wiley-Liss, Inc., New York, N.Y. 1994.  
      Those proteins which exhibit hematopoiesis regulatory activity may then be formulated as pharmaceuticals and used to treat clinical conditions in which regulation of hematopoeisis is beneficial. For example, a protein of the present invention may be useful in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell deficiencies. Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantion, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy. Alternatively, as described in more detail below, genes encoding these proteins or nucleic acids regulating the expression of these proteins may be introduced into appropriate host cells to increase or decrease the expression of the proteins as desired.  
     EXAMPLE 23  
      Assaying the Proteins Expressed from cDNAs or Fragments thereof for Regulation of Tissue Growth  
      The proteins encoded by the cDNAs or fragments thereof may also be evaluated for their effect on tissue growth. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in International Patent Publication No. WO95/16035, International Patent Publication No. WO95/05846 and International Patent Publication No. WO91/07491, which are incorporated herein by reference.  
      Assays for wound healing activity include, without limitation, those described in: Winter,  Epidermal Wound Healing , pps. 71-112 (Maibach, H1 and Rovee, D T, eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978) which are incorporated herein by reference.  
      Those proteins which are involved in the regulation of tissue growth may then be formulated as pharmaceuticals and used to treat clinical conditions in which regulation of tissue growth is beneficial. For example, a protein of the present invention also may have utility in compositions used for bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, incisions and ulcers.  
      A protein of the present invention, which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals. Such a preparation employing a protein of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.  
      A protein of this invention may also be used in the treatment of periodontal disease, and in other tooth repair processes. Such agents may provide an environment to attract bone-forming cells, stimulate growth of bone-forming cells or induce differentiation of progenitors of bone-forming cells. A protein of the invention may also be useful in the treatment of osteoporosis or osteoarthritis, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes.  
      Another category of tissue regeneration activity that may be attributable to the protein of the present invention is tendon/ligament formation. A protein of the present invention, which induces tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments. The compositions of the present invention may provide an environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair. The compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.  
      The protein of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e., for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a protein may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer&#39;s, Parkinson&#39;s disease, Huntington&#39;s disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a protein of the invention.  
      Proteins of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.  
      It is expected that a protein of the present invention may also exhibit activity for generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium) muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues. Part of the desired effects may be by inhibition or modulation of fibrotic scarring to allow normal tissue to generate. A protein of the invention may also exhibit angiogenic activity.  
      A protein of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokinc damage.  
      A protein of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.  
      Alternatively, as described in more detail below, genes encoding these proteins or nucleic acids regulating the expression of these proteins may be introduced into appropriate host cells to increase or decrease the expression of the proteins as desired.  
     EXAMPLE 24  
      Assaying the Proteins Expressed from cDNAs or Fragments Thereof for Regulation of Reproductive Hormones or Cell Movement  
      The proteins encoded by the cDNAs or fragments thereof may also be evaluated for their ability to regulate reproductive hormones, such as follicle stimulating hormone. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Vale et al.,  Endocrinology  91:562-572, 1972; Ling et al.,  Nature  321:779-782, 1986; Vale et al.,  Nature  321:776-779, 1986; Mason et al.,  Nature  318:659-663, 1985; Forage et al.,  Proc. Natl. Acad. Sci. USA  83:3091-3095, 1986. Chapter 6.12 (Measurement of Alpha and Beta Chemokines)  Current Protocols in Immunology , J. E. Coligan et al. Eds. Greene Publishing Associates and Wiley-Intersciece; Taub et al.  J. Clin. Invest.  95:1370-1376, 1995; Lind et al.  APMIS  103:140-146, 1995; Muller et al.  Eur. J. Immunol.  25:1744-1748; Gruber et al.  J. of Immunol.  152:5860-5867, 1994; Johnston et al.  J. of Immunol  153:1762-1768, 1994.  
      Those proteins which exhibit activity as reproductive hormones or regulators of cell movement may then be formulated as pharmaceuticals and used to treat clinical conditions in which regulation of reproductive hormones or cell movement are beneficial. For example, a protein of the present invention may also exhibit activin- or inhibin-related activities. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins are characterized by their ability to stimulate the release of folic stimulating hormone (FSH). Thus, a protein of the present invention, alone or in heterodimers with a member of the inhibin α family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility in these mammals. Alternatively, the protein of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin-B group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary. See, for example, U.S. Pat. No. 4,798,885, the disclosure of which is incorporated herein by reference. A protein of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as cows, sheep and pigs.  
      Alternatively, as described in more detail below, genes encoding these proteins or nucleic acids regulating the expression of these proteins may be introduced into appropriate host cells to increase or decrease the expression of the proteins as desired.  
     EXAMPLE 25  
      Assaying the Proteins Expressed from cDNAs or Fragments thereof for Chemotactic/Chemokinetic Activity  
      The proteins encoded by the cDNAs or fragments thereof may also be evaluated for chemotactic/chemokinetic activity. For example, a protein of the present invention may have chemotactic or chemokinetic activity (e.g., act as a chemokine) for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, cosinophils, epithelial and/or endothelial cells. Chemotactic and chmokinetic proteins can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic proteins provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.  
      A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.  
      The activity of a protein of the invention may, among other means, be measured by the following methods:  
      Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhension of one cell population to another cell population. Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokincs 6.12.1-6.12.28; Taub et al. J. Clin. Invest. 95:1370-1376, 1995; Lind et al. APMIS 103:140-146, 1995; Mueller et al Eur. J. Immunol. 25:1744-1748; Gruber et al. J. of Immunol. 152:5860-5867, 1994; Johnston et al. J. of Immunol, 153:1762-1768, 1994.  
     EXAMPLE 26  
      Assaying the Proteins Expressed from cDNAs or Fragments Thereof for Regulation of Blood Clotting  
      The proteins encoded by the cDNAs or fragments thereof may also be evaluated for their effects on blood clotting. Numerous assays for such activity are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Linet et al.,  J. Clin. Pharmacol.  26:131-140, 1986; Burdick et al.,  Thrombosis Res.  45:413-419, 1987; Humphrey et al.,  Fibrinolysis  5:71-79 (1991); Schaub,  Prostaglandins  35:467-474, 1988.  
      Those proteins which are involved in the regulation of blood clotting may then be formulated as pharmaceuticals and used to treat clinical conditions in which regulation of blood clotting is beneficial. For example, a protein of the invention may also exhibit hemostatic or thrombolytic activity. As a result, such a protein is expected to be useful in treatment of various coagulations disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes. A protein of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke)). Alternatively, as described in more detail below, genes encoding these proteins or nucleic acids regulating the expression of these proteins may be introduced into appropriate host cells to increase or decrease the expression of the proteins as desired.  
     EXAMPLE 27  
      Assaying the Proteins Expressed from cDNAs or Fragments Thereof for Involvement in Receptor/Ligand Interactions  
      The proteins encoded by the cDNAs or a fragment thereof may also be evaluated for their involvement in receptor/ligand interactions. Numerous assays for such involvement are familiar to those skilled in the art, including the assays disclosed in the following references, which are incorporated herein by reference: Chapter 7.28 (Measurement of Cellular Adhesion under Static Conditions 7.28.1-7.28.22) in  Current Protocols in Immunology , J. E. Coligan et al. Eds. Greene Publishing Associates and Wiley-Interscience; Takai et al.,  Proc. Natl. Acad. Sci. USA  84:6864-6868, 1987; Bierer et al.,  J. Exp. Med.  168:1145-1156, 1988; Rosenstein et al.,  J. Exp. Med.  169:149-160, 1989; Stoltenborg et al.,  J. Immunol. Methods  175:59-68, 1994; Stitt et al.,  Cell  80:661-670, 1995; Gyuris et al.,  Cell  75:791-803, 1993.  
      For example, the proteins of the present invention may also demonstrate activity as receptors, receptor ligands or inhibitors or agonists of receptor/ligand interactions. Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selecting, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune respones). Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.  
     EXAMPLE 28  
      Assaying the Proteins Expressed from cDNAs or Fragments Thereof for Anti-Inflammatory Activity  
      The proteins encoded by the cDNAs or a fragment thereof may also be evaluated for anti-inflammatory activity. The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response. Proteins exhibiting such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation inflammation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusioninury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn&#39;s disease or resulting from over production of cytokines such as TNF or IL-1. Proteins of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.  
     EXAMPLE 29  
      Assaying the Proteins Expressed from cDNAs or Fragments Thereof for Tumor Inhibition Activity  
      The proteins encoded by the cDNAs or a fragment thereof may also be evaluated for tumor inhibition activity. In addition to the activities described above for immunological treatment or prevention of tumors, a protein of the invention may exhibit other anti-tumor activities. A protein may inhibit tumor growth directly or indirectly (such as, for example, via ADCC). A protein may exhibit its tumor inhibitory activity by acting on tumor tissue or tumor precursor tissue, by inhibiting formation of tissues necessary to support tumor growth (such as, for example, by inhibiting angiogenesis), by causing production of other factors, agents or cell types which inhibit tumor growth, or by suppressing, eliminating or inhibiting factors, agents or cell types which promote tumor growth.  
      A protein of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or circadian cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional factors or component(s); effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.  
     EXAMPLE 30  
      Identification of Proteins which Interact with Polypeptides Encoded by cDNAs  
      Proteins which interact with the polypeptides encoded by cDNAs or fragments thereof, such as receptor proteins, may be identified using two hybrid systems such as the Matchmaker Two Hybrid System 2 (Catalog No. K1604-1, Clontech). As described in the manual accompanying the Matchmaker Two Hybrid System 2 (Catalog No. K1604-1, Clontech), which is incorporated herein by reference, the cDNAs or fragments thereof, are inserted into an expression vector such that they are in frame with DNA encoding the DNA binding domain of the yeast transcriptional activator GAL4. cDNAs in a cDNA library which encode proteins which might interact with the polypeptides encoded by the cDNAs or fragments thereof are inserted into a second expression vector such that they are in frame with DNA encoding the activation domain of GAL4. The two expression plasmids are transformed into yeast and the yeast are plated on selection medium which selects for expression of selectable markers on each of the expression vectors as well as GAL4 dependent expression of the HIS3 gene. Transformants capable of growing on medium lacking histidine are screened for GAL4 dependent lacZ expression. Those cells which are positive in both the histidine selection and the lacZ assay contain plasmids encoding proteins which interact with the polypeptide encoded by the cDNAs or fragments thereof.  
      Alternatively, the system described in Lustig et al., Methods in Enzymology 283: 83-99 (1997), the disclosure of which is incorporated herein by reference, may be used for identifying molecules which interact with the polypeptides encoded by cDNAs. In such systems, in vitro transcription reactions are performed on a pool of vectors containing cDNA inserts cloned downstream of a promoter which drives in vitro transcription. The resulting pools of mRNAs are introduced into  Xenopus laevis  oocytes. The oocytes are then assayed for a desired acitivity.  
      Alternatively, the pooled in vitro transcription products produced as described above may be translated in vitro. The pooled in vitro translation products can be assayed for a desired activity or for interaction with a known polypeptide.  
      Proteins or other molecules interacting with polypeptides encoded by cDNAs can be found by a variety of additional techniques. In one method, affinity columns containing the polypeptide encoded by the cDNA or a fragment thereof can be constructed. In some versions, of this method the affinity column contains chimeric proteins in which the protein encoded by the cDNA or a fragment thereof is fused to glutathione S-transferase. A mixture of cellular proteins or pool of expressed proteins as described above and is applied to the affinity column. Proteins interacting with the polypeptide attached to the column can then be isolated and analyzed on 2-D electrophoresis gel as described in Ramunsen et al. Electrophoresis, 18, 588-598 (1997), the disclosure of which is incorporated herein by reference. Alternatively, the proteins retained on the affinity column can be purified by electrophoresis based methods and sequenced. The same method can be used to isolate antibodies, to screen phage display products, or to screen phage display human antibodies.  
      Proteins interacting with polypeptides encoded by cDNAs or fragments thereof can also be screened by using an Optical Biosensor as described in Edwards &amp; Leatherbarrow, Analytical Biochemistry, 246, 1-6 (1997), the disclosure of which is incorporated herein by reference. The main advantage of the method is that it allows the determination of the association rate between the protein and other interacting molecules. Thus, it is possible to specifically select interacting molecules with a high or low association rate. Typically a target molecule is linked to the sensor surface (through a carboxymethl dextran matrix) and a sample of test molecules is placed in contact with the target molecules. The binding of a test molecule to the target molecule causes a change in the refractive index and/or thickness. This change is detected by the Biosensor provided it occurs in the evanescent field (which extend a few hundred manometers from the sensor surface). In these screening assays, the target molecule can be one of the polypeptides encoded by cDNAs or a fragment thereof and the test sample can be a collection of proteins extracted from tissues or cells, a pool of expressed proteins, combinatorial peptide and/or chemical libraries, or phage displayed peptides. The tissues or cells from which the test proteins are extracted can originate from any species.  
      In other methods, a target protein is immobilized and the test population is a collection of unique polypeptides encoded by the cDNAs or fragments thereof.  
      To study the interaction of the proteins encoded by the cDNAs or fragments thereof with drugs, the microdialysis coupled to HPLC method described by Wang et al., Chromatographia, 44, 205-208(1997) or the affinity capillary electrophoresis method described by Busch et al, J. Chromatogr. 777:311-328 (1997), the disclosures of which are incorporated herein by reference can be used.  
      The system described in U.S. Pat. No. 5,654,150, the disclosure of which is incorporated herein by reference, may also be used to identify molecules which interact with the polypeptides encoded by the cDNAs. In this system, pools of cDNAs are transcribed and translated in vitro and the reaction products are assayed for interaction with a known polypeptide or antibody.  
      It will be appreciated by those skilled in the art that the proteins expressed from the cDNAs or fragments may be assayed for numerous activities in addition to those specifically enumerated above. For example, the expressed proteins may be evaluated for applications involving control and regulation of inflammation, tumor proliferation or metastasis, infection, or other clinical conditions. In addition, the proteins expressed from the cDNAs or fragments thereof may be useful as nutritional agents or cosmetic agents.  
      The proteins expressed from the cDNAs or fragments thereof may be used to generate antibodies capable of specifically binding to the expressed protein or fragments thereof as described below. The antibodies may capable of binding a full length protein encoded by one of the sequences of SEQ ID NOs. 1-405, a mature protein encoded by one of the sequences of SEQ ID NOs. 1-405, or a signal peptide encoded by one of the sequences of SEQ ID Nos. 1-405. Alternatively, the antibodies may be capable of binding fragments of the proteins expressed from the cDNAs which comprise at least 10 amino acids of the sequences of SEQ ID NOs: 406-810. In some embodiments, the antibodies may be capable of binding fragments of the proteins expressed from the cDNAs which comprise at least 15 amino acids of the sequences of SEQ ID NOs: 406-810. In other embodiments, the antibodies may be capable of binding fragments of the proteins expressed from the cDNAs which comprise at least 25 amino acids of the sequences of SEQ ID NOs: 406-810. In further embodiments, the antibodies may be capable of binding fragments of the proteins expressed from the cDNAs which comprise at least 40 amino acids of the sequences of SEQ ID NOs: 406-810.  
     EXAMPLE 31  
      Epitopes and Antibody Fusions  
      A preferred embodiment of the present invention is directed to eiptope-bearing polypeptides and epitope-bearing polypeptide fragments. These epitopes may be “antigenic epitopes” or both an “antigenic epitope” and an “immunogenic epitope”. An “immunogenic epitope” is defined as a part of a protein that elicits an antibody response in vivo when the polypeptide is the immunogen. On the other hand, a region of polypeptide to which an antibody binds is defined as an “antigenic determinant” or “antigenic epitope.” The number of immunogenic epitopes of a protein generally is less than the number of antigenic epitopes (See, e.g., Geysen, et al., 1983). It is particularly noted that although a particular epitope may not be immunogenic, it is nonetheless useful since antibodies can be made to both immunogenic and antigenic epitopes.  
      An epitope can comprise as few as 3 amino acids in a spatial conformation, which is unique to the epitope. Generally an epitope consists of at least 6 such amino acids, and more often at least 8-10 such amino acids. In preferred embodiment, antigenic epitopes comprise a number of amino acids that is any integer between 3 and 50. Fragments which function as epitopes may be produced by any conventional means (See, e.g., Houghten, R. A., 1985), also, further described in U.S. Pat. No. 4,631,211. Methods for determining the amino acids which make up an epitope include x-ray crystallography, 2-dimensional nuclear magnetic resonance, and epitope mapping, e.g., the Pepscan method described by Mario H. Geysen et al. (1984); PCT Publication No. WO 84/03564; and PCT Publication No. WO 84/03506. Epitopes may also be delineated using an algorithm, such as the algorithm of Jameson and Wolf, (Jameson and Wolf, Comp. Appl. Biosci. 4:181-186 (1988). The Jameson-Wolf antigenic analysis, for example, may be performed using the computer program PROTEAN, using default parameters (Version 4.0 Windows, DNASTAR, Inc., 1228 South Park Street Madison, Wis.  
      Table X lists antigenic peaks of predicted antigenic epitopes identified by the Jameson-Wolf algorithm. For each polypeptide referred to by its sequence identification number in the first column, the second colmun gives a list of antigenic peaks separated by a coma. Preferred antigenic epitopes of the present invention comprise an additional 6 amino acid residues both N-terminal and C-terminal to the positions listed in the Table. For example, for SEQ ID NO:406, the first preferred immunogenic epitope comprises amino acid residues 52 to 64. Note that for the purposes of this Table, position 1 is the N-terminal methionine residue, i.e., the leader sequence is not numbered negatively.  
      It is pointed out that the immunogenic epitope list describe only amino acid residues comprising epitopes predicted to have the highest degree of immunogenicity by a particular algorithm. Polypeptides of the present invention that are not specifically described as immunogenic are not considered non-antigenic. This is because they may still be antigenic in vivo but merely not recognized as such by the particular algorithm used. Alternatively, the polypeptides are probably antigenic in vitro using methods such a phage display. In fact, all fragments of the polypeptides of the present invention, at least 6 amino acids residues in length, are included in the present invention as being useful as antigenic epitope. Moreover, listed in Table IX are only the critical residues of the epitopes determined by the Jameson-Wolf analysis. Thus, additional flanking residues on either the N-terminal, C-terminal, or both N- and C-terminal ends may be added to the sequences listed to generate an epitope-bearing portion at least 6 residues in length. Amino acid residues comprising other immunogenic epitopes may be determined by algorithms similar to the Jameson-Wolf analysis or by in vivo testing for an antigenic response using the methods described herein or those known in the art.  
      The epitope-bearing fragments of the present invention preferably comprises 6 to 50 amino acids (i.e. any integer between 6 and 50, inclusive) of a polypeptide of the present invention. Also, included in the present invention are antigenic fragments between the integers of 6 and the full length polypeptide sequence of the sequence listing. All combinations of sequences between the integers of 6 and the full-length sequence of a polypeptide are included. The epitope-bearing fragments may be specified by either the number of contiguous amino acid residues (as a sub-genus) or by specific N-terminal and C-terminal positions (as species) as described above for the polypeptide fragments of the present invention. Any number of epitope-bearing fragments of the present invention may also be excluded in the same manner.  
      Antigenic epitopes are useful, for example, to raise antibodies, including monoclonal antibodies that specifically bind the epitope (See, Wilson et al., 1984; and Sutcliffe, J. G. et al., 1983). The antibodies are then used in various techniques such as diagnostic and tissue/cell identification techniques, as described herein, and in purification methods.  
      Similarly, immunogenic epitopes can be used to induce antibodies according to methods well known in the art (See, Sutcliffe et al., supra; Wilson et al., supra; Chow, M. et al.; (1985) and Bittle, F. J. et al., (1985)). The immunogenic epitopes may be presented together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse) or, if it is long enough (at least about 25 amino acids), without a carrier. However, immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting.).  
      Epitope-bearing polypeptides of the present invention are used to induce antibodies according to methods well known in the art including, but not limited to, in vivo immunization, in vitro immunization, and phage display methods (See, e.g., Sutcliffe, et al., supra; Wilson, et al., supra, and Bittle, et al., 1985). If in vivo immunization is used, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling of the peptide to a macromolecular carrier, such as keyhole limpet hemacyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine residues may be coupled to a carrier using a linker such as maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carriers using a more general linking agent such as glutaraldehyde. Animals such as rabbits, rats and mice are immunized with either free or carrier-coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 μgs of peptide or carrier protein and Freund&#39;s adjuvant. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody, which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art.  
      As one of skill in the art will appreciate, and discussed above, the polypeptides of the present invention comprising an immunogenic or antigenic epitope can be fused to heterologous polypeptide sequences. For example, the polypeptides of the present invention may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, any combination thereof including both entire domains and portions thereof) resulting in chimeric polypeptides. These fusion proteins facilitate purification, and show an increased half-life in vivo. This has been shown, e.g., for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins (See, e.g., EPA 0,394,827; and Traunecker et al., 1988). Fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion can also be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone (See, e.g., Fountoulakis et al., 1995). Nucleic acids encoding the above epitopes can also be recombined with a gene of interest as an epitope tag to aid in detection and purification of the expressed polypeptide.  
      Additonal fusion proteins of the invention may be generated through the techniques of gene-shuffling, motif-shuffling, exon-shuffling, or codon-shuffling (collectively referred to as “DNA shuffling”). DNA shuffling may be employed to modulate the activities of polypeptides of the present invention thereby effectively generating agonists and antagonists of the polypeptides. See, for example, U.S. Pat. Nos. 5,605,793; 5,811,238; 5,834,252; 5,837,458; and Patten, P. A., et al., (1997); Harayama, S., (1998); Hansson, L. O., et al (1999); and Lorenzo, M. M. and Blasco, R., (1998). In one embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of coding polynucleotides of the invention, or the polypeptides encoded thereby may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.  
      Antibodies:  
      The present invention further relates to antibodies and T-cell antigen receptors (TCR), which specifically bind the polypeptides, and more specifically, the epitopes of the polyepeptides of the present invention. The antibodies of the present invention include IgG (including IgG1, IgG2, IgG3, and IgG4), IgA (including IgA1 and IgA2), IgD, IgE, or IgM, and IgY. As used herein, the term “antibody” (Ab) is meant to include whole antibodies, including single-chain whole antibodies, and antigen binding fragments thereof. In a preferred embodiment the antibodies are human antigen binding antibody fragments of the present invention include, but are not limited to, Fab, Fab′F(ab)2 and F(ab′)2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a V L  or V H  domain. The antibodies may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine, rabbit, goat, guinea pig, camel, horse, or chicken.  
      Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entire or partial of the following: hinge region, CH1, CH2, and CH3 domains. Also included in the invention are any combinations of variable region(s) and hinge region, CH1, CH2, and CH3 domains. The present invention further includes chimeric, humanized, and human monoclonal and polyclonal antibodies, which specifically bind the polypeptides of the present invention. The present invention further includes antibodies that are anti-idiotypic to the antibodies of the present invention.  
      The antibodies of the present invention may be monospecific, bispecific, and trispecific or have greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for heterologous compositions, such as a heterologous polypeptide or solid support material. See, e.g., WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, A. et al. (1991); U.S. Pat. Nos. 5,573,920, 4,474,893, 5,601,819, 4,714,681, 4,925,648; Kostelny, S. A. et al. (1992).  
      Antibodies of the present invention may be described or specified in terms of the epitope(s) or epitope-bearing portion(s) of a polypeptide of the present invention, which are recognized or specifically bound by the antibody. In the case of proteins of the present invention secreted proteins, the antibodies may specifically bind a full-length protein encoded by a nucleic acid of the present invention, a mature protein (i.e., the protein generated by cleavage of the signal peptide) encoded by a nucleic acid of the present invention, a signal peptide encoded by a nucleic acid of the present invention, or any other polypeptide of the present invention. Therefore, the epitope(s) or epitope bearing polypeptide portion(s) may be specified as described herein, e.g., by N-terminal and C-terminal positions, by size in contiguous amino acid residues, or otherwise described herein (including the squence listing). Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded as individual species. Therefore, the present invention includes antibodies that specifically bind specified polypeptides of the present invention, and allows for the exclusion of the same.  
      Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not specifically bind any other analog, ortholog, or homolog of the polypeptides of the present invention are included. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein, eg., using FASTDB and the parameters set forth herein) to a polypeptide of the present invention are also included in the present invention. Further included in the present invention are antibodies, which only bind polypeptides encoded by polynucleotides, which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10 −6  M, 10 −6  M, 5×10 −7  M, 10 −7  M, 5×10 −8  M, 10 −8  M, 5×10 −9  M, 10 −9  M, 5×10 −10  M, 10 −10  M, 5×10 −11  M, 10 −11  M, 5×10 −12  M, 10 −12  M, 5×10 −13  M, 10 −13  M, 5×10 −14  M, 10 −14  M, 5×10 15  M, and 10 −15  M.  
      Antibodies of the present invention have uses that include, but are not limited to, methods known in the art to purify, detect, and target the polypeptides of the present invention including both in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies have use in immunoassays for qualitatively and quantitatively measuring levels of the polypeptides of the present invention in biological samples (See, e.g., Harlow et al., 1988).  
      The antibodies of the present invention may be used either alone or in combination with other compositions. The antibodies may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalent and non-covalent conjugations) to polypeptides or other compositions. For example, antibodies of the resent invention may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, or toxins. See, e.g., WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No. 5,314,995; and EP 0 396 387.  
      The antibodies of the present invention may be prepared by any suitable method known in the art. For example, a polypeptide of the present invention or an antigenic fragment thereof can be administered to an animal in order to induce the production of sera containing polyclonal antibodies. The term “monoclonal antibody” is not limited to antibodies produced through hybridoma technology. The term “antibody” refers to a polypeptide or group of polypeptides which are comprised of at least one binding domain, where a binding domain is formed from the folding of variable domains of an antibody molecule to form three-dimensional binding spaces with an internal surface shape and charge distribution complementary to the features of an antigenic determinant of an antigen, which allows an immunological reaction with the antigen. The term “monoclonal antibody” refers to an antibody that is derived from a single clone, including eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced. Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technology.  
      Hybridoma techniques include those known in the art (See, e.g., Harlow et al. 1988); Hammerling, et al, 1981). (Said references incorporated by reference in their entireties). Fab and F(ab′)2 fragments may be produced, for example, from hybridoma-produced antibodies by proteolytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab′)2 fragments).  
      Alternatively, antibodies of the present invention can be produced through the application of recombinant DNA technology or through synthetic chemistry using methods known in the art. For example, the antibodies of the present invention can be prepared using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of a phage particle, which carries polynucleotide sequences encoding them. Phage with a desired binding property are selected from a repertoire or combinatorial antibody library (e.g. human or murine) by selecting directly with antigen, typically antigen bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. Examples of phage display methods that can be used to make the antibodies of the present invention include those disclosed in Brinkman U. et al. (1995); Ames, R. S. et al. (1995); Kettleborough, C. A. et al. (1994); Persic, L. et al. (1997); Burton, D. R. et al. (1994); PCT/GB91/01134; WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426, 5,223,409, 5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698, 5,427,908, 5,516,637, 5,780,225, 5,658,727 and 5,733,743.  
      As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host including mammalian cells, insect cells, plant cells, yeast, and bacteria. For example, techniques to recombinantly produce Fab, Fab′ F(ab)2 and F(ab′)2 fragments can also be employed using methods known in the art such as those disclosed in WO 92/22324; Mullinax, R. L. et al. (1992); and Sawai, H. et al. (1995); and Better, M. et al. (1988).  
      Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Pat. Nos. 4,946,778 and 5,258,498; Huston et al. (1991); Shu, L. et al. (1993); and Skerra, A. et al. (1988). For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, (1985); Oi et al., (1986); Gillies, S. D. et al. (1989); and U.S. Pat. No. 5,807,715. Antibodies can be humanized using a variety of techniques including CDR-grafting (EP 0 239 400; WO 91/09967; U.S. Pat. No. 5,530,101; and 5,585,089), veneering or resurfacing, (EP 0 592 106; EP 0 519 596; Padlan E. A., 1991; Studnicka G. M. et al., 1994; Roguska M. A. et al., 1994), and chain shuffling (U.S. Pat. No. 5,565,332). Human antibodies can be made by a variety of methods known in the art including phage display methods described above. See also, U.S. Pat. Nos. 4,444,887, 4,716,111, 5,545,806, and 5,814,318; WO 98/46645; WO 98/50433; WO 98/24893; WO 96/34096; WO 96/33735; and WO 91/10741.  
      Further included in the present invention are antibodies recombinantly fused or chemically conjugated (including both covalently and non-covalently conjugations) to a polypeptide of the present invention. The antibodies may be specific for antigens other than polypeptides of the present invention. For example, antibodies may be used to target the polypeptides of the present invention to particular cell types, either in vitro or in vivo, by fusing or conjugating the polypeptides of the present invention to antibodies specific for particular cell surface receptors. Antibodies fused or conjugated to the polypeptides of the present invention may also be used in in vitro immunoassays and purification methods using methods known in the art (See e.g., Harbor et al. supra; WO 93/21232; EP 0 439 095; Naramura, M. et al. 1994; U.S. Pat. No. 5,474,981; Gillies, S. O. et al., 1992; Fell, H. P. et al., 1991).  
      The present invention further includes compositions comprising the polypeptides of the present invention fused or conjugated to antibody domains other than the variable regions. For example, the polypeptides of the present invention may be fused or conjugated to an antibody Fc region, or portion thereof. The antibody portion fused to a polypeptide of the present invention may comprise the hinge region, CH1 domain, CH2 domain, and CH3 domain or any combination of whole domains or portions thereof. The polypeptides of the present invention may be fused or conjugated to the above antibody portions to increase the in vivo half-life of the polypeptides or for use in immunoassays using methods known in the art. The polypeptides may also be fused or conjugated to the above antibody portions to form multimers. For example, Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bonding between the Fc portions. Higher multimeric forms can be made by fusing the polypeptides to portions of IgA and IgM. Methods for fusing or conjugating the polypeptides of the present invention to antibody portions are known in the art. See e.g., U.S. Pat. Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, 5,112,946; EP 0 307 434, EP 0 367 166; WO 96/04388, WO 91/06570; Ashkenazi, A. et al. (1991); Zheng, X.X. et al. (1995); and Vil, H. et al. (1992).  
      The invention further relates to antibodies that act as agonists or antagonists of the polypeptides of the present invention. For example, the present invention includes antibodies that disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully. Included are both receptor-specific antibodies and ligand-specific antibodies. Included are receptor-specific antibodies, which do not prevent ligand binding but prevent receptor activation. Receptor activation (i.e., signaling) may be determined by techniques described herein or otherwise known in the art. Also include are receptor-specific antibodies which both prevent ligand binding and receptor activation. Likewise, included are neutralizing antibodies that bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies that bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor. Further included are antibodies that activate the receptor. These antibodies may act as agonists for either all or less than all of the biological activities affected by ligand-mediated receptor activation. The antibodies may be specified as agonists or antagonists for biological activities comprising specific activities disclosed herein. The above antibody agonists can be made using methods known in the art. See e.g., WO 96/40281; U.S. Pat. No. 5,811,097; Deng, B. et al. (1998); Chen, Z. et al. (1998); Harrop, J. A. et al. (1998); Zhu, Z. et al. (1998); Yoon, D. Y. et al. (1998); Prat, M. et al. (1998) J.; Pitard, V. et al. (1997); Liautard, J. et al. (1997); Carlson, N. G. et al. (1997) J.; Taryman, R. E. et al. (1995); Muller, Y. A. et al. (1998); Bartunek, P. et al. (1996).  
      As discussed above, antibodies of the polypeptides of the invention can, in turn, be utilized to generate anti-idiotypic antibodies that “mimic” polypeptides of the invention using techniques well known to those skilled in the art (See, e.g. Greenspan and Bona (1989); and Nissinoff (1991). For example, antibodies which bind to and competitively inhibit polypeptide multimerization or binding of a polypeptide of the invention to ligand can be used to generate anti-idiotypes that “mimic” the polypeptide multimerization or binding domain and, as a consequence, bind to and neutralize polypeptide or its ligand. Such neutralization anti-idiotypic antibodies can be used to bind a polypeptide of the invention or to bind its ligands/receptors, and therby block its biological activity,  
      The invention also concerns a purified or isolated antibody capable of specifically binding to a mutated full length or mature polypeptide of the present invention or to a fragment or variant thereof comprising an epitope of the mutated polypeptide. In another preferred embodiment, the present invention concerns an antibody capable of binding to a polypeptide comprising at least 10 consecutive amino acids of a polypeptide of the present invention and including at least one of the amino acids which can be encoded by the trait causing mutations.  
      Non-human animals or mammals, whether wild-type or transgenic, which express a different species of a polypeptide of the present invention than the one to which antibody binding is desired, and animals which do not express a polypeptide of the present invention (i.e. a knock out animal) are particularly useful for preparing antibodies. Gene knock out animals will recognize all or most of the exposed regions of a polypeptide of the present invention as foreign antigens, and therefore produce antibodies with a wider array of epitopes. Moreover, smaller polypeptides with only 10 to 30 amino acids may be useful in obtaining specific binding to any one of the polypeptides of the present invention. In addition, the humoral immune system of animals which produce a species of a polypeptide of the present invention that resembles the antigenic sequence will preferentially recognize the differences between the animal&#39;s native polypeptide species and the antigen sequence, and produce antibodies to these unique sites in the antigen sequence. Such a technique will be particularly useful in obtaining antibodies that specifically bind to any one of the polypeptides of the present invention.  
      Antibody preparations prepared according to either protocol are useful in quantitative immunoassays which determine concentrations of antigen-bearing substances in biological samples; they are also used semi-quantitatively or qualitatively to identify the presence of antigen in a biological sample. The antibodies may also be used in therapeutic compositions for killing cells expressing the protein or reducing the levels of the protein in the body.  
      The antibodies of the invention may be labeled by any one of the radioactive, fluorescent or enzymatic labels known in the art.  
      Consequently, the invention is also directed to a method for detecting specifically the presence of a polypeptide of the present invention according to the invention in a biological sample, said method comprising the following steps: 
          a) bringing into contact the biological sample with a polyclonal or monoclonal antibody that specifically binds a polypeptide of the present invention; and     b) detecting the antigen-antibody complex formed.        

      The invention also concerns a diagnostic kit for detecting in vitro the presence of a polypeptide of the present invention in a biological sample, wherein said kit comprises: 
          a) a polyclonal or monoclonal antibody that specifically binds a polypeptide of the present invention, optionally labeled;     b) a reagent allowing the detection of the antigen-antibody complexes formed, said reagent carrying optionally a label, or being able to be recognized itself by a labeled reagent, more particularly in the case when the above-mentioned monoclonal or polyclonal antibody is not labeled by itself. 
 
 A. Monoclonal Antibody Production by Hybridoma Fusion 
       

      Monoclonal antibody to epitopes of any of the peptides identified and isolated as described can be prepared from murine hybridomas according to the classical method of Kohler, G. and Milstein, C.,  Nature  256:495 (1975) or derivative methods thereof. Briefly, a mouse is repetitively inoculated with a few micrograms of the selected protein or peptides derived therefrom over a period of a few weeks. The mouse is then sacrificed, and the antibody producing cells of the spleen isolated. The spleen cells are fused by means of polyethylene glycol with mouse myeloma cells, and the excess unfused cells destroyed by growth of the system on selective media comprising aminopterin (HAT media). The successfully fused cells are diluted and aliquots of the dilution placed in wells of a microtiter plate where growth of the culture is continued. Antibody-producing clones are identified by detection of antibody in the supernatant fluid of the wells by immunoassay procedures, such as Elisa, as originally described by Engvall, E.,  Meth. Enzymol.  70:419 (1980), and derivative methods thereof. Selected positive clones can be expanded and their monoclonal antibody product harvested for use. Detailed procedures for monoclonal antibody production are described in Davis, L. et al.  Basic Methods in Molecular Biology Elsevier , New York. Section 21-2.  
      B. Polyclonal Antibody Production by Immunization  
      Polyclonal antiserum containing antibodies to heterogenous epitopes of a single protein can be prepared by immunizing suitable animals with the expressed protein or peptides derived therefrom described above, which can be unmodified or modified to enhance immunogenicity. Effective polyclonal antibody production is affected by many factors related both to the antigen and the host species. For example, small molecules tend to be less immunogenic than others and may require the use of carriers and adjuvant. Also, host animals vary in response to site of inoculations and dose, with both inadequate or excessive doses of antigen resulting in low titer antisera. Small doses (ng level) of antigen administered at multiple intradermal sites appears to be most reliable. An effective immunization protocol for rabbits can be found in Vaitukaitis, J. et al.  J. Clin. Endocrinol. Metab.  33:988-991(1971).  
      Booster injections can be given at regular intervals, and antiserum harvested when antibody titer thereof, as determined semi-quantitatively, for example, by double immunodiffusion in agar against known concentrations of the antigen, begins to fall. See, for example, Ouchterlony, O. et al., Chap. 19 in:  Handbook of Experimental Immunology  D. Wier (ed) Blackwell (1973). Plateau concentration of antibody is usually in the range of 0.1 to 0.2 mg/ml of serum (about 12 μM). Affinity of the antisera for the antigen is determined by preparing competitive binding curves, as described, for example, by Fisher, D., Chap. 42 in:  Manual of Clinical Immunology,  2d Ed. (Rose and Friedman, Eds.) Amer. Soc. For Microbiol., Washington, D.C. (1980).  
      Antibody preparations prepared according to either protocol are useful in quantitative immunoassays which determine concentrations of antigen-bearing substances in biological samples; they are also used semi-quantitatively or qualitatively to identify the presence of antigen in a biological sample. The antibodies may also be used in therapeutic compositions for killing cells expressing the protein or reducing the levels of the protein in the body.  
      V. Use of cDNAs or Fragments thereof as Reagents  
      The cDNAs of the present invention may be used as reagents in isolation procedures, diagnostic assays, and forensic procedures. For example, sequences from the cDNAs (or genomic DNAs obtainable therefrom) may be detectably labeled and used as probes to isolate other sequences capable of hybridizing to them. In addition, sequences from the cDNAs (or genomic DNAs obtainable therefrom) may be used to design PCR primers to be used in isolation, diagnostic, or forensic procedures.  
     EXAMPLE 32  
      Preparation of PCR Primers and Amplification of DNA  
      The cDNAs (or genomic DNAs obtainable therefrom) may be used to prepare PCR primers for a variety of applications, including isolation procedures for cloning nucleic acids capable of hybridizing to such sequences, diagnostic techniques and forensic techniques. The PCR primers are at least 10 bases, and preferably at least 12, 15, or 17 bases in length. More preferably, the PCR primers are at least 20-30 bases in length. In some embodiments, the PCR primers may be more than 30 bases in length. It is preferred that the primer pairs have approximately the same G/C ratio, so that melting temperatures are approximately the same. A variety of PCR techniques are familiar to those skilled in the art. For a review of PCR technology, see Molecular Cloning to Genetic Engineering White, B. A. Ed. in Methods in Molecular Biology 67: Humana Press, Totowa 1997. In each of these PCR procedures, PCR primers on either side of the nucleic acid sequences to be amplified are added to a suitably prepared nucleic acid sample along with dNTPs and a thermostable polymerase such as Taq polymerase, Pfu polymerase, or Vent polymerase. The nucleic acid in the sample is denatured and the PCR primers are specifically hybridized to complementary nucleic acid sequences in the sample. The hybridized primers are extended. Thereafter, another cycle of denaturation, hybridization, and extension is initiated. The cycles are repeated multiple times to produce an amplified fragment containing the nucleic acid sequence between the primer sites.  
     EXAMPLE 33  
      Use of cDNAs as Probes  
      Probes derived from cDNAs or fragments thereof (or genomic DNAs obtainable therefrom) may be labeled with detectable labels familiar to those skilled in the art, including radioisotopes and non-radioactive labels, to provide a detectable probe. The detectable probe may be single stranded or double stranded and may be made using techniques known in the art, including in vitro transcription, nick translation, or kinase reactions. A nucleic acid sample containing a sequence capable of hybridizing to the labeled probe is contacted with the labeled probe. If the nucleic acid in the sample is double stranded, it may be denatured prior to contacting the probe. In some applications, the nucleic acid sample may be immobilized on a surface such as a nitrocellulose or nylon membrane. The nucleic acid sample may comprise nucleic acids obtained from a variety of sources, including genomic DNA, cDNA libraries, RNA, or tissue samples.  
      Procedures used to detect the presence of nucleic acids capable of hybridizing to the detectable probe include well known techniques such as Southern blotting, Northern blotting, dot blotting, colony hybridization, and plaque hybridization. In some applications, the nucleic acid capable of hybridizing to the labeled probe may be cloned into vectors such as expression vectors, sequencing vectors, or in vitro transcription vectors to facilitate the characterization and expression of the hybridizing nucleic acids in the sample. For example, such techniques may be used to isolate and clone sequences in a genomic library or cDNA library which are capable of hybridizing to the detectable probe as described in example 17 above.  
      PCR primers made as described in example 32 above may be used in forensic analyses, such as the DNA fingerprinting techniques described in Examples 34-38 below. Such analyses may utilize detectable probes or primers based on the sequences of the cDNAs or fragments thereof (or genomic DNAs obtainable therefrom).  
     EXAMPLE 34  
      Forensic Matching by DNA Sequencing  
      In one exemplary method, DNA samples are isolated from forensic specimens of, for example, hair, semen, blood or skin cells by conventional methods. A panel of PCR primers based on a number of the cDNAs (or genomic DNAs obtainable therefrom), is then utilized in accordance with example 32 to amplify DNA of approximately 100-200 bases in length from the forensic specimen. Corresponding sequences are obtained from a test subject. Each of these identification DNAs is then sequenced using standard techniques, and a simple database comparison determines the differences, if any, between the sequences from the subject and those from the sample. Statistically significant differences between the suspect&#39;s DNA sequences and those from the sample conclusively prove a lack of identity. This lack of identity can be proven, for example, with only one sequence. Identity, on the other hand, should be demonstrated with a large number of sequences, all matching. Preferably, a minimum of 50 statistically identical sequences of 100 bases in length are used to prove identity between the suspect and the sample.  
     EXAMPLE 35  
      Positive Identification by DNA Sequencing  
      The technique outlined in the previous example may also be used on a larger scale to provide a unique fingerprint-type identification of any individual. In this technique, primers are prepared from a large number of sequences from Table I and the appended sequence listing. Preferably, 20 to 50 different primers are used. These primers are used to obtain a corresponding number of PCR-generated DNA segments from the individual in question in accordance with example 32. Each of these DNA segments is sequenced, using the methods set forth in example 34. The database of sequences generated through this procedure uniquely identifies the individual from whom the sequences were obtained. The same panel of primers may then be used at any later time to absolutely correlate tissue or other biological specimen with that individual.  
     EXAMPLE 36  
      Southern Blot Forensic Identification  
      The procedure of example 35 is repeated to obtain a panel of at least 10 amplified sequences from an individual and a specimen. Preferably, the panel contains at least 50 amplified sequences. More preferably, the panel contains 100 amplified sequences. In some embodiments, the panel contains 200 amplified sequences. This PCR-generated DNA is then digested with one or a combination of, preferably, four base specific restriction enzymes. Such enzymes are commercially available and known to those of skill in the art. After digestion, the resultant gene fragments are size separated in multiple duplicate wells on an agarose gel and transferred to nitrocellulose using Southern blotting techniques well known to those with skill in the art. For a review of Southern blotting see Davis et al. ( Basic Methods in Molecular Biology,  1986, Elsevier Press. pp 62-65).  
      A panel of probes based on the sequences of the cDNAs (or genomic DNAs obtainable therefrom), or fragments thereof of at least 10 bases, are radioactively or calorimetrically labeled using methods known in the art, such as nick translation or end labeling, and hybridized to the Southern blot using techniques known in the art (Davis et al., supra). Preferably, the probe comprises at least 12, 15, or 17 consecutive nucleotides from the cDNA (or genomic DNAs obtainable therefrom). More preferably, the probe comprises at least 20-30 consecutive nucleotides from the cDNA (or genomic DNAs obtainable therefrom). In some embodiments, the probe comprises more than 30 nucleotides from the cDNA (or genomic DNAs obtainable therefrom). In other embodiments, the probe comprises at least 40, at least 50, at least 75, at least 100, at least 150, or at least 200 consecutive nucleotides from the cDNA (or genomic DNAs obtainable therefrom).  
      Preferably, at least 5 to 10 of these labeled probes are used, and more preferably at least about 20 or 30 are used to provide a unique pattern. The resultant bands appearing from the hybridization of a large sample of cDNAs (or genomic DNAs obtainable therefrom) will be a 20 unique identifier. Since the restriction enzyme cleavage will be different for every individual, the band pattern on the Southern blot will also be unique. Increasing the number of cDNA probes will provide a statistically higher level of confidence in the identification since there will be an increased number of sets of bands used for identification.  
     EXAMPLE 37  
      Dot Blot Identification Procedure  
      Another technique for identifying individuals using the cDNA sequences disclosed herein utilizes a dot blot hybridization technique.  
      Genomic DNA is isolated from nuclei of subject to be identified. Oligonucleotide probes of approximately 30 bp in length are synthesized that correspond to at least 10, preferably 50 sequences from the cDNAs or genomic DNAs obtainable therefrom. The probes are used to hybridize to the genomic DNA through conditions known to those in the art. The oligonucleotides are end labeled with p 32  using polynucleotide kinase (Pharmacia). Dot Blots are created by spotting the genomic DNA onto nitrocellulose or the like using a vacuum dot blot manifold (BioRad, Richmond Calif.). The nitrocellulose filter containing the genomic sequences is baked or UV linked to the filter, prehybridized and hybridized with labeled probe using techniques known in the art (Davis et al. supra). The  32 p labeled DNA fragments are sequentially hybridized with successively stringent conditions to detect minimal differences between the 30 bp sequence and the DNA. Tetramethylammonium chloride is useful for identifying clones containing small numbers of nucleotide mismatches (Wood et al.,  Proc. Natl. Acad. Sci. USA  82(6):1585-1588 (1985)) which is hereby incorporated by reference. A unique pattern of dots distinguishes one individual from another individual. 
          cDNAs or oligonucleotides containing at least 10 consecutive bases from these sequences can be used as probes in the following alternative fingerprinting technique. Preferably, the probe comprises at least 12, 15, or 17 consecutive nucleotides from the cDNA (or genomic DNAs obtainable therefrom). More preferably, the probe comprises at least 20-30 consecutive nucleotides from the cDNA (or genomic DNAs obtainable therefrom). In some embodiments, the probe comprises more than 30 nucleotides from the cDNA (or genomic DNAs obtainable therefrom). In other embodiments, the probe comprises at least 40, at least 50, at least 75, at least 100, at least 150, or at least 200 consecutive nucleotides from the cDNA (or genomic DNAs obtainable therefrom).        

      Preferably, a plurality of probes having sequences from different genes are used in the alternative fingerprinting technique. Example 38 below provides a representative alternative fingerprinting procedure in which the probes are derived from cDNAs.  
     EXAMPLE 38  
      Alternative “Fingerprint” Identification Technique  
      20-mer oligonucleotides are prepared from a large number, e.g. 50, 100, or 200, of cDNA sequences (or genomic DNAs obtainable therefrom) using commercially available oligonucleotide services such as Genset, Paris, France. Cell samples from the test subject are processed for DNA using techniques well known to those with skill in the art. The nucleic acid is digested with restriction enzymes such as EcoRI and XbaI. Following digestion, samples are applied to wells for electrophoresis. The procedure, as known in the art, may be modified to accommodate polyacrylamide electrophoresis, however in this example, samples containing 5 ug of DNA are loaded into wells and separated on 0.8% agarose gels. The gels are transferred onto nitrocellulose using standard Southern blotting techniques.  
      ng of each of the oligonucleotides are pooled and end-labeled with p 32 . The nitrocellulose is prehybridized with blocking solution and hybridized with the labeled probes. Following hybridization and washing, the nitrocellulose filter is exposed to X-Omat AR X-ray film. The resulting hybridization pattern will be unique for each individual.  
      It is additionally contemplated within this example that the number of probe sequences used can be varied for additional accuracy or clarity.  
      The antibodies generated in Examples 18 and 31 above may be used to identify the tissue type or cell species from which a sample is derived as described above.  
     EXAMPLE 39  
      Identification of Tissue Types or Cell Species by Means of Labeled Tissue Specific Antibodies  
      Identification of specific tissues is accomplished by the visualization of tissue specific antigens by means of antibody preparations according to Examples 18 and 31 which are conjugated, directly or indirectly to a detectable marker. Selected labeled antibody species bind to their specific antigen binding partner in tissue sections, cell suspensions, or in extracts of soluble proteins from a tissue sample to provide a pattern for qualitative or semi-qualitative interpretation.  
      Antisera for these procedures must have a potency exceeding that of the native preparation, and for that reason, antibodies are concentrated to a mg/ml level by isolation of the gamma globulin fraction, for example, by ion-exchange chromatography or by ammonium sulfate fractionation. Also, to provide the most specific antisera, unwanted antibodies, for example to common proteins, must be removed from the gamma globulin fraction, for example by means of insoluble immunoabsorbents, before the antibodies are labeled with the marker. Either monoclonal or heterologous antisera is suitable for either procedure.  
      A. Immunohistochemical Techniques  
      Purified, high-titer antibodies, prepared as described above, are conjugated to a detectable marker, as described, for example, by Fudenberg, H., Chap. 26 in:  Basic  503  Clinical Immunology,  3rd Ed. Lange, Los Altos, Calif. (1980) or Rose, N. et al., Chap. 12 in:  Methods in Immunodiagnosis,  2d Ed. John Wiley 503 Sons, New York (1980).  
      A fluorescent marker, either fluorescein or rhodamine, is preferred, but antibodies can also be labeled with an enzyme that supports a color producing reaction with a substrate, such as horseradish peroxidase. Markers can be added to tissue-bound antibody in a second step, as described below. Alternatively, the specific antitissue antibodies can be labeled with ferritin or other electron dense particles, and localization of the ferritin coupled antigen-antibody complexes achieved by means of an electron microscope. In yet another approach, the antibodies are radiolabeled, with, for example  125 I, and detected by overlaying the antibody treated preparation with photographic emulsion.  
      Preparations to carry out the procedures can comprise monoclonal or polyclonal antibodies to a single protein or peptide identified as specific to a tissue type, for example, brain tissue, or antibody preparations to several antigenically distinct tissue specific antigens can be used in panels, independently or in mixtures, as required.  
      Tissue sections and cell suspensions are prepared for immunohistochemical examination according to common histological techniques. Multiple cryostat sections (about 4 μm, unfixed) of the unknown tissue and known control, are mounted and each slide covered with different dilutions of the antibody preparation. Sections of known and unknown tissues should also be treated with preparations to provide a positive control, a negative control, for example, pre-immune sera, and a control for non-specific staining, for example, buffer.  
      Treated sections are incubated in a humid chamber for 30 min at room temperature, rinsed, then washed in buffer for 30-45 min. Excess fluid is blotted away, and the marker developed.  
      If the tissue specific antibody was not labeled in the first incubation, it can be labeled at this time in a second antibody-antibody reaction, for example, by adding fluorescein- or enzyme-conjugated antibody against the immunoglobulin class of the antiserum-producing species, for example, fluorescein labeled antibody to mouse IgG. Such labeled sera are commercially available.  
      The antigen found in the tissues by the above procedure can be quantified by measuring the intensity of color or fluorescence on the tissue section, and calibrating that signal using appropriate standards.  
      B. Identification of Tissue Specific Soluble Proteins  
      The visualization of tissue specific proteins and identification of unknown tissues from that procedure is carried out using the labeled antibody reagents and detection strategy as described for immunohistochemistry; however the sample is prepared according to an electrophoretic technique to distribute the proteins extracted from the tissue in an orderly array on the basis of molecular weight for detection.  
      A tissue sample is homogenized using a Virtis apparatus; cell suspensions are disrupted by Dounce homogenization or osmotic lysis, using detergents in either case as required to disrupt cell membranes, as is the practice in the art. Insoluble cell components such as nuclei, microsomes, and membrane fragments are removed by ultracentrifugation, and the soluble protein-containing fraction concentrated if necessary and reserved for analysis.  
      A sample of the soluble protein solution is resolved into individual protein species by conventional SDS polyacrylamide electrophoresis as described, for example, by Davis, L. et al., Section 19-2 in:  Basic Methods in Molecular Biology  (P. Leder, ed), Elsevier, New York (1986), using a range of amounts of polyacrylamide in a set of gels to resolve the entire molecular weight range of proteins to be detected in the sample. A size marker is run in parallel for purposes of estimating molecular weights of the constituent proteins. Sample size for analysis is a convenient volume of from 5 to 55 μl, and containing from about 1 to 100 μg protein. An aliquot of each of the resolved proteins is transferred by blotting to a nitrocellulose filter paper, a process that maintains the pattern of resolution. Multiple copies are prepared. The procedure, known as Western Blot Analysis, is well described in Davis, L. et al., (above) Section 19-3. One set of nitrocellulose blots is stained with Coomassie Blue dye to visualize the entire set of proteins for comparison with the antibody bound proteins. The remaining nitrocellulose filters are then incubated with a solution of one or more specific antisera to tissue specific proteins prepared as described in Examples 18 and 31. In this procedure, as in procedure A above, appropriate positive and negative sample and reagent controls are run.  
      In either procedure A or B, a detectable label can be attached to the primary tissue antigen-primary antibody complex according to various strategies and permutations thereof. In a straightforward approach, the primary specific antibody can be labeled; alternatively, the unlabeled complex can be bound by a labeled secondary anti-IgG antibody. In other approaches, either the primary or secondary antibody is conjugated to a biotin molecule, which can, in a subsequent step, bind an avidin conjugated marker. According to yet another strategy, enzyme labeled or radioactive protein A, which has the property of binding to any IgG, is bound in a final step to either the primary or secondary antibody.  
      The visualization of tissue specific antigen binding at levels above those seen in control tissues to one or more tissue specific antibodies, prepared from the gene sequences identified from cDNA sequences, can identify tissues of unknown origin, for example, forensic samples, or differentiated tumor tissue that has metastasized to foreign bodily sites.  
      In addition to their applications in forensics and identification, cDNAs (or genomic DNAs obtainable therefrom) may be mapped to their chromosomal locations. example 40 below describes radiation hybrid (RH) mapping of human chromosomal regions using cDNAs. example 41 below describes a representative procedure for mapping a cDNA (or a genomic DNA obtainable therefrom) to its location on a human chromosome. example 42 below describes mapping of cDNAs (or genomic DNAs obtainable therefrom) on metaphase chromosomes by Fluorescence In Situ Hybridization (FISH).  
     EXAMPLE 40  
      Radiation Hybrid Mapping of cDNAs to the Human Genome  
      Radiation hybrid (RH) mapping is a somatic cell genetic approach that can be used for high resolution mapping of the human genome. In this approach, cell lines containing one or more human chromosomes are lethally irradiated, breaking each chromosome into fragments whose size depends on the radiation dose. These fragments are rescued by fusion with cultured rodent cells, yielding subclones containing different fragments of the human genome. This technique is described by Benham et al. ( Genomics  4:509-517, 1989) and Cox et al., ( Science  250:245-250, 1990), the entire contents of which are hereby incorporated by reference. The random and independent nature of the subclones permits efficient mapping of any human genome marker. Human DNA isolated from a panel of 80-100 cell lines provides a mapping reagent for ordering cDNAs (or genomic DNAs obtainable therefrom). In this approach, the frequency of breakage between markers is used to measure distance, allowing construction of fine resolution maps as has been done using conventional ESTs (Schuler et al.,  Science  274:540-546, 1996, hereby incorporated by reference).  
      RH mapping has been used to generate a high-resolution whole genome radiation hybrid map of human chromosome 17q22-q25.3 across the genes for growth hormone (GH) and thymidine kinase (TK) (Foster et al.,  Genomics  33:185-192, 1996), the region surrounding the Gorlin syndrome gene (Obermayr et al.,  Eur. J. Hum. Genet.  4:242-245, 1996), 60 loci covering the entire short arm of chromosome 12 (Raeymaekers et al.,  Genomics  29:170-178, 1995), the region of human chromosome 22 containing the neurofibromatosis type 2 locus (Frazer et al.,  Genomics  14:574-584, 1992) and 13 loci on the long arm of chromosome 5 (Warrington et al.,  Genomics  11:701-708, 1991).  
     EXAMPLE 41  
      Mapping of cDNAs to Human Chromosomes using PCR Techniques  
      cDNAs (or genomic DNAs obtainable therefrom) may be assigned to human chromosomes using PCR based methodologies. In such approaches, oligonucleotide primer pairs are designed from the cDNA sequence (or the sequence of a genomic DNA obtainable therefrom) to minimize the chance of amplifying through an intron. Preferably, the oligonucleotide primers are 18-23 bp in length and are designed for PCR amplification. The creation of PCR primers from known sequences is well known to those with skill in the art. For a review of PCR technology see Erlich, H. A.,  PCR Technology; Principles and Applications for DNA Amplification.  1992. W. H. Freeman and Co., New York.  
      The primers are used in polymerase chain reactions (PCR) to amplify templates from total human genomic DNA. PCR conditions are as follows: 60 ng of genomic DNA is used as a template for PCR with 80 ng of each oligonucleotide primer, 0.6 unit of Taq polymerase, and 1 μCu of a  32 P-labeled deoxycytidine triphosphate. The PCR is performed in a microplate thermocycler (Techne) under the following conditions: 30 cycles of 94° C., 1.4 min; 55° C., 2 min; and 72° C., 2 min; with a final extension at 72° C. for 10 min. The amplified products are analyzed on a 6% polyacrylamide sequencing gel and visualized by autoradiography. If the length of the resulting PCR product is identical to the distance between the ends of the primer sequences in the cDNA from which the primers are derived, then the PCR reaction is repeated with DNA templates from two panels of human-rodent somatic cell hybrids, BIOS PCRable DNA (BIOS Corporation) and NIGMS Human-Rodent Somatic Cell Hybrid Mapping Panel Number 1 (NIGMS, Camden, N.J.).  
      PCR is used to screen a series of somatic cell hybrid cell lines containing defined sets of human chromosomes for the presence of a given cDNA (or genomic DNA obtainable therefrom). DNA is isolated from the somatic hybrids and used as starting templates for PCR reactions using the primer pairs from the cDNAs (or genomic DNAs obtainable therefrom). Only those somatic cell hybrids with chromosomes containing the human gene corresponding to the cDNA (or genomic DNA obtainable therefrom) will yield an amplified fragment. The cDNAs (or genomic DNAs obtainable therefrom) are assigned to a chromosome by analysis of the segregation pattern of PCR products from the somatic hybrid DNA templates. The single human chromosome present in all cell hybrids that give rise to an amplified fragment is the chromosome containing that cDNA (or genomic DNA obtainable therefrom). For a review of techniques and analysis of results from somatic cell gene mapping experiments. (See Ledbetter et al.,  Genomics  6:475-481 (1990).)  
      Alternatively, the cDNAs (or genomic DNAs obtainable therefrom) may be mapped to individual chromosomes using FISH as described in example 42 below.  
     EXAMPLE 42  
      Mapping of cDNAs to Chromosomes using Fluorescence in Situ Hybridization  
      Fluorescence in situ hybridization allows the cDNA (or genomic DNA obtainable therefrom) to be mapped to a particular location on a given chromosome. The chromosomes to be used for fluorescence in situ hybridization techniques may be obtained from a variety of sources including cell cultures, tissues, or whole blood.  
      In a preferred embodiment, chromosomal localization of a cDNA (or genomic DNA obtainable therefrom) is obtained by FISH as described by Cherif et al. ( Proc. Natl. Acad. Sci. U.S.A.,  87:6639-6643, 1990). Metaphase chromosomes are prepared from phytohemagglutinin (PHA)-stimulated blood cell donors. PHA-stimulated lymphocytes from healthy males are cultured for 72 h in RPMI-1640 medium. For synchronization, methotrexate (10 μM) is added for 17 h, followed by addition of 5-bromodeoxyuridine (5-BudR, 0.1 mM) for 6 h. Colcemid (1 μg/ml) is added for the last 15 min before harvesting the cells. Cells are collected, washed in RPMI, incubated with a hypotonic solution of KCl (75 MM) at 37° C. for 15 min and fixed in three changes of methanol:acetic acid (3:1). The cell suspension is dropped onto a glass slide and air dried. The cDNA (or genomic DNA obtainable therefrom) is labeled with biotin-16 dUTP by nick translation according to the manufacturer&#39;s instructions (Bethesda Research Laboratories, Bethesda, Md.), purified using a Sephadex G-50 column (Pharmacia, Upssala, Sweden) and precipitated. Just prior to hybridization, the DNA pellet is dissolved in hybridization buffer (50% formamide, 2×SSC, 10% dextran sulfate, 1 mg/ml sonicated salmon sperm DNA, pH 7) and the probe is denatured at 70° C. for 5-10 min.  
      Slides kept at −20° C. are treated for 1 h at 37° C. with RNase A (100 μg/ml), rinsed three times in 2×SSC and dehydrated in an ethanol series. Chromosome preparations are denatured in 70% formamide, 2×SSC for 2 min at 70° C., then dehydrated at 4° C. The slides are treated with proteinase K (10 μg/100 ml in 20 mM Tris-HCl, 2 mM CaCl 2 ) at 37° C. for 8 min and dehydrated. The hybridization mixture containing the probe is placed on the slide, covered with a coverslip, sealed with rubber cement and incubated overnight in a humid chamber at 37° C. After hybridization and post-hybridization washes, the biotinylated probe is detected by avidin-FITC and amplified with additional layers of biotinylated goat anti-avidin and avidin-FITC. For chromosomal localization, fluorescent R-bands are obtained as previously described (Cherif et al., supra.). The slides are observed under a LEICA fluorescence microscope (DMRXA). Chromosomes are counterstained with propidium iodide and the fluorescent signal of the probe appears as two symmetrical yellow-green spots on both chromatids of the fluorescent R-band chromosome (red). Thus, a particular cDNA (or genomic DNA obtainable therefrom) may be localized to a particular cytogenetic R-band on a given chromosome.  
     EXAMPLE 43  
      Use of cDNAs to Construct or Expand Chromosome Maps  
      Once the cDNAs (or genomic DNAs obtainable therefrom) have been assigned to particular chromosomes using the techniques described in Examples 40-42 above, they may be utilized to construct a high resolution map of the chromosomes on which they are located or to identify the chromosomes in a sample.  
      Chromosome mapping involves assigning a given unique sequence to a particular chromosome as described above. Once the unique sequence has been mapped to a given chromosome, it is ordered relative to other unique sequences located on the same chromosome. One approach to chromosome mapping utilizes a series of yeast artificial chromosomes (YACs) bearing several thousand long inserts derived from the chromosomes of the organism from which the cDNAs (or genomic DNAs obtainable therefrom) are obtained. This approach is described in Ramaiah Nagaraja et al.  Genome Research  7:210-222, March 1997. Briefly, in this approach each chromosome is broken into overlapping pieces which are inserted into the YAC vector. The YAC inserts are screened using PCR or other methods to determine whether they include the cDNA (or genomic DNA obtainable therefrom) whose position is to be determined. Once an insert has been found which includes the cDNA (or genomic DNA obtainable therefrom), the insert can be analyzed by PCR or other methods to determine whether the insert also contains other sequences known to be on the chromosome or in the region from which the cDNA (or genomic DNA obtainable therefrom) was derived. This process can be repeated for each insert in the YAC library to determine the location of each of the cDNAs (or genomic DNAs obtainable therefrom) relative to one another and to other known chromosomal markers. In this way, a high resolution map of the distribution of numerous unique markers along each of the organisms chromosomes may be obtained.  
      As described in example 44 below cDNAs (or genomic DNAs obtainable therefrom) may also be used to identify genes associated with a particular phenotype, such as hereditary disease or drug response.  
     EXAMPLE 44  
      Identification of Genes Associated with Hereditary Diseases or Drug Response  
      This example illustrates an approach useful for the association of cDNAs (or genomic DNAs obtainable therefrom) with particular phenotypic characteristics. In this example, a particular cDNA (or genomic DNA obtainable therefrom) is used as a test probe to associate that cDNA (or genomic DNA obtainable therefrom) with a particular phenotypic characteristic.  
      cDNAs (or genomic DNAs obtainable therefrom) are mapped to a particular location on a human chromosome using techniques such as those described in Examples 40 and 41 or other techniques known in the art. A search of Mendelian Inheritance in Man (V. McKusick,  Mendelian Inheritance in Man  (available on line through Johns Hopkins University Welch Medical Library) reveals the region of the human chromosome which contains the cDNA (or genomic DNA obtainable therefrom) to be a very gene rich region containing several known genes and several diseases or phenotypes for which genes have not been identified. The gene corresponding to this cDNA (or genomic DNA obtainable therefrom) thus becomes an immediate candidate for each of these genetic diseases.  
      Cells from patients with these diseases or phenotypes are isolated and expanded in culture. PCR primers from the cDNA (or genomic DNA obtainable therefrom) are used to screen genomic DNA, mRNA or cDNA obtained from the patients. cDNAs (or genomic DNAs obtainable therefrom) that are not amplified in the patients can be positively associated with a particular disease by further analysis. Alternatively, the PCR analysis may yield fragments of different lengths when the samples are derived from an individual having the phenotype associated with the disease than when the sample is derived from a healthy individual, indicating that the gene containing the cDNA may be responsible for the genetic disease.  
      VI. Use of cDNAs (or Genomic DNAs Obtainable Therefrom) to Construct Vectors  
      The present cDNAs (or genomic DNAs obtainable therefrom) may also be used to construct secretion vectors capable of directing the secretion of the proteins encoded by genes inserted in the vectors. Such secretion vectors may facilitate the purification or enrichment of the proteins encoded by genes inserted therein by reducing the number of background proteins from which the desired protein must be purified or enriched. Exemplary secretion vectors are described below.  
     EXAMPLE 45  
      Construction of Secretion Vectors  
      The secretion vectors of the present invention include a promoter capable of directing gene expression in the host cell, tissue, or organism of interest. Such promoters include the Rous Sarcoma Virus promoter, the SV40 promoter, the human cytomegalovirus promoter, and other promoters familiar to those skilled in the art.  
      A signal sequence from a cDNA (or genomic DNA obtainable therefrom), such as one of the signal sequences in SEQ ID NOs: 1-405 as defined in Table I above, is operably linked to the promoter such that the mRNA transcribed from the promoter will direct the translation of the signal peptide. The host cell, tissue, or organism may be any cell, tissue, or organism which recognizes the signal peptide encoded by the signal sequence in the cDNA (or genomic DNA obtainable therefrom). Suitable hosts include mammalian cells, tissues or organisms, avian cells, tissues, or organisms, insect cells, tissues or organisms, or yeast.  
      In addition, the secretion vector contains cloning sites for inserting genes encoding the proteins which are to be secreted. The cloning sites facilitate the cloning of the insert gene in frame with the signal sequence such that a fusion protein in which the signal peptide is fused to the protein encoded by the inserted gene is expressed from the mRNA transcribed from the promoter. The signal peptide directs the extracellular secretion of the fusion protein.  
      The secretion vector may be DNA or RNA and may integrate into the chromosome of the host, be stably maintained as an extrachromosomal replicon in the host, be an artificial chromosome, or be transiently present in the host. Preferably, the secretion vector is maintained in multiple copies in each host cell. As used herein, multiple copies means at least 2, 5, 10, 20, 25, 50 or more than 50 copies per cell. In some embodiments, the multiple copies are maintained extrachromosomally. In other embodiments, the multiple copies result from amplification of a chromosomal sequence.  
      Many nucleic acid backbones suitable for use as secretion vectors are known to those skilled in the art, including retroviral vectors, SV40 vectors, Bovine Papilloma Virus vectors, yeast integrating plasmids, yeast episomal plasmids, yeast artificial chromosomes, human artificial chromosomes, P element vectors, baculovirus vectors, or bacterial plasmids capable of being transiently introduced into the host.  
      The secretion vector may also contain a polyA signal such that the polyA signal is located downstream of the gene inserted into the secretion vector.  
      After the gene encoding the protein for which secretion is desired is inserted into the secretion vector, the secretion vector is introduced into the host cell, tissue, or organism using calcium phosphate precipitation, DEAE-Dextran, electroporation, liposome-mediated transfection, viral particles or as naked DNA. The protein encoded by the inserted gene is then purified or enriched from the supernatant using conventional techniques such as ammonium sulfate precipitation, immunoprecipitation, immunochromatography, size exclusion chromatography, ion exchange chromatography, and hplc. Alternatively, the secreted protein may be in a sufficiently enriched or pure state in the supernatant or growth media of the host to permit it to be used for its intended purpose without further enrichment.  
      The signal sequences may also be inserted into vectors designed for gene therapy. In such vectors, the signal sequence is operably linked to a promoter such that mRNA transcribed from the promoter encodes the signal peptide. A cloning site is located downstream of the signal sequence such that a gene encoding a protein whose secretion is desired may readily be inserted into the vector and fused to the signal sequence. The vector is introduced into an appropriate host cell. The protein expressed from the promoter is secreted extracellularly, thereby producing a therapeutic effect.  
      The cDNAs or 5′ ESTs may also be used to clone sequences located upstream of the cDNAs or 5′ ESTs which are capable of regulating gene expression, including promoter sequences, enhancer sequences, and other upstream sequences which influence transcription or translation levels. Once identified and cloned, these upstream regulatory sequences may be used in expression vectors designed to direct the expression of an inserted gene in a desired spatial, temporal, developmental, or quantitative fashion. The next example describes a method for cloning sequences upstream of the cDNAs or 5′ ESTs.  
     EXAMPLE 46  
      Use of cDNAs or Fragments thereof to Clone Upstream Sequences from Genomic DNA  
      Sequences derived from cDNAs or 5′ ESTs may be used to isolate the promoters of the corresponding genes using chromosome walking techniques. In one chromosome walking technique, which utilizes the GenomeWalker™ kit available from Clontech, five complete genomic DNA samples are each digested with a different restriction enzyme which has a 6 base recognition site and leaves a blunt end. Following digestion, oligonucleotide adapters are ligated to each end of the resulting genomic DNA fragments.  
      For each of the five genomic DNA libraries, a first PCR reaction is performed according to the manufacturer&#39;s instructions (which are incorporated herein by reference) using an outer adaptor primer provided in the kit and an outer gene specific primer. The gene specific primer should be selected to be specific for the cDNA or 5′ EST of interest and should have a melting temperature, length, and location in the cDNA or 5′ EST which is consistent with its use in PCR reactions. Each first PCR reaction contains 5ng of genomic DNA, 5 μl of 10×Tth reaction buffer, 0.2 mM of each dNTP, 0.2 μM each of outer adaptor primer and outer gene specific primer, 1.1 mM of Mg(OAc) 2 , and 1 μl of the Tth polymerase 50× mix in a total volume of 50 μl. The reaction cycle for the first PCR reaction is as follows: 1 min at 94° C./2 sec at 94° C., 3 min at 72° C. (7 cycles)/2 sec at 94° C., 3 min at 67° C. (32 cycles)/5 min at 67° C.  
      The product of the first PCR reaction is diluted and used as a template for a second PCR reaction according to the manufacturer&#39;s instructions using a pair of nested primers which are located internally on the amplicon resulting from the first PCR reaction. For example, 5 μl of the reaction product of the first PCR reaction mixture may be diluted 180 times. Reactions are made in a 50 μl volume having a composition identical to that of the first PCR reaction except the nested primers are used. The first nested primer is specific for the adaptor, and is provided with the GenomeWalker™ kit. The second nested primer is specific for the particular cDNA or 5′ EST for which the promoter is to be cloned and should have a melting temperature, length, and location in the cDNA or 5′ EST which is consistent with its use in PCR reactions. The reaction parameters of the second PCR reaction are as follows: 1 min at 94° C./2 sec at 94° C., 3 min at 72° C. (6 cycles)/2 sec at 94° C., 3 min at 67° C. (25 cycles)/5 min at 67° C.  
      The product of the second PCR reaction is purified, cloned, and sequenced using standard techniques. Alternatively, two or more human genomic DNA libraries can be constructed by using two or more restriction enzymes. The digested genomic DNA is cloned into vectors which can be converted into single stranded, circular, or linear DNA. A biotinylated oligonucleotide comprising at least 15 nucleotides from the cDNA or 5′ EST sequence is hybridized to the single stranded DNA. Hybrids between the biotinylated oligonucleotide and the single stranded DNA containing the cDNA or EST sequence are isolated as described in example 17 above. Thereafter, the single stranded DNA containing the cDNA or EST sequence is released from the beads and converted into double stranded DNA using a primer specific for the cDNA or 5′ EST sequence or a primer corresponding to a sequence included in the cloning vector. The resulting double stranded DNA is transformed into bacteria. DNAs containing the 5′ EST or cDNA sequences are identified by colony PCR or colony hybridization.  
      Once the upstream genomic sequences have been cloned and sequenced as described above, prospective promoters and transcription start sites within the upstream sequences may be identified by comparing the sequences upstream of the cDNAs or 5′ ESTs with databases containing known transcription start sites, transcription factor binding sites, or promoter sequences.  
      In addition, promoters in the upstream sequences may be identified using promoter reporter vectors as described below.  
     EXAMPLE 47  
      Identification of Promoters in Cloned Upstream Sequences  
      The genomic sequences upstream of the cDNAs or fragment thereof are cloned into a suitable promoter reporter vector, such as the pSEAP-Basic, pSEAP-Enhancer, pβgal-Basic, pβgal-Enhancer, or pEGFP-1 Promoter Reporter vectors available from Clontech. Briefly, each of these promoter reporter vectors include multiple cloning sites positioned upstream of a reporter gene encoding a readily assayable protein such as secreted alkaline phosphatase, β galactosidase, or green fluorescent protein. The sequences upstream of the cDNAs or 5′ ESTs are inserted into the cloning sites upstream of the reporter gene in both orientations and introduced into an appropriate host cell. The level of reporter protein is assayed and compared to the level obtained from a vector which lacks an insert in the cloning site. The presence of an elevated expression level in the vector containing the insert with respect to the control vector indicates the presence of a promoter in the insert. If necessary, the upstream sequences can be cloned into vectors which contain an enhancer for augmenting transcription levels from weak promoter sequences. A significant level of expression above that observed with the vector lacking an insert indicates that a promoter sequence is present in the inserted upstream sequence.  
      Appropriate host cells for the promoter reporter vectors may be chosen based on the results of the above described determination of expression patterns of the cDNAs and ESTs. For example, if the expression pattern analysis indicates that the mRNA corresponding to a particular cDNA or fragment thereof is expressed in fibroblasts, the promoter reporter vector may be introduced into a human fibroblast cell line.  
      Promoter sequences within the upstream genomic DNA may be further defined by constructing nested deletions in the upstream DNA using conventional techniques such as Exonuclease III digestion. The resulting deletion fragments can be inserted into the promoter reporter vector to determine whether the deletion has reduced or obliterated promoter activity. In this way, the boundaries of the promoters may be defined. If desired, potential individual regulatory sites within the promoter may be identified using site directed mutagenesis or linker scanning to obliterate potential transcription factor binding sites within the promoter individually or in combination. The effects of these mutations on transcription levels may be determined by inserting the mutations into the cloning sites in the promoter reporter vectors.  
     EXAMPLE 48  
      Cloning and Identification of Promoters  
      Using the method described in example 47 above with 5′ ESTs, sequences upstream of several genes were obtained.  
      The promoters and other regulatory sequences located upstream of the cDNAs or 5′ ESTs may be used to design expression vectors capable of directing the expression of an inserted gene in a desired spatial, temporal, developmental, or quantitative manner. A promoter capable of directing the desired spatial, temporal, developmental, and quantitative patterns may be selected using the results of the expression analysis described in example 10 above. For example, if a promoter which confers a high level of expression in muscle is desired, the promoter sequence upstream of a cDNA or 5′ EST derived from an mRNA which is expressed at a high level in muscle, as determined by the method of example 10, may be used in the expression vector.  
      Preferably, the desired promoter is placed near multiple restriction sites to facilitate the cloning of the desired insert downstream of the promoter, such that the promoter is able to drive expression of the inserted gene. The promoter may be inserted in conventional nucleic acid backbones designed for extrachromosomal replication, integration into the host chromosomes or transient expression. Suitable backbones for the present expression vectors include retroviral backbones, backbones from eukaryotic episomes such as SV40 or Bovine Papilloma Virus, backbones from bacterial episomes, or artificial chromosomes.  
      Preferably, the expression vectors also include a polyA signal downstream of the multiple restriction sites for directing the polyadenylation of mRNA transcribed from the gene inserted into the expression vector.  
      Following the identification of promoter sequences using the procedures of Examples 4648, proteins which interact with the promoter may be identified as described in example 49 below.  
     EXAMPLE 49  
      Identification of Proteins which Interact with Promoter Sequences, Upstream Regulatory Sequences, or mRNA  
      Sequences within the promoter region which are likely to bind transcription factors may be identified by identity to known transcription factor binding sites or through conventional mutagenesis or deletion analyses of reporter plasmids containing the promoter sequence. For example, deletions may be made in a reporter plasmid containing the promoter sequence of interest operably linked to an assayable reporter gene. The reporter plasmids carrying various deletions within the promoter region are transfected into an appropriate host cell and the effects of the deletions on expression levels is assessed. Transcription factor binding sites within the regions in which deletions reduce expression levels may be further localized using site directed mutagenesis, linker scanning analysis, or other techniques familiar to those skilled in the art. Nucleic acids encoding proteins which interact with sequences in the promoter may be identified using one-hybrid systems such as those described in the manual accompanying the Matchmaker One-Hybrid System kit avalilabe from Clontech (Catalog No. K1603-1), the disclosure of which is incorporated herein by reference. Briefly, the Matchmaker One-hybrid system is used as follows. The target sequence for which it is desired to identify binding proteins is cloned upstream of a selectable reporter gene and integrated into the yeast genome. Preferably, multiple copies of the target sequences are inserted into the reporter plasmid in tandem.  
      A library comprised of fusions between cDNAs to be evaluated for the ability to bind to the promoter and the activation domain of a yeast transcription factor, such as GAL4, is transformed into the yeast strain containing the integrated reporter sequence. The yeast are plated on selective media to select cells expressing the selectable marker linked to the promoter sequence. The colonies which grow on the selective media contain genes encoding proteins which bind the target sequence. The inserts in the genes encoding the fusion proteins are further characterized by sequencing. In addition, the inserts may be inserted into expression vectors or in vitro transcription vectors. Binding of the polypeptides encoded by the inserts to the promoter DNA may be confirmed by techniques familiar to those skilled in the art, such as gel shift analysis or DNAse protection analysis.  
      VII. Use of cDNAs (or Genomic DNAs Obtainable therefrom) in Gene Therapy  
      The present invention also comprises the use of cDNAs (or genomic DNAs obtainable therefrom) in gene therapy strategies, including antisense and triple helix strategies as described in Examples 50 and 51 below. In antisense approaches, nucleic acid sequences complementary to an mRNA are hybridized to the mRNA intracellularly, thereby blocking the expression of the protein encoded by the mRNA. The antisense sequences may prevent gene expression through a variety of mechanisms. For example, the antisense sequences may inhibit the ability of ribosomes to translate the mRNA. Alternatively, the antisense sequences may block transport of the mRNA from the nucleus to the cytoplasm, thereby limiting the amount of mRNA available for translation. Another mechanism through which antisense sequences may inhibit gene expression is by interfering with mRNA splicing. In yet another strategy, the antisense nucleic acid may be incorporated in a ribozyme capable of specifically cleaving the target mRNA.  
     EXAMPLE 50  
      Preparation and use of Antisense Oligonucleotides  
      The antisense nucleic acid molecules to be used in gene therapy may be either DNA or RNA sequences. They may comprise a sequence complementary to the sequence of the cDNA (or genomic DNA obtainable therefrom). The antisense nucleic acids should have a length and melting temperature sufficient to permit formation of an intracellular duplex having sufficient stability to inhibit the expression of the mRNA in the duplex. Strategies for designing antisense nucleic acids suitable for use in gene therapy are disclosed in Green et al.,  Ann. Rev. Biochem.,  55:569-597 (1986) and Izant and Weintraub,  Cell,  36:1007-1015 (1984), which are hereby incorporated by reference.  
      In some strategies, antisense molecules are obtained from a nucleotide sequence encoding a protein by reversing the orientation of the coding region with respect to a promoter so as to transcribe the opposite strand from that which is normally transcribed in the cell. The antisense molecules may be transcribed using in vitro transcription systems such as those which employ T7 or SP6 polymerase to generate the transcript. Another approach involves transcription of the antisense nucleic acids in vivo by operably linking DNA containing the antisense sequence to a promoter in an expression vector.  
      Alternatively, oligonucleotides which are complementary to the strand normally transcribed in the cell may be synthesized in vitro. Thus, the antisense nucleic acids are complementary to the corresponding mRNA and are capable of hybridizing to the mRNA to create a duplex. In some embodiments, the antisense sequences may contain modified sugar phosphate backbones to increase stability and make them less sensitive to RNase activity. Examples of modifications suitable for use in antisense strategies include 2′ O-methyl RNA oligonucleotides and Protein-nucleic acid (PNA) oligonucleotides. Further examples are described by Rossi et al., Pharmacol. Ther., 50(2):245-254, (1991).  
      Various types of antisense oligonucleotides complementary to the sequence of the cDNA (or genomic DNA obtainable therefrom) may be used. In one preferred embodiment, stable and semi-stable antisense oligonucleotides described in International Application No. PCT WO94/23026, hereby incorporated by reference, are used. In these moleucles, the 3′ end or both the 3′ and 5′ ends are engaged in intramolecular hydrogen bonding between complementary base pairs. These molecules are better able to withstand exonuclease attacks and exhibit increased stability compared to conventional antisense oligonucleotides.  
      In another preferred embodiment, the antisense oligodeoxynucleotides against herpes simplex virus types 1 and 2 described in International Application No. WO 95/04141, hereby incorporated by reference, are used.  
      In yet another preferred embodiment, the covalently cross-linked antisense oligonucleotides described in International Application No. WO 96/31523, hereby incorporated by reference, are used. These double- or single-stranded oligonucleotides comprise one or more, respectively, inter- or intra-oligonucleotide covalent cross-linkages, wherein the linkage consists of an amide bond between a primary amine group of one strand and a carboxyl group of the other strand or of the same strand, respectively, the primary amine group being directly substituted in the 2′ position of the strand nucleotide monosaccharide ring, and the carboxyl group being carried by an aliphatic spacer group substituted on a nucleotide or nucleotide analog of the other strand or the same strand, respectively.  
      The antisense oligodeoxynucleotides and oligonucleotides disclosed in International Application No. WO 92/18522, incorporated by reference, may also be used. These molecules are stable to degradation and contain at least one transcription control recognition sequence which binds to control proteins and are effective as decoys therefor. These molecules may contain “hairpin” structures, “dumbbell” structures, “modified dumbbell” structures, “cross-linked” decoy structures and “loop” structures.  
      In another preferred embodiment, the cyclic double-stranded oligonucleotides described in European Patent Application No. 0 572 287 A2, hereby incorporated by reference are used. These ligated oligonucleotide “dumbbells” contain the binding site for a transcription factor and inhibit expression of the gene under control of the transcription factor by sequestering the factor.  
      Use of the closed antisense oligonucleotides disclosed in International Application No. WO 92/19732, hereby incorporated by reference, is also contemplated. Because these molecules have no free ends, they are more resistant to degradation by exonucleases than are conventional oligonucleotides. These oligonucleotides may be multifunctional, interacting with several regions which are not adjacent to the target mRNA.  
      The appropriate level of antisense nucleic acids required to inhibit gene expression may be determined using in vitro expression analysis. The antisense molecule may be introduced into the cells by diffusion, injection, infection or transfection using procedures known in the art. For example, the antisense nucleic acids can be introduced into the body as a bare or naked oligonucleotide, oligonucleotide encapsulated in lipid, oligonucleotide sequence encapsidated by viral protein, or as an oligonucleotide operably linked to a promoter contained in an expression vector. The expression vector may be any of a variety of expression vectors known in the art, including retroviral or viral vectors, vectors capable of extrachromosomal replication, or integrating vectors. The vectors may be DNA or RNA.  
      The antisense molecules are introduced onto cell samples at a number of different concentrations preferably between 1×10 −10 M to 1×1 −4 M. Once the minimum concentration that can adequately control gene expression is identified, the optimized dose is translated into a dosage suitable for use in vivo. For example, an inhibiting concentration in culture of 1×10 −7  translates into a dose of approximately 0.6 mg/kg bodyweight. Levels of oligonucleotide approaching 100 mg/kg bodyweight or higher may be possible after testing the toxicity of the oligonucleotide in laboratory animals. It is additionally contemplated that cells from the vertebrate are removed, treated with the antisense oligonucleotide, and reintroduced into the vertebrate.  
      It is further contemplated that the antisense oligonucleotide sequence is incorporated into a ribozyme sequence to enable the antisense to specifically bind and cleave its target mRNA. For technical applications of ribozyme and antisense oligonucleotides see Rossi et al., supra.  
      In a preferred application of this invention, the polypeptide encoded by the gene is first identified, so that the effectiveness of antisense inhibition on translation can be monitored using techniques that include but are not limited to antibody-mediated tests such as RIAs and ELISA, functional assays, or radiolabeling.  
      The cDNAs of the present invention (or genomic DNAs obtainable therefrom) may also be used in gene therapy approaches based on intracellular triple helix formation. Triple helix oligonucleotides are used to inhibit transcription from a genome. They are particularly useful for studying alterations in cell activity as it is associated with a particular gene. The cDNAs (or genomic DNAs obtainable therefrom) of the present invention or, more preferably, a fragment of those sequences, can be used to inhibit gene expression in individuals having diseases associated with expression of a particular gene. Similarly, a fragment of the cDNA (or genomic DNA obtainable therefrom) can be used to study the effect of inhibiting transcription of a particular gene within a cell. Traditionally, homopurine sequences were considered the most useful for triple helix strategies. However, homopyrimidine sequences can also inhibit gene expression. Such homopyrimidine oligonucleotides bind to the major groove at homopurine:homopyrimidine sequences. Thus, both types of sequences from the cDNA or from the gene corresponding to the cDNA are contemplated within the scope of this invention.  
     EXAMPLE 51  
      Preparation and use of Triple Helix Probes  
      The sequences of the cDNAs (or genomic DNAs obtainable therefrom) are scanned to identify 10-mer to 20-mer homopyrimidine or homopurine stretches which could be used in triple-helix based strategies for inhibiting gene expression. Following identification of candidate homopyrimidine or homopurine stretches, their efficiency in inhibiting gene expression is assessed by introducing varying amounts of oligonucleotides containing the candidate sequences into tissue culture cells which normally express the target gene. The oligonucleotides may be prepared on an oligonucleotide synthesizer or they may be purchased commercially from a company specializing in custom oligonucleotide synthesis, such as GENSET, Paris, France.  
      The oligonucleotides may be introduced into the cells using a variety of methods known to those skilled in the art, including but not limited to calcium phosphate precipitation, DEAE-Dextran, electroporation, liposome-mediated transfection or native uptake.  
      Treated cells are monitored for altered cell function or reduced gene expression using techniques such as Northern blotting, RNase protection assays, or PCR based strategies to monitor the transcription levels of the target gene in cells which have been treated with the oligonucleotide. The cell functions to be monitored are predicted based upon the homologies of the target gene corresponding to the cDNA from which the oligonucleotide was derived with known gene sequences that have been associated with a particular function. The cell functions can also be predicted based on the presence of abnormal physiologies within cells derived from individuals with a particular inherited disease, particularly when the cDNA is associated with the disease using techniques described in example 44.  
      The oligonucleotides which are effective in inhibiting gene expression in tissue culture cells may then be introduced in vivo using the techniques described above and in example 50 at a dosage calculated based on the in vitro results, as described in example 50.  
      In some embodiments, the natural (beta) anomers of the oligonucleotide units can be replaced with alpha anomers to render the oligonucleotide more resistant to nucleases. Further, an intercalating agent such as ethidium bromide, or the like, can be attached to the 3′ end of the alpha oligonucleotide to stabilize the triple helix. For information on the generation of oligonucleotides suitable for triple helix formation see Griffin et al. ( Science,  245:967-971 (1989), which is hereby incorporated by this reference).  
     EXAMPLE 52  
      Use of cDNAs to Express an Encoded Protein in a Host Organism  
      The cDNAs of the present invention may also be used to express an encoded protein in a host organism to produce a beneficial effect. In such procedures, the encoded protein may be transiently expressed in the host organism or stably expressed in the host organism. The encoded protein may have any of the activities described above. The encoded protein may be a protein which the host organism lacks or, alternatively, the encoded protein may augment the existing levels of the protein in the host organism.  
      A full length cDNA encoding the signal peptide and the mature protein, or a cDNA encoding only the mature protein is introduced into the host organism. The cDNA may be introduced into the host organism using a variety of techniques known to those of skill in the art. For example, the cDNA may be injected into the host organism as naked DNA such that the encoded protein is expressed in the host organism, thereby producing a beneficial effect.  
      Alternatively, the cDNA may be cloned into an expression vector downstream of a promoter which is active in the host organism. The expression vector may be any of the expression vectors designed for use in gene therapy, including viral or retroviral vectors.  
      The expression vector may be directly introduced into the host organism such that the encoded protein is expressed in the host organism to produce a beneficial effect. In another approach, the expression vector may be introduced into cells in vitro. Cells containing the expression vector are thereafter selected and introduced into the host organism, where they express the encoded protein to produce a beneficial effect.  
     EXAMPLE 53  
      Use of Signal Peptides to Import Proteins into Cells  
      The short core hydrophobic region (h) of signal peptides encoded by the cDNAs of the present invention or fragment thereof may also be used as a carrier to import a peptide or a protein of interest, so-called cargo, into tissue culture cells (Lin et al.,  J. Biol. Chem.,  270: 14225-14258 (1995); Du et al.,  J. Peptide Res.,  51: 235-243 (1998); Rojas et al.,  Nature Biotech.,  16: 370-375 (1998)).  
      When cell permeable peptides of limited size (approximately up to 25 amino acids) are to be translocated across cell membrane, chemical synthesis may be used in order to add the h region to either the C-terminus or the N-terminus to the cargo peptide of interest. Alternatively, when longer peptides or proteins are to be imported into cells, nucleic acids can be genetically engineered, using techniques familiar to those skilled in the art, in order to link the cDNA sequence or fragment thereof encoding the h region to the 5′ or the 3′ end of a DNA sequence coding for a cargo polypeptide. Such genetically engineered nucleic acids are then translated either in vitro or in vivo after transfection into appropriate cells, using conventional techniques to produce the resulting cell permeable polypeptide. Suitable hosts cells are then simply incubated with the cell permeable polypeptide which is then translocated across the membrane.  
      This method may be applied to study diverse intracellular functions and cellular processes. For instance, it has been used to probe functionally relevant domains of intracellular proteins and to examine protein-protein interactions involved in signal transduction pathways (Lin et al., supra; Lin et al.,  J. Biol. Chem.,  271: 5305-5308 (1996); Rojas et al.,  J. Biol. Chem.,  271: 27456-27461 (1996); Liu et al.,  Proc. Natl. Acad. Sci. USA,  93: 11819-11824 (1996); Rojas et al.,  Bioch. Biophys. Res. Commun.,  234: 675-680 (1997)).  
      Such techniques may be used in cellular therapy to import proteins producing therapeutic effects. For instance, cells isolated from a patient may be treated with imported therapeutic proteins and then re-introduced into the host organism.  
      Alternatively, the h region of signal peptides of the present invention could be used in combination with a nuclear localization signal to deliver nucleic acids into cell nucleus. Such oligonucleotides may be antisense oligonucleotides or oligonucleotides designed to form triple helixes, as described in examples 50 and 51 respectively, in order to inhibit processing and maturation of a target cellular RNA.  
     EXAMPLE 54  
      Computer Embodiments  
      As used herein the term “cDNA codes of SEQ ID NOs. 1-405” encompasses the nucleotide sequences of SEQ ID NOs. 1-405, fragments of SEQ ID NOs. 1-405, nucleotide sequences homologous to SEQ ID NOs. 1-405 or homologous to fragments of SEQ ID NOs. 1-405, and sequences complementary to all of the preceding sequences. The fragments include fragments of SEQ ID NOs. 1-405 comprising at least 8, 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 consecutive nucleotides of SEQ ID NOs. 1-405. Preferably, the fragments are novel fragments. Preferably the fragments include polynucleotides described in Table III or fragments thereof comprising at least 8, 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 consecutive nucleotides of the polynucleotides described in Table III. Homologous sequences and fragments of SEQ ID NOs. 1-405 refer to a sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, or 75% identity to these sequences. Identity may be determined using any of the computer programs and parameters described in example 17, including BLAST2N with the default parameters or with any modified parameters. Homologous sequences also include RNA sequences in which uridines replace the thymines in the cDNA codes of SEQ ID NOs. 1-405. The homologous sequences may be obtained using any of the procedures described herein or may result from the correction of a sequencing error as described above. Preferably the homologous sequences and fragments of SEQ ID NOs. 1-405 include polynucleotides described in Table III or fragments comprising at least 8, 10, 12, 15, 18, 20, 25, 28, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, 1000 or 2000 consecutive nucleotides of the polynucleotides described in Table III. It will be appreciated that the cDNA codes of SEQ ID NOs. 1-405 can be represented in the traditional single character format (See the inside back cover of Styer, Lubert.  Biochemistry,  3 rd  edition. W. H Freeman &amp; Co., New York.) or in any other format which records the identity of the nucleotides in a sequence.  
      As used herein the term “polypeptide codes of SEQ ID NOS. 406-810” encompasses the polypeptide sequences of SEQ ID NOs. 406-810 which are encoded by the cDNAs of SEQ ID NOs. 1-405, polypeptide sequences homologous to the polypeptides of SEQ ID NOS. 406-810, or fragments of any of the preceding sequences. Homologous polypeptide sequences refer to a polypeptide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% identity to one of the polypeptide sequences of SEQ ID NOS. 406-810. Identity may be determined using any of the computer programs and parameters described herein, including FASTA with the default parameters or with any modified parameters. The homologous sequences may be obtained using any of the procedures described herein or may result from the correction of a sequencing error as described above. The polypeptide fragments comprise at least 5, 8, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 150 or 200 consecutive amino acids of the polypeptides of SEQ ID NOS. 406-810. Preferably, the fragments are novel fragments. Preferably, the fragments include polypeptides encoded by the polynucleotides described in Table III, or fragments thereof comprising at least 5, 10, 15, 20, 25, 30, 35, 40, 50, 75, 100, or 150 consecutive amino acids of the polypeptides encoded by the polynucleotides described in Table III. It will be appreciated that the polypeptide codes of the SEQ ID NOS. 406-810 can be represented in the traditional single character format or three letter format (See the inside back cover of Starrier, Lubert.  Biochemistry,  3 rd  edition. W. H Freeman &amp; Co., New York.) or in any other format which relates the identity of the polypeptides in a sequence.  
      It will be appreciated by those skilled in the art that the cDNA codes of SEQ ID NOs. 1-405 and polypeptide codes of SEQ ID NOS. 406-810 can be stored, recorded, and manipulated on any medium which can be read and accessed by a computer. As used herein, the words “recorded” and “stored” refer to a process for storing information on a computer medium. A skilled artisan can readily adopt any of the presently known methods for recording information on a computer readable medium to generate manufactures comprising one or more of the cDNA codes of SEQ ID NOs. 1-405, one or more of the polypeptide codes of SEQ ID NOS. 406-810. Another aspect of the present invention is a computer readable medium having recorded thereon at least 2, 5, 10, 15, 20, 25, 30, or 50 cDNA codes of SEQ ID NOs. 1-405. Another aspect of the present invention is a computer readable medium having recorded thereon at least 2, 5, 10, 15, 20, 25, 30, or 50 polypeptide codes of SEQ ID NOS. 406-810.  
      Computer readable media include magnetically readable media, optically readable media, electronically readable media and magnetic/optical media. For example, the computer readable media may be a hard disk, a floppy disk, a magnetic tape, CD-ROM, Digital Versatile Disk (DVD), Random Access Memory (RAM), or Read Only Memory (ROM) as well as other types of other media known to those skilled in the art.  
      Embodiments of the present invention include systems, particularly computer systems which store and manipulate the sequence information described herein. One example of a computer system  100  is illustrated in block diagram form in  FIG. 6 . As used herein, “a computer system” refers to the hardware components, software components, and data storage components used to analyze the nucleotide sequences of the cDNA codes of SEQ ID NOs. 1-405, or the amino acid sequences of the polypeptide codes of SEQ ID NOS. 406-810. In one embodiment, the computer system  100  is a Sun Enterprise 1000 server (Sun Microsystems, Palo Alto, Calif.). The computer system  100  preferably includes a processor for processing, accessing and manipulating the sequence data. The processor  105  can be any well-known type of central processing unit, such as the Pentium III from Intel Corporation, or similar processor from Sun, Motorola, Compaq or International Business Machines.  
      Preferably, the computer system  100  is a general purpose system that comprises the processor  105  and one or more internal data storage components  110  for storing data, and one or more data retrieving devices for retrieving the data stored on the data storage components. A skilled artisan can readily appreciate that any one of the currently available computer systems are suitable.  
      In one particular embodiment, the computer system  100  includes a processor  105  connected to a bus which is connected to a main memory  115  (preferably implemented as RAM) and one or more internal data storage devices  110 , such as a hard drive and/or other computer readable media having data recorded thereon. In some embodiments, the computer system  100  further includes one or more data retrieving device  118  for reading the data stored on the internal data storage devices  110 .  
      The data retrieving device  118  may represent, for example, a floppy disk drive, a compact disk drive, a magnetic tape drive, etc. In some embodiments, the internal data storage device  110  is a removable computer readable medium such as a floppy disk, a compact disk, a magnetic tape, etc. containing control logic and/or data recorded thereon. The computer system  100  may advantageously include or be programmed by appropriate software for reading the control logic and/or the data from the data storage component once inserted in the data retrieving device.  
      The computer system  100  includes a display  120  which is used to display output to a computer user. It should also be noted that the computer system  100  can be linked to other computer systems  125   a - c  in a network or wide area network to provide centralized access to the computer system  100 .  
      Software for accessing and processing the nucleotide sequences of the cDNA codes of SEQ ID NOs. 1-405, or the amino acid sequences of the polypeptide codes of SEQ ID NOS. 406-810 (such as search tools, compare tools, and modeling tools etc.) may reside in main memory  115  during execution.  
      In some embodiments, the computer system  100  may further comprise a sequence comparer for comparing the above-described cDNA codes of SEQ ID NOs. 1-405 or polypeptide codes of SEQ ID NOS. 406-810 stored on a computer readable medium to reference nucleotide or polypeptide sequences stored on a computer readable medium. A “sequence comparer” refers to one or more programs which are implemented on the computer system  100  to compare a nucleotide or polypeptide sequence with other nucleotide or polypeptide sequences and/or compounds including but not limited to peptides, peptidomimetics, and chemicals stored within the data storage means. For example, the sequence comparer may compare the nucleotide sequences of the cDNA codes of SEQ ID NOs1-405, or the amino acid sequences of the polypeptide codes of SEQ ID NOS. 406-810 stored on a computer readable medium to reference sequences stored on a computer readable medium to identify homologies, motifs implicated in biological function, or structural motifs. The various sequence comparer programs identified elsewhere in this patent specification are particularly contemplated for use in this aspect of the invention.  
       FIG. 7  is a flow diagram illustrating one embodiment of a process  200  for comparing a new nucleotide or protein sequence with a database of sequences in order to determine the identity levels between the new sequence and the sequences in the database. The database of sequences can be a private database stored within the computer system  100 , or a public database such as GENBANK, PIR or SWISSPROT that is available through the Internet.  
      The process  200  begins at a start state  201  and then moves to a state  202  wherein the new sequence to be compared is stored to a memory in a computer system  100 . As discussed above, the memory could be any type of memory, including RAM or an internal storage device.  
      The process  200  then moves to a state  204  wherein a database of sequences is opened for analysis and comparison. The process  200  then moves to a state  206  wherein the first sequence stored in the database is read into a memory on the computer. A comparison is then performed at a state  210  to determine if the first sequence is the same as the second sequence. It is important to note that this step is not limited to performing an exact comparison between the new sequence and the first sequence in the database. Well-known methods are known to those of skill in the art for comparing two nucleotide or protein sequences, even if they are not identical. For example, gaps can be introduced into one sequence in order to raise the identity level between the two tested sequences. The parameters that control whether gaps or other features are introduced into a sequence during comparison are normally entered by the user of the computer system.  
      Once a comparison of the two sequences has been performed at the state  210 , a determination is made at a decision state  210  whether the two sequences are the same. Of course, the term “same” is not limited to sequences that are absolutely identical. Sequences that are within the identity parameters entered by the user will be marked as “same” in the process  200 .  
      If a determination is made that the two sequences are the same, the process  200  moves to a state  214  wherein the name of the sequence from the database is displayed to the user. This state notifies the user that the sequence with the displayed name fulfills the identity constraints that were entered. Once the name of the stored sequence is displayed to the user, the process  200  moves to a decision state  218  wherein a determination is made whether more sequences exist in the database. If no more sequences exist in the database, then the process  200  terminates at an end state  220 . However, if more sequences do exist in the database, then the process  200  moves to a state  224  wherein a pointer is moved to the next sequence in the database so that it can be compared to the new sequence. In this manner, the new sequence is aligned and compared with every sequence in the database.  
      It should be noted that if a determination had been made at the decision state  212  that the sequences were not homologous, then the process  200  would move immediately to the decision state  218  in order to determine if any other sequences were available in the database for comparison.  
      Accordingly, one aspect of the present invention is a computer system comprising a processor, a data storage device having stored thereon a nucleic acid code of SEQ ID NOs. 1-405 or a polypeptide code of SEQ ID NOS. 406-810, a data storage device having retrievably stored thereon reference nucleotide sequences or polypeptide sequences to be compared to the nucleic acid code of SEQ ID NOs. 1-405 or polypeptide code of SEQ ID NOS. 406-810 and a sequence comparer for conducting the comparison. The sequence comparer may indicate a identity level between the sequences compared or identify structural motifs in the above described nucleic acid code of SEQ ID NOs. 1-405 and polypeptide codes of SEQ ID NOS. 406-810 or it may identify structural motifs in sequences which are compared to these cDNA codes and polypeptide codes. In some embodiments, the data storage device may have stored thereon the sequences of at least 2, 5, 10, 15, 20, 25, 30, or 50 of the cDNA codes of SEQ ID NOs.1-405 or polypeptide codes of SEQ ID NOS. 406-810.  
      Another aspect of the present invention is a method for determining the level of identity between a nucleic acid code of SEQ ID NOs. 1-405 and a reference nucleotide sequence, comprising the steps of reading the nucleic acid code and the reference nucleotide sequence through the use of a computer program which determines identity levels and determining identity between the nucleic acid code and the reference nucleotide sequence with the computer program. The computer program may be any of a number of computer programs for determining identity levels, including those specifically enumerated herein, including BLAST2N with the default parameters or with any modified parameters. The method may be implemented using the computer systems described above. The method may also be performed by reading 2, 5, 10, 15, 20, 25, 30, or 50 of the above described cDNA codes of SEQ ID NOs. 1-405 through use of the computer program and determining identity between the cDNA codes and reference nucleotide sequences.  
       FIG. 8  is a flow diagram illustrating one embodiment of a process  250  in a computer for determining whether two sequences are homologous. The process  250  begins at a start state  252  and then moves to a state  254  wherein a first sequence to be compared is stored to a memory. The second sequence to be compared is then stored to a memory at a state  256 . The process  250  then moves to a state  260  wherein the first character in the first sequence is read and then to a state  262  wherein the first character of the second sequence is read. It should be understood that if the sequence is a nucleotide sequence, then the character would normally be either A, T, C, G or U. If the sequence is a protein sequence, then it should be in the single letter amino acid code so that the first and sequence sequences can be easily compared.  
      A determination is then made at a decision state  264  whether the two characters are the same. If they are the same, then the process  250  moves to a state  268  wherein the next characters in the first and second sequences are read. A determination is then made whether the next characters are the same. If they are, then the process  250  continues this loop until two characters are not the same. If a determination is made that the next two characters are not the same, the process  250  moves to a decision state  274  to determine whether there are any more characters either sequence to read.  
      If there aren&#39;t any more characters to read, then the process  250  moves to a state  276  wherein the level of identity between the first and second sequences is displayed to the user. The level of identity is determined by calculating the profragment of characters between the sequences that were the same out of the total number of sequences in the first sequence. Thus, if every character in a first 100 nucleotide sequence aligned with a every character in a second sequence, the identity level would be 100%.  
      Alternatively, the computer program may be a computer program which compares the nucleotide sequences of the cDNA codes of the present invention, to reference nucleotide sequences in order to determine whether the nucleic acid code of SEQ ID NOs. 1-405 differs from a reference nucleic acid sequence at one or more positions. Optionally such a program records the length and identity of inserted, deleted or substituted nucleotides with respect to the sequence of either the reference polynucleotide or the nucleic acid code of SEQ ID NOs. 1-405. In one embodiment, the computer program may be a program which determines whether the nucleotide sequences of the cDNA codes of SEQ ID NOs. 1-405 contain a biallelic marker or single nucleotide polymorphism (SNP) with respect to a reference nucleotide sequence. This single nucleotide polymorphism may comprise a single base substitution, insertion, or deletion, while this biallelic marker may comprise about one to ten consecutive bases substituted, inserted or deleted.  
      Another aspect of the present invention is a method for determining the level of identity between a polypeptide code of SEQ ID NOS. 406-810 and a reference polypeptide sequence, comprising the steps of reading the polypeptide code of SEQ ID NOS. 406-810 and the reference polypeptide sequence through use of a computer program which determines identity levels and determining identity between the polypeptide code and the reference polypeptide sequence using the computer program.  
      Accordingly, another aspect of the present invention is a method for determining whether a nucleic acid code of SEQ ID NOs. 1-405 differs at one or more nucleotides from a reference nucleotide sequence comprising the steps of reading the nucleic acid code and the reference nucleotide sequence through use of a computer program which identifies differences between nucleic acid sequences and identifying differences between the nucleic acid code and the reference nucleotide sequence with the computer program. In some embodiments, the computer program is a program which identifies single nucleotide polymorphisms. The method may be implemented by the computer systems described above and the method illustrated in  FIG. 8 . The method may also be performed by reading at least 2, 5, 10, 15, 20, 25, 30, or 50 of the cDNA codes of SEQ ID NOs. 1-405 and the reference nucleotide sequences through the use of the computer program and identifying differences between the cDNA codes and the reference nucleotide sequences with the computer program.  
      In other embodiments the computer based system may further comprise an identifier for identifying features within the nucleotide sequences of the cDNA codes of SEQ ID NOs. 1-405 or the amino acid sequences of the polypeptide codes of SEQ ID NOS. 406-810.  
      An “identifier” refers to one or more programs which identifies certain features within the above-described nucleotide sequences of the cDNA codes of SEQ ID NOs. 1-405 or the amino acid sequences of the polypeptide codes of SEQ ID NOS. 406-810. In one embodiment, the identifier may comprise a program which identifies an open reading frame in the cDNAs codes of SEQ ID NOs. 1-405.  
       FIG. 9  is a flow diagram illustrating one embodiment of an identifier process  300  for detecting the presence of a feature in a sequence. The process  300  begins at a start state  302  and then moves to a state  304  wherein a first sequence that is to be checked for features is stored to a memory  115  in the computer system  100 . The process  300  then moves to a state  306  wherein a database of sequence features is opened. Such a database would include a list of each feature&#39;s attributes along with the name of the feature. For example, a feature name could be “Initiation Codon” and the attribute would be “ATG”. Another example would be the feature name “TAATAA Box” and the feature attribute would be “TAATAA”. An example of such a database is produced by the University of Wisconsin Genetics Computer Group (www.gcg.com).  
      Once the database of features is opened at the state  306 , the process  300  moves to a state  308  wherein the first feature is read from the database. A comparison of the attribute of the first feature with the first sequence is then made at a state  310 . A determination is then made at a decision state  316  whether the attribute of the feature was found in the first sequence. If the attribute was found, then the process  300  moves to a state  318  wherein the name of the found feature is displayed to the user.  
      The process  300  then moves to a decision state  320  wherein a determination is made whether move features exist in the database. If no more features do exist, then the process  300  terminates at an end state  324 . However, if more features do exist in the database, then the process  300  reads the next sequence feature at a state  326  and loops back to the state  310  wherein the attribute of the next feature is compared against the first sequence.  
      It should be noted, that if the feature attribute is not found in the first sequence at the decision state  316 , the process  300  moves directly to the decision state  320  in order to determine if any more features exist in the database.  
      In another embodiment, the identifier may comprise a molecular modeling program which determines the 3-dimensional structure of the polypeptides codes of SEQ ID NOS. 406-810. In some embodiments, the molecular modeling programidentifies target sequences that are most compatible with profiles representing the structural environments of the residues in known three-dimensional protein structures. (See, e.g., Eisenberg et al., U.S. Pat. No. 5,436,850 issued Jul. 25, 1995). In another technique, the known three-dimensional structures of proteins in a given family are superimposed to define the structurally conserved regions in that family. This protein modeling technique also uses the known three-dimensional structure of a homologous protein to approximate the structure of the polypeptide codes of SEQ ID NOS. 406-810. (See e.g., Srinivasan, et al., U.S. Pat. No. 5,557,535 issued Sep. 17, 1996). Conventional identity modeling techniques have been used routinely to build models of proteases and antibodies. (Sowdhamini et al., Protein Engineering 10:207, 215 (1997)). Comparative approaches can also be used to develop three-dimensional protein models when the protein of interest has poor sequence identity to template proteins. In some cases, proteins fold into similar three-dimensional structures despite having very weak sequence identities. For example, the three-dimensional structures of a number of helical cytokines fold in similar three-dimensional topology in spite of weak sequence identity.  
      The recent development of threading methods now enables the identification of likely folding patterns in a number of situations where the structural relatedness between target and template(s) is not detectable at the sequence level. Hybrid methods, in which fold recognition is performed using Multiple Sequence Threading (MST), structural equivalencies are deduced from the threading output using a distance geometry program DRAGON to construct a low resolution model, and a full-atom representation is constructed using a molecular modeling package such as QUANTA.  
      According to this 3-step approach, candidate templates are first identified by using the novel fold recognition algorithm MST, which is capable of performing simultaneous threading of multiple aligned sequences onto one or more 3-D structures. In a second step, the structural equivalencies obtained from the MST output are converted into inter-residue distance restraints and fed into the distance geometry program DRAGON, together with auxiliary information obtained from secondary structure predictions. The program combines the restraints in an unbiased manner and rapidly generates a large number of low resolution model confirmations. In a third step, these low resolution model confirmations are converted into full-atom models and subjected to energy minimization using the molecular modeling package QUANTA. (See e.g., Asz6di et al., Proteins:Structure, Function, and Genetics, Supplement 1:38-42 (1997)).  
      The results of the molecular modeling analysis may then be used in rational drug design techniques to identify agents which modulate the activity of the polypeptide codes of SEQ ID NOS. 74-123.  
      Accordingly, another aspect of the present invention is a method of identifying a feature within the cDNA codes of SEQ ID NOs. 1-405 or the polypeptide codes of SEQ ID NOS. 406-810 comprising reading the nucleic acid code(s) or the polypeptide code(s) through the use of a computer program which identifies features therein and identifying features within the nucleic acid code(s) or polypeptide code(s) with the computer program. In one embodiment, computer program comprises a computer program which identifies open reading frames. In a further embodiment, the computer program comprises a computer program which identifies linear or structural motifs in a polypeptide sequence. In another embodiment, the computer program comprises a molecular modeling program. The method may be performed by reading a single sequence or at least 2, 5, 10, 15, 20, 25, 30, or 50 of the cDNA codes of SEQ ID NOs. 1-405 or the polypeptide codes of SEQ ID NOS. 406-810 through the use of the computer program and identifying features within the cDNA codes or polypeptide codes with the computer program.  
      The cDNA codes of SEQ ID NOs. 1-405 or the polypeptide codes of SEQ ID NOS. 406-810 may be stored and manipulated in a variety of data processor programs in a variety of formats. For example, the cDNA codes of SEQ ID NOs. 1-405 or the polypeptide codes of SEQ ID NOS. 406-810 may be stored as text in a word processing file, such as MicrosoftWORD or WORDPERFECT or as an ASCII file in a variety of database programs familiar to those of skill in the art, such as DB2, SYBASE, or ORACLE. In addition, many computer programs and databases may be used as sequence comparers, identifiers, or sources of reference nucleotide or polypeptide sequences to be compared to the cDNA codes of SEQ ID NOs.1-405 or the polypeptide codes of SEQ ID NOS406-810. The following list is intended not to limit the invention but to provide guidance to programs and databases which are useful with the cDNA codes of SEQ ID NOs. 1-405 or the polypeptide codes of SEQ ID NOS. 406-810. The programs and databases which may be used include, but are not limited to: MacPattern (EMBL), DiscoveryBase (Molecular Applications Group), GeneMine (Molecular Applications Group), Look (Molecular Applications Group), MacLook (Molecular Applications Group), BLAST and BLAST2 (NCB1), BLASTN and BLASTX (Altschul et al,  J. Mol. Biol.  215: 403 (1990)), FASTA (Pearson and Lipman,  Proc. Natl. Acad. Sci. USA,  85: 2444 (1988)), FASTDB (Brutlag et al. Comp. App. Biosci. 6:237-245, 1990), Catalyst (Molecular Simulations Inc.), Catalyst/SHAPE (Molecular Simulations Inc.), Cerius 2 .DBAccess (Molecular Simulations Inc.), HypoGen (Molecular Simulations Inc.), Insight II, (Molecular Simulations Inc.), Discover (Molecular Simulations Inc.), CHARMm (Molecular Simulations Inc.), Felix (Molecular Simulations Inc.), DelPhi, (Molecular Simulations Inc.), QuanteMM, (Molecular Simulations Inc.), Homology (Molecular Simulations Inc.), Modeler (Molecular Simulations Inc.), ISIS (Molecular Simulations Inc.), Quanta/Protein Design (Molecular Simulations Inc.), WebLab (Molecular Simulations Inc.), WebLab Diversity Explorer (Molecular Simulations Inc.), Gene Explorer (Molecular Simulations Inc.), SeqFold (Molecular Simulations Inc.), the EMBL/Swissprotein database, the MDL Available Chemicals Directory database, the MDL Drug Data Report data base, the Comprehensive Medicinal Chemistry database, Derwents&#39;s World Drug Index database, the BioByteMasterFile database, the Genbank database, and the Genseqn database. Many other programs and data bases would be apparent to one of skill in the art given the present disclosure.  
      Motifs which may be detected using the above programs include sequences encoding leucine zippers, helix-turn-helix motifs, glycosylation sites, ubiquitination sites, alpha helices, and beta sheets, signal sequences encoding signal peptides which direct the secretion of the encoded proteins, sequences implicated in transcription regulation such as homeoboxes, acidic stretches, enzymatic active sites, substrate binding sites, and enzymatic cleavage sites.  
     EXAMPLE 55  
      Methods of Making Nucleic Acids  
      The present invention also comprises methods of making the cDNA of SEQ ID Nos. 406-810, genomic DNA obtainable therefrom, or fragment thereof. The methods comprise sequentially linking together nucleotides to produce the nucleic acids having the preceding sequences. A variety of methods of synthesizing nucleic acids are known to those skilled in the art.  
      In many of these methods, synthesis is conducted on a solid support. These included the 3′ phosphoramidite methods in which the 3′ terminal base of the desired oligonucleotide is immobilized on an insoluble carrier. The nucleotide base to be added is blocked at the 5′ hydroxyl and activated at the 3′ hydroxyl so as to cause coupling with the immobilized nucleotide base. Deblocking of the new immobilized nucleotide compound and repetition of the cycle will produce the desired polynucleotide. Alternatively, polynucleotides may be prepared as described in U.S. Pat. No. 5,049,656. In some embodiments, several polynucleotides prepared as described above are ligated together to generate longer polynucleotides having a desired sequence.  
     EXAMPLE 56  
      Methods of Making Polypeptides  
      The present invention also comprises methods of making the polynucleotides encoded by the cDNA of SEQ ID Nos. 1-405, genomic DNA obtainable therefrom, or fragments thereof and methods of making the polypeptides of SEQ ID Nos. 406-810 or fragments thereof. The methods comprise sequentially linking together amino acids to produce the nucleic polypeptides having the preceding sequences. In some embodiments, the polypeptides made by these methods are 150 amino acids or less in length. In other embodiments, the polypeptides made by these methods are 120 amino acids or less in length.  
      A variety of methods of making polypeptides are known to those skilled in the art, including methods in which the carboxyl terminal amino acid is bound to polyvinyl benzene or another suitable resin. The amino acid to be added possesses blocking groups on its amino moiety and any side chain reactive groups so that only its carboxyl moiety can react. The carboxyl group is activated with carbodiimide or another activating agent and allowed to couple to the immobilized amino acid. After removal of the blocking group, the cycle is repeated to generate a polypeptide having the desired sequence. Alternatively, the methods described in U.S. Pat. No. 5,049,656 may be used.  
     EXAMPLE 57  
      Immunoaffinity Chromatography  
      Antibodies prepared as described above are coupled to a support. Preferably, the antibodies are monoclonal antibodies, but polyclonal antibodies may also be used. The support may be any of those typically employed in immunoaffinity chromatography, including Sepharose CL-4B (Pharmacia, Piscataway, N.J.), Sepharose CL-2B (Pharmacia, Piscataway, N.J.), Affi-gel 10 (Biorad, Richmond, Calif.), or glass beads.  
      The antibodies may be coupled to the support using any of the coupling reagents typically used in immunoaffinity chromatography, including cyanogen bromide. After coupling the antibody to the support, the support is contacted with a sample which contains a target polypeptide whose isolation, purification or enrichment is desired. The target polypeptide may be a polypeptide of SEQ ID NOs. 406-810, a fragment thereof, or a fusion protein comprising a polypeptide of SEQ ID NOs. 406-810 or a fragment thereof.  
      Preferably, the sample is placed in contact with the support for a sufficient amount of time and under appropriate conditions to allow at least 50% of the target polypeptide to specifically bind to the antibody coupled to the support.  
      Thereafter, the support is washed with an appropriate wash solution to remove polypeptides which have non-specifically adhered to the support. The wash solution may be any of those typically employed in immunoaffinity chromatography, including PBS, Tris-lithium chloride buffer (0.1M lysine base and 0.5M lithium chloride, pH 8.0), Tris-hydrochloride buffer (0.05M Tris-hydrochloride, pH 8.0), or Tris/Triton/NaCl buffer (50 mM Tris.cl, pH 8.0 or 9.0, 0.1% Triton X-100, and 0.5 MNaCl).  
      After washing, the specifically bound target polypeptide is eluted from the support using the high pH or low pH elution solutions typically employed in immunoaffinity chromatography. In particular, the elution solutions may contain an eluant such as triethanolamine, diethylamine, calcium chloride, sodium thiocyanate, potasssium bromide, acetic acid, or glycine. In some embodiments, the elution solution may also contain a detergent such as Triton X-100 or octyl-β-D-glucoside.  
      As discussed above, the cDNAs of the present invention or fragments thereof can be used for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on Southern gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; for selecting and making oligomers for attachment to a “gene chip” or other support, including for examination for expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.  
      The proteins or polypeptides provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Where the protein binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.  
      Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.  
      Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include without limitation “Molecular Cloning; A Laboratory Manual”, 2d ed., Cole Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and “Methods in Enzymology; Guide to Molecular Cloning Techniques”, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987.  
      Polynucleotides and proteins of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the protein or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the protein or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.  
      Although this invention has been described in terms of certain preferred embodiments, other embodiments which will be apparent to those of ordinary skill in the art in view of the disclosure herein are also within the scope of this invention. Accordingly, the scope of the invention is intended to be defined only by reference to the appended claims. All documents cited herein are incorporated herein by reference in their entirety.  
                                       TABLE I                                   Mature                       FCS   SigPep   Polypeptide   Stop Codon   PolyA Signal   PolyA Site       Id   Location   Location   Location   Location   Location   Location                                                            1   153/1127   153/230     231/1127   1128   1415/1420   1434/1450       2   261/1166   261/314     315/1166   1167   —   1524/1556       3   67/813   67/111   112/813   814   1023/1028   1042/1058       4   187/438    —   187/438   439   612/617   632/648       5    92/1753   92/130    131/1753   1754   2070/2075   2090/2104       6   144/440    144/287    288/440   441   457/462   500/515       7   174/443    174/269    270/443   444   623/628   647/661       8   55/399   55/192   193/399   400   654/659   680/694       9   90/287   90/146   147/287   288   1078/1083   1096/1110       10   49/447   49/111   112/447   448   579/584   602/623       11   199/618    199/408    409/618   619   626/631   643/657       12   271/969    271/366    367/969   970   1092/1097   1123/1137       13   192/440    192/278    279/440   441   590/595   622/636       14   59/703   59/181   182/703   704   783/788   804/818       15   139/1389   139/198     199/1389   1390   1854/1859   1873/1888       16    21/1118   21/89    90/1118   1119   1858/1863   1879/1894       17   143/592    143/277    278/592   593   1877/1882   1899/1913       18   76/999   76/279   280/999   1000   1711/1716   1729/1744       19   123/464    123/269    270/464   465   908/913   931/946       20    85/1230   85/129    130/1230   1231   1589/1594   1607/1622       21   29/664   29/619   620/664   665   657/662   699/715       22   18/878   18/95     96/878   879   1500/1505   1533/1549       23    73/1008   73/147    148/1008   1009   1286/1291   1312/1328       24   165/842    165/251    252/842   843   1474/1479   1500/1515       25    31/1248   31/135    136/1248   1249   1580/1585   1607/1622       26   131/490    131/301    302/490   491   1411/1416   1434/1448       27   61/690   61/168   169/690   691   858/863   879/894       28   501/1253   501/1229   1230/1253   1254   1392/1397   1432/1447       29   25/402   25/96     97/402   403   1500/1505   1525/1540       30   280/678    280/411    412/678   679   1606/1611   1628/1643       31   64/726   64/147   148/726   727   1279/1284   1300/1314       32    42/1097   42/110    111/1097   1098   2323/2328   2341/2356       33   245/1399   245/796     797/1399   1400   1669/1674   1687/1701       34   235/441    235/303    304/441   442   —   758/772       35   88/411   88/234   235/411   412   938/943   964/987       36   129/452    129/212    213/452   453   1290/1295   1309/1324       37   238/612    238/348    349/612   613   1885/1890   1905/1918       38   229/735    229/492    493/735   736   816/821   841/852       39   168/413    168/335    336/413   414   684/689   708/726       40   100/852    100/159    160/852   853    998/1003   1019/1039       41   238/1152   238/339     340/1152   1153   1298/1303   1324/1355       42   187/369    187/312    313/369   370   489/494   558/572       43   121/459    121/165    166/459   460   497/502   521/535       44   34/336   34/123   124/336   337   536/541   556/572       45   119/409    119/388    389/409   410   769/774   789/804       46   232/534    232/306    307/534   535   595/600   615/629       47   140/595   140/442    443/595   596   630/635   655/669       48   32/658   32/289   290/658   659   936/941   959/973       49   14/280   14/76     77/280   281   —   776/791       50   93/290   93/149   150/290   291   1078/1083   1096/1110       51   131-1042   131-169     170-1042   —   —   1042-1053       52   100-276    —   100-276   277   638-643   662-675       53   111-401    111-194    195-401   402   1080-1085   1101-1112       54   359-514    359-454    455-514   515   —   536-547       55   26-397   26-316   317-397   398   1164-1169   1187-1198       56   36-725   36-107   108-725   726   1302-1307   1389-1400       57   35-250   35-130   131-250   251   505-510   526-538       58   169-432    169-267    268-432   433   1132-1137   1155-1167       59   143-460    143-238    239-460   461   697-702   721-730       60   108-908    108-170    171-908   909   1141-1146   1161-1174       61   209-532    —   209-532   533   1133-1138   1146-1158       62    5-211    5-142   143-211   212   716-721   742-754       63   98-850   98-181   182-850   851   1035-1040   1060-1073       64   46-342   46-189   190-342   343   377-382   402-413       65   139-381    139-231    232-381   382   579-584   598-609       66   72-512   —    72-512   —   —   512-522       67   126-944    126-260    261-944   945   1283-1288   1309-1322       68    50-1279   50-160    161-1279   —   —   1280-1290       69    83-1261   83-139    140-1261   1262   —   —       70    57-1199   57-95     96-1199   1200   1438-1443   1458-1470       71   72-944   72-197   198-944   945   —   970-982       72    4-279   —    4-279   280   425-430   443-455       73   90-470   90-278   279-470   471   704-709   724-738       74   88-339   88-147   148-339   340   619-624   637-649       75   33-578   33-92     93-578   579   —   703-714       76   33-245   33-107   108-245   246   546-551   584-596       77   125-343    —   125-343   344   375-380   390-403       78   126-632    126-575    576-632   633   670-675   721-727       79   90-317   90-155   156-317   318   913-918   932-944       80   126-410    126-287    288-410   411   561-566   587-598       81   85-348   85-150   151-348   —   —   349-360       82   77-343   77-124   125-343   344   461-466   477-490       83   38-364   —    38-364   365   458-463   475-488       84   48-389   48-356   357-389   390   742-747   760-771       85   69-440   69-359   360-440   441   927-932   947-959       86   33-311   33-98     99-311   312   437-442   455-464       87   110-730    110-235    236-730   731   764-769   787-799       88   38-214   —    38-214   215   —   308-320       89   129-296    129-209    209-296   297   —   318-331       90   78-563   78-359   340-563   564   1042-1047   1063-1075       91   62-523   62-265   266-523   524   602-607   621-632       92   24-320   —    24-320   321   402407   419-430       93   42-170   42-113   114-170   171   —   172-185       94   108-314    108-170    171-314   315   550-555   574-585       95   118-351    118-171    172-351   352   583-588   602-613       96   128-367    128-268    269-367   368   410-415   424-427       97   149-871    149-457    458-871   872   —   893-912       99    7-471   7-99   100-471   472   537-542   554-568       100   168 / 332    —   168 / 332   333   —   —       101   51 / 251   51 / 110   111 / 251   252   849 / 854   882 / 895       102   20 / 613   20 / 82     83 / 613   614   —   —       103   12 / 416   12 / 86     87 / 416   417   425 / 430   445 / 458       104   276 / 1040   276 / 485     486 / 1040   1041   —   2024 / 2036       105   443 / 619    443 / 589    590 / 619   620   —   1267 / 1276       106   206 / 747    —   206 / 747   —   —   —       107   36 / 521   36 / 104   105 / 521   522   528 / 533   548 / 561       108   36 / 395   36 / 104   105 / 395   396   599 / 604   619 / 632       109   21 / 41    —   21 / 41   42   328 / 333   357 / 370       110   35 / 631   35 / 160   161 / 631   632   901 / 906   979 / 994       111   271 / 399    —   271 / 399   400   —   —       112   103 / 252    103 / 213    214 / 252   253   —   588 / 597       113    2 / 460   —    2 / 460   461   713 / 718   735 / 748       114   31 / 231   —    31 / 231   232   769 / 774   690 / 703       115   305 / 565    —   305 / 565   566   694 / 699   713 / 725       116   124 / 873    124 / 378    379 / 873   874   1673 / 1678   1694 / 1705       117   135 / 206    —   135 / 206   207   850 / 855   1056 / 1069       118   135 / 818    —   135 / 818   819   909 / 914   1071 / 1084       119   33 / 290   33 / 92     93 / 290   291   —   —       120   485 / 616    —   485 / 616   617   —   669 / 682       121   54 / 995   54 / 227   228 / 995   996   1130 / 1135   1181 / 1191       122   657 / 923    657 / 896    897 / 923   924   957 / 962    974 / 1008       123   18 / 311   18 / 62     63 / 311   312   —   —       124   151 / 426    151 / 258    259 / 426   427   505 / 510   527 / 538       125    10 / 1062   10 / 57     58 / 1062   1063   1710 / 1715   1735 / 1747       126   78 / 491   78 / 218   219 / 491   492   1652 / 1657   1673 / 1686       127   69 / 371   69 / 287   288 / 371   372   510 / 515   530 / 542       128    2 / 757    2 / 205   206 / 757   758   —   1160 / 1174       129     2 / 1051    2 / 205    206 / 1051   1052   1248 / 1253   1272 / 1285       130     2 / 1171    2 / 205    206 / 1171   1172   1368 / 1373   1386 / 1398       131   42 / 611   42 / 287   288 / 611   612   787 / 792   808 / 821       132   62 / 916   62 / 757   758 / 916   —   —   904 / 916       133   62 / 520   —    62 / 520   521   1124 / 1129   1141 / 1153       134   21 / 167   —    21 / 167   168   —   —       135   22 / 318   22 / 93     94 / 318   319   497 / 502   516 / 526       136    8 / 292    8 / 118   119 / 292   293   317 / 322   339 / 352       137   16 / 378   16 / 84     85 / 378   379   502 / 507   522 / 542       138   57 / 233   —    57 / 233   —   —   —       139   83 / 340   83 / 124   125 / 340   341   573 / 578   607 / 660       140   47 / 541   47 / 220   221 / 541   542   —   597 / 605       141   46 / 285   46 / 150   151 / 285   286   364 / 369   385 / 396       142   22 / 240   22 / 84     85 / 240   241   397 / 402   421 / 432       143   89 / 382   —    89 / 382   383   —   408 / 420       144   80 / 415   80 / 142   143 / 415   —   471 / 476   488 / 501       145   152 / 361    152 / 283    284 / 361   362   —   —       146   32 / 307   32 / 70     71 / 307   308   1240 / 1245   1261 / 1272       147   114 / 734    114 / 239    240 / 734   735   768 / 773   793 / 804       148   199 / 802    —   199 / 802   —   780 / 785   791 / 802       149    38 / 1174   38 / 148    149 / 1174   1175   1452 / 1457   1478 / 1490       150   26 / 361   —    26 / 361   —   —   350 / 361       151    3 / 131   —    3 / 131   132   —   591 / 605       152   33 / 185   33 / 80     81 / 185   186   570 / 575   586 / 591       153   184 / 915    184 / 237    238 / 915   916   1119 / 1124   1139 / 1150       154    58 / 1116   58 / 159    160 / 1116   1117   1486 / 1491   1504 / 1513       155   327 / 417    —   327 / 417   —   —   404 / 417       156   63 / 398   63 / 206   207 / 398   399   —   —       157    2 / 163   —    2 / 163       488 / 493   511 / 522       158   13 / 465   13 / 75     76 / 465   466   —   —       159   20 / 703   20 / 94     95 / 703   704   1000 / 1005   1023 / 1041       160   103 / 294    103 / 243    244 / 294   295   —   —       161   81 / 518   81 / 173   174 / 518   519   —   —       162   66 / 326   —    66 / 326   327   1066 / 1071   1087 / 1098       163   170 / 289    170 / 250    251 / 289   290   —   —       164   36 / 497   —    36 / 497   498   650 / 655   663 / 685       165   18 / 320   —    18 / 320   321   539 / 544   542 / 554       166    71 / 1438   71 / 136    137 / 1438   1439   1644 / 1649   1665 / 1678       167   25 / 318   25 / 75     76 / 318   319   452 / 457   482 / 494       168   84 / 332   84 / 170   171 / 332   333   —   702 / 714       169   32 / 718   32 / 100   101 / 718   719   770 / 775   793 / 805       170   26 / 481   26 / 88     89 / 481   482   755 / 760   775 / 787       171   26 / 562   26 / 187   188 / 562   563   —   —       172    4 / 810    4 / 279   280 / 810   811   858 / 863   881 / 893       173   55 / 459   55 / 120   121 / 459   460   1444 / 1449   1462 / 1475       174   48 / 248   48 / 161   162 / 248   249   283 / 288   308 / 321       175   25 / 399   25 / 186   187 / 399   400   —   —       176    10 / 1137   10 / 72     73 / 1137   1138   1144 / 1149   1162 / 1173       177   72 / 704   72 / 161   162 / 704   705   772 / 777   —       178   44 / 505   44 / 223   224 / 505   506   —   —       179   25 / 393   25 / 150   151 / 393   394   734 / 739   757 / 770       180    58 / 1095   58 / 114    115 / 1095   1096   —   1202 / 1213       181   31 / 660   31 / 90     91 / 660   661   1288 / 1293   1307 / 1318       182   31 / 582   31 / 90     91 / 582   583   816 / 821   840 / 853       183   15 / 695   15 / 80     81 / 695   696   795 / 800   814 / 826       184   74 / 295   74 / 196   197 / 295   296   545 / 550   561 / 571       185   440 / 659    —   440 / 659   —   601 / 606   —       186   38 / 283   38 / 85     86 / 283   284   257 / 262   —       187   121 / 477    121 / 288    289 / 477   —   —   —       188    2 / 163   —    2 / 163   164   292 / 297   310 / 323       189   46 / 675   46 / 87     88 / 675       1364 / 1369   1383 / 1392       190   62 / 385   —    62 / 385   386   974 / 979   987 / 999       191   422 / 550    422 / 475    476 / 550   551   —   714 / 725       192   124 / 231    —   124 / 231   232   —   387 / 400       193   131 /1053   131 / 169     170 / 1053   —   1019 / 1024   —       194   86 / 403   86 / 181   182 / 403   404   1097 / 1102   1117 / 1128       195   37 / 162   37 / 93     94 / 162   163   224 / 229   243 / 254       196   31 / 381   31 / 90     91 / 381   382   —   875 / 886       197   46 / 579   46 / 156   157 / 579   580   —   —       198   92 / 471   92 / 172   173 / 471   —   454 / 459   458 / 471       199   154 / 675    154 / 498    499 / 675   676   819 / 824   838 / 849       200   18 / 173   18 / 77     78 / 173   174   864 / 869   882 / 893       201   17 / 595   17 / 85     86 / 595   596   820 / 825   840 / 851       202   89 / 334   89 / 130   131 / 334   335   462 / 467   484 / 495       203   21 / 614   21 / 83     84 / 614   615   849 / 854   873 / 884       204   94 / 573   94 / 258   259 / 573   574   862 / 867   886 / 897       205   74 / 397   74 / 127   128 / 397   398   472 / 477   507 / 518       206   51 / 242   51 / 116   117 / 242   243   319 / 324   339 / 350       207   111 / 191    111/ 155   156 / 191   192   965 / 970   986 / 996       208   45 / 602   45 / 107   108 / 602   603   828 / 833   850 / 860       209   24 / 560   24 / 101   102 / 560   561   563 / 568   583 / 593       210   109 / 558    109/ 273   274 / 558   559   —   1104 / 1114       211   128 / 835    128/ 220   221 / 835   836   1145 / 1150   1170 / 1181       212   59 / 505   59 / 358   359 / 505   506   1042 / 1047   1062 / 1073       213    1 / 207    1 / 147   148 / 207   208   784 / 789   807 / 818       214   12 / 734   12 / 101   102 / 734   735   914 / 919   961 / 971       215   378 / 518    378/ 467   468 / 518   519   607 / 612   628 / 640       216   110 / 304    110/ 193   194 / 304   305   708 / 713   732 / 743       217   201 / 419    201/ 272   273 / 419   420   601 / 606   627 / 637       218   123 / 302    123/ 176   177 / 302   303   1279 / 1284   1301 / 1312       219   98 / 673   98 / 376   377 / 673   674   —   1025 / 1035       220   17 / 463   17 / 232   233 / 463   464   657 / 662   684 / 696       221   263 / 481    263/ 322   323 / 481   482   —   858 / 868       222   42 / 299   42 / 101   102 / 299   300   —   762 / 775       223   198 / 431    198/ 260   261 / 431   432   —   1064 / 1074       224   279 / 473    279/ 362   363 / 473   474   944 / 949   970 / 981       225   12 / 644   12 / 92     93 / 644   645   1002 / 1007   1020 / 1031       226   91 / 459   91 / 330   331 / 459   460   —   1271 / 1281       227   70 / 327   70 / 147   148 / 327   328   1741 / 1746   1763 / 1774       228   12 / 497   12 / 104   105 / 497   498   935 / 940   955 / 967       229   90 / 383   90 / 200   201 / 383   384   609 / 614   632 / 643       230   332 / 541    332/ 376   377 / 541   542   739 / 744   761 / 773       231   43 / 222   43 / 177   178 / 222   223   530 / 535   555 / 566       232   115 / 231    115/ 180   181 / 231   232   419 / 424   445 / 455       233   232 / 384    232/ 300   301 / 384   385   650 / 655   662 / 673       234   143 / 427    143/ 286   287 / 427   428   606 / 611   628 / 639       235   284 / 463    284/ 379   380 / 463   464   —   762 / 772       236   162 / 671    162/ 398   399 / 671   672   805 / 810   830 / 840       237   63 / 632   63 / 308   309 / 632   633   808 / 813   829 / 840       238   21 / 362   21 / 200   201 / 362   363   821 / 826   838 / 849       239   21 / 503   21 / 344   345 / 503   504   1305 / 1310   1330 / 1341       240    1 / 201   1 / 63    64 / 201   202   637 / 642   660 / 671       241    39 / 1034   39 / 134   135 / 1034   1035   1566 / 1571   1587 / 1597       242   69 / 263   69 / 125   126 / 263   264   1173 / 1178   1196 / 1205       243   115 / 285    115/ 204   205 / 285   286   505 / 510   525 / 536       244   90 / 344   90 / 140   141 / 344   345   500 / 505   515 / 527       245   57 / 311   57 / 107   108 / 311   312   467 / 472   482 / 493       246   96 / 302   96 / 182   183 / 302   303   —   501 / 514       247   161 / 526    161/ 328   329 / 526   527   —   799 / 811       248   210 / 332    210/ 299   300 / 332   333   594 / 599   613 / 625       249   212 / 361    212/ 319   320 / 361   362   650 / 655   673 / 684       250   75 / 482   75 / 128   129 / 482   483   595 / 600   618 / 627       251   50 / 631   50 / 244   245 / 631   632   777 / 782   801 / 812       252   154 / 576    154/ 360   361 / 576   577   737 / 742   763 / 775       253   154 / 897    154/ 360   361 / 897   898   1017 / 1022   1044 / 1054       254   146 / 292    146/ 253   254 / 292   293   395 / 400   433 / 444       255   126 / 383    126/ 167   168 / 383   384   726 / 731   743 / 754       256   66 / 497   66 / 239   240 / 497   498   594 / 599   618 / 629       257   49 / 411   49 / 96     97 / 411   412   732 / 737   750 / 763       258   49 / 534   49 / 96     97 / 534   535   593 / 598   612 / 623       259   86 / 415   86 / 145   146 / 415   416   540 / 545   560 / 571       260   56 / 268   56 / 100   101 / 268   269   584 / 589   601 / 612       261   32 / 328   32 / 103   104 / 328   329   508 / 513   528 / 539       262   21 / 527   21 / 95     96 / 527   528   921 / 926   953 / 963       263   147 / 647    147/ 374   375 / 647   648   —   668 / 681       264   262 / 471    262/ 306   307 / 471   472   663 / 668   682 / 693       265    74 / 1216   74 / 172    173 / 1216   1217   1627 / 1632   1640 / 1652       266   48 / 164   48 / 89     90 / 164   165   482 / 487   505 / 517       267   185 / 334    185/ 295   296 / 334   335   355 / 360   392 / 405       268   195 / 347    195/ 272   273 / 347   348   1037 / 1042   1071 / 1082       269   90 / 815   90 / 179   180 / 815   816   883 / 888   905 / 916       270   52 / 513   52 / 231   232 / 513   514   553 / 558   572 / 583       271   172 / 438    172/ 354   355 / 438   439   682 / 687   685 / 697       272   148 / 366    148/ 225   226 / 366   367   770 / 775   792 / 803       273   175 / 336    17 / 276   277 / 336   337   —   812 / 823       274   191 / 553    191/ 304   305 / 553   554   766 / 771   804 / 817       275   106 / 603    106/ 216   217 / 603   604   —   1102 / 1112       276   47 / 586   47 / 124   125 / 586   587   1583 / 1588   1614 / 1623       277   99 / 371   99 / 290   291 / 371   372   491 / 496   513 / 524       278   44 / 814   44 / 112   113 / 814   815   —   978 / 989       279    3 / 581    3 / 182   183 / 581   582   —   1006 / 1016       280   107 / 427    107/ 190   191 / 427   428   499 / 504   516 / 529       281   45 / 407   45 / 83     84 / 407   408   1008 / 1013   1032 / 1042       282   201 / 332    201/ 251   252 / 332   333   —   869 / 880       283   217 / 543    217/ 255   256 / 543   544   —   1206 / 1217       284   18 / 446   18 / 140   141 / 446   447   930 / 935   948 / 959       285   29 / 724   29 / 118   119 / 724   725   886 / 891   910 / 920       286   404 / 586    404/ 466   467 / 586   587   1304 / 1309   1334 / 1344       287   331 / 432    331/ 387   388 / 432   433   548 / 553   573 / 585       288   59 / 703   59 / 220   221 / 703   704   886 / 891   903 / 914       289   672 / 752    672/ 722   723 / 752   753   —   1150 / 1161       290   57 / 311   57 / 128   129 / 311   312   332 / 337   351 / 363       291   80 / 232   80 / 127   128 / 232   233   617 / 622   634 / 645       292   91 / 291   91 / 219   220 / 291   292   367 / 372   389 / 400       293   196 / 384    196/ 240   241 / 384   385   461 / 466   485 / 496       294   54 / 590   54 / 227   228 / 590   591   —   955 / 965       295   133 / 846    133/ 345   346 / 846   847   —   890 / 901       296   138 / 671    138/ 248   249 / 671   672   1319 / 1324   1338 / 1347       297   124 / 411    124/ 186   187 / 411   412   948 / 953   971 / 983       298   372 / 494    372/ 443   444 / 494   495   708 / 713   732 / 745       299   112 / 450    112/ 192   193 / 450   451   1053 / 1058   1095 / 1106       300   117 / 866    117/ 170   171 / 866   867   1159 / 1164   1178 / 1190       301   13 / 465   13 / 75     76 / 465   466   1035 / 1040   1060 / 1070       302    2 / 718   2 / 76    77 / 718   719   1170 / 1175   1203 / 1213       303   86 / 709   86 / 361   362 / 709   710   943 / 948   963 / 973       304   63 / 320   63 / 179   180 / 320   321   771 / 776   799 / 810       305   299 / 418    299/ 379   380 / 418   419   739 / 744   762 / 771       306   186 / 380    186/ 233   234 / 380   381   383 / 388   396 / 409       307   69 / 458   69 / 233   234 / 458   459   564 / 569   602 / 613       308   12 / 638   12 / 263   264 / 638   639   951 / 956   975 / 985       309   282 / 389    282/ 332   333 / 389   390   1413 / 1418   1437 / 1447       310   208 / 339    208/ 294   295 / 339   340   —   1631 / 1641       311   69 / 557   69 / 224   225 / 557   558   849 / 854   870 / 883       312   134 / 325    134/ 274   275 / 325   326   —   718 / 729       313   78 / 731   78 / 227   228 / 731   732   —   1002 / 1013       314   46 / 693   46 / 90     91 / 693   694   937 / 942   962 / 973       315   126 / 527    126/ 182   183 / 527   528   834 / 839   856 / 867       316   66 / 320   66 / 113   114 / 320   321   490 / 495   508 / 519       317   73 / 948   73 / 159   160 / 948   949   —   1016 / 1028       318   69 / 434   69 / 236   237 / 434   435   419 / 424   441 / 452       319   628 / 804    628/ 711   712 / 804   805   —   864 / 875       320   70 / 366   70 / 108   109 / 366   367   496 / 501   521 / 531       321   70 / 366   70 / 108   109 / 366   367   —   1233 / 1244       322   111 / 434    111/ 185   186 / 434   435   —   618 / 631       323   19 / 567   19 / 63     64 / 567   568   749 / 754   771 / 781       324   19 / 312   19 / 63     64 / 312   313   896 / 901   921 / 931       325   64 / 612   64 / 234   235 / 612   613   —   839 / 849       326   39 / 458   39 / 80     81 / 458   459   613 / 618   633 / 644       327    9 / 185   9 / 50    51 / 185   186   —   906 / 918       328   14 / 316   14 / 121   122 / 316   317   442 / 447   458 / 471       329    70 / 1092   70 / 234    235 / 1092   1093   1475 / 1480   1493 / 1504       330   274 / 597    274/ 399   400 / 597   598   731 / 736   754 / 765       331   230 / 469    230/ 307   308 / 469   470   1004 / 1009   1027 / 1040       332   72 / 545   72 / 203   204 / 545   546   —   1151 / 1162       333   36 / 425   36 / 119   120 / 425   426   1215 / 1220   1240 / 1250       334   155 / 751    155/ 340   341 / 751   752   912 / 917   937 / 947       335   46 / 585   46 / 120   121 / 585   586   584 / 589   606 / 619       336   35 / 568   35 / 100   101 / 568   569   667 / 672   685 / 699       337   68 / 337   68 / 124   125 / 337   338   462 / 467   482 / 497       338   39 / 413   39 / 83     84 / 413   414   566 / 571   583 / 598       339   235 / 642    235 / 336    337 / 642   643   1540 / 1545   1564 / 1579       340   42 / 755   42 / 200   201 / 755   756   860 / 865   878 / 893       341   23 / 340   23 / 235   236 / 340   341   611 / 616   629 / 644       342   12 / 380   12 / 263   264 / 380   381   —   523 / 538       343    8 / 232    8 / 154   155 / 232   233   —   737 / 752       344   183 / 422    183 / 302    303 / 422   423   505 / 510   523 / 537       345    24 / 1004   24 / 170    171 / 1004   1005   —   1586 / 1602       346   80 / 784   80 / 139   140 / 784   785   910 / 915   933 / 948       347   67 / 222   67 / 159   160 / 222   223   —   673 / 687       348   46 / 732   46 / 186   187 / 732   733   781 / 786   806 / 821       349   81 / 356   81 / 152   153 / 356   357   406 / 411   429 / 445       350    72 / 1346   72 / 140    141 / 1346   1347   1482 / 1487   1502 / 1517       351   194 / 454    194 / 379    380 / 454   455   —   1545 / 1560       352   48 / 494   48 / 347   348 / 494   495   1031 / 1036   1051 / 1066       353   111 / 671    111 / 215    216 / 671   672   990 / 995   1045 / 1061       354    5 / 373   5 / 82    83 / 373   374   1986 / 1991   2010 / 2025       355   14 / 472   14 / 319   320 / 472   473   555 / 560   576 / 591       356    2 / 217   —    2 / 217   218   489 / 494   529 / 544       357   51 / 575   51 / 110   111 / 575   576   1653 / 1658   1674 / 1689       358   69 / 977   69 / 128   129 / 977   978   1076 / 1081   1096 / 1111       359   44 / 238   44 / 160   161 / 238   239   443 / 448   540 / 554       360   114 / 524    114 / 164    165 / 524   525   1739 / 1744   1758 / 1773       361   26 / 487   26 / 64     65 / 487   488   883 / 888   901 / 917       362   80 / 388   80 / 187   188 / 388   389   609 / 614   627 / 641       363   186 / 443    186 / 407    408 / 443   444   827 / 832   839 / 854       364    75 / 1259    75 / 1004   1005 / 1259   1260   1536 / 1541   1553 / 1568       365   98 / 376   98 / 151   152 / 376   377   471 / 476   491 / 506       366   72 / 254   72 / 134   135 / 254   255   506 / 511   528 / 542       367   148 / 1140   148 / 240     241 / 1140   1141   1590 / 1595   1614 / 1629       368   109 / 738    109 / 405    406 / 738   739   1633 / 1638   1650 / 1665       369   55 / 291   55 / 255   256 / 291   292   390 / 395   410 / 425       370   25 / 276   —    25 / 276   277   508 / 513   533 / 546       371   32 / 307   32 / 91     92 / 307   308   452 / 457   472 / 485       372   46 / 675   46 / 87     88 / 675   676   1363 / 1368   1382 / 1394       373   329 / 943    329 / 745    746 / 943   944   —   1322 / 1333       374   27 / 281   27 / 77     78 / 281   282   —   —       375   61 / 405   61 / 213   214 / 405   406   675 / 680   692 / 703       376   137 / 379    137 / 229    230 / 379   380   728 / 733   755 / 768       377   37 / 741   37 / 153   154 / 741   742   969 / 974    994 / 1007       378   80 / 265   80 / 142   143 / 265   266   491 / 496   517 / 527       379   612 / 644    —   612 / 644   645   829 / 834   850 / 861       380   61 / 228   61 / 162   163 / 228   229   208 / 213   —       381   15 / 311   15 / 110   111 / 311   312   507 / 512   531 / 542       382   50 / 529   50 / 130   131 / 529   530   877 / 882   899 / 909       383   240 / 416    240 / 305    306 / 416   417   1117 / 1122   1139 / 1149       384   111 / 446    111 / 254    255 / 446   447   890 / 895   909 / 921       385   123 / 455    123 / 290    291 / 455   456   886 / 891   904 / 916       386    2 / 433    2 / 232   233 / 433   434   488 / 493   510 / 520       387   34 / 363   34 / 87     88 / 363   364   536 / 541   558 / 568       388   50 / 286   50 / 157   158 / 286   287   385 / 390   405 / 416       389   50 / 637   50 / 151   152 / 637   638   —   1277 / 1289       390   72 / 602   72 / 125   126 / 602   603   —   704 / 715       391   120 / 434    120 / 185    186 / 434   435   899 / 904   918 / 931       392    4 / 447    4 / 147   148 / 447   448   858 / 863   880 / 891       393   28 / 804   28 / 96     97 / 804   805   —   806 / 817       394   27 / 359   27 / 212   213 / 359   360   988 / 993   1009 / 1020       395   25 / 957   25 / 93     94 / 957   958   1368 / 1373   1388 / 1399       396   47 / 319   47 / 226   227 / 319   320   —   656 / 666       397   80 / 940   80 / 130   131 / 940   941   1101 / 1106   1119 / 1130       398   146 / 457    146 / 292    293 / 457   458   442 / 447   465 / 475       399   100 / 351    100 / 207    208 / 351   352   —   940 / 949       400   177 / 569    177 / 236    237 / 569   570   —   931 / 939       401   67 / 459   67 / 135   136 / 459   460   856 / 861   875 / 887       402    65 / 1069   65 / 112    113 / 1069   1070   1978 / 1983   1999 / 2010       403   70 / 321   70 / 234   235 / 321   322   364 / 369   375 / 387       404   38 / 877   38 / 91     92 / 877   878   947 / 952   974 / 983       405   51 / 470   51 / 203   204 / 470   471   1585 / 1590   1604 / 1614                  
 
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE II 
               
               
                   
                   
               
               
                   
                   
               
               
                   
                   
                 Full Length 
                 Signal 
                 Mature 
               
               
                   
                   
                 Polypeptide 
                 Peptide 
                 Polypeptide 
               
               
                   
                 Seq Id No 
                 Location 
                 Location 
                 Location 
               
               
                   
                   
               
             
            
               
                   
                 406 
                  −26 / 299 
                 −26 / −1 
                  1 / 299 
               
               
                   
                 407 
                  −18 / 284 
                 −18 / −1 
                  1 / 284 
               
               
                   
                 408 
                  −15 / 234 
                 −15 / −1 
                  1 / 234 
               
               
                   
                 409 
                      1 / 84  
                 — 
                 1 / 84 
               
               
                   
                 410 
                  −13 / 541 
                 −13 / −1 
                  1 / 541 
               
               
                   
                 411 
                 −48 / 51 
                 −48 / −1 
                 1 / 51 
               
               
                   
                 412 
                 −32 / 58 
                 −32 / −1 
                 1 / 58 
               
               
                   
                 413 
                 −46 / 69 
                 −46 / −1 
                 1 / 69 
               
               
                   
                 414 
                 −19 / 47 
                 −19 / −1 
                 1 / 47 
               
               
                   
                 415 
                  −21 / 112 
                 −21 / −1 
                  1 / 112 
               
               
                   
                 416 
                 −70 / 70 
                 −70 / −1 
                 1 / 70 
               
               
                   
                 417 
                  −32 / 201 
                 −32 / −1 
                  1 / 201 
               
               
                   
                 418 
                 −29 / 54 
                 −29 / −1 
                 1 / 54 
               
               
                   
                 419 
                  −41 / 174 
                 −41 / −1 
                  1 / 174 
               
               
                   
                 420 
                  −20 / 397 
                 −20 / −1 
                  1 / 397 
               
               
                   
                 421 
                  −23 / 343 
                 −23 / −1 
                  1 / 343 
               
               
                   
                 422 
                  −45 / 105 
                 −45 / −1 
                  1 / 105 
               
               
                   
                 423 
                  −68 / 240 
                 −68 / −1 
                  1 / 240 
               
               
                   
                 424 
                 −49 / 65 
                 −49 / −1 
                 1 / 65 
               
               
                   
                 425 
                  −15 / 367 
                 −15 / −1 
                  1 / 367 
               
               
                   
                 426 
                 −197 / 15  
                 −197 / −1  
                 1 / 15 
               
               
                   
                 427 
                  −26 / 261 
                 −26 / −1 
                  1 / 261 
               
               
                   
                 428 
                  −25 / 287 
                 −25 / −1 
                  1 / 287 
               
               
                   
                 429 
                  −29 / 197 
                 −29 / −1 
                  1 / 197 
               
               
                   
                 430 
                  −35 / 371 
                 −35 / −1 
                  1 / 371 
               
               
                   
                 431 
                 −57 / 63 
                 −57 / −1 
                 1 / 63 
               
               
                   
                 432 
                  −36 / 174 
                 −36 / −1 
                  1 / 174 
               
               
                   
                 433 
                 −243 / 8  
                 −243 / −1  
                 1 / 8  
               
               
                   
                 434 
                  −24 / 102 
                 −24 / −1 
                  1 / 102 
               
               
                   
                 435 
                 −44 / 89 
                 −44 / −1 
                 1 / 89 
               
               
                   
                 436 
                  −28 / 193 
                 −28 / −1 
                  1 / 193 
               
               
                   
                 437 
                  −23 / 329 
                 −23 / −1 
                  1 / 329 
               
               
                   
                 438 
                 −184 / 201 
                 −184 / −1  
                  1 / 201 
               
               
                   
                 439 
                 −23 / 46 
                 −23 / −1 
                 1 / 46 
               
               
                   
                 440 
                 −49 / 59 
                 −49 / −1 
                 1 / 59 
               
               
                   
                 441 
                 −28 / 80 
                 −28 / −1 
                 1 / 80 
               
               
                   
                 442 
                 −37 / 88 
                 −37 / −1 
                 1 / 88 
               
               
                   
                 443 
                 −88 / 81 
                 −88 / −1 
                 1 / 81 
               
               
                   
                 444 
                 −56 / 26 
                 −56 / −1 
                 1 / 26 
               
               
                   
                 445 
                  −20 / 231 
                 −20 / −1 
                  1 / 231 
               
               
                   
                 446 
                  −34 / 271 
                 −34 / −1 
                  1 / 271 
               
               
                   
                 447 
                 −42 / 19 
                 −42 / −1 
                 1 / 19 
               
               
                   
                 448 
                 −15 / 98 
                 −15 / −1 
                 1 / 98 
               
               
                   
                 449 
                 −30 / 71 
                 −30 / −1 
                 1 / 71 
               
               
                   
                 450 
                 −90 / 7  
                 −90 / −1 
                 1 / 7  
               
               
                   
                 451 
                 −25 / 76 
                 −25 / −1 
                 1 / 76 
               
               
                   
                 452 
                 −101 / 51  
                 −101 / −1  
                 1 / 51 
               
               
                   
                 453 
                  −86 / 123 
                 −86 / −1 
                  1 / 123 
               
               
                   
                 454 
                 −21 / 68 
                 −21 / −1 
                 1 / 68 
               
               
                   
                 455 
                 −19 / 47 
                 −19 / −1 
                 1 / 47 
               
               
                   
                 693 
                  −13 / 291 
                 −13 / −1 
                  1 / 291 
               
               
                   
                 694 
                      1 / 59  
                 — 
                 1 / 59 
               
               
                   
                 695 
                 −28 / 69 
                 −28 / −1 
                 1 / 69 
               
               
                   
                 696 
                 −32 / 20 
                 −32 / −1 
                 1 / 20 
               
               
                   
                 697 
                 −97 / 27 
                 −97 / −1 
                 1 / 27 
               
               
                   
                 698 
                  −24 / 206 
                 −24 / −1 
                  1 / 206 
               
               
                   
                 699 
                 −32 / 40 
                 −32 / −1 
                 1 / 40 
               
               
                   
                 700 
                 −33 / 55 
                 −33 / −1 
                 1 / 55 
               
               
                   
                 701 
                 −32 / 74 
                 −32 / −1 
                 1 / 74 
               
               
                   
                 702 
                  −21 / 246 
                 −21 / −1 
                  1 / 246 
               
               
                   
                 703 
                    1 / 108 
                 — 
                  1 / 108 
               
               
                   
                 704 
                 −46 / 23 
                 −46 / −1 
                 1 / 23 
               
               
                   
                 705 
                  −28 / 223 
                 −28 / −1 
                  1 / 223 
               
               
                   
                 706 
                 −48 / 51 
                 −48 / −1 
                 1 / 51 
               
               
                   
                 707 
                 −31 / 50 
                 −31 / −1 
                 1 / 50 
               
               
                   
                 708 
                    1 / 147 
                 — 
                  1 / 147 
               
               
                   
                 709 
                  −45 / 228 
                 −45 / −1 
                  1 / 228 
               
               
                   
                 710 
                  −37 / 373 
                 −37 / −1 
                  1 / 373 
               
               
                   
                 711 
                  −19 / 374 
                 −19 / −1 
                  1 / 374 
               
               
                   
                 712 
                  −13 / 368 
                 −13 / −1 
                  1 / 368 
               
               
                   
                 713 
                  −42 / 249 
                 −42 / −1 
                  1 / 249 
               
               
                   
                 714 
                      1 / 92  
                 — 
                 1 / 92 
               
               
                   
                 715 
                 −63 / 64 
                 −63 / −1 
                 1 / 64 
               
               
                   
                 716 
                 −20 / 64 
                 −20 / −1 
                 1 / 64 
               
               
                   
                 717 
                  −20 / 162 
                 −20 / −1 
                  1 / 162 
               
               
                   
                 718 
                 −25 / 46 
                 −25 / −1 
                 1 / 46 
               
               
                   
                 719 
                      1 / 73  
                 — 
                 1 / 73 
               
               
                   
                 720 
                 −150 / 19  
                 −150 / −1  
                 1 / 19 
               
               
                   
                 721 
                 −22 / 54 
                 −22 / −1 
                 1 / 54 
               
               
                   
                 722 
                 −54 / 41 
                 −54 / −1 
                 1 / 41 
               
               
                   
                 723 
                 −22 / 66 
                 −22 / −1 
                 1 / 66 
               
               
                   
                 724 
                 −16 / 73 
                 −16 / −1 
                 1 / 73 
               
               
                   
                 725 
                    1 / 109 
                 — 
                  1 / 109 
               
               
                   
                 726 
                 −103 / 11  
                 −103 / −1  
                 1 / 11 
               
               
                   
                 727 
                 −97 / 27 
                 −97 / −1 
                 1 / 27 
               
               
                   
                 728 
                 −22 / 71 
                 −22 / −1 
                 1 / 71 
               
               
                   
                 729 
                  −42 / 165 
                 −42 / −1 
                  1 / 165 
               
               
                   
                 730 
                      1 / 59  
                 — 
                 1 / 59 
               
               
                   
                 731 
                 −27 / 29 
                 −27 / −1 
                 1 / 29 
               
               
                   
                 732 
                 −94 / 68 
                 −94 / −1 
                 1 / 68 
               
               
                   
                 733 
                 −68 / 86 
                 −68 / −1 
                 1 / 86 
               
               
                   
                 734 
                      1 / 99  
                 — 
                 1 / 99 
               
               
                   
                 735 
                 −24 / 19 
                 −24 / −1 
                 1 / 19 
               
               
                   
                 736 
                 −21 / 48 
                 −21 / −1 
                 1 / 48 
               
               
                   
                 737 
                 −18 / 60 
                 −18 / −1 
                 1 / 60 
               
               
                   
                 738 
                 −47 / 33 
                 −47 / −1 
                 1 / 33 
               
               
                   
                 739 
                 −103 / 138 
                 −103 / −1  
                  1 / 138 
               
               
                   
                 456 
                  −31 / 124 
                 −31 / −1 
                  1 / 124 
               
               
                   
                 456 
                  −31 / 124 
                 −31 / −1 
                  1 / 124 
               
               
                   
                 457 
                      1 / 55  
                 — 
                 1 / 55 
               
               
                   
                 458 
                 −20 / 47 
                 −20 / −1 
                 1 / 47 
               
               
                   
                 459 
                  −21 / 177 
                 −21 / −1 
                  1 / 177 
               
               
                   
                 460 
                  −25 / 110 
                 −25 / −1 
                  1 / 110 
               
               
                   
                 461 
                  −70 / 185 
                 −70 / −1 
                  1 / 185 
               
               
                   
                 462 
                 −49 / 10 
                 −49 / −1 
                 1 / 10 
               
               
                   
                 463 
                    1 / 180 
                 — 
                  1 / 180 
               
               
                   
                 464 
                  −23 / 139 
                 −23 / −1 
                  1 / 139 
               
               
                   
                 465 
                 −23 / 97 
                 −23 / −1 
                 1 / 97 
               
               
                   
                 466 
                   1 / 7 
                 — 
                 1 / 7  
               
               
                   
                 467 
                  −42 / 157 
                 −42 / −1 
                  1 / 157 
               
               
                   
                 468 
                      1 / 43  
                 — 
                 1 / 43 
               
               
                   
                 469 
                 −37 / 13 
                 −37 / −1 
                 1 / 13 
               
               
                   
                 470 
                    1 / 153 
                 — 
                  1 / 153 
               
               
                   
                 471 
                      1 / 67  
                 — 
                 1 / 67 
               
               
                   
                 472 
                      1 / 87  
                 — 
                 1 / 87 
               
               
                   
                 473 
                  −85 / 165 
                 −85 / −1 
                  1 / 165 
               
               
                   
                 474 
                      1 / 24  
                 — 
                 1 / 24 
               
               
                   
                 475 
                    1 / 228 
                 — 
                  1 / 228 
               
               
                   
                 476 
                 −20 / 66 
                 −20 / −1 
                 1 / 66 
               
               
                   
                 477 
                      1 / 44  
                 — 
                 1 / 44 
               
               
                   
                 478 
                  −58 / 256 
                 −58 / −1 
                  1 / 256 
               
               
                   
                 479 
                 −80 / 9  
                 −80 / −1 
                 1 / 9  
               
               
                   
                 480 
                 −15 / 83 
                 −15 / −1 
                 1 / 83 
               
               
                   
                 481 
                 −36 / 56 
                 −36 / −1 
                 1 / 56 
               
               
                   
                 482 
                  −16 / 335 
                 −16 / −1 
                  1 / 335 
               
               
                   
                 483 
                 −47 / 91 
                 −47 / −1 
                 1 / 91 
               
               
                   
                 484 
                 −73 / 28 
                 −73 / −1 
                 1 / 28 
               
               
                   
                 485 
                  −68 / 184 
                 −68 / −1 
                  1 / 184 
               
               
                   
                 486 
                  −68 / 282 
                 −68 / −1 
                  1 / 282 
               
               
                   
                 487 
                  −68 / 322 
                 −68 / −1 
                  1 / 322 
               
               
                   
                 488 
                  −82 / 108 
                 −82 / −1 
                  1 / 108 
               
               
                   
                 489 
                 −232 / 53  
                 −232 / −1  
                 1 / 53 
               
               
                   
                 490 
                    1 / 153 
                 — 
                  1 / 153 
               
               
                   
                 491 
                      1 / 49  
                 — 
                 1 / 49 
               
               
                   
                 492 
                 −24 / 75 
                 −24 / −1 
                 1 / 75 
               
               
                   
                 493 
                 −37 / 58 
                 −37 / −1 
                 1 / 58 
               
               
                   
                 494 
                 −23 / 98 
                 −23 / −1 
                 1 / 98 
               
               
                   
                 495 
                      1 / 59  
                 — 
                 1 / 59 
               
               
                   
                 496 
                 −14 / 72 
                 −14 / −1 
                 1 / 72 
               
               
                   
                 497 
                  −58 / 107 
                 −58 / −1 
                  1 / 107 
               
               
                   
                 498 
                 −35 / 45 
                 −35 / −1 
                 1 / 45 
               
               
                   
                 499 
                 −21 / 52 
                 −21 / −1 
                 1 / 52 
               
               
                   
                 500 
                      1 / 98  
                 — 
                 1 / 98 
               
               
                   
                 501 
                 −21 / 91 
                 −21 / −1 
                 1 / 91 
               
               
                   
                 502 
                 −44 / 26 
                 −44 / −1 
                 1 / 26 
               
               
                   
                 503 
                 −13 / 79 
                 −13 / −1 
                 1 / 79 
               
               
                   
                 504 
                  −42 / 165 
                 −42 / −1 
                  1 / 165 
               
               
                   
                 505 
                    1 / 201 
                 — 
                  1 / 201 
               
               
                   
                 506 
                  −37 / 342 
                 −37 / −1 
                  1 / 342 
               
               
                   
                 507 
                    1 / 112 
                 — 
                  1 / 112 
               
               
                   
                 508 
                      1 / 43  
                 — 
                 1 / 43 
               
               
                   
                 509 
                 −16 / 35 
                 −16 / −1 
                 1 / 35 
               
               
                   
                 510 
                  −18 / 226 
                 −18 / −1 
                  1 / 226 
               
               
                   
                 511 
                  −34 / 319 
                 −34 / −1 
                  1 / 319 
               
               
                   
                 512 
                      1 / 30  
                 — 
                 1 / 30 
               
               
                   
                 513 
                 −48 / 64 
                 −48 / −1 
                 1 / 64 
               
               
                   
                 514 
                      1 / 54  
                 — 
                 1 / 54 
               
               
                   
                 515 
                  −21 / 130 
                 −21 / −1 
                  1 / 130 
               
               
                   
                 516 
                  −25 / 203 
                 −25 / −1 
                  1 / 203 
               
               
                   
                 517 
                 −47 / 17 
                 −47 / −1 
                 1 / 17 
               
               
                   
                 518 
                  −31 / 115 
                 −31 / −1 
                  1 / 115 
               
               
                   
                 519 
                      1 / 87  
                 — 
                 1 / 87 
               
               
                   
                 520 
                 −27 / 13 
                 −27 / −1 
                 1 / 13 
               
               
                   
                 521 
                    1 / 154 
                 — 
                  1 / 154 
               
               
                   
                 522 
                    1 / 101 
                 — 
                  1 / 101 
               
               
                   
                 523 
                  −22 / 434 
                 −22 / −1 
                  1 / 434 
               
               
                   
                 524 
                 −17 / 81 
                 −17 / −1 
                 1 / 81 
               
               
                   
                 525 
                 −29 / 54 
                 −29 / −1 
                 1 / 54 
               
               
                   
                 526 
                  −23 / 206 
                 −23 / −1 
                  1 / 206 
               
               
                   
                 527 
                  −21 / 131 
                 −21 / −1 
                  1 / 131 
               
               
                   
                 528 
                  −54 / 125 
                 −54 / −1 
                  1 / 125 
               
               
                   
                 529 
                  −92 / 177 
                 −92 / −1 
                  1 / 177 
               
               
                   
                 530 
                  −22 / 113 
                 −22 / −1 
                  1 / 113 
               
               
                   
                 531 
                 −38 / 29 
                 −38 / −1 
                 1 / 29 
               
               
                   
                 532 
                 −54 / 71 
                 −54 / −1 
                 1 / 71 
               
               
                   
                 533 
                  −21 / 355 
                 −21 / −1 
                  1 / 355 
               
               
                   
                 534 
                  −30 / 181 
                 −30 / −1 
                  1 / 181 
               
               
                   
                 535 
                 −60 / 94 
                 −60 / −1 
                 1 / 94 
               
               
                   
                 536 
                 −42 / 81 
                 −42 / −1 
                 1 / 81 
               
               
                   
                 537 
                  −19 / 327 
                 −19 / −1 
                  1 / 327 
               
               
                   
                 538 
                  −20 / 190 
                 −20 / −1 
                  1 / 190 
               
               
                   
                 539 
                  −20 / 164 
                 −20 / −1 
                  1 / 164 
               
               
                   
                 540 
                  −22 / 205 
                 −22 / −1 
                  1 / 205 
               
               
                   
                 541 
                 −41 / 33 
                 −41 / −1 
                 1 / 33 
               
               
                   
                 542 
                      1 / 73  
                 — 
                 1 / 73 
               
               
                   
                 543 
                 −16 / 66 
                 −16 / −1 
                 1 / 66 
               
               
                   
                 544 
                 −56 / 63 
                 −56 / −1 
                 1 / 63 
               
               
                   
                 545 
                      1 / 54  
                 — 
                 1 / 54 
               
               
                   
                 546 
                  −14 / 196 
                 −14 / −1 
                  1 / 196 
               
               
                   
                 547 
                    1 / 108 
                 — 
                  1 / 108 
               
               
                   
                 548 
                 −18 / 25 
                 −18 / −1 
                 1 / 25 
               
               
                   
                 549 
                      1 / 36  
                 — 
                 1 / 36 
               
               
                   
                 550 
                  −13 / 294 
                 −13 / −1 
                  1 / 294 
               
               
                   
                 551 
                 −32 / 74 
                 −32 / −1 
                 1 / 74 
               
               
                   
                 552 
                 −19 / 23 
                 −19 / −1 
                 1 / 23 
               
               
                   
                 553 
                 −20 / 97 
                 −20 / −1 
                 1 / 97 
               
               
                   
                 554 
                  −37 / 141 
                 −37 / −1 
                  1 / 141 
               
               
                   
                 555 
                 −27 / 99 
                 −27 / −1 
                 1 / 99 
               
               
                   
                 556 
                 −115 / 59  
                 −115 / −1  
                 1 / 59 
               
               
                   
                 557 
                 −20 / 32 
                 −20 / −1 
                 1 / 32 
               
               
                   
                 558 
                  −23 / 170 
                 −23 / −1 
                  1 / 170 
               
               
                   
                 559 
                 −14 / 68 
                 −14 / −1 
                 1 / 68 
               
               
                   
                 560 
                  −21 / 177 
                 −21 / −1 
                  1 / 177 
               
               
                   
                 561 
                  −55 / 105 
                 −55 / −1 
                  1 / 105 
               
               
                   
                 562 
                 −18 / 90 
                 −18 / −1 
                 1 / 90 
               
               
                   
                 563 
                 −22 / 42 
                 −22 / −1 
                 1 / 42 
               
               
                   
                 564 
                 −15 / 12 
                 −15 / −1 
                 1 / 12 
               
               
                   
                 565 
                  −21 / 165 
                 −21 / −1 
                  1 / 165 
               
               
                   
                 566 
                  −26 / 153 
                 −26 / −1 
                  1 / 153 
               
               
                   
                 567 
                 −55 / 95 
                 −55 / −1 
                 1 / 95 
               
               
                   
                 568 
                  −31 / 205 
                 −31 / −1 
                  1 / 205 
               
               
                   
                 569 
                 −100 / 49  
                 −100 / −1  
                 1 / 49 
               
               
                   
                 570 
                 −49 / 20 
                 −49 / −1 
                 1 / 20 
               
               
                   
                 571 
                  −30 / 211 
                 −30 / −1 
                  1 / 211 
               
               
                   
                 572 
                 −30 / 17 
                 −30 / −1 
                 1 / 17 
               
               
                   
                 573 
                 −28 / 37 
                 −28 / −1 
                 1 / 37 
               
               
                   
                 574 
                 −24 / 49 
                 −24 / −1 
                 1 / 49 
               
               
                   
                 575 
                 −18 / 42 
                 −18 / −1 
                 1 / 42 
               
               
                   
                 576 
                 −93 / 99 
                 −93 / −1 
                 1 / 99 
               
               
                   
                 577 
                 −72 / 77 
                 −72 / −1 
                 1 / 77 
               
               
                   
                 578 
                 −20 / 53 
                 −20 / −1 
                 1 / 53 
               
               
                   
                 579 
                 −20 / 66 
                 −20 / −1 
                 1 / 66 
               
               
                   
                 580 
                 −21 / 57 
                 −21 / −1 
                 1 / 57 
               
               
                   
                 581 
                 −28 / 37 
                 −28 / −1 
                 1 / 37 
               
               
                   
                 582 
                  −27 / 184 
                 −27 / −1 
                  1 / 184 
               
               
                   
                 583 
                 −80 / 43 
                 −80 / −1 
                 1 / 43 
               
               
                   
                 584 
                 −26 / 60 
                 −26 / −1 
                 1 / 60 
               
               
                   
                 585 
                  −31 / 131 
                 −31 / −1 
                  1 / 131 
               
               
                   
                 586 
                 −37 / 61 
                 −37 / −1 
                 1 / 61 
               
               
                   
                 587 
                 −15 / 55 
                 −15 / −1 
                 1 / 55 
               
               
                   
                 588 
                 −45 / 15 
                 −45 / −1 
                 1 / 15 
               
               
                   
                 589 
                 −22 / 17 
                 −22 / −1 
                 1 / 17 
               
               
                   
                 590 
                 −23 / 28 
                 −23 / −1 
                 1 / 28 
               
               
                   
                 591 
                 −48 / 47 
                 −48 / −1 
                 1 / 47 
               
               
                   
                 592 
                 −32 / 28 
                 −32 / −1 
                 1 / 28 
               
               
                   
                 593 
                 −79 / 91 
                 −79 / −1 
                 1 / 91 
               
               
                   
                 594 
                  −82 / 108 
                 −82 / −1 
                  1 / 108 
               
               
                   
                 595 
                 −60 / 54 
                 −60 / −1 
                 1 / 54 
               
               
                   
                 596 
                 −108 / 53  
                 −108 / −1  
                 1 / 53 
               
               
                   
                 597 
                 −21 / 46 
                 −21 / −1 
                 1 / 46 
               
               
                   
                 598 
                  −32 / 300 
                 −32 / −1 
                  1 / 300 
               
               
                   
                 599 
                 −19 / 46 
                 −19 / −1 
                 1 / 46 
               
               
                   
                 600 
                 −30 / 27 
                 −30 / −1 
                 1 / 27 
               
               
                   
                 601 
                 −17 / 68 
                 −17 / −1 
                 1 / 68 
               
               
                   
                 602 
                 −17 / 68 
                 −17 / −1 
                 1 / 68 
               
               
                   
                 603 
                 −29 / 40 
                 −29 / −1 
                 1 / 40 
               
               
                   
                 604 
                 −56 / 66 
                 −56 / −1 
                 1 / 66 
               
               
                   
                 605 
                 −30 / 11 
                 −30 / −1 
                 1 / 11 
               
               
                   
                 606 
                 −36 / 14 
                 −36 / −1 
                 1 / 14 
               
               
                   
                 607 
                  −18 / 118 
                 −18 / −1 
                  1 / 118 
               
               
                   
                 608 
                  −65 / 129 
                 −65 / −1 
                  1 / 129 
               
               
                   
                 609 
                 −69 / 72 
                 −69 / −1 
                 1 / 72 
               
               
                   
                 610 
                  −69 / 179 
                 −69 / −1 
                  1 / 179 
               
               
                   
                 611 
                 −36 / 13 
                 −36 / −1 
                 1 / 13 
               
               
                   
                 612 
                 −14 / 72 
                 −14 / −1 
                 1 / 72 
               
               
                   
                 613 
                 −58 / 86 
                 −58 / −1 
                 1 / 86 
               
               
                   
                 614 
                  −16 / 105 
                 −16 / −1 
                  1 / 105 
               
               
                   
                 615 
                  −16 / 146 
                 −16 / −1 
                  1 / 146 
               
               
                   
                 616 
                 −20 / 90 
                 −20 / −1 
                 1 / 90 
               
               
                   
                 617 
                 −15 / 56 
                 −15 / −1 
                 1 / 56 
               
               
                   
                 618 
                 −24 / 75 
                 −24 / −1 
                 1 / 75 
               
               
                   
                 619 
                  −25 / 144 
                 −25 / −1 
                  1 / 144 
               
               
                   
                 620 
                 −76 / 91 
                 −76 / −1 
                 1 / 91 
               
               
                   
                 621 
                 −15 / 55 
                 −15 / −1 
                 1 / 55 
               
               
                   
                 622 
                  −33 / 348 
                 −33 / −1 
                  1 / 348 
               
               
                   
                 623 
                 −14 / 25 
                 −14 / −1 
                 1 / 25 
               
               
                   
                 624 
                 −37 / 13 
                 −37 / −1 
                 1 / 13 
               
               
                   
                 625 
                 −26 / 25 
                 −26 / −1 
                 1 / 25 
               
               
                   
                 626 
                  −30 / 212 
                 −30 / −1 
                  1 / 212 
               
               
                   
                 627 
                 −60 / 94 
                 −60 / −1 
                 1 / 94 
               
               
                   
                 628 
                 −61 / 28 
                 −61 / −1 
                 1 / 28 
               
               
                   
                 629 
                 −26 / 47 
                 −26 / −1 
                 1 / 47 
               
               
                   
                 630 
                 −34 / 20 
                 −34 / −1 
                 1 / 20 
               
               
                   
                 631 
                 −38 / 83 
                 −38 / −1 
                 1 / 83 
               
               
                   
                 632 
                  −37 / 129 
                 −37 / −1 
                  1 / 129 
               
               
                   
                 633 
                  −26 / 154 
                 −26 / −1 
                  1 / 154 
               
               
                   
                 634 
                 −64 / 27 
                 −64 / −1 
                 1 / 27 
               
               
                   
                 635 
                  −23 / 234 
                 −23 / −1 
                  1 / 234 
               
               
                   
                 636 
                  −60 / 133 
                 −60 / −1 
                  1 / 133 
               
               
                   
                 637 
                 −28 / 79 
                 −28 / −1 
                 1 / 79 
               
               
                   
                 638 
                  −13 / 108 
                 −13 / −1 
                  1 / 108 
               
               
                   
                 639 
                 −17 / 27 
                 −17 / −1 
                 1 / 27 
               
               
                   
                 640 
                 −13 / 96 
                 −13 / −1 
                 1 / 96 
               
               
                   
                 641 
                  −41 / 102 
                 −41 / −1 
                  1 / 102 
               
               
                   
                 642 
                  −30 / 202 
                 −30 / −1 
                  1 / 202 
               
               
                   
                 643 
                 −21 / 40 
                 −21 / −1 
                 1 / 40 
               
               
                   
                 644 
                 −19 / 15 
                 −19 / −1 
                 1 / 15 
               
               
                   
                 645 
                  −54 / 161 
                 −54 / −1 
                  1 / 161 
               
               
                   
                 646 
                 −17 / 10 
                 −17 / −1 
                 1 / 10 
               
               
                   
                 647 
                 −24 / 61 
                 −24 / −1 
                 1 / 61 
               
               
                   
                 648 
                 −16 / 35 
                 −16 / −1 
                 1 / 35 
               
               
                   
                 649 
                 −43 / 24 
                 −43 / −1 
                 1 / 24 
               
               
                   
                 650 
                 −15 / 48 
                 −15 / −1 
                 1 / 48 
               
               
                   
                 651 
                  −58 / 121 
                 −58 / −1 
                  1 / 121 
               
               
                   
                 652 
                  −71 / 167 
                 −71 / −1 
                  1 / 167 
               
               
                   
                 653 
                  −37 / 141 
                 −37 / −1 
                  1 / 141 
               
               
                   
                 654 
                 −21 / 75 
                 −21 / −1 
                 1 / 75 
               
               
                   
                 655 
                 −24 / 17 
                 −24 / −1 
                 1 / 17 
               
               
                   
                 656 
                 −27 / 86 
                 −27 / −1 
                 1 / 86 
               
               
                   
                 657 
                  −18 / 232 
                 −18 / −1 
                  1 / 232 
               
               
                   
                 658 
                  −21 / 130 
                 −21 / −1 
                  1 / 130 
               
               
                   
                 659 
                  −25 / 214 
                 −25 / −1 
                  1 / 214 
               
               
                   
                 660 
                  −92 / 116 
                 −92 / −1 
                  1 / 116 
               
               
                   
                 661 
                 −39 / 47 
                 −39 / −1 
                 1 / 47 
               
               
                   
                 662 
                 −27 / 13 
                 −27 / −1 
                 1 / 13 
               
               
                   
                 663 
                 −16 / 49 
                 −16 / −1 
                 1 / 49 
               
               
                   
                 664 
                 −55 / 75 
                 −55 / −1 
                 1 / 75 
               
               
                   
                 665 
                  −84 / 125 
                 −84 / −1 
                  1 / 125 
               
               
                   
                 666 
                 −17 / 19 
                 −17 / −1 
                 1 / 19 
               
               
                   
                 667 
                 −29 / 15 
                 −29 / −1 
                 1 / 15 
               
               
                   
                 668 
                  −52 / 111 
                 −52 / −1 
                  1 / 111 
               
               
                   
                 669 
                 −47 / 17 
                 −47 / −1 
                 1 / 17 
               
               
                   
                 670 
                  −50 / 168 
                 −50 / −1 
                  1 / 168 
               
               
                   
                 671 
                  −15 / 201 
                 −15 / −1 
                  1 / 201 
               
               
                   
                 672 
                  −19 / 115 
                 −19 / −1 
                  1 / 115 
               
               
                   
                 673 
                 −16 / 69 
                 −16 / −1 
                 1 / 69 
               
               
                   
                 674 
                  −29 / 263 
                 −29 / −1 
                  1 / 263 
               
               
                   
                 675 
                 −56 / 66 
                 −56 / −1 
                 1 / 66 
               
               
                   
                 676 
                 −28 / 31 
                 −28 / −1 
                 1 / 31 
               
               
                   
                 677 
                 −13 / 86 
                 −13 / −1 
                 1 / 86 
               
               
                   
                 678 
                 −13 / 86 
                 −13 / −1 
                 1 / 86 
               
               
                   
                 679 
                 −25 / 83 
                 −25 / −1 
                 1 / 83 
               
               
                   
                 680 
                  −15 / 168 
                 −15 / −1 
                  1 / 168 
               
               
                   
                 681 
                 −15 / 83 
                 −15 / −1 
                 1 / 83 
               
               
                   
                 682 
                  −57 / 126 
                 −57 / −1 
                  1 / 126 
               
               
                   
                 683 
                  −14 / 126 
                 −14 / −1 
                  1 / 126 
               
               
                   
                 684 
                 −14 / 45 
                 −14 / −1 
                 1 / 45 
               
               
                   
                 685 
                 −36 / 65 
                 −36 / −1 
                 1 / 65 
               
               
                   
                 686 
                  −55 / 286 
                 −55 / −1 
                  1 / 286 
               
               
                   
                 687 
                 −42 / 66 
                 −42 / −1 
                 1 / 66 
               
               
                   
                 688 
                 −26 / 54 
                 −26 / −1 
                 1 / 54 
               
               
                   
                 689 
                  −44 / 114 
                 −44 / −1 
                  1 / 114 
               
               
                   
                 690 
                  −28 / 102 
                 −28 / −1 
                  1 / 102 
               
               
                   
                 691 
                  −62 / 137 
                 −62 / −1 
                  1 / 137 
               
               
                   
                 692 
                  −25 / 155 
                 −25 / −1 
                  1 / 155 
               
               
                   
                 741 
                  −22 / 156 
                 −22 / −1 
                  1 / 156 
               
               
                   
                 742 
                 −19 / 71 
                 −19 / −1 
                 1 / 71 
               
               
                   
                 743 
                  −15 / 110 
                 −15 / −1 
                  1 / 110 
               
               
                   
                 744 
                  −34 / 102 
                 −34 / −1 
                  1 / 102 
               
               
                   
                 745 
                  −53 / 185 
                 −53 / −1 
                  1 / 185 
               
               
                   
                 746 
                 −71 / 35 
                 −71 / −1 
                 1 / 35 
               
               
                   
                 747 
                 −84 / 39 
                 −84 / −1 
                 1 / 39 
               
               
                   
                 748 
                 −49 / 26 
                 −49 / −1 
                 1 / 26 
               
               
                   
                 749 
                 −40 / 40 
                 −40 / −1 
                 1 / 40 
               
               
                   
                 750 
                  −49 / 278 
                 −49 / −1 
                  1 / 278 
               
               
                   
                 751 
                  −20 / 215 
                 −20 / −1 
                  1 / 215 
               
               
                   
                 752 
                 −31 / 21 
                 −31 / −1 
                 1 / 21 
               
               
                   
                 753 
                  −47 / 182 
                 −47 / −1 
                  1 / 182 
               
               
                   
                 754 
                 −24 / 68 
                 −24 / −1 
                 1 / 68 
               
               
                   
                 755 
                  −23 / 402 
                 −23 / −1 
                  1 / 402 
               
               
                   
                 756 
                 −62 / 25 
                 −62 / −1 
                 1 / 25 
               
               
                   
                 757 
                 −100 / 49  
                 −100 / −1  
                 1 / 49 
               
               
                   
                 758 
                  −35 / 152 
                 −35 / −1 
                  1 / 152 
               
               
                   
                 759 
                 −26 / 97 
                 −26 / −1 
                 1 / 97 
               
               
                   
                 760 
                 −102 / 51  
                 −102 / −1  
                 1 / 51 
               
               
                   
                 761 
                      1 / 72  
                 — 
                 1 / 72 
               
               
                   
                 762 
                  −20 / 155 
                 −20 / −1 
                  1 / 155 
               
               
                   
                 763 
                  −20 / 283 
                 −20 / −1 
                  1 / 283 
               
               
                   
                 764 
                 −39 / 26 
                 −39 / −1 
                 1 / 26 
               
               
                   
                 765 
                  −17 / 120 
                 −17 / −1 
                  1 / 120 
               
               
                   
                 766 
                  −13 / 141 
                 −13 / −1 
                  1 / 141 
               
               
                   
                 767 
                 −36 / 67 
                 −36 / −1 
                 1 / 67 
               
               
                   
                 768 
                 −74 / 12 
                 −74 / −1 
                 1 / 12 
               
               
                   
                 769 
                 −310 / 85  
                 −310 / −1  
                 1 / 85 
               
               
                   
                 770 
                 −18 / 75 
                 −18 / −1 
                 1 / 75 
               
               
                   
                 771 
                 −21 / 40 
                 −21 / −1 
                 1 / 40 
               
               
                   
                 772 
                  −31 / 300 
                 −31 / −1 
                  1 / 300 
               
               
                   
                 773 
                  −99 / 111 
                 −99 / −1 
                  1 / 111 
               
               
                   
                 774 
                 −67 / 12 
                 −67 / −1 
                 1 / 12 
               
               
                   
                 775 
                      1 / 84  
                 — 
                 1 / 84 
               
               
                   
                 776 
                 −20 / 72 
                 −20 / −1 
                 1 / 72 
               
               
                   
                 777 
                  −14 / 196 
                 −14 / −1 
                  1 / 196 
               
               
                   
                 778 
                 −139 / 66  
                 −139 / −1  
                 1 / 66 
               
               
                   
                 779 
                 −17 / 68 
                 −17 / −1 
                 1 / 68 
               
               
                   
                 780 
                 −51 / 64 
                 −51 / −1 
                 1 / 64 
               
               
                   
                 781 
                 −31 / 50 
                 −31 / −1 
                 1 / 50 
               
               
                   
                 782 
                  −39 / 196 
                 −39 / −1 
                  1 / 196 
               
               
                   
                 783 
                 −21 / 41 
                 −21 / −1 
                 1 / 41 
               
               
                   
                 784 
                      1 / 11  
                 — 
                 1 / 11 
               
               
                   
                 785 
                 −34 / 22 
                 −34 / −1 
                 1 / 22 
               
               
                   
                 786 
                 −32 / 67 
                 −32 / −1 
                 1 / 67 
               
               
                   
                 787 
                  −27 / 133 
                 −27 / −1 
                  1 / 133 
               
               
                   
                 788 
                 −22 / 37 
                 −22 / −1 
                 1 / 37 
               
               
                   
                 789 
                 −48 / 64 
                 −48 / −1 
                 1 / 64 
               
               
                   
                 790 
                 −56 / 55 
                 −56 / −1 
                 1 / 55 
               
               
                   
                 791 
                 −77 / 67 
                 −77 / −1 
                 1 / 67 
               
               
                   
                 792 
                 −18 / 92 
                 −18 / −1 
                 1 / 92 
               
               
                   
                 793 
                 −36 / 43 
                 −36 / −1 
                 1 / 43 
               
               
                   
                 794 
                  −34 / 162 
                 −34 / −1 
                  1 / 162 
               
               
                   
                 795 
                  −18 / 159 
                 −18 / −1 
                  1 / 159 
               
               
                   
                 796 
                 −22 / 83 
                 −22 / −1 
                 1 / 83 
               
               
                   
                 797 
                  −48 / 100 
                 −48 / −1 
                  1 / 100 
               
               
                   
                 798 
                  −23 / 236 
                 −23 / −1 
                  1 / 236 
               
               
                   
                 799 
                 −62 / 49 
                 −62 / −1 
                 1 / 49 
               
               
                   
                 800 
                  −23 / 288 
                 −23 / −1 
                  1 / 288 
               
               
                   
                 801 
                 −60 / 31 
                 −60 / −1 
                 1 / 31 
               
               
                   
                 802 
                  −17 / 270 
                 −17 / −1 
                  1 / 270 
               
               
                   
                 803 
                 −49 / 55 
                 −49 / −1 
                 1 / 55 
               
               
                   
                 804 
                 −36 / 48 
                 −36 / −1 
                 1 / 48 
               
               
                   
                 805 
                  −20 / 111 
                 −20 / −1 
                  1 / 111 
               
               
                   
                 806 
                  −23 / 108 
                 −23 / −1 
                  1 / 108 
               
               
                   
                 807 
                  −16 / 319 
                 −16 / −1 
                  1 / 319 
               
               
                   
                 808 
                 −55 / 29 
                 −55 / −1 
                 1 / 29 
               
               
                   
                 809 
                  −18 / 262 
                 −18 / −1 
                  1 / 262 
               
               
                   
                 810 
                 −51 / 89 
                 −51 / −1 
                 1 / 89 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE III 
               
               
                   
               
               
                   
               
               
                 Id 
                 Positions of preferred fragments 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 1-126, 164-259, 420-432, 1404-1450 
               
               
                 2 
                 32-44, 4199-1556 
               
               
                 3 
                 1-19, 1011-1058 
               
               
                 4 
                 1-16, 108-159, 595-648 
               
               
                 5 
                 1-119, 486-665, 1968-2009, 2055-2104 
               
               
                 6 
                 424-435, 500-515 
               
               
                 7 
                 1-122, 242-661 
               
               
                 8 
                 1-16, 649-694 
               
               
                 9 
                 1-663, 1070-110 
               
               
                 10 
                 1-129, 541-623 
               
               
                 11 
                 1-200, 614-657 
               
               
                 12 
                 1-419, 1094-1137 
               
               
                 13 
                 1-127, 323-331, 595-636 
               
               
                 14 
                 804-818 
               
               
                 15 
                 1-47, 438-611, 1005-1133, 1846-1888 
               
               
                 16 
                 1-430, 527-1894 
               
               
                 17 
                 1-119, 1743-1792, 1866-1913 
               
               
                 18 
                 1-70, 133-1235, 1729-1744 
               
               
                 19 
                 575-615, 896-946 
               
               
                 20 
                 513-526, 950-960, 1577-1622 
               
               
                 21 
                 1-2, 210-265, 674-715 
               
               
                 22 
                 1400-1441, 1508-1549 
               
               
                 23 
                 1-4, 1284, 1328 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE IVa 
               
               
                   
               
               
                   
               
               
                 Seq Id N° 
                 Preferred fragments 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 1-58: 343-1359: 1434-1450 
               
               
                 2 
                 455-1556 
               
               
                 3 
                 553-634: 1042-1058 
               
               
                 4 
                 608-648 
               
               
                 5 
                 452-481: 620-2104 
               
               
                 6 
                 424-515 
               
               
                 7 
                 497-661 
               
               
                 8 
                 529-694 
               
               
                 9 
                 639-1110 
               
               
                 10 
                 505-623 
               
               
                 11 
                 536-657 
               
               
                 12 
                 444-1137 
               
               
                 13 
                 593-636 
               
               
                 14 
                 448-818 
               
               
                 15 
                 643-1346: 1809-1888 
               
               
                 16 
                 276-1894 
               
               
                 17 
                 332-1913 
               
               
                 18 
                 392-1744 
               
               
                 19 
                 578-946 
               
               
                 20 
                 1-240: 645-1224: 1341-1622 
               
               
                 21 
                 695-715 
               
               
                 22 
                 472-706: 924-1549 
               
               
                 23 
                 495-1328 
               
               
                 24 
                 440-1193: 1494-1515 
               
               
                 25 
                 532-1024: 1065-1622 
               
               
                 26 
                 495-582: 1412-1448 
               
               
                 27 
                 427-894 
               
               
                 28 
                 500-1321: 1424-1447 
               
               
                 29 
                 487-1540 
               
               
                 30 
                 441-1272: 1330-1643 
               
               
                 31 
                 915-1314 
               
               
                 32 
                 453-2356 
               
               
                 33 
                 519-1701 
               
               
                 34 
                 550-772 
               
               
                 35 
                 340-987 
               
               
                 36 
                 467-1324 
               
               
                 37 
                 442-1918 
               
               
                 38 
                 521-852 
               
               
                 39 
                 452-726 
               
               
                 40 
                 128-143: 481-1039 
               
               
                 41 
                 492-1355 
               
               
                 42 
                 527-572 
               
               
                 43 
                 521-535 
               
               
                 44 
                 526-572 
               
               
                 45 
                 512-804 
               
               
                 46 
                 552-629 
               
               
                 47 
                 655-669 
               
               
                 48 
                 423-973 
               
               
                 49 
                 529-791 
               
               
                 50 
                 642-1110 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE IVb 
               
               
                   
               
               
                   
               
               
                 Seq Id N° 
                 Excluded fragments 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 59-342: 1360-1433 
               
               
                 2 
                 1-454 
               
               
                 3 
                 1-552: 635-1041 
               
               
                 4 
                 1-607 
               
               
                 5 
                 1-451: 482-619 
               
               
                 6 
                 1-423 
               
               
                 7 
                 1-496 
               
               
                 8 
                 1-528 
               
               
                 9 
                 1-638 
               
               
                 10 
                 1-504 
               
               
                 11 
                 1-535 
               
               
                 12 
                 1-443 
               
               
                 13 
                 1-592 
               
               
                 14 
                 1-447 
               
               
                 15 
                 1-642: 1347-1808 
               
               
                 16 
                 1-275 
               
               
                 17 
                 1-331 
               
               
                 18 
                 1-391 
               
               
                 19 
                 1-577 
               
               
                 20 
                 241-644: 1225-1340 
               
               
                 21 
                 1-694 
               
               
                 22 
                 1-471: 707-923 
               
               
                 23 
                 1-494 
               
               
                 24 
                 1-439: 1194-1493 
               
               
                 25 
                 1-531: 1025-1064 
               
               
                 26 
                 1-494: 583-1411 
               
               
                 27 
                 1-426 
               
               
                 28 
                 1-499: 1322-1423 
               
               
                 29 
                 1-486 
               
               
                 30 
                 1-440: 1273-1329 
               
               
                 31 
                 1-914 
               
               
                 32 
                 1-452 
               
               
                 33 
                 1-518 
               
               
                 34 
                 1-549 
               
               
                 35 
                 1-339 
               
               
                 36 
                 1-466 
               
               
                 37 
                 1-441 
               
               
                 38 
                 1-520 
               
               
                 39 
                 1-451 
               
               
                 40 
                 1-127: 144-480 
               
               
                 41 
                 1-491 
               
               
                 42 
                 1-526 
               
               
                 43 
                 1-520 
               
               
                 44 
                 1-525 
               
               
                 45 
                 1-511 
               
               
                 46 
                 1-551 
               
               
                 47 
                 1-654 
               
               
                 48 
                 1-422 
               
               
                 49 
                 1-528 
               
               
                 50 
                 1-641 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE V 
               
               
                   
                   
               
               
                   
                   
               
               
                   
                   
                 Nucleotide 
                 Protein 
               
               
                   
                 Internal designation 
                 SEQ ID NO 
                 SEQ ID NO 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 105-016-3-0-E3-FL 
                 1 
                 406 
               
               
                   
                 105-031-3-0-D6-FL 
                 2 
                 407 
               
               
                   
                 105-095-1-0-D10-FL 
                 3 
                 408 
               
               
                   
                 105-118-4-0-E6-FL 
                 4 
                 409 
               
               
                   
                 114-025-2-0-F11-FL 
                 5 
                 410 
               
               
                   
                 116-005-4-0-G11-FL 
                 6 
                 411 
               
               
                   
                 116-032-2-0-F9-FL 
                 7 
                 412 
               
               
                   
                 116-047-3-0-B1-FL 
                 8 
                 413 
               
               
                   
                 116-048-4-0-A6-FL 
                 9 
                 414 
               
               
                   
                 116-049-1-0-F2-FL 
                 10 
                 415 
               
               
                   
                 116-050-2-0-A11-FL 
                 11 
                 416 
               
               
                   
                 116-054-3-0-E6-FL 
                 12 
                 417 
               
               
                   
                 116-054-3-0-G12-FL 
                 13 
                 418 
               
               
                   
                 116-073-4-0-C8-FL 
                 14 
                 419 
               
               
                   
                 117-002-3-0-G3-FL 
                 15 
                 420 
               
               
                   
                 117-005-2-0-E10-FL 
                 16 
                 421 
               
               
                   
                 117-005-3-0-F2-FL 
                 17 
                 422 
               
               
                   
                 117-005-4-0-E5-FL 
                 18 
                 423 
               
               
                   
                 117-007-2-0-B5-FL 
                 19 
                 424 
               
               
                   
                 117-007-2-0-C4-FL 
                 20 
                 425 
               
               
                   
                 121-004-3-0-F6-FL 
                 21 
                 426 
               
               
                   
                 122-005-2-0-F11-FL 
                 22 
                 427 
               
               
                   
                 122-007-3-0-D10-FL 
                 23 
                 428 
               
               
                   
                 108-004-5-0-B12-FL 
                 24 
                 429 
               
               
                   
                 108-004-5-0-C10-FL 
                 25 
                 430 
               
               
                   
                 108-004-5-0-G10-FL 
                 26 
                 431 
               
               
                   
                 108-005-5-0-D4-FL 
                 27 
                 432 
               
               
                   
                 108-005-5-0-F9-FL 
                 28 
                 433 
               
               
                   
                 108-006-5-0-C7-FL 
                 29 
                 434 
               
               
                   
                 108-006-5-0-E1-FL 
                 30 
                 435 
               
               
                   
                 108-008-5-0-C5-FL 
                 31 
                 436 
               
               
                   
                 108-008-5-0-G5-FL 
                 32 
                 437 
               
               
                   
                 108-011-5-0-B12-FL 
                 33 
                 438 
               
               
                   
                 108-011-5-0-C7-FL 
                 34 
                 439 
               
               
                   
                 108-011-5-0-G8-FL 
                 35 
                 440 
               
               
                   
                 108-011-5-0-H2-FL 
                 36 
                 441 
               
               
                   
                 108-013-5-0-G5-FL 
                 37 
                 442 
               
               
                   
                 108-013-5-0-H9-FL 
                 38 
                 443 
               
               
                   
                 108-014-5-0-A10-FL 
                 39 
                 444 
               
               
                   
                 108-014-5-0-C7-FL 
                 40 
                 445 
               
               
                   
                 108-014-5-0-D12-FL 
                 41 
                 446 
               
               
                   
                 108-014-5-0-H8-FL 
                 42 
                 447 
               
               
                   
                 108-015-5-0-E2-FL 
                 43 
                 448 
               
               
                   
                 108-016-5-0-C12-FL 
                 44 
                 449 
               
               
                   
                 108-016-5-0-D4-FL 
                 45 
                 450 
               
               
                   
                 108-019-5-0-F10-FL 
                 46 
                 451 
               
               
                   
                 108-019-5-0-F5-FL 
                 47 
                 452 
               
               
                   
                 108-019-5-0-H3-FL 
                 48 
                 453 
               
               
                   
                 108-020-5-0-D4-FL 
                 49 
                 454 
               
               
                   
                 108-020-5-0-E3-FL 
                 50 
                 455 
               
               
                   
                 20-5-2-C3-CL0_4 
                 99 
                 456 
               
               
                   
                 20-8-4-A11-CL2_6 
                 100 
                 457 
               
               
                   
                 21-1-4-F2-CL11_1 
                 101 
                 458 
               
               
                   
                 22-11-2-H9-CL1_1 
                 102 
                 459 
               
               
                   
                 25-7-3-D4-CL0_2 
                 103 
                 460 
               
               
                   
                 26-27-3-D7-CL0_1 
                 104 
                 461 
               
               
                   
                 26-35-4-H9-CL1_1 
                 105 
                 462 
               
               
                   
                 26-45-2-C4-CL2_6 
                 106 
                 463 
               
               
                   
                 27-1-2-B3-CL0_1 
                 107 
                 464 
               
               
                   
                 27-1-2-B3-CL0_2 
                 108 
                 465 
               
               
                   
                 27-19-3-G7-CL11_2 
                 109 
                 466 
               
               
                   
                 33-10-4-E2-CL13_4 
                 110 
                 467 
               
               
                   
                 33-10-4-H2-CL2_2 
                 111 
                 468 
               
               
                   
                 33-110-4-A5-CL1_1 
                 112 
                 469 
               
               
                   
                 33-13-1-C1-CL1_1 
                 113 
                 470 
               
               
                   
                 33-30-2-A6-CL0_1 
                 114 
                 471 
               
               
                   
                 33-35-4-F4-CL1_2 
                 115 
                 472 
               
               
                   
                 33-35-4-G1-CL1_2 
                 116 
                 473 
               
               
                   
                 33-36-3-E2-CL1_1 
                 117 
                 474 
               
               
                   
                 33-36-3-E2-CL1_2 
                 118 
                 475 
               
               
                   
                 33-36-3-F2-CL2_2 
                 119 
                 476 
               
               
                   
                 33-4-2-G5-CL2_1 
                 120 
                 477 
               
               
                   
                 33-49-1-H4-CL1_1 
                 121 
                 478 
               
               
                   
                 33-66-2-B10-CL4_1 
                 422 
                 479 
               
               
                   
                 33-97-4-G8-CL2_2 
                 123 
                 480 
               
               
                   
                 33-98-4-C1-CL1_3 
                 124 
                 481 
               
               
                   
                 47-14-1-C3-CL0_5 
                 125 
                 482 
               
               
                   
                 47-15-1-E11-CL0_1 
                 126 
                 483 
               
               
                   
                 47-15-1-H8-CL0_2 
                 127 
                 484 
               
               
                   
                 48-1-1-H7-CL0_1 
                 128 
                 485 
               
               
                   
                 48-1-1-H7-CL0_4 
                 129 
                 486 
               
               
                   
                 48-1-1-H7-CL0_5 
                 130 
                 487 
               
               
                   
                 48-3-1-H9-CL0_6 
                 131 
                 488 
               
               
                   
                 48-54-1-G9-CL2_1 
                 132 
                 489 
               
               
                   
                 48-54-1-G9-CL3_1 
                 133 
                 490 
               
               
                   
                 48-7-4-H2-CL2_2 
                 134 
                 491 
               
               
                   
                 51-11-3-D5-CL1_3 
                 135 
                 492 
               
               
                   
                 51-11-3-G9-CL0_1 
                 136 
                 493 
               
               
                   
                 51-15-4-A12-CL11_3 
                 137 
                 494 
               
               
                   
                 51-17-4-A4-CL3_1 
                 138 
                 495 
               
               
                   
                 51-2-3-F10-CL1_5 
                 139 
                 496 
               
               
                   
                 51-2-4-F5-CL11_2 
                 140 
                 497 
               
               
                   
                 51-27-4-F2-CL0_2 
                 141 
                 498 
               
               
                   
                 51-34-3-F8-CL0_2 
                 142 
                 499 
               
               
                   
                 57-1-4-E2-CL1_2 
                 143 
                 500 
               
               
                   
                 57-19-2-G8-CL2_1 
                 144 
                 501 
               
               
                   
                 57-27-3-G10-CL2_2 
                 145 
                 502 
               
               
                   
                 58-33-3-B4-CL1_2 
                 146 
                 503 
               
               
                   
                 58-34-3-C9-CL1_2 
                 147 
                 504 
               
               
                   
                 58-4-4-G2-CL2_1 
                 148 
                 505 
               
               
                   
                 58-48-1-G3-CL2_4 
                 149 
                 506 
               
               
                   
                 58-6-1-H4-CL1_1 
                 150 
                 507 
               
               
                   
                 60-12-1-E11-CL1_2 
                 151 
                 508 
               
               
                   
                 65-4-4-H3-CL1_1 
                 152 
                 509 
               
               
                   
                 74-5-1-E4-CL1_2 
                 153 
                 510 
               
               
                   
                 76-13-3-A9-CL1_2 
                 154 
                 511 
               
               
                   
                 76-16-1-D6-CL1_1 
                 155 
                 512 
               
               
                   
                 76-28-3-A12-CL1_5 
                 156 
                 513 
               
               
                   
                 76-42-2-F3-CL0_1 
                 157 
                 514 
               
               
                   
                 77-16-4-G3-CL1_3 
                 158 
                 515 
               
               
                   
                 77-39-4-H4-CL11_4 
                 159 
                 516 
               
               
                   
                 78-24-3-H4-CL2_1 
                 160 
                 517 
               
               
                   
                 78-27-3-D1-CL1_6 
                 161 
                 518 
               
               
                   
                 78-28-3-D2-CL0_2 
                 162 
                 519 
               
               
                   
                 78-7-1-G5-CL2_6 
                 163 
                 520 
               
               
                   
                 84-3-1-G10-CL11_6 
                 164 
                 521 
               
               
                   
                 58-48-4-E2-CL0_1 
                 165 
                 522 
               
               
                   
                 23-12-2-G6-CL1_2 
                 166 
                 523 
               
               
                   
                 25-8-4-B12-CL0_5 
                 167 
                 524 
               
               
                   
                 26-44-3-C5-CL2_1 
                 168 
                 525 
               
               
                   
                 27-1-2-B3-CL0_3 
                 169 
                 526 
               
               
                   
                 30-12-3-G5-CL0_1 
                 170 
                 527 
               
               
                   
                 33-106-2-F10-CL1_3 
                 171 
                 528 
               
               
                   
                 33-28-4-D1-CL0_1 
                 172 
                 529 
               
               
                   
                 33-31-3-C8-CL2_1 
                 173 
                 530 
               
               
                   
                 48-24-1-D2-CL3_2 
                 174 
                 531 
               
               
                   
                 48-46-4-A11-CL1_4 
                 175 
                 532 
               
               
                   
                 51-1-4-C1-CL0_2 
                 176 
                 533 
               
               
                   
                 51-39-3-H2-CL1_2 
                 177 
                 534 
               
               
                   
                 51-42-3-F9-CL1_1 
                 178 
                 535 
               
               
                   
                 51-5-3-G2-CL0_4 
                 179 
                 536 
               
               
                   
                 57-18-4-H5-CL2_1 
                 180 
                 537 
               
               
                   
                 76-23-3-G8-CL1_1 
                 181 
                 538 
               
               
                   
                 76-23-3-G8-CL1_3 
                 182 
                 539 
               
               
                   
                 78-8-3-E6-CL0_1 
                 183 
                 540 
               
               
                   
                 19-10-1-C2-CL1_3 
                 184 
                 541 
               
               
                   
                 33-11-1-B11-CL1_2 
                 185 
                 542 
               
               
                   
                 33-113-2-B8-CL1_2 
                 186 
                 543 
               
               
                   
                 33-19-1-C11-CL1_1 
                 187 
                 544 
               
               
                   
                 33-61-2-F6-CL0_2 
                 188 
                 545 
               
               
                   
                 47-4-4-C6-CL2_2 
                 189 
                 546 
               
               
                   
                 48-54-1-G9-CL1_1 
                 190 
                 547 
               
               
                   
                 51-43-3-G3-CL0_1 
                 191 
                 548 
               
               
                   
                 55-1-3-D11-CL0_1 
                 192 
                 549 
               
               
                   
                 58-14-2-D3-CL1_2 
                 193 
                 550 
               
               
                   
                 58-35-2-B6-CL2_3 
                 194 
                 551 
               
               
                   
                 76-18-1-F6-CL1_1 
                 195 
                 552 
               
               
                   
                 76-23-3-G8-CL2_2 
                 196 
                 553 
               
               
                   
                 76-30-3-B7-CL1_1 
                 197 
                 554 
               
               
                   
                 78-21-3-G7-CL2_1 
                 198 
                 555 
               
               
                   
                 58-45-4-B11-CL13_2 
                 199 
                 556 
               
               
                   
                 20-6-1-D11-FL2 
                 200 
                 557 
               
               
                   
                 20-8-4-A11-FL2 
                 201 
                 558 
               
               
                   
                 22-6-2-C1-FL2 
                 202 
                 559 
               
               
                   
                 22-11-2-H9-FL1 
                 203 
                 560 
               
               
                   
                 23-8-3-B1-FL1 
                 204 
                 561 
               
               
                   
                 24-3-3-C6-FL1 
                 205 
                 562 
               
               
                   
                 24-4-1-H3-FL1 
                 206 
                 563 
               
               
                   
                 26-45-2-C4-FL2 
                 207 
                 564 
               
               
                   
                 26-48-1-H10-FL1 
                 208 
                 565 
               
               
                   
                 26-49-1-A5-FL2 
                 209 
                 566 
               
               
                   
                 30-6-4-E3-FL3 
                 210 
                 567 
               
               
                   
                 33-6-1-G11-FL1 
                 211 
                 568 
               
               
                   
                 33-8-1-A3-FL2 
                 212 
                 569 
               
               
                   
                 33-11-3-C6-FL1 
                 213 
                 570 
               
               
                   
                 33-14-4-E1-FL1 
                 214 
                 571 
               
               
                   
                 33-21-2-D5-FL1 
                 215 
                 572 
               
               
                   
                 33-26-4-E10-FL1 
                 216 
                 573 
               
               
                   
                 33-27-1-E11-FL1 
                 217 
                 574 
               
               
                   
                 33-28-4-D1-FL1 
                 218 
                 575 
               
               
                   
                 33-28-4-E2-FL2 
                 219 
                 576 
               
               
                   
                 33-30-4-C4-FL1 
                 220 
                 577 
               
               
                   
                 33-35-4-F4-FL1 
                 221 
                 578 
               
               
                   
                 33-36-3-F2-FL2 
                 222 
                 579 
               
               
                   
                 33-52-4-F9-FL2 
                 223 
                 580 
               
               
                   
                 33-52-4-H3-FL1 
                 224 
                 581 
               
               
                   
                 33-59-1-B7-FL1 
                 225 
                 582 
               
               
                   
                 33-71-1-A8-FL1 
                 226 
                 583 
               
               
                   
                 33-72-2-B2-FL1 
                 227 
                 584 
               
               
                   
                 33-105-2-C3-FL1 
                 228 
                 585 
               
               
                   
                 33-107-4-C3-FL1 
                 229 
                 586 
               
               
                   
                 33-110-2-G4-FL1 
                 230 
                 587 
               
               
                   
                 47-7-4-D2-FL2 
                 231 
                 588 
               
               
                   
                 47-10-2-G12-FL1 
                 232 
                 589 
               
               
                   
                 47-14-3-D8-FL1 
                 233 
                 590 
               
               
                   
                 47-18-3-C2-FL1 
                 234 
                 591 
               
               
                   
                 47-18-3-G5-FL2 
                 235 
                 592 
               
               
                   
                 47-18-4-E3-FL2 
                 236 
                 593 
               
               
                   
                 48-3-1-H9-FL3 
                 237 
                 594 
               
               
                   
                 48-4-2-H3-FL1 
                 238 
                 595 
               
               
                   
                 48-6-1-C9-FL1 
                 239 
                 596 
               
               
                   
                 48-7-4-H2-FL2 
                 240 
                 597 
               
               
                   
                 48-8-1-D8-FL3 
                 241 
                 598 
               
               
                   
                 48-13-3-H8-FL1 
                 242 
                 599 
               
               
                   
                 48-19-3-A7-FL1 
                 243 
                 600 
               
               
                   
                 48-19-3-G1-FL1 
                 244 
                 601 
               
               
                   
                 48-25-4-D8-FL1 
                 245 
                 602 
               
               
                   
                 48-21-4-H4-FL1 
                 246 
                 603 
               
               
                   
                 48-26-3-B8-FL2 
                 247 
                 604 
               
               
                   
                 48-29-1-E2-FL1 
                 248 
                 605 
               
               
                   
                 48-31-3-F7-FL1 
                 249 
                 606 
               
               
                   
                 48-47-3-A5-FL1 
                 250 
                 607 
               
               
                   
                 51-1-1-G12-FL1 
                 251 
                 608 
               
               
                   
                 51-1-4-E9-FL3 
                 252 
                 609 
               
               
                   
                 51-1-4-E9-FL2 
                 253 
                 610 
               
               
                   
                 51-2-1-E10-FL1 
                 254 
                 611 
               
               
                   
                 51-2-3-F10-FL1 
                 255 
                 612 
               
               
                   
                 51-2-4-F5-FL1 
                 256 
                 613 
               
               
                   
                 51-3-3-B10-FL2 
                 257 
                 614 
               
               
                   
                 51-3-3-B10-FL3 
                 258 
                 615 
               
               
                   
                 51-7-3-G3-FL1 
                 259 
                 616 
               
               
                   
                 51-10-3-D11-FL1 
                 260 
                 617 
               
               
                   
                 51-11-3-D5-FL1 
                 261 
                 618 
               
               
                   
                 51-13-1-F7-FL3 
                 262 
                 619 
               
               
                   
                 51-15-4-H10-FL1 
                 263 
                 620 
               
               
                   
                 51-17-4-A4-FL1 
                 264 
                 621 
               
               
                   
                 51-18-1-C3-FL1 
                 265 
                 622 
               
               
                   
                 51-25-3-F3-FL1 
                 266 
                 623 
               
               
                   
                 51-27-1-E8-FL1 
                 267 
                 624 
               
               
                   
                 51-28-2-G1-FL2 
                 268 
                 625 
               
               
                   
                 51-39-3-H2-FL1 
                 269 
                 626 
               
               
                   
                 51-42-3-F9-FL1 
                 270 
                 627 
               
               
                   
                 51-44-4-H4-FL1 
                 271 
                 628 
               
               
                   
                 55-1-3-H10-FL1 
                 272 
                 629 
               
               
                   
                 55-5-4-A6-FL1 
                 273 
                 630 
               
               
                   
                 58-26-3-D1-FL1 
                 274 
                 631 
               
               
                   
                 57-18-1-D5-FL1 
                 275 
                 632 
               
               
                   
                 57-27-3-A11-FL1 
                 276 
                 633 
               
               
                   
                 57-27-3-G10-FL2 
                 277 
                 634 
               
               
                   
                 58-10-3-D12-FL1 
                 278 
                 635 
               
               
                   
                 58-26-3-D1-FL1 
                 274 
                 631 
               
               
                   
                 58-11-1-G10-FL1 
                 279 
                 636 
               
               
                   
                 58-11-2-G8-FL2 
                 280 
                 637 
               
               
                   
                 58-36-3-A9-FL2 
                 281 
                 638 
               
               
                   
                 58-38-1-A2-FL2 
                 282 
                 639 
               
               
                   
                 58-38-1-E5-FL1 
                 283 
                 640 
               
               
                   
                 58-44-2-B3-FL3 
                 284 
                 641 
               
               
                   
                 58-45-3-H11-FL1 
                 285 
                 642 
               
               
                   
                 58-53-2-B12-FL2 
                 286 
                 643 
               
               
                   
                 59-9-4-A10-FL1 
                 287 
                 644 
               
               
                   
                 60-16-3-A6-FL1 
                 288 
                 645 
               
               
                   
                 60-17-3-G8-FL2 
                 289 
                 646 
               
               
                   
                 62-5-4-B10-FL1 
                 290 
                 647 
               
               
                   
                 65-4-4-H3-FL1 
                 291 
                 648 
               
               
                   
                 74-3-1-B9-FL1 
                 292 
                 649 
               
               
                   
                 76-4-1-G5-FL1 
                 293 
                 650 
               
               
                   
                 76-7-3-A12-FL1 
                 294 
                 651 
               
               
                   
                 76-16-4-C9-FL3 
                 295 
                 652 
               
               
                   
                 76-30-3-B7-FL1 
                 296 
                 653 
               
               
                   
                 77-5-1-C2-FL1 
                 297 
                 654 
               
               
                   
                 77-5-4-E7-FL1 
                 298 
                 655 
               
               
                   
                 77-11-1-A3-FL1 
                 299 
                 656 
               
               
                   
                 77-16-3-D7-FL1 
                 300 
                 657 
               
               
                   
                 77-16-4-G3-FL1 
                 301 
                 658 
               
               
                   
                 77-25-1-A6-FL1 
                 302 
                 659 
               
               
                   
                 77-26-2-F2-FL3 
                 303 
                 660 
               
               
                   
                 78-6-2-E3-FL2 
                 304 
                 661 
               
               
                   
                 78-7-1-G5-FL2 
                 305 
                 662 
               
               
                   
                 78-16-2-C2-FL1 
                 306 
                 663 
               
               
                   
                 78-18-3-B4-FL3 
                 307 
                 664 
               
               
                   
                 78-20-1-G11-FL1 
                 308 
                 665 
               
               
                   
                 78-22-3-E10-FL1 
                 309 
                 666 
               
               
                   
                 78-24-2-B8-FL1 
                 310 
                 667 
               
               
                   
                 78-24-3-A8-FL1 
                 311 
                 668 
               
               
                   
                 78-24-3-H4-FL2 
                 312 
                 669 
               
               
                   
                 78-25-1-F11-FL1 
                 313 
                 670 
               
               
                   
                 78-26-1-B5-FL1 
                 314 
                 671 
               
               
                   
                 78-27-3-D1-FL1 
                 315 
                 672 
               
               
                   
                 78-29-1-B2-FL1 
                 316 
                 673 
               
               
                   
                 78-29-4-B6-FL1 
                 317 
                 674 
               
               
                   
                 14-1-3-E6-FL1 
                 318 
                 675 
               
               
                   
                 30-9-1-G8-FL2 
                 319 
                 676 
               
               
                   
                 33-10-4-H2-FL2 
                 320 
                 677 
               
               
                   
                 33-10-4-H2-FL1 
                 321 
                 678 
               
               
                   
                 74-10-3-C9-FL2 
                 322 
                 679 
               
               
                   
                 33-97-4-G8-FL3 
                 323 
                 680 
               
               
                   
                 33-97-4-G8-FL2 
                 324 
                 681 
               
               
                   
                 33-104-4-H4-FL1 
                 325 
                 682 
               
               
                   
                 47-2-3-B3-FL1 
                 326 
                 683 
               
               
                   
                 47-37-4-G11-FL1 
                 327 
                 684 
               
               
                   
                 57-25-1-F10-FL2 
                 328 
                 685 
               
               
                   
                 58-19-3-D3-FL1 
                 329 
                 686 
               
               
                   
                 58-34-3-C9-FL2 
                 330 
                 687 
               
               
                   
                 58-48-4-E2-FL2 
                 331 
                 688 
               
               
                   
                 76-21-1-C4-FL1 
                 332 
                 689 
               
               
                   
                 78-26-2-H7-FL1 
                 333 
                 690 
               
               
                   
                 77-20-2-E11-FL1 
                 334 
                 691 
               
               
                   
                 47-1-3-F7-FL2 
                 335 
                 692 
               
               
                   
                 108-002-5-0-B1-FL 
                 336 
                 741 
               
               
                   
                 108-002-5-0-F3-FL 
                 337 
                 742 
               
               
                   
                 108-002-5-0-F4-FL 
                 338 
                 743 
               
               
                   
                 108-003-5-0-A8-FL 
                 339 
                 744 
               
               
                   
                 108-003-5-0-D2-FL 
                 340 
                 745 
               
               
                   
                 108-003-5-0-E5-FL 
                 341 
                 746 
               
               
                   
                 108-003-5-0-H2-FL 
                 342 
                 747 
               
               
                   
                 108-004-5-0-B7-FL 
                 343 
                 748 
               
               
                   
                 108-004-5-0-C8-FL 
                 344 
                 749 
               
               
                   
                 108-004-5-0-D10-FL 
                 345 
                 750 
               
               
                   
                 108-004-5-0-E8-FL 
                 346 
                 751 
               
               
                   
                 108-004-5-0-F5-FL 
                 347 
                 752 
               
               
                   
                 108-004-5-0-G6-FL 
                 348 
                 753 
               
               
                   
                 108-005-5-0-B11-FL 
                 349 
                 754 
               
               
                   
                 108-005-5-0-C1-FL 
                 350 
                 755 
               
               
                   
                 108-005-5-0-F11-FL 
                 351 
                 756 
               
               
                   
                 108-005-5-0-F6-FL 
                 352 
                 757 
               
               
                   
                 108-006-5-0-C2-FL 
                 353 
                 758 
               
               
                   
                 108-006-5-0-E6-FL 
                 354 
                 759 
               
               
                   
                 108-006-5-0-G2-FL 
                 355 
                 760 
               
               
                   
                 108-006-5-0-G4-FL 
                 356 
                 761 
               
               
                   
                 108-008-5-0-A6-FL 
                 357 
                 762 
               
               
                   
                 108-008-5-0-A8-FL 
                 358 
                 763 
               
               
                   
                 108-008-5-0-C10-FL 
                 359 
                 764 
               
               
                   
                 108-008-5-0-E6-FL 
                 360 
                 765 
               
               
                   
                 108-008-5-0-F6-FL 
                 361 
                 766 
               
               
                   
                 108-008-5-0-G12-FL 
                 362 
                 767 
               
               
                   
                 108-008-5-0-G4-FL 
                 363 
                 768 
               
               
                   
                 108-009-5-0-A2-FL 
                 364 
                 769 
               
               
                   
                 108-013-5-0-C12-FL 
                 365 
                 770 
               
               
                   
                 108-013-5-0-G11-FL 
                 366 
                 771 
               
               
                   
                 108-003-5-0-E4-FL 
                 367 
                 772 
               
               
                   
                 108-005-5-0-D6-FL 
                 368 
                 773 
               
               
                   
                 108-008-5-0-G3-FL 
                 369 
                 774 
               
               
                   
                 108-013-5-0-B5-FL 
                 370 
                 775 
               
               
                   
                 26-44-1-B5-CL3_1 
                 371 
                 776 
               
               
                   
                 47-4-4-C6-CL2_3 
                 372 
                 777 
               
               
                   
                 47-40-4-G9-CL1_1 
                 373 
                 778 
               
               
                   
                 48-25-4-D8-CL1_7 
                 374 
                 779 
               
               
                   
                 48-28-3-A9-CL0_1 
                 375 
                 780 
               
               
                   
                 51-25-1-A2-CL3_1 
                 376 
                 781 
               
               
                   
                 55-10-3-F5-CL0_3 
                 377 
                 782 
               
               
                   
                 57-19-2-G8-CL1_3 
                 378 
                 783 
               
               
                   
                 58-34-2-H8-CL1_3 
                 379 
                 784 
               
               
                   
                 76-13-3-A9-CL1_1 
                 380 
                 785 
               
               
                   
                 78-7-2-B8-FL1 
                 381 
                 786 
               
               
                   
                 77-8-4-F9-FL1 
                 382 
                 787 
               
               
                   
                 58-8-1-F2-FL2 
                 383 
                 788 
               
               
                   
                 77-13-1-A7-FL2 
                 384 
                 789 
               
               
                   
                 47-2-3-G9-FL1 
                 385 
                 790 
               
               
                   
                 33-75-4-H7-FL1 
                 386 
                 791 
               
               
                   
                 51-41-1-F10-FL1 
                 387 
                 792 
               
               
                   
                 48-51-4-C11-FL1 
                 388 
                 793 
               
               
                   
                 33-58-3-C8-FL1 
                 389 
                 794 
               
               
                   
                 76-20-4-C11-FL1 
                 390 
                 795 
               
               
                   
                 76-28-3-A12-FL1 
                 391 
                 796 
               
               
                   
                 76-25-4-F11-FL1 
                 392 
                 797 
               
               
                   
                 58-20-4-G7-FL1 
                 393 
                 798 
               
               
                   
                 33-54-1-B9-FL1 
                 394 
                 799 
               
               
                   
                 76-20-3-H1-FL1 
                 395 
                 800 
               
               
                   
                 47-20-2-G3-FL1 
                 396 
                 801 
               
               
                   
                 78-25-1-H11-FL1 
                 397 
                 802 
               
               
                   
                 78-6-2-B10-FL1 
                 398 
                 803 
               
               
                   
                 58-49-3-G10-FL1 
                 399 
                 804 
               
               
                   
                 78-21-1-B7-FL1 
                 400 
                 805 
               
               
                   
                 57-28-4-B12-FL1 
                 401 
                 806 
               
               
                   
                 33-77-4-E2-FL1 
                 402 
                 807 
               
               
                   
                 58-19-3-D3-FL2 
                 403 
                 808 
               
               
                   
                 37-7-4-E7-FL1 
                 404 
                 809 
               
               
                   
                 60-14-2-H10-FL1 
                 405 
                 810 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE VI 
               
               
                   
               
               
                   
               
               
                 Seq Id No 
                 Tissue expression 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 prostate: 2 
               
               
                 2 
                 fetal kidney: 1 prostate: 3 
               
               
                 4 
                 prostate: 1 
               
               
                 5 
                 liver: 1 
               
               
                 6 
                 testis: 1 
               
               
                 7 
                 testis: 3 
               
               
                 8 
                 testis: 1 
               
               
                 9 
                 testis: 1 
               
               
                 10 
                 testis: 1 
               
               
                 11 
                 liver: 1 testis: 3 
               
               
                 12 
                 liver: 1 testis: 3 
               
               
                 13 
                 testis: 1 
               
               
                 14 
                 testis: 1 
               
               
                 15 
                 liver: 2 
               
               
                 16 
                 liver: 3 
               
               
                 17 
                 liver: 1 
               
               
                 18 
                 liver: 1 
               
               
                 19 
                 brain: 2 liver: 1 placenta: 6 
               
               
                   
                 salivary gland: 1 
               
               
                 20 
                 fetal brain: 6 
               
               
                 21 
                 fetal brain: 6 placenta: 2 
               
               
                 22 
                 fetal brain: 9 
               
               
                 23 
                 prostate: 2 
               
               
                 24 
                 prostate: 3 
               
               
                 25 
                 prostate: 1 
               
               
                 26 
                 prostate: 1 
               
               
                 27 
                 prostate: 3 
               
               
                 28 
                 prostate: 3 
               
               
                 29 
                 prostate: 2 
               
               
                 30 
                 prostate: 1 
               
               
                 31 
                 prostate: 1 
               
               
                 32 
                 liver: 15 testis: 3 
               
               
                 33 
                 liver: 1 testis: 8 
               
               
                 34 
                 brain: 1 
               
               
                 35 
                 prostate: 1 
               
               
                 36 
                 liver: 15 
               
               
                 37 
                 prostate: 2 
               
               
                 38 
                 testis: 1 
               
               
                 39 
                 testis: 3 
               
               
                 40 
                 liver: 2 
               
               
                 41 
                 liver: 1 testis: 2 
               
               
                 42 
                 liver: 5 testis: 20 
               
               
                 43 
                 brain: 4 fetal brain: 10 
               
               
                   
                 fetal kidney: 1 fetal livery: 1 
               
               
                   
                 placenta: 1 prostate: 1 
               
               
                 44 
                 brain: 3 fetal brain: 4 
               
               
                   
                 fetal kidney: 7 prostate: 1 
               
               
                   
                 salivary gland: 1 testis: 2 
               
               
                 45 
                 liver: 1 testis: 1 
               
               
                 46 
                 fetal livery: 1 prostate: 1 
               
               
                   
                 salivary gland: 3 
               
               
                   
                 stomach/intestine: 2 testis: 1 
               
               
                 47 
                 testis: 1 
               
               
                 48 
                 fetal brain: 4 
               
               
                 49 
                 brain: 85 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE VII 
               
               
                   
               
               
                   
               
               
                 Seq Id No 
                 Preferential expression 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 Prostate 
               
               
                 2 
                 Prostate 
               
               
                 4 
                 Prostate 
               
               
                 5 
                 None 
               
               
                 6 
                 None 
               
               
                 7 
                 Testis 
               
               
                 8 
                 None 
               
               
                 9 
                 None 
               
               
                 10 
                 None 
               
               
                 11 
                 Testis 
               
               
                 12 
                 Testis 
               
               
                 13 
                 None 
               
               
                 14 
                 None 
               
               
                 15 
                 Liver 
               
               
                 16 
                 Liver 
               
               
                 17 
                 None 
               
               
                 18 
                 None 
               
               
                 19 
                 Placenta 
               
               
                 20 
                 Fetal brain 
               
               
                 21 
                 None 
               
               
                 22 
                 Fetal brain 
               
               
                 23 
                 Prostate 
               
               
                 24 
                 Prostate 
               
               
                 25 
                 Prostate 
               
               
                 26 
                 Prostate 
               
               
                 27 
                 Prostate 
               
               
                 28 
                 Prostate 
               
               
                 29 
                 Prostate 
               
               
                 30 
                 Prostate 
               
               
                 31 
                 Prostate 
               
               
                 32 
                 Liver 
               
               
                 33 
                 Testis 
               
               
                 34 
                 None 
               
               
                 35 
                 Prostate 
               
               
                 36 
                 Liver 
               
               
                 37 
                 Prostate 
               
               
                 38 
                 None 
               
               
                 39 
                 Testis 
               
               
                 40 
                 Liver 
               
               
                 41 
                 None 
               
               
                 42 
                 Testis 
               
               
                 43 
                 None 
               
               
                 44 
                 Fetal kidney 
               
               
                 45 
                 None 
               
               
                 46 
                 Salivary gland, Stomach/Intestine 
               
               
                 47 
                 None 
               
               
                 48 
                 Fetal brain 
               
               
                 49 
                 Brain 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE VIII 
               
               
                   
               
               
                   
               
               
                 Seq Id No 
                 Public expression 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 frontal lobe(2) 
               
               
                 2 
                 B-cell, chronic lymphotic leukemia(2), 
               
               
                   
                 “adenocarcinoma”(2), “germinal 
               
               
                   
                 center B cell”(2), “liver”(1), 
               
               
                   
                 “lung”(1), “tumor”(1) 
               
               
                 4 
                 2 pooled tumors (clear cell type)(5), 
               
               
                   
                 “adenocarcinoma”(1), “anaplastic 
               
               
                   
                 oligodendroglioma”(4), “brain”(3), 
               
               
                   
                 “breast”(4), “breast tumor”(1), 
               
               
                   
                 “carcinoid”(5), “cerebellum”(1), 
               
               
                   
                 “colon”(4), “colon tumor RER+”(2), 
               
               
                   
                 “frontal lobe”(5), “germinal center B 
               
               
                   
                 cell”(4), “glioblastoma (pooled)”(2), 
               
               
                   
                 “moderately-differentiated adenocarcinoma”(1), 
               
               
                   
                 “normal prostate”(3), “ovary”(2), “parathyroid 
               
               
                   
                 tumor”(4), “pectoral muscle (after mastectomy)”(1), 
               
               
                   
                 “pooled germ cell tumors”(5), “senescent 
               
               
                   
                 fibroblast”(4), “tumor”(1), “tumor, 5 
               
               
                   
                 pooled (see description)”(1) 
               
               
                 5 
                 colon(1), “neuroepithelial cells”(1) 
               
               
                 6 
                 2 pooled tumors (clear cell type)(2), 
               
               
                   
                 “anaplastic oligodendroglioma”(2), 
               
               
                   
                 “borderline ovarian carcinoma”(1), 
               
               
                   
                 “carcinoid”(3), “colon”(1), “epithelium 
               
               
                   
                 (cell line)”(1), “glioblastoma (pooled)”(1), 
               
               
                   
                 “ovarian tumor”(1), “pooled germ 
               
               
                   
                 cell tumors”(2) 
               
               
                 7 
                 NONE 
               
               
                 8 
                 2 pooled tumors (clear cell type)(5), 
               
               
                   
                 “breast”(1), “carcinoid”(1), “colon tumor, 
               
               
                   
                 RER+”(1), “kidney tumor”(1), “pooled 
               
               
                   
                 germ cell tumors”(1) 
               
               
                 9 
                 NONE 
               
               
                 10 
                 2 pooled tumors (clear cell type)(2) 
               
               
                 11 
                 NONE 
               
               
                 12 
                 NONE 
               
               
                 13 
                 2 pooled tumors (clear cell type)(4), “breast”(1), 
               
               
                   
                 “prostate”(1) 
               
               
                 14 
                 pooled germ cell tumors(1) 
               
               
                 15 
                 NONE 
               
               
                 16 
                 liver(2) 
               
               
                 17 
                 B-cell, chronic lymphotic leukemia(2), “brain”(1), 
               
               
                   
                 “carcinoid”(1), “colon”(1) 
               
               
                 18 
                 NONE 
               
               
                 19 
                 anaplastic oligodendroglioma(2), “cerebellum”(1), 
               
               
                   
                 “colon”(1), “glioblastoma (pooled)”(5), 
               
               
                   
                 “metastatic prostate bone lesion”(1), “normal 
               
               
                   
                 epithelium”(1), “parathyroid tumor”(1), 
               
               
                   
                 “pooled germ cell tumors”(1), “renal cell 
               
               
                   
                 tumor”(1), “retina”(2), “squamous cell 
               
               
                   
                 carcinoma”(1), “squamous cell carcinoma from 
               
               
                   
                 base of tongue”(1), “three pooled meningiomas”(1) 
               
               
                 20 
                 anaplastic oligodendroglioma(1), “brain”(1), 
               
               
                   
                 “frontal lobe”(6), “total brain”(2) 
               
               
                 21 
                 Lung(1), “muscle”(1), “parathyroid 
               
               
                   
                 tumor”(1), “synovial membrane”(1) 
               
               
                 22 
                 neuroepithelial cells(1), “total brain”(1) 
               
               
                 23 
                 Bone(1), “bone marrow stroma”(1), “brain”(1), 
               
               
                   
                 “testis”(1) 
               
               
                 24 
                 NONE 
               
               
                 25 
                 parathyroid tumor(1), “retina”(1), 
               
               
                   
                 “total brain”(2) 
               
               
                 26 
                 NONE 
               
               
                 27 
                 ovarian tumor(3), “retina”(1), “senescent 
               
               
                   
                 fibroblast”(1) 
               
               
                 28 
                 normal prostate(1) 
               
               
                 29 
                 NONE 
               
               
                 30 
                 foreskin(1) 
               
               
                 31 
                 NONE 
               
               
                 32 
                 NONE 
               
               
                 33 
                 NONE 
               
               
                 34 
                 NONE 
               
               
                 35 
                 adenocarcinoma(1), “pectoral muscle (after 
               
               
                   
                 mastectomy)”(1) 
               
               
                 36 
                 juvenile granulosa rumor(1), “liver”(1), 
               
               
                   
                 “senescent fibroblast”(1) 
               
               
                 37 
                 2 pooled tumors (clear cell type)(2), “germinal 
               
               
                   
                 center B cell”(6) 
               
               
                 38 
                 NONE 
               
               
                 39 
                 NONE 
               
               
                 40 
                 NONE 
               
               
                 41 
                 NONE 
               
               
                 42 
                 NONE 
               
               
                 43 
                 B-cell, chronic lymphotic leukemia(1), 
               
               
                   
                 “adenocarcinoma”(1), “anaplastic 
               
               
                   
                 oligodendroglioma”(3), “carcinoid”(3), 
               
               
                   
                 “frontal lobe”(2), “glioblastoma 
               
               
                   
                 (pooled)”(4), “normal epithelium”(1), 
               
               
                   
                 “pooled germ cell tumors”(1) 
               
               
                 44 
                 2 pooled tumors (clear cell type)(5), 
               
               
                   
                 “Lung”(1), “adenocarcinoma”(4), 
               
               
                   
                 “adipose tissue, white”(1), “adrenal 
               
               
                   
                 adenoma”(1), “anaplastic 
               
               
                   
                 oligodendroglioma”(2), “breast tumor”(1), 
               
               
                   
                 “carcinoid”(1), “colon”(4), 
               
               
                   
                 “epithelium (cell line)”(1), “liver”(1), 
               
               
                   
                 “melanocyte”(1), “ovarian tumor”(1), 
               
               
                   
                 “parathyroid tumor”(6), “pectoral muscle 
               
               
                   
                 (after mastectomy)”(4), “squamous 
               
               
                   
                 cell carcinoma”(1), “synovial membrane”(3) 
               
               
                 45 
                 NONE 
               
               
                 46 
                 2 pooled tumors (clear cell type)(1), “anaplastic 
               
               
                   
                 oligodendroglioma”(2), “carcinoid”(3), 
               
               
                   
                 “colon”(4), “epithelium (cell line)”(1), 
               
               
                   
                 “glioblastoma (pooled)”(1), “normal 
               
               
                   
                 prostate”(2), “ovarian tumor”(2), “pooled 
               
               
                   
                 germ cell tumors”(3), “senescent 
               
               
                   
                 fibroblast”(2), “testis”(1) 
               
               
                 47 
                 NONE 
               
               
                 48 
                 anaplastic oligodendroglioma(2), 
               
               
                   
                 “astrocytoma”(1), “glioblastoma 
               
               
                   
                 (pooled)”(1), “total brain”(1) 
               
               
                 49 
                 NONE 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE IX 
               
               
                   
               
               
                   
               
               
                 Seq 
                   
                   
                   
               
               
                 Id 
               
               
                 No 
                 Positions 
                 Motif designation 
                 Database 
               
               
                   
               
             
            
               
                 406 
                 none 
                 none 
                 none 
               
               
                 407 
                 none 
                 none 
                 none 
               
               
                 408 
                 none 
                 none 
                 none 
               
               
                 409 
                      33-79 
                 PHD 
                 Pfam 
               
               
                 410 
                 none 
                 none 
                 none 
               
               
                 411 
                 none 
                 none 
                 none 
               
               
                 412 
                 none 
                 none 
                 none 
               
               
                 413 
                      28-94 
                 pfkB 
                 Pfam 
               
               
                 414 
                 none 
                 none 
                 none 
               
               
                 415 
                 none 
                 none 
                 none 
               
               
                 416 
                 none 
                 none 
                 none 
               
               
                 417 
                 none 
                 none 
                 none 
               
               
                 418 
                 none 
                 none 
                 none 
               
               
                 419 
                       88-213 
                 lys 
                 Pfam 
               
               
                 419 
                      183-202 
                 BL00128C Alpha-lactalbumin / 
                 BLOCKSPLUS 
               
               
                   
                   
                 lysozyme C signature 
               
               
                 419 
                      111-120 
                 PR00135B lysozyme/alpha- 
                 BLOCKSPLUS 
               
               
                   
                   
                 lactalbumin superfamily 
               
               
                   
                   
                 signature 
               
               
                 419 
                      162-180 
                 Alpha-lactalbumin / 
                 PROSITE 
               
               
                   
                   
                 lysozyme C signature 
               
               
                 420 
                      246-266 
                 PSAP 
                 Pfam 
               
               
                 421 
                       92-207 
                 NusB 
                 Pfam 
               
               
                 421 
                       4-251 
                 Apolipoprotein 
                 Pfam 
               
               
                 421 
                      110-263 
                 Nop 
                 Pfam 
               
               
                 422 
                 none 
                 none 
                 none 
               
               
                 423 
                       2-134 
                 mito_carr 1/2 
                 Pfam 
               
               
                 423 
                      156-303 
                 mito_carr 2/2 
                 Pfam 
               
               
                 423 
                       5-29 
                 BL00215A Mitochondrial 
                 BLOCKSPLUS 
               
               
                   
                   
                 energy transfer proteins 
               
               
                 423 
                      223-247 
                 BL00215A Mitochondrial 
                 BLOCKSPLUS 
               
               
                   
                   
                 energy transfer proteins 
               
               
                 423 
                      102-125 
                 BL00215A Mitochondrial 
                 BLOCKSPLUS 
               
               
                   
                   
                 energy transfer proteins 
               
               
                 423 
                      169-182 
                 BL00215B Mitochondrial 
                 BLOCKSPLUS 
               
               
                   
                   
                 energy transfer proteins 
               
               
                 424 
                 none 
                 none 
                 none 
               
               
                 425 
                       37-104 
                 cystatin 1/2 
                 Pfam 
               
               
                 425 
                      157-254 
                 cystatin 2/2 
                 Pfam 
               
               
                 426 
                      105-154 
                 GST 
                 Pfam 
               
               
                 427 
                       27-131 
                 Cyt_reductase 
                 Pfam 
               
               
                 427 
                      158-272 
                 oxidored_fad 
                 Pfam 
               
               
                 427 
                      256-265 
                 PR00406F cytochrome b5 
                 BLOCKSPLUS 
               
               
                   
                   
                 reductase signature 
               
               
                 427 
                      123-138 
                 PR00406C cytochrome b5 
                 BLOCKSPLUS 
               
               
                   
                   
                 reductase signature 
               
               
                 427 
                      256-268 
                 BL00559L Eukaryotic 
                 BLOCKSPLUS 
               
               
                   
                   
                 molybdopterin oxidoreductases 
               
               
                   
                   
                 proteins 
               
               
                 427 
                      163-180 
                 PR00406D cytochrome b5 
                 BLOCKSPLUS 
               
               
                   
                   
                 reductase signature 
               
               
                 427 
                      163-179 
                 PR00371D flavoprotein 
                 BLOCKSPLUS 
               
               
                   
                   
                 pyridine nucleotide 
               
               
                   
                   
                 cytochrome reductase 
               
               
                   
                   
                 signature 
               
               
                 427 
                      110-120 
                 PR00371C flavoprotein 
                 BLOCKSPLUS 
               
               
                   
                   
                 pyridine nucleotide 
               
               
                   
                   
                 cytochrome reductase 
               
               
                   
                   
                 signature 
               
               
                 428 
                       7-27 
                 PR00953B flagellar 
                 BLOCKSPLUS 
               
               
                   
                   
                 biosynthetic protein 
               
               
                   
                   
                 flir signature 
               
               
                 429 
                 none 
                 none 
                 none 
               
               
                 430 
                 none 
                 none 
                 none 
               
               
                 431 
                 none 
                 none 
                 none 
               
               
                 432 
                 none 
                 none 
                 none 
               
               
                 433 
                       7-214 
                 Hydrolase 
                 Pfam 
               
               
                 434 
                      48-53 
                 Cytochrome c family 
                 PROSITE 
               
               
                   
                   
                 heme-binding site 
               
               
                 434 
                      24-26 
                 Protein kinase C 
                 PROSITE 
               
               
                   
                   
                 phosphorylation site 
               
               
                 435 
                 none 
                 none 
                 none 
               
               
                 436 
                 none 
                 none 
                 none 
               
               
                 437 
                      302-339 
                 zf-C3HC4 
                 Pfam 
               
               
                 438 
                 none 
                 none 
                 none 
               
               
                 439 
                      17-67 
                 rnaseA 
                 Pfam 
               
               
                 440 
                 none 
                 none 
                 none 
               
               
                 441 
                 none 
                 none 
                 none 
               
               
                 442 
                      17-40 
                 A2M_N 
                 Pfam 
               
               
                 443 
                      52-66 
                 PR00111B alpha/beta 
                 BLOCKSPLUS 
               
               
                   
                   
                 hydrolase fold signature 
               
               
                 444 
                 none 
                 none 
                 none 
               
               
                 445 
                      59-61 
                 Cell attachment sequence 
                 PROSITE 
               
               
                 446 
                      258-298 
                 zf-C3HC4 
                 Pfam 
               
               
                 446 
                      257-301 
                 PHD 
                 Pfam 
               
               
                 447 
                 none 
                 none 
                 none 
               
               
                 448 
                 none 
                 none 
                 none 
               
               
                 449 
                 none 
                 none 
                 none 
               
               
                 450 
                 none 
                 none 
                 none 
               
               
                 451 
                 none 
                 none 
                 none 
               
               
                 452 
                 none 
                 none 
                 none 
               
               
                 453 
                 none 
                 none 
                 none 
               
               
                 454 
                 none 
                 none 
                 none 
               
               
                 455 
                 none 
                 none 
                 none 
               
               
                 510 
                      110-121 
                 Aldehyde dehydrogenase 
                 PROSITE 
               
               
                   
                   
                 cysteine active site 
               
               
                 536 
                      28-37 
                 ATP synthase alpha and 
                 PROSITE 
               
               
                   
                   
                 beta subunits signature 
               
               
                 538 
                      171-181 
                 Regulator of chromosome 
                 PROSITE 
               
               
                   
                   
                 condensation (RCC1) 
               
               
                   
                   
                 signature 2 
               
               
                 540 
                       90-112 
                 Phosphatidylethanolamine- 
                 PROSITE 
               
               
                   
                   
                 binding protein family 
               
               
                   
                   
                 signature 
               
               
                 541 
                      10-34 
                 Protein kinases 
                 PROSITE 
               
               
                   
                   
                 ATP-binding region 
               
               
                   
                   
                 signature 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE X 
               
               
                   
               
               
                   
               
               
                 Seq 
                   
               
               
                 Id No 
                 Antigenic epitopes 
               
               
                   
               
             
            
               
                 406 
                 58, 86-88, 148-149, 175-177, 238-239, 319 
               
               
                 407 
                 43-45, 58, 63-64, 72-74, 202, 204-205, 207, 237-238, 
               
               
                   
                 298 
               
               
                 408 
                 119, 121 
               
               
                 409 
                 21, 40-43 
               
               
                 410 
                 41, 43-44, 83, 103-104, 184-185, 187-188, 210-212, 
               
               
                   
                 366-367, 372-373, 396-397, 421, 475-477 
               
               
                 411 
                 84, 86-87 
               
               
                 412 
                 17, 37-38, 40-41, 43-44 
               
               
                 413 
                 97-98 
               
               
                 414 
                 34 
               
               
                 415 
                 20, 26-30, 83-86, 103, 111-112, 131 
               
               
                 416 
                 9-10, 96-97 
               
               
                 417 
                 220-222, 230-231 
               
               
                 418 
                 36, 44-47, 50-51, 67-68, 81-83 
               
               
                 419 
                 44-45, 105-106, 108-109, 147-149, 173, 202-203 
               
               
                 420 
                 129-130, 178, 311-312, 333-335, 368-369 
               
               
                 421 
                 34, 36-37, 319-320, 331-333 
               
               
                 422 
                 60 
               
               
                 423 
                 31-32, 157-158, 180, 215-216, 250 
               
               
                 424 
                 60-61 
               
               
                 425 
                 35, 37-38, 54-55, 57-58, 75-76, 160-161, 183-184, 215- 
               
               
                   
                 216, 230, 291-292, 296, 302, 309 
               
               
                 426 
                 5, 9, 11, 99, 184 
               
               
                 427 
                 61-62, 87-88, 109-110, 147-148, 216-217, 229-231, 252, 273 
               
               
                 428 
                 83, 89, 249-250 
               
               
                 429 
                 34-35, 209-211 
               
               
                 430 
                 104-106, 199-200, 228-229, 245-246, 292, 326-327, 
               
               
                   
                 342-343 
               
               
                 431 
                 25-28, 105-106, 108-109 
               
               
                 432 
                 59-60, 97-98, 101-102, 106-107, 159-160, 193-194, 
               
               
                   
                 207-208 
               
               
                 433 
                 61 
               
               
                 434 
                 56-57, 61-63, 83-84 
               
               
                 435 
                 47-48, 77-80, 100, 107 
               
               
                 436 
                 92-93 
               
               
                 437 
                 3-5, 59, 112-113, 213-214 
               
               
                 438 
                 31-32, 66, 108-109, 148-149, 165-167, 170-172, 290- 
               
               
                   
                 291, 339-340 
               
               
                 439 
                 32-34, 37-38, 57 
               
               
                 440 
                 6-7, 9, 11-12, 56-57 
               
               
                 441 
                 47-49, 91-92 
               
               
                 442 
                 38-39, 74, 92-93, 108-109, 116 
               
               
                 443 
                 17, 96 
               
               
                 444 
                 41-43 
               
               
                 445 
                 34-34, 84-85 
               
               
                 446 
                 83-84, 135-136, 264-265 
               
               
                 447 
                 19-23, 41 
               
               
                 448 
                 44-44, 109-109 
               
               
                 449 
                 4-5, 7-8, 55-56, 94-95 
               
               
                 450 
                 31-32, 38-40, 59-60 
               
               
                 451 
                 54-55, 59 
               
               
                 452 
                 137-137, 139-140 
               
               
                 453 
                 56, 86 
               
               
                 454 
                 4-5, 58-58, 67-68, 70-72, 74-77, 82-83 
               
               
                 455 
                 34 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                   
                 TABLE XI 
               
               
                   
                   
               
               
                   
                   
               
               
                   
                 Seq Id No 
                 Chromosomal location 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 1 
                 none 
               
               
                   
                 2 
                 9 
               
               
                   
                 3 
                 20 
               
               
                   
                 4 
                 17 
               
               
                   
                 5 
                 8 
               
               
                   
                 6 
                 16 
               
               
                   
                 7 
                 1 
               
               
                   
                 8 
                 none 
               
               
                   
                 9 
                 none 
               
               
                   
                 10 
                 none 
               
               
                   
                 11 
                 none 
               
               
                   
                 12 
                 none 
               
               
                   
                 13 
                 none 
               
               
                   
                 14 
                 17 
               
               
                   
                 15 
                 12q 
               
               
                   
                 16 
                 11 
               
               
                   
                 17 
                 18 
               
               
                   
                 18 
                 14 
               
               
                   
                 19 
                 6p23-25.1 
               
               
                   
                 20 
                 none 
               
               
                   
                 21 
                 20q12 
               
               
                   
                 22 
                 none 
               
               
                   
                 23 
                 3 
               
               
                   
                 24 
                 none 
               
               
                   
                 25 
                 1 
               
               
                   
                 26 
                 20 
               
               
                   
                 27 
                 none 
               
               
                   
                 28 
                 9 
               
               
                   
                 29 
                 11q24 
               
               
                   
                 30 
                 17 
               
               
                   
                 31 
                 none 
               
               
                   
                 32 
                 1 
               
               
                   
                 33 
                 3 
               
               
                   
                 34 
                 14 
               
               
                   
                 35 
                 16 
               
               
                   
                 36 
                 11 
               
               
                   
                 37 
                 10 
               
               
                   
                 38 
                 none 
               
               
                   
                 39 
                 none 
               
               
                   
                 40 
                 19 
               
               
                   
                 41 
                 none 
               
               
                   
                 42 
                 6 
               
               
                   
                 43 
                 X 
               
               
                   
                 44 
                 6p12.3-21.2 
               
               
                   
                 45 
                 5 
               
               
                   
                 46 
                 none 
               
               
                   
                 47 
                 16 
               
               
                   
                 48 
                 9 
               
               
                   
                 49 
                 20 
               
               
                   
                 50 
                 none