Patent Publication Number: US-2002009786-A1

Title: Novel nucleic acids and polypeptides

Description:
1. CROSS REFERENCE TO RELATED APPLICATIONS  
     [0001] This application is a continuation-in-part application of U.S. application Ser. No. 09/552,929, filed Apr. 18, 2000, Attorney Docket No. 791, incorporated herein by reference in its entirety. 
    
    
     
       2. BACKGROUND OF THE INVENTION  
       2.1 TECHNICAL FIELD  
       [0002] The present invention provides novel polynucleotides and proteins encoded by such polynucleotides, along with uses for these polynucleotides and proteins, for example in therapeutic, diagnostic and research methods.  
       2.2 BACKGROUND  
       [0003] Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, CSFs, chemokines, and interleukins) has matured rapidly over the past decade. The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides “directly” in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning). More recent “indirect” cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.  
       [0004] Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences.  
       3. SUMMARY OF THE INVENTION  
       [0005] The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.  
       [0006] The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides and cells genetically engineered to express such polynucleotides.  
       [0007] The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases. The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins. These nucleic acid sequences are designated as SEQ ID NO: 1-14 and are provided in the Sequence Listing. In the nucleic acids provided in the Sequence Listing, A is adenine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases. In the amino acids provided in the Sequence Listing, * corresponds to the stop codon.  
       [0008] The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1-14 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ ID NO: 1-14. A polynucleotide comprising a nucleotide sequence having at least 90% identity to an identifying sequence of SEQ ID NO: 1-14 or a degenerate variant or fragment thereof. The identifying sequence can be 100 base pairs in length.  
       [0009] The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-14. The sequence information can be a segment of any one of SEQ ID NO: 1-14 that uniquely identifies or represents the sequence information of SEQ ID NO: 1-14.  
       [0010] A collection as used in this application can be a collection of only one polynucleotide. The collection of sequence information or identifying information of each sequence can be provided on a nucleic acid array. In one embodiment, segments of sequence information is provided on a nucleic acid array to detect the polynucleotide that contains the segment. The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment. The collection can also be provided in a computer-readable format.  
       [0011] This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences; and host cells or organisms transformed with these expression vectors. Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA or RNA, their chemical analogs and the like.  
       [0012] In a preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-14 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well known in the art. In a particularly preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-14 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.  
       [0013] The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set forth in SEQ ID NO: 1-14; a polynucleotide comprising any of the full length protein coding sequences of SEQ ID NO: 1-14; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ ID NO: 1-14. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ ID NO: 1-14; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in the Sequence Listing; (c) a polynucleotide which is an allelic variant of any polynucleotides recited above; (d) a polynucleotide which encodes a species homolog (e.g. orthologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in the Sequence Listing.  
       [0014] The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing; or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ ID NO: 1-14; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions. Biologically or immunologically active variants of any of the polypeptide sequences in the Sequence Listing, and “substantial equivalents” thereof (e.g., with at least about 65%, 70%, 75%, 80% 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated. The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g. host cells) of the invention.  
       [0015] The invention also provides compositions comprising a polypeptide of the invention. Polypeptide compositions of the invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.  
       [0016] The invention also provides host cells transformed or transfected with a polynucleotide of the invention.  
       [0017] The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells. Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.  
       [0018] Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology. These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like. For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type, polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue mRNA in a sample using, e.g., in situ hybridization.  
       [0019] In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.  
       [0020] The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins. For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide. Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue. The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.  
       [0021] Methods are also provided for preventing. treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier.  
       [0022] In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention and/or treatment of disorders involving aberrant protein expression or biological activity.  
       [0023] The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample. Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions. The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected. The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.  
       [0024] The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention. Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.  
       [0025] The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention. Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein. Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention. The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound the binds to a polypeptide of the invention is identified.  
       [0026] The methods of the invention also provides methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies. In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products. Compounds and other substances can effect such modulation either on the level of target gene/protein expression or target protein activity.  
       [0027] The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in Table 2); for which they have a signature region (as set forth in Table 3); or for which they have homology to a gene family (as set forth in Table 4). If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.  
       4. DETAILED DESCRIPTION OF THE INVENTION  
         4 . 1  DEFINITONS  
       [0028] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.  
       [0029] The term “active” refers to those forms of the polypeptide which retain the biologic and/or immunologic activities of any naturally occurring polypeptide. According to the invention, the terms “biologically active” or “biological activity” refer to a protein or peptide having structural, regulatory or biochemical functions of a naturally occurring molecule. Likewise “immunologically active” or “immunological activity” refers to the capability of the natural, recombinant or synthetic polypeptide to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.  
       [0030] The term “activated cells” as used in this application are those cells which are engaged in extracellular or intracellular membrane trafficking, including the export of secretory or enzymatic molecules as part of a normal or disease process.  
       [0031] The terms “complementary” or “complementarity” refer to the natural binding of polynucleotides by base pairing. For example, the sequence 5′-AGT-3′ binds to the complementary sequence 3′-TCA-5′. Complementarity between two single-stranded molecules may be “partial” such that only some of the nucleic acids bind or it may be “complete” such that total complementarity exists between the single stranded molecules. The degree of complementarity between the nucleic acid strands has significant effects on the efficiency and strength of the hybridization between the nucleic acid strands.  
       [0032] The term “embryonic stem cells (ES)” refers to a cell that can give rise to many differentiated cell types in an embryo or an adult, including the germ cells. The term “germ line stem cells (GSCs)” refers to stem cells derived from primordial stem cells that provide a steady and continuous source of germ cells for the production of gametes. The term “primordial germ cells (PGCs)” refers to a small population of cells set aside from other cell lineages particularly from the yolk sac, mesenteries, or gonadal ridges during embryogenesis that have the potential to differentiate into germ cells and other cells. PGCs are the source from which GSCs and ES cells are derived The PGCs, the GSCs and the ES cells are capable of self-renewal. Thus these cells not only populate the germ line and give rise to a plurality of terminally differentiated cells that comprise the adult specialized organs, but are able to regenerate themselves.  
       [0033] The term “expression modulating fragment,” EMF, means a series of nucleotides which modulates the expression of an operably linked ORF or another EMF.  
       [0034] As used herein, a sequence is said to “modulate the expression of an operably linked sequence” when the expression of the sequence is altered by the presence of the EMF. EMFs include, but are not limited to, promoters, and promoter modulating sequences (inducible elements). One class of EMFs are nucleic acid fragments which induce the expression of an operably linked ORF in response to a specific regulatory factor or physiological event.  
       [0035] The terms “nucleotide sequence” or “nucleic acid” or “polynucleotide” or “oligonculeotide” are used interchangeably and refer to a heteropolymer of nucleotides or the sequence of these nucleotides. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA) or to any DNA-like or RNA-like material. In the sequences herein A is adenine, C is cytosine, T is thymine, G is guanine and N is A, C, G or T (U). It is contemplated that where the polynucleotide is RNA, the T (thymine) in the sequences provided herein is substituted with U (uracil). Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene.  
       [0036] The terms “oligonucleotide fragment” or a “polynucleotide fragment”, “portion,” or “segment” or “probe” or “primer” are used interchangeably and refer to a sequence of nucleotide residues which are at least about 5 nucleotides, more preferably at least about 7 nucleotides, more preferably at least about 9 nucleotides, more preferably at least about 11 nucleotides and most preferably at least about 17 nucleotides. The fragment is preferably less than about 500 nucleotides, preferably less than about 200 nucleotides, more preferably less than about 100 nucleotides, more preferably less than about 50 nucleotides and most preferably less than 30 nucleotides. Preferably the probe is from about 6 nucleotides to about 200 nucleotides, preferably from about 15 to about 50 nucleotides, more preferably from about 17 to 30 nucleotides and most preferably from about 20 to 25 nucleotides. Preferably the fragments can be used in polymerase chain reaction (PCR), various hybridization procedures or microarray procedures to identify or amplify identical or related parts of mRNA or DNA molecules. A fragment or segment may uniquely identify each polynucleotide sequence of the present invention. Preferably the fragment comprises a sequence substantially similar to any one of SEQ ID NOs:1-14.  
       [0037] Probes may, for example, be used to determine whether specific mRNA molecules are present in a cell or tissue or to isolate similar nucleic acid sequences from chromosomal DNA as described by Walsh et al. (Walsh, P. S. et al., 1992, PCR Methods Appl 1:241-250). They may be labeled by nick translation, Klenow fill-in reaction, PCR, or other methods well known in the art. Probes of the present invention, their preparation and/or labeling are elaborated in Sambrook, J. et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, N.Y.; or Ausubel, F. M. et al., 1989, Current Protocols in Molecular Biology, John Wiley &amp; Sons, New York N.Y., both of which are incorporated herein by reference in their entirety.  
       [0038] The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NOs: 1-14. The sequence information can be a segment of any one of SEQ ID NOs: 1-4 that uniquely identifies or represents the sequence information of that sequence of SEQ ID NO: 1-14. One such segment can be a twenty-mer nucleic acid sequence because the probability that a twenty-mer is fully matched in the human genome is 1 in 300. In the human genome, there are three billion base pairs in one set of chromosomes. Because 4 20  possible twenty-mers exist, there are 300 times more twenty-mers than there are base pairs in a set of human chromosomes. Using the same analysis, the probability for a seventeen-mer to be fully matched in the human genome is approximately 1 in 5. When these segments are used in arrays for expression studies, fifteen-mer segments can be used. The probability that the fifteen-mer is fully matched in the expressed sequences is also approximately one in five because expressed sequences comprise less than approximately 5% of the entire genome sequence.  
       [0039] Similarly, when using sequence information for detecting a single mismatch, a segment can be a twenty-five mer. The probability that the twenty-five mer would appear in a human genome with a single mismatch is calculated by multiplying the probability for a full match (1÷4 25 ) times the increased probability for mismatch at each nucleotide position (3×25). The probability that an eighteen mer with a single mismatch can be detected in an array for expression studies is approximately one in five. The probability that a twenty-mer with a single mismatch can be detected in a human genome is approximately one in five.  
       [0040] The term “open reading frame,” ORF, means a series of nucleotide triplets coding for amino acids without any termination codons and is a sequence translatable into protein.  
       [0041] The terms “operably linked” or “operably associated” refer to functionally related nucleic acid sequences. For example, a promoter is operably associated or operably linked with a coding sequence if the promoter controls the transcription of the coding sequence. While operably linked nucleic acid sequences can be contiguous and in the same reading frame, certain genetic elements e.g. repressor genes are not contiguously linked to the coding sequence but still control transcription/translation of the coding sequence.  
       [0042] The term “pluripotent” refers to the capability of a cell to differentiate into a number of differentiated cell types that are present in an adult organism. A pluripotent cell is restricted in its differentiation capability in comparison to a totipotent cell.  
       [0043] The terms “polypeptide” or “peptide” or “amino acid sequence” refer to an oligopeptide, peptide, polypeptide or protein sequence or fragment thereof and to naturally occurring or synthetic molecules. A polypeptide “fragment,” “portion,” or “segment” is a stretch of amino acid residues of at least about 5 amino acids, preferably at least about 7 amino acids, more preferably at least about 9 amino acids and most preferably at least about 17 or more amino acids. The peptide preferably is not greater than about 200 amino acids, more preferably less than 150 amino acids and most preferably less than 100 amino acids. Preferably the peptide is from about 5 to about 200 amino acids. To be active, any polypeptide must have sufficient length to display biological and/or immunological activity.  
       [0044] The term “naturally occurring polypeptide” refers to polypeptides produced by cells that have not been genetically engineered and specifically contemplates various polypeptides arising from post-translational modifications of the polypeptide including, but not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation.  
       [0045] The term “translated protein coding portion” means a sequence which encodes for the full length protein which may include any leader sequence or any processing sequence.  
       [0046] The term “mature protein coding sequence” means a sequence which encodes a peptide or protein without a signal or leader sequence. The “mature protein portion” means that portion of the protein which does not include a signal or leader sequence. The peptide may have been produced by processing in the cell which removes any leader/signal sequence. The mature protein portion may or may not include the initial methionine residue. The methionine residue may be removed from the protein during processing in the cell. The peptide may be produced synthetically or the protein may have been produced using a polynucleotide only encoding for the mature protein coding sequence.  
       [0047] The term “derivative” refers to polypeptides chemically modified by such techniques as ubiquitination, labeling (e.g., with radionuclides or various enzymes), covalent polymer attachment such as pegylation (derivatization with polyethylene glycol) and insertion or substitution by chemical synthesis of amino acids such as ornithine, which do not normally occur in human proteins.  
       [0048] The term “variant” (or “analog”) refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using, e g., recombinant DNA techniques. Guidance in determining which amino acid residues may be replaced, added or deleted without abolishing activities of interest, may be found by comparing the sequence of the particular polypeptide with that of homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology (conserved regions) or by replacing amino acids with consensus sequence.  
       [0049] Alternatively, recombinant variants encoding these same or similar polypeptides may be synthesized or selected by making use of the “redundancy” in the genetic code. Various codon substitutions, such as the silent changes which produce various restriction sites, may be introduced to optimize cloning into a plasmid or viral vector or expression in a particular prokaryotic or eukaryotic system. Mutations in the polynucleotide sequence may be reflected in the polypeptide or domains of other peptides added to the polypeptide to modify the properties of any part of the polypeptide, to change characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.  
       [0050] Preferably, amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements. “Conservative” amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophi icity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid. “Insertions” or “deletions” are preferably in the range of about 1 to 20 amino acids, more preferably 1 to 10 amino acids. The variation allowed may be experimentally determined by systematically making insertions, deletions, or substitutions of amino acids in a polypeptide molecule using recombinant DNA techniques and assaying the resulting recombinant variants for activity.  
       [0051] Alternatively, where alteration of function is desired, insertions, deletions or non-conservative alterations can be engineered to produce altered polypeptides. Such alterations can, for example, alter one or more of the biological functions or biochemical characteristics of the polypeptides of the invention. For example, such alterations may change polypeptide characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate. Further, such alterations can be selected so as to generate polypeptides that are better suited for expression, scale up and the like in the host cells chosen for expression. For example, cysteine residues can be deleted or substituted with another amino acid residue in order to eliminate disulfide bridges.  
       [0052] The terms “purified” or “substantially purified” as used herein denotes that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like. In one embodiment, the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).  
       [0053] The term “isolated” as used herein refers to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) present with the nucleic acid or polypeptide in its natural source. In one embodiment, the nucleic acid or polypeptide is found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same. The terms “isolated” and “purified” do not encompass nucleic acids or polypeptides present in their natural source.  
       [0054] The term “recombinant,” when used herein to refer to a polypeptide or protein, means that a polypeptide or protein is derived from recombinant (e.g., microbial, insect, or mammalian) expression systems. “Microbial” refers to recombinant polypeptides or proteins made in bacterial or fungal (e.g., yeast) expression systems. As a product, “recombinant microbial” defines a polypeptide or protein essentially free of native endogenous substances and unaccompanied by associated native glycosylation. Polypeptides or proteins expressed in most bacterial cultures, e.g.,  E. coli,  will be free of glycosylation modifications; polypeptides or proteins expressed in yeast will have a glycosylation pattern in general different from those expressed in mammalian cells.  
       [0055] The term “recombinant expression vehicle or vector” refers to a plasmid or phage or virus or vector, for expressing a polypeptide from a DNA (RNA) sequence. An expression vehicle can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences. Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell. Alternatively, where recombinant protein is expressed without a leader or transport sequence, it may include an amino terminal methionine residue. This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product.  
       [0056] The term “recombinant expression system” means host cells which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit extrachromosomally. Recombinant expression systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory elements linked to the DNA segment or synthetic gene to be expressed. This term also means host cells which have stably integrated a recombinant genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers. Recombinant expression systems as defined herein will express polypeptides or proteins endogenous to the cell upon induction of the regulatory elements linked to the endogenous DNA segment or gene to be expressed. The cells can be prokaryotic or eukaryotic.  
       [0057] The term “secreted” includes a protein that is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence when it is expressed in a suitable host cell. “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 that are transported across the membrane of the endoplasmic reticulum. “Secreted” proteins are also intended to include proteins containing non-typical signal sequences (e.g. Interleukin-I Beta. see Krasney, P. A. and Young, P. R. (1992) Cytokine 4(2):134 -143) and factors released from damaged cells (e.g. Interleukin-I Receptor Antagonist, see Arend, W. P. et. al. (1998) Annu. Rev. Immunol. 166:27-55)  
       [0058] Where desired, an expression vector may be designed to contain a “signal or leader sequence” which will direct the polypeptide through the membrane of a cell. Such a sequence may be naturally present on the polypeptides of the present invention or provided from heterologous protein sources by recombinant DNA techniques.  
       [0059] The term “stringent” is used to refer to conditions that are commonly understood in the art as stringent. Stringent conditions can include highly stringent conditions (i.e., hybridization to filter-bound DNA in 0.5 M NaHPO 4 , 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1X SSC/0.1% SDS at 68° C.), and moderately stringent conditions (i.e., washing in 0.2X SSC/0.1% SDS at 42° C.). Other exemplary hybridization conditions are described herein in the examples.  
       [0060] In instances of hybridization of deoxyoligonucleotides, additional exemplary stringent hybridization conditions include washing in 6X SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligonucleotides), 48° C. (for 17-base oligos), 55° C. (for 20-base oligonucleotides), and 60° C. (for 23-base oligonucleotides).  
       [0061] As used herein, “substantially equivalent” can refer both to nucleotide and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between the reference and subject sequences. Typically, such a substantially equivalent sequence varies from one of those listed herein by no more than about 35% (i.e., the number of individual residue substitutions, additions, and/or deletions in a substantially equivalent sequence, as compared to the corresponding reference sequence, divided by the total number of residues in the substantially equivalent sequence is about 0.35 or less). Such a sequence is said to have 65% sequence identity to the listed sequence. In one embodiment, a substantially equivalent, e.g., mutant, sequence of the invention varies from a listed sequence by no more than 30% (70% sequence identity); in a variation of this embodiment, by no more than 25% (75% sequence identity); and in a further variation of this embodiment, by no more than 20% (80% sequence identity) and in a further variation of this embodiment, by no more than 10% (90% sequence identity) and in a further variation ofthis embodiment, by no more that 5% (95% sequence identity). Substantially equivalent, e.g., mutant, amino acid sequences according to the invention preferably have at least 80% sequence identity with a listed amino acid sequence, more preferably at least 90% sequence identity. Substantially equivalent nucleotide sequences of the invention can have lower percent sequence identities, taking into account, for example, the redundancy or degeneracy of the genetic code. Preferably, nucleotide sequence has at least about 65% identity, more preferably at least about 75% identity, and most preferably at least about 95% identity. For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent expression characteristics are considered substantially equivalent. For the purposes of determining equivalence, truncation of the mature sequence (e.g., via a mutation which creates a spurious stop codon) should be disregarded. Sequence identity may be determined, e.g., using the Jotun Hein method (Hein, J. (1990) Methods Enzymol. 183:626-645). Identity between sequences can also be determined by other methods known in the art, e.g. by varying hybridization conditions.  
       [0062] The term “totipotent” refers to the capability of a cell to differentiate into all of the cell types of an adult organism.  
       [0063] The term “transformation” means introducing DNA into a suitable host cell so that the DNA is replicable, either as an extrachromosomal element, or by chromosomal integration. The term “transfection” refers to the taking up of an expression vector by a suitable host cell, whether or not any coding sequences are in fact expressed. The term “infection” refers to the introduction of nucleic acids into a suitable host cell by use of a virus or viral vector.  
       [0064] As used herein, an “uptake modulating fragment,” UMF, means a series of nucleotides which mediate the uptake of a linked DNA fragment into a cell. UMFs can be readily identified using known UMFs as a target sequence or target motif with the computer-based systems described below. The presence and activity of a UMF can be confirmed by attaching the suspected UMF to a marker sequence. The resulting nucleic acid molecule is then incubated with an appropriate host under appropriate conditions and the uptake of the marker sequence is determined. As described above, a UMF will increase the frequency of uptake of a linked marker sequence.  
       [0065] Each ofthe above terms is meant to encompass all that is described for each, unless the context dictates otherwise.  
       4.2 NUCLEIC ACIDS OF THE INVENTION  
       [0066] Nucleotide sequences of the invention are set forth in the Sequence Listing.  
       [0067] The isolated polynucleotides of the invention include a polynucleotide comprising the nucleotide sequences of SEQ ID NO: 1-14; a polynucleotide encoding any one of the peptide sequences of SEQ ID NO:1-14; and a polynucleotide comprising the nucleotide sequence encoding the mature protein coding sequence of the polynucleotides of any one of SEQ ID NO: 1-14. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent conditions to (a) the complement of any of the nucleotide sequences of SEQ ID NO: 1-14; (b) nucleotide sequences encoding any one of the amino acid sequences set forth in the Sequence Listing; (c) a polynucleotide which is an allelic variant of any polynucleotide recited above; (d) a polynucleotide which encodes a species homolog of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptides of SEQ ID NO: 1-14. Domains of interest may depend on the nature of the encoded polypeptide; e.g., domains in receptor-like polypeptides include ligand-binding, extracellular, transmembrane, or cytoplasmic domains, or combinations thereof; domains in immunoglobulin-like proteins include the variable immunoglobulin-like domains; domains in enzyme-like polypeptides include catalytic and substrate binding domains; and domains in ligand polypeptides include receptor-binding domains.  
       [0068] The polynucleotides of the invention include naturally occurring or wholly or partially synthetic DNA, e.g., cDNA and genomic DNA, and RNA, e.g., mRNA. The polynucleotides may include all of the coding region of the cDNA or may represent a portion of the coding region of the cDNA.  
       [0069] The present invention also provides genes corresponding to the cDNA sequences disclosed herein. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials. Further 5′ and 3′ sequence can be obtained using methods known in the art. For example, full length cDNA or genomic DNA that corresponds to any of the polynucleotides of SEQ ID NO: 1-14 can be obtained by screening appropriate cDNA or genomic DNA libraries under suitable hybridization conditions using any of the polynucleotides of SEQ ID NO: 1-14 or a portion thereof as a probe. Alternatively, the polynucleotides of SEQ ID NO: 1-14 may be used as the basis for suitable primer(s) that allow identification and/or amplification of genes in appropriate genomic DNA or cDNA libraries.  
       [0070] The nucleic acid sequences of the invention can be assembled from ESTs and sequences (including cDNA and genomic sequences) obtained from one or more public databases, such as dbEST, gbpri. and UniGene. The EST sequences can provide identify ng sequence information, representative fragment or segment information, or novel segment information for the full-length gene.  
       [0071] The polynucleotides of the invention also provide polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides recited above. Polynucleotides according to the invention can have, e.g., at least about 65%, at least about 70%, at least about 75%, at least about 80%, more typically at least about 90%, and even more typically at least about 95%, sequence identity to a polynucleotide recited above.  
       [0072] Included within the scope of the nucleic acid sequences of the invention are nucleic acid sequence fragments that hybridize under stringent conditions to any of the nucleotide sequences of SEQ ID NO: 1-14, or complements thereof, which fragment is greater than about 5 nucleotides, preferably 7 nucleotides, more preferably greater than 9 nucleotides and most preferably greater than 17 nucleotides. Fragments of, e.g. 15, 17, or 20 nucleotides or more that are selective for (i.e. specifically hybridize to any one of the polynucleotides of the invention) are contemplated. Probes capable of specifically hybridizing to a polynucleotide can differentiate polynucleotide sequences of the invention from other polynucleotide sequences in the same family of genes or can differentiate human genes from genes of other species, and are preferably based on unique nucleotide sequences.  
       [0073] The sequences falling within the scope of the present invention are not limited to these specific sequences, but also include allelic and species variations thereof. Allelic and species variations can be routinely determined by comparing the sequence provided in SEQ ID NO: 1-14, a representative fragment thereof, or a nucleotide sequence at least 90% identical. preferably 95% identical, to SEQ ID NOs: 1-14 with a sequence from another isolate of the same species. Furthermore, to accommodate codon variability, the invention includes nucleic acid molecules coding for the same amino acid sequences as do the specific ORFs disclosed herein. In other words, in the coding region of an ORF, substitution of one codon for another codon that encodes the same amino acid is expressly contemplated.  
       [0074] The nearest neighbor or homology result for the nucleic acids of the present invention, including SEQ ID NOs: 1-14, can be obtained by searching a database using an algorithm or a program. Preferably, a BLAST which stands for Basic Local Alignment Search Tool is used to search for local sequence alignments (Altshul, S. F. J Mol. Evol. 36 290-300 (1993) and Altschul S. F. et al. J. Mol. Biol. 21:403-410 (1990)). Alternatively a FASTA version 3 search against Genpept, using Fastxy algorithm.  
       [0075] Species homologs (or orthologs) of the disclosed polynucleotides and proteins are also provided by the present invention. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.  
       [0076] The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides.  
       [0077] The nucleic acid sequences of the invention are further directed to sequences which encode variants of the described nucleic acids. These amino acid sequence variants may be prepared by methods known in the art by introducing appropriate nucleotide changes into a native or variant polynucleotide. There are two variables in the construction of amino acid sequence variants: the location of the mutation and the nature of the mutation. Nucleic acids encoding the amino acid sequence variants are preferably constructed by mutating the polynucleotide to encode an amino acid sequence that does not occur in nature. These nucleic acid alterations can be made at sites that differ in the nucleic acids from different species (variable positions) or in highly conserved regions (constant regions). Sites at such locations will typically be modified in series, e.g., by substituting first with conservative choices (e.g., hydrophobic amino acid to a different hydrophobic amino acid) and then with more distant choices (e.g., hydrophobic amino acid to a charged amino acid), and then deletions or insertions may be made at the target site. Amino acid sequence deletions generally range from about 1 to 30 residues, preferably about 1 to 10 residues, and are typically contiguous. Amino acid insertions include amino- and/or carboxyl-terminal fusions ranging in length from one to one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Intrasequence insertions may range generally from about 1 to 10 amino residues, preferably from 1 to 5 residues. Examples of terminal insertions include the heterologous signal sequences necessary for secretion or for intracellular targeting in different host cells and sequences such as FLAG or poly-histidine sequences useful for purifying the expressed protein.  
       [0078] In a preferred method, polynucleotides encoding the novel amino acid sequences are changed via site-directed mutagenesis. This method uses oligonucleotide sequences to alter a polynucleotide to encode the desired amino acid variant, as well as sufficient adjacent nucleotides on both sides of the changed amino acid to form a stable duplex on either side of the site of being changed. In general, the techniques of site-directed mutagenesis are well known to those of skill in the art and this technique is exemplified by publications such as, Edelman et al.,  DNA  2:183 (1983). A versatile and efficient method for producing site-specific changes in a polynucleotide sequence was published by Zoller and Smith,  Nucleic Acids Res.  10:6487-6500 (1982). PCR may also be used to create amino acid sequence variants of the novel nucleic acids. When small amounts of template DNA are used as starting material, primer(s) that differs slightly in sequence from the corresponding region in the template DNA can generate the desired amino acid variant. PCR amplification results in a population of product DNA fragments that differ from the polynucleotide template encoding the polypeptide at the position specified by the primer. The product DNA fragments replace the corresponding region in the plasmid and this gives a polynucleotide encoding the desired amino acid variant.  
       [0079] A further technique for generating amino acid variants is the cassette mutagenesis technique described in Wells et al.,  Gene  34:315 (1985); and other mutagenesis techniques well known in the art, such as, for example, the techniques in Sambrook et al., supra, and  Current Protocols in Molecular Biology,  Ausubel et al. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be used in the practice of the invention for the cloning and expression of these novel nucleic acids. Such DNA sequences include those which are capable of hybridizing to the appropriate novel nucleic acid sequence under stringent conditions.  
       [0080] Polynucleotides encoding preferred polypeptide truncations of the invention can be used to generate polynucleotides encoding chimeric or fusion proteins comprising one or more domains of the invention and heterologous protein sequences.  
       [0081] The polynucleotides of the invention additionally include the complement of any of the polynucleotides recited above. The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA. Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions that can routinely isolate polynucleotides of the desired sequence identities.  
       [0082] In accordance with the invention, polynucleotide sequences comprising the mature protein coding sequences corresponding to any one of SEQ ID NO: 1-14, or functional equivalents thereof, may be used to generate recombinant DNA molecules that direct the expression of that nucleic acid, or a functional equivalent thereof, in appropriate host cells. Also included are the cDNA inserts of any of the clones identified herein.  
       [0083] A polynucleotide according to the invention can be joined to any of a variety of other nucleotide sequences by well-established recombinant DNA techniques (see Sambrook J et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, N.Y.). Useful nucleotide sequences forjoining to polynucleotides include an assortment of vectors, e.g., plasmids, cosmids, lambda phage derivatives, phagemids, and the like, that are well known in the art. Accordingly, the invention also provides a vector including a polynucleotide of the invention and a host cell containing the polynucleotide. In general, the vector contains an origin of replication functional in at least one organism, convenient restriction endonuclease sites, and a selectable marker for the host cell. Vectors according to the invention include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. A host cell according to the invention can be a prokaryotic or eukaryotic cell and can be a unicellular organism or part of a multicellular organism.  
       [0084] The present invention further provides recombinant constructs comprising a nucleic acid having any of the nucleotide sequences of SEQ ID NOs: 1-14 or a fragment thereof or any other polynucleotides of the invention. In one embodiment, the recombinant constructs of the present invention comprise a vector, such as a plasmid or viral vector, into which a nucleic acid having any of the nucleotide sequences of SEQ ID NOs: 1-14 or a fragment thereof is inserted, in a forward or reverse orientation. In the case of a vector comprising one of the ORFs of the present invention, the vector may further comprise regulatory sequences, including for example, a promoter, operably linked to the ORF. Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available for generating the recombinant constructs of the present invention. The following vectors are provided by way of example. Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene); pTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia). Eukaryotic: pWLneo, pSV2cat, pOG44, PXTI, pSG (Stratagene) pSVK3, pBPV, pMSG, pSVL (Pharmacia).  
       [0085] The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufman et al.,  Nucleic Acids Res.  19, 4485-4490 (1991), in order to produce the protein recombinantly. Many suitable expression control sequences are known in the art. General methods of expressing recombinant proteins are also known and are exemplified in R. Kaufman,  Methods in Enzymology  185, 537-566 (1990). As defined herein “operably linked” means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.  
       [0086] Promoter regions can be selected from any desired gene using CAT (chloramphenicol transferase) vectors or other vectors with selectable markers. Two appropriate vectors are pKK232-8 and pCM7. Particular named bacterial promoters include lac, lacZ, T3, T7, gpt, lambda PR, and trc. Eukaryotic promoters include CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art. Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene of  E. coIi  and  S. cerevisiae  TRP1 gene, and a promoter derived from a highly-expressed gene to direct transcription of a downstream structural sequence. Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), a-factor, acid phosphatase, or heat shock proteins, among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium. Optionally, the heterologous sequence can encode a fusion protein including an amino terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product. Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter. The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host. Suitable prokaryotic hosts for transformation include  E. coli, Bacillus subtilis, Salmonella typhimurium  and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, although others may also be employed as a matter of choice.  
       [0087] As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM 1 (Promega Biotech, Madison, Wis., U.S.A.). These pBR322 “backbone” sections are combined with an appropriate promoter and the structural sequence to be expressed. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced or derepressed by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.  
       [0088] Polynucleotides of the invention can also be used to induce immune responses. For example, as described in Fan et al.,  Nat. Biotech.  17:870-872 (1999), incorporated herein by reference, nucleic acid sequences encoding a polypeptide may be used to generate antibodies against the encoded polypeptide following topical administration of naked plasmid DNA or following injection, and preferably intramuscular injection of the DNA. The nucleic acid sequences are preferably inserted in a recombinant expression vector and may be in the form of naked DNA.  
       4.3 HOSTS  
       [0089] The present invention further provides host cells genetically engineered to contain the polynucleotides of the invention. For example, such host cells may contain nucleic acids of the invention introduced into the host cell using known transformation, transfection or infection methods. The present invention still further provides host cells genetically engineered to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.  
       [0090] Knowledge of nucleic acid sequences allows for modification of cells to permit, or increase, expression of endogenous polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the polypeptide at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the encoding sequences. See, for example, PCT International Publication No. WO94/12650, PCT International Publication No. WO92/20808, and PCT International Publication No. WO91/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.  
       [0091] The host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. Introduction of the recombinant construct into the host cell can be effected by calcium phosphate transfection, DEAE, dextran mediated transfection, or electroporation (Davis, L. et al.,  Basic Methods in Molecular Biology  (1986)). The host cells containing one of the polynucleotides of the invention. can be used in conventional manners to produce the gene product encoded by the isolated fragment (in the case of an ORF) or can be used to produce a heterologous protein under the control of the EMF.  
       [0092] Any host/vector system can be used to express one or more of the ORFs of the present invention. These include, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-1 cell, COS cells, 293 cells, and Sf9 cells, as well as prokaryotic host such as  E. coli  and  B. subtilis.  The most preferred cells are those which do not normally express the particular polypeptide or protein or which expresses the polypeptide or protein at low natural level. Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook. et al., in  Molecular Cloning: A Laboratory Manual,  Second Edition, Cold Spring Harbor, New York (1989), the disclosure of which is hereby incorporated by reference.  
       [0093] Various mammalian cell culture systems can also be employed to express recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman, Cell 23:175 (1981). Other cell lines capable of expressing a compatible vector are, for example, the C127, monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Colo205 cells. 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells. Mammalian expression vectors will comprise an origin of replication, a suitable promoter and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5′ flanking nontranscribed sequences. DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements. Recombinant polypeptides and proteins produced in bacterial culture are usually isolated by initial extraction from cell pellets, followed by one or more salting-out, aqueous ion exchange or size exclusion chromatography steps. Protein refolding steps can be used, as necessary, in completing configuration of the mature protein. Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.  
       [0094] Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or insects or in prokaryotes such as bacteria. Potentially suitable yeast strains include  Saccharomyces cerevisiae, Schizosaccharomyces pombe,  Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins. Potentially suitable bacterial strains include  Escherichia coli, Bacillus subtilis, Salmonella typhimurium,  or any bacterial strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Such covalent attachments may be accomplished using known chemical or enzymatic methods.  
       [0095] In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene targeting can be used to replace a gene&#39;s existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences. Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting. These sequence include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.  
       [0096] The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the host cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker. Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.  
       [0097] The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat. No. 5,272,071 to Chappel; U.S. Pat. No. 5,578,461 to Sherwin et al.; International Application No. PCT/US92/09627 (WO93/09222) by Selden et al.; and International Application No. PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.  
       4.4 POLYPEPTIDES OF THE INVENTION  
       [0098] The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising: the amino acid sequences set forth as any one of SEQ ID NO: 1-14 or an amino acid sequence encoded by any one of the nucleotide sequences SEQ ID NOs: 1-14 or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides preferably with biological or immunological activity that are encoded by: (a) a polynucleotide having any one of the nucleotide sequences set forth in SEQ ID NOs: 1-14 or (b) polynucleotides encoding any one of the amino acid sequences set forth as SEQ ID NO: 1-14 or (c) polynucleotides that hybridize to the complement of the polynucleotides of either (a) or (b) under stringent hybridization conditions. The invention also provides biologically active or immunologically active variants of any of the amino acid sequences set forth as SEQ ID NO: 1-14 or the corresponding full length or mature protein; and “substantial equivalents” thereof (e.g., with at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, typically at least about 95%, more typically at least about 98%, or most typically at least about 99% amino acid identity) that retain biological activity. Polypeptides encoded by allelic variants may have a similar, increased, or decreased activity compared to polypeptides comprising SEQ ID NO: 1-14.  
       [0099] Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention. Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H. U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and in R. S. McDowell, et al., J. Amer. Chem. Soc. 114, 9245-9253 (1992), both of which are incorporated herein by reference. Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites.  
       [0100] The present invention also provides both full-length and mature forms (for example, without a signal sequence or precursor sequence) of the disclosed proteins. The protein coding sequence is identified in the sequence listing by translation of the disclosed nucleotide sequences. The mature form of such protein may be obtained by expression of a full-length polynucleotide in a suitable mammalian cell or other host cell. The sequence of the mature form of the protein is also determinable from the amino acid sequence of the full-length form. Where proteins of the present invention are membrane bound, soluble forms of the proteins are also provided. In such forms, part or all of the regions causing the proteins to be membrane bound are deleted so that the proteins are fully secreted from the cell in which they are expressed.  
       [0101] Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.  
       [0102] The present invention further provides isolated polypeptides encoded by the nucleic acid fragments of the present invention or by degenerate variants of the nucleic acid fragments of the present invention. By “degenerate variant” is intended nucleotide fragments which differ from a nucleic acid fragment of the present invention (e.g., an ORF) by nucleotide sequence but, due to the degeneracy of the genetic code, encode an identical polypeptide sequence. Preferred nucleic acid fragments of the present invention are the ORFs that encode proteins.  
       [0103] A variety of methodologies known in the art can be utilized to obtain any one of the isolated polypeptides or proteins of the present invention. At the simplest level, the amino acid sequence can be synthesized using commercially available peptide synthesizers. The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity. This technique is particularly useful in producing small peptides and fragments of larger polypeptides. Fragments are useful, for example, in generating antibodies against the native polypeptide. Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.  
       [0104] The polypeptides and proteins of the present invention can alternatively be purified from cells which have been altered to express the desired polypeptide or protein. As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to produce a polypeptide or protein which it normally does not produce or which the cell normally produces at a lower level. One skilled in the art can readily adapt procedures for introducing and expressing either recombinant or synthetic sequences into eukaryotic or prokaryotic cells in order to generate a cell which produces one of the polypeptides or proteins of the present invention.  
       [0105] The invention also relates to methods for producing a polypeptide comprising growing a culture of host cells of the invention in a suitable culture medium, and purifying the protein from the cells or the culture in which the cells are grown. For example, the methods of the invention include a process for producing a polypeptide in which a host cell containing a suitable expression vector that includes a polynucleotide of the invention is cultured under conditions that allow expression of the encoded polypeptide. The polypeptide can be recovered from the culture, conveniently from the culture medium, or from a lysate prepared from the host cells and further purified. Preferred embodiments include those in which the protein produced by such process is a full length or mature form of the protein.  
       [0106] In an alternative method, the polypeptide or protein is purified from bacterial cells which naturally produce the polypeptide or protein. One skilled in the art can readily follow known methods for isolating polypeptides and proteins in order to obtain one of the isolated polypeptides or proteins of the present invention. These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography, and immuno-affinity chromatography. See, e.g., Scopes,  Protein Purification: Principles and Practice,  Springer-Verlag (1994); Sambrook, et al., in Molecular Cloning:  A Laboratory Manual;  Ausubel et al.,  Current Protocols in Molecular Biology.  Polypeptide fragments that retain biological/immunological activity include fragments comprising greater than about 100 amino acids, or greater than about 200 amino acids, and fragments that encode specific protein domains.  
       [0107] The purified polypeptides can be used in in vitro binding assays which are well known in the art to identify molecules which bind to the polypeptides. These molecules include but are not limited to, for e.g., small molecules, molecules from combinatorial libraries, antibodies or other proteins. The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.  
       [0108] In addition, the peptides of the invention or molecules capable of binding to the peptides may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for SEQ ID NO: 1-14.  
       [0109] The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.  
       [0110] The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered. For example, modifications, in the peptide or DNA sequence, can be made by those skilled in the art using known techniques. Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence. For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule. Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Pat. No. 4,518,584). Preferably, such alteration, substitution, replacement, insertion or deletion retains the desired activity of the protein. Regions of the protein that are important for the protein function can be determined by various methods known in the art including the alanine-scanning method which involved systematic substitution of single or strings of amino acids with alanine, followed by testing the resulting alanine-containing variant for biological activity. This type of analysis determines the importance of the substituted amino acid(s) in biological activity. Regions of the protein that are important for protein function may be determined by the eMATRIX program.  
       [0111] Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and are useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein. Such modifications are encompassed by the present invention.  
       [0112] The protein may also be produced by operably linking the isolated polynucleotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system. Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, Calif., U.S.A. (the MaxBat™ kit), and such methods are well known in the art, as described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987), incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide ofthe present invention is “transformed.” 
       [0113] The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein. The resulting expressed protein may then be purified from such culture (i.e, from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography. The purification of the protein may also include an affinity column containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearl™ or Cibacrom blue 3GA Sepharose™; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or immunoaffinity chromatography.  
       [0114] Alternatively, the protein of the invention may also be expressed in a form which will facilitate purification. For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX), or as a His tag. Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, Mass.), Pharmacia (Piscataway, N.J.) and Invitrogen, respectively. The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope. One such epitope (“FLAG®”) is commercially available from Kodak (New Haven, Conn.).  
       [0115] Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an “isolated protein.” 
       [0116] The polypeptides of the invention include analogs (variants). This embraces fragments, as well as peptides in which one or more amino acids has been deleted, inserted, or substituted. Also, analogs of the polypeptides of the invention embrace fusions of the polypeptides or modifications of the polypeptides of the invention, wherein the polypeptide or analog is fused to another moiety or moieties, e.g., targeting moiety or another therapeutic agent. Such analogs may exhibit improved properties such as activity and/or stability. Examples of moieties which may be fused to the polypeptide or an analog include. for example, targeting moieties which provide for the delivery of polypeptide to pancreatic cells, e.g., antibodies to pancreatic cells, antibodies to immune cells such as T-cells, monocytes, dendritic cells, granulocytes, etc., as well as receptor and ligands expressed on pancreatic or immune cells. Other moieties which may be fused to the polypeptide include therapeutic agents which are used for treatment, for example, immunosuppressive drugs such as cyclosporin, SK506, azathioprine, CD3 antibodies and steroids. Also, polypeptides may be fused to immune modulators. and other cytokines such as alpha or beta interferon.  
       4.4.1 DETERMINING POLYPEPTIDE AND POLYNUCLEOTIDE IDENTITY AND SIMILARITY  
       [0117] Preferred identity and/or similarity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in computer programs including, but are not limited to, the GCG program package, including GAP (Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, BLASTX, FASTA (Altschul, S. F. et al., J. Molec. Biol. 215:403-410 (1990), PSI-BLAST (Altschul S. F. et al.. Nucleic Acids Res. vol. 25, pp. 3389-3402, herein incorporated by reference), eMatrix software (Wu et al., J. Comp. Biol., Vol. 6, pp. 219-235 (1999), herein incorporated by reference), eMotif software (Nevill-Manning et al, ISMB-97, Vol. 4, pp. 202-209, herein incorporated by reference), pFAM software (Sonnhammer et al., Nucleic Acids Res., Vol. 26(1), pp. 320-322 (1998), herein incorporated by reference) and the Kyte-Doolittle hydrophobocity prediction algorithm (J. Mol Biol, 157, pp. 105-31 (1982), incorporated herein by reference). The BLAST programs are publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul, S., et al. NCB NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990).  
       4.5 GENE THERAPY  
       [0118] Mutations in the polynucleotides of the invention gene may result in loss of normal function of the encoded protein. The invention thus provides gene therapy to restore normal activity of the polypeptides of the invention; or to treat disease states involving polypeptides of the invention. Delivery of a functional gene encoding polypeptides of the invention to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus), or ex vivo by use of physical DNA transfer methods (e.g., liposomes or chemical treatments). See, for example, Anderson, Nature, supplement to vol. 392, no. 6679, pp.25-20 (1998). For additional reviews of gene therapy technology see Friedmann, Science, 244: 1275-1281 (1989); Verma, Scientific American: 68-84 (1990); and Miller, Nature, 357: 455-460 (1992). Introduction of any one of the nucleotides of the present invention or a gene encoding the polypeptides of the present invention can also be accomplished with extrachromosomal substrates (transient expression) or artificial chromosomes (stable expression). Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes. Alternatively, it is contemplated that in other human disease states, preventing the expression of or inhibiting the activity of polypeptides of the invention will be useful in treating the disease states. It is contemplated that antisense therapy or gene therapy could be applied to negatively regulate the expression of polypeptides of the invention.  
       [0119] Other methods inhibiting expression of a protein include the introduction of antisense molecules to the nucleic acids of the present invention, their complements, or their translated RNA sequences, by methods known in the art. Further, the polypeptides of the present invention can be inhibited by using targeted deletion methods, or the insertion of a negative regulatory element such as a silencer, which is tissue specific.  
       [0120] The present invention still further provides cells genetically engineered in vivo to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell. These methods can be used to increase or decrease the expression of the polynucleotides of the present invention.  
       [0121] Knowledge of DNA sequences provided by the invention allows for modification of cells to permit, increase, or decrease, expression of endogenous polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the protein at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the desired protein encoding sequences. See, for example, PCT International Publication No. WO 94/12650, PCT International Publication No. WO 92/20808, and PCT International Publication No. WO 91/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the desired protein coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.  
       [0122] In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene targeting can be used to replace a gene&#39;s existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences. Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting. These sequences include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.  
       [0123] The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker. Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.  
       [0124] The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat. No.5,272,071 to Chappel; U.S. Pat. No. 5,578,461 to Sherwin et al.; International Application No. PCT/US92/09627 (WO93/09222) by Selden et al.; and International Application No. PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.  
       4.6 TRANSGENIC ANIMALS  
       [0125] In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals. Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals. Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat. No. 5,557,032, incorporated herein by reference. Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Pat. No 5,489,743 and PCT Publication No. WO94/28122, incorporated herein by reference.  
       [0126] Transgenic animals can be prepared wherein all or part of a promoter of the polynucleotides of the invention is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.  
       [0127] The polynucleotides of the present invention also make possible the development, through, e.g., homologous recombination or knock out strategies, of animals that fail to express polypeptides of the invention or that express a variant polypeptide. Such animals are useful as models for studying the in vivo activities of polypeptide as well as for studying modulators of the polypeptides of the invention.  
       [0128] In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals. Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals. Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat. No. 5,557,032, incorporated herein by reference. Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Pat. No 5,489,743 and PCT Publication No. WO94/28 122, incorporated herein by reference.  
       [0129] Transgenic animals can be prepared wherein all or part of the polynucleotides of the invention promoter is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.  
       4.7 USES AND BIOLOGICAL ACTIVITY  
       [0130] The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified herein. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA). The mechanism underlying the particular condition or pathology will dictate whether the polypeptides of the invention, the polynucleotides of the invention or modulators (activators or inhibitors) thereof would be beneficial to the subject in need of treatment. Thus, “therapeutic compositions of the invention” include compositions comprising isolated polynucleotides (including recombinant DNA molecules, cloned genes and degenerate variants thereof) or polypeptides of the invention (including full length protein, mature protein and truncations or domains thereof), or compounds and other substances that modulate the overall activity of the target gene products, either at the level of target gene/protein expression or target protein activity. Such modulators include polypeptides, analogs, (variants), including fragments and fusion proteins, antibodies and other binding proteins; chemical compounds that directly or indirectly activate or inhibit the polypeptides of the invention (identified, e.g., via drug screening assays as described herein); antisense polynucleotides and polynucleotides suitable for triple helix formation; and in particular antibodies or other binding partners that specifically recognize one or more epitopes of the polypeptides of the invention.  
       [0131] The polypeptides of the present invention may likewise be involved in cellular activation or in one of the other physiological pathways described herein.  
       4.7.1 RESEARCH USES AND UTILITIES  
       [0132] The polynucleotides provided by the present invention can be used by the research community 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 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; as a probe to “subtract-out” known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a “gene chip” or other support, including for examination of 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.  
       [0133] The 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 polypeptide 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. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.  
       [0134] Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.  
       [0135] 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., Cold 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.  
       4.7.2 NUTRITIONAL USES  
       [0136] Polynucleotides and polypeptides 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 polypeptide 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 polypeptide or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.  
       4.7.3 CYTOKINE AND CELL PROLIFERATION/DIFFERENTIATION ACTIVITY  
       [0137] A polypeptide of the present invention may exhibit activity relating to cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. 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 therapeutic compositions 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, Mo7e, CMK, HUVEC, and Caco. Therapeutic compositions of the invention can be used in the following:  
       [0138] Assays for T-cell or thymocyte proliferation 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 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); 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., I. Immunol. 149:3778-3783, 1992; Bowman et al., I. Immunol. 152:1756-1761, 1994.  
       [0139] Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A. M. and Shevach, E. M. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 3.12.1 -3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human interleukin-γ, Schreiber, R. D. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994.  
       [0140] Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L. S. and Lipsky, P. E. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol I 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 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983; Measurement of mouse and human interleukin 6—Nordan, R. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Natl. Aced. Sci. U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin 11—Bennett, F., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991; Measurement of mouse and human Interleukin 9—Ciarletta, A., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991.  
       [0141] Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) 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 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans); 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.  
       4.7.4 STEM CELL GROWTH FACTOR ACTIVITY  
       [0142] A polypeptide of the present invention may exhibit stem cell growth factor activity and be involved in the proliferation, differentiation and survival of pluripotent and totipotent stem cells including primordial germ cells, embryonic stem cells, hematopoietic stem cells and/or germ line stem cells. Administration of the polypeptide of the invention to stem cells in vivo or ex vivo is expected to maintain and expand cell populations in a totipotential or pluripotential state which would be useful for re-engineering damaged or diseased tissues, transplantation, manufacture of bio-pharmaceuticals and the development of bio-sensors. The ability to produce large quantities of human cells has important working applications for the production of human proteins which currently must be obtained from non-human sources or donors, implantation of cells to treat diseases such as Parkinson&#39;s, Alzheimer&#39;s and other neurodegenerative diseases; tissues for grafting such as bone marrow, skin, cartilage, tendons, bone, muscle (including cardiac muscle), blood vessels, cornea, neural cells, gastrointestinal cells and others; and organs for transplantation such as kidney, liver, pancreas (including islet cells), heart and lung.  
       [0143] It is contemplated that multiple different exogenous growth factors and/or cytokines may be administered in combination with the polypeptide of the invention to achieve the desired effect, including any of the growth factors listed herein, other stem cell maintenance factors, and specifically including stem cell factor (SCF), leukemia inhibitory factor (LIF), Flt-3 ligand (Flt-3L), any of the interleukins, recombinant soluble IL-6 receptor fused to IL-6, macrophage inflammatory protein 1-alpha (MIP-1-alpha), G-CSF, GM-CSF, thrombopoietin (TPO), platelet factor 4 (PF-4), platelet-derived growth factor (PDGF), neural growth factors and basic fibroblast growth factor (bFGF).  
       [0144] Since totipotent stem cells can give rise to virtually any mature cell type, expansion of these cells in culture will facilitate the production of large quantities of mature cells. Techniques for culturing stem cells are known in the art and administration of polypeptides of the invention, optionally with other growth factors and/or cytokines, is expected to enhance the survival and proliferation of the stem cell populations. This can be accomplished by direct administration of the polypeptide of the invention to the culture medium. Alternatively, stroma cells transfected with a polynucleotide that encodes for the polypeptide of the invention can be used as a feeder layer for the stem cell populations in culture or in vivo. Stromal support cells for feeder layers may include embryonic bone marrow fibroblasts, bone marrow stromal cells, fetal liver cells, or cultured embryonic fibroblasts (see U.S. Pat. No. 5,690,926).  
       [0145] Stem cells themselves can be transfected with a polynucleotide of the invention to induce autocrine expression of the polypeptide of the invention. This will allow for generation of undifferentiated totipotential/pluripotential stem cell lines that are useful as is or that can then be differentiated into the desired mature cell types. These stable cell lines can also serve as a source of undifferentiated totipotential/pluripotential mRNA to create cDNA libraries and templates for polymerase chain reaction experiments. These studies would allow for the isolation and identification of differentially expressed genes in stem cell populations that regulate stem cell proliferation and/or maintenance.  
       [0146] Expansion and maintenance of totipotent stem cell populations will be useful in the treatment of many pathological conditions. For example, polypeptides of the present invention may be used to manipulate stem cells in culture to give rise to neuroepithelial cells that can be used to augment or replace cells damaged by illness, autoimmune disease, accidental damage or genetic disorders. The polypeptide of the invention may be useful for inducing the proliferation of neural cells and for the 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. In addition, the expanded stem cell populations can also be genetically altered for gene therapy purposes and to decrease host rejection of replacement tissues after grafting or implantation.  
       [0147] Expression of the polypeptide of the invention and its effect on stem cells can also be manipulated to achieve controlled differentiation of the stem cells into more differentiated cell types. A broadly applicable method of obtaining pure populations of a specific differentiated cell type from undifferentiated stem cell populations involves the use of a cell-type specific promoter driving a selectable marker. The selectable marker allows only cells of the desired type to survive. For example, stem cells can be induced to differentiate into cardiomyocytes (Wobus et al., Differentiation, 48:173-182, (1991); Klug et al., J. Clin. Invest., 98(1):216-224, (1998)) or skeletal muscle cells (Browder, L. W. In:  Principles of Tissue Engineering eds.  Lanza et al., Academic Press (1997)). Alternatively, directed differentiation of stem cells can be accomplished by culturing the stem cells in the presence of a differentiation factor such as retinoic acid and an antagonist of the polypeptide of the invention which would inhibit the effects of endogenous stem cell factor activity and allow differentiation to proceed.  
       [0148] In vitro cultures of stem cells can be used to determine if the polypeptide of the invention exhibits stem cell growth factor activity. Stem cells are isolated from any one of various cell sources (including hematopoietic stem cells and embryonic stem cells) and cultured on a feeder layer, as described by Thompson et al. Proc. Natl. Acad. Sci, U.S.A., 92: 7844-7848 (1995), in the presence of the polypeptide of the invention alone or in combination with other growth factors or cytokines. The ability of the polypeptide of the invention to induce stem cells proliferation is determined by colony formation on semi-solid support e.g. as described by Bernstein et al., Blood, 77:2316-2321 (1991).  
       4.7.5 HEMATOPOIESIS REGULATING ACTIVITY  
       [0149] A polypeptide of the present invention may be involved in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell disorders. 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 transplantation, 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.  
       [0150] Therapeutic compositions of the invention can be used in the following:  
       [0151] Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.  
       [0152] Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: 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.  
       [0153] Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M. G. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I. K. and Briddell, R. A. 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; Cobblestone area forming cell assay, Ploemacher, R. E. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 1-21, Wiley-Liss, Inc., New York, N.Y. 1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, N.Y. 1994; Long term culture initiating cell assay, Sutherland, H. J. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, N.Y. 1994.  
         4 . 7 . 6  TISSUE GROWTH ACTIVITY  
       [0154] A polypeptide of the present invention also may be involved in bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as in wound healing and tissue repair and replacement, and in healing of burns, incisions and ulcers.  
       [0155] A polypeptide 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. Compositions of a polypeptide, antibody, binding partner, or other modulator 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.  
       [0156] A polypeptide of this invention may also be involved in attracting bone-forming cells, stimulating growth of bone-forming cells, or inducing differentiation of progenitors of bone-forming cells. Treatment of osteoporosis, osteoarthritis, bone degenerative disorders, or periodontal disease, 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 may also be possible using the composition of the invention.  
       [0157] Another category of tissue regeneration activity that may involve the polypeptide of the present invention is tendon/ligament formation. Induction of 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 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.  
       [0158] The compositions 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 composition 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 composition of the invention.  
       [0159] Compositions 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.  
       [0160] Compositions of the present invention may also be involved in the 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 may allow normal tissue to regenerate. A polypeptide of the present invention may also exhibit angiogenic activity.  
       [0161] A composition 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 cytokine damage.  
       [0162] A composition 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.  
       [0163] Therapeutic compositions of the invention can be used in the following:  
       [0164] Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No. WO95/16035 (bone, cartilage, tendon); International Patent Publication No. WO95/05846 (nerve, neuronal); International Patent Publication No. WO91/07491 (skin, endothelium).  
       [0165] Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, H. I. and Rovee, D. T., eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978).  
       4.7.7 IMMUNE STIMULATING OR SUPPRESSING ACTIVITY  
       [0166] A polypeptide of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A polynucleotide of the invention can encode a polypeptide exhibiting such activities. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (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 causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpes viruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis. Of course, in this regard, proteins 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.  
       [0167] 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 (or antagonists thereof, including antibodies) of the present invention may also to be useful in the treatment of allergic reactions and conditions (e.g., anaphylaxis, serum sickness, drug reactions, food allergies, insect venom allergies, mastocytosis, allergic rhinitis, hypersensitivity pneumonitis, urticaria, angioedema, eczema, atopic dermatitis, allergic contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, allergic conjunctivitis, atopic keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis and contact allergies), 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 (or antagonists thereof) of the present invention. The therapeutic effects of the polypeptides or antagonists thereof on allergic reactions can be evaluated by in vivo animals models such as the cumulative contact enhancement test (Lastbom et al., Toxicology 125:59-66, 1998), skin prick test (Hoffmann et al., Allergy 54:446-54, 1999), guinea pig skin sensitization test (Vohr et al., Arch. Toxocol. 73:501-9), and murine local lymph node assay (Kimber et al., J. Toxicol. Environ. Health 53:563-79).  
       [0168] Using the proteins of the invention it may also be possible to modulate 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.  
       [0169] 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 therapeutic composition of the invention may prevent cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant. Moreover, a 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.  
       [0170] The efficacy of particular therapeutic compositions 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 therapeutic compositions of the invention on the development of that disease.  
       [0171] 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 stimulation of T cells 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/lpr/lpr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856).  
       [0172] Upregulation of an antigen function (e.g., 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 may be useful in cases of viral infection, including systemic viral diseases such as influenza, the common cold, and encephalitis.  
       [0173] 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. Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.  
       [0174] A polypeptide of the present invention may provide the necessary stimulation 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 mounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I alpha chain protein and β 2  microglobulin protein or an MHC class II alpha chain protein and an MHC class II beta chain protein to thereby express MHC class I or MHC class II proteins on the cell surface. Expression of the appropriate class I 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.  
       [0175] The activity of a protein of the invention may, among other means, be measured by the following methods:  
       [0176] Suitable assays for thymocyte or splenocyte cytotoxicity 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 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); 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., I. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988; Bowman et al., J. Virology 61:1992-1998; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol. 153:3079-3092, 1994.  
       [0177] Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Th1/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol. 144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J. J. and Brunswick, M. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994.  
       [0178] Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly ThI and CTL responses) 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 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); 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.  
       [0179] Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: 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 67:4062-4069, 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.  
       [0180] Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: 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 of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.  
       [0181] Assays for proteins that influence early steps of T-cell commitment and development 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.  
       4.7.8 ACTIVIN/INHIBIN ACTIVITY  
       [0182] A polypeptide of the present invention may also exhibit activin- or inhibin-related activities. A polynucleotide of the invention may encode a polypeptide exhibiting such characteristics. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH). Thus, a polypeptide of the present invention, alone or in heterodimers with a member of the inhibin 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 polypeptide of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin 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. A polypeptide 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, but not limited to, cows, sheep and pigs.  
       [0183] The activity of a polypeptide of the invention may, among other means, be measured by the following methods.  
       [0184] Assays for activin/inhibin activity include, without limitation, those described in: 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.  
       4.7.9 CHEMOTACTIC/CHEMOKINETIC ACTIVITY  
       [0185] A polypeptide of the present invention may be involved in chemotactic or chemokinetic activity for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Chemotactic and chemokinetic receptor activation can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic compositions (e.g. proteins, antibodies, binding partners, or modulators of the invention) 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.  
       [0186] 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.  
       [0187] Therapeutic compositions of the invention can be used in the following:  
       [0188] 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 adhesion 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. Marguiles, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; 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.  
       4.7.10 HEMOSTATIC AND THROMBOLYTIC ACTIVITY  
       [0189] A polypeptide of the invention may also be involved in hemostatis or thrombolysis or thrombosis. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Compositions may be useful in treatment of various coagulation 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 composition 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).  
       [0190] Therapeutic compositions of the invention can be used in the following:  
       [0191] Assay for hemostatic and thrombolytic activity include, without limitation, those described in: 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.  
       4.7.11 CANCER DIAGNOSIS AND THERAPY  
       [0192] Polypeptides of the invention may be involved in cancer cell generation, proliferation or metastasis. Detection of the presence or amount of polynucleotides or polypeptides of the invention may be useful for the diagnosis and/or prognosis of one or more types of cancer. For example, the presence or increased expression of a polynucleotide/polypeptide of the invention may indicate a hereditary risk of cancer, a precancerous condition, or an ongoing malignancy. Conversely, a defect in the gene or absence of the polypeptide may be associated with a cancer condition. Identification of single nucleotide polymorphisms associated with cancer or a predisposition to cancer may also be useful for diagnosis or prognosis.  
       [0193] Cancer treatments promote tumor regression by inhibiting tumor cell proliferation, inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) and/or prohibiting metastasis by reducing tumor cell motility or invasiveness. Therapeutic compositions of the invention may be effective in adult and pediatric oncology including in solid phase tumors/malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple mycloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and Karposi&#39;s sarcoma.  
       [0194] Polypeptides, polynucleotides, or modulators of polypeptides of the invention (including inhibitors and stimulators of the biological activity of the polypeptide of the invention) may be administered to treat cancer. Therapeutic compositions can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e.g. reducing tumor size, slowing rate of tumor growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.  
       [0195] The composition can also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail. An anti-cancer cocktail is a mixture of the polypeptide or modulator of the invention with one or more anti-cancer drugs in addition to a pharmaceutically acceptable carrier for delivery. The use of anti-cancer cocktails as a cancer treatment is routine. Anti-cancer drugs that are well known in the art and can be used as a treatment in combination with the polypeptide or modulator of the invention include: Actinomycin D, Aminoglutethimide, Asparaginase, Bleomycin, Busulfan. Carboplatin, Carmustine, Chlorambucil, Cisplatin (cis-DDP), Cyclophosphamide, Cytarabine HCI (Cytosine arabinoside), Dacarbazine, Dactinomycin, Daunorubicin HCI, Doxorubicin HCI, Estramustine phosphate sodium, Etoposide (V16-213), Floxuridine, 5-Fluorouracil (5-Fu), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alpha-2a, Interferon Alpha-2b, Leuprolide acetate (LHRH-releasing factor analog), Lomustine, Mechlorethamine HCl (nitrogen mustard), Melphalan, Mercaptopurine, Mesna, Methotrexate (MTX), Mitomycin, Mitoxantrone HCl, Octreotide, Plicamycin, Procarbazine HCl, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Vincristine sulfate, Amsacrine, Azacitidine, Hexamethylmelamine, Interleukin-2, Mitoguazone, Pentostatin, Semustine, Teniposide, and Vindesine sulfate.  
       [0196] In addition, therapeutic compositions of the invention may be used for prophylactic treatment of cancer. There are hereditary conditions and/or environmental situations (e.g. exposure to carcinogens) known in the art that predispose an individual to developing cancers. Under these circumstances, it may be beneficial to treat these individuals with therapeutically effective doses of the polypeptide of the invention to reduce the risk of developing cancers.  
       [0197] In vitro models can be used to determine the effective doses of the polypeptide of the invention as a potential cancer treatment. These in vitro models include proliferation assays of cultured tumor cells, growth of cultured tumor cells in soft agar (see Freshney, (1987) Culture of Animal Cells: A Manual of Basic Technique, Wily-Liss, New York, NY Ch 18 and Ch 21), tumor systems in nude mice as described in Giovanella et al., J. Natl. Can. Inst., 52: 921-30 (1974), mobility and invasive potential of tumor cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17: 4107-9 (1997), and angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl. J. Dev. Biol., 40: 1189-97 (1999) and Li et al., Clin. Exp. Metastasis, 17:423-9 (1999), respectively. Suitable tumor cells lines are available, e.g. from American Type Tissue Culture Collection catalogs.  
       4.7.12 RECEPTOR/LIGAND ACTIVITY  
       [0198] A polypeptide of the present invention may also demonstrate activity as receptor, receptor ligand or inhibitor or agonist of receptor/ligand interactions. A polynucleotide of the invention can encode a polypeptide exhibiting such characteristics. 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 selectins integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses. 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.  
       [0199] The activity of a polypeptide of the invention may, among other means, be measured by the following methods:  
       [0200] Suitable assays for receptor-ligand activity 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 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), 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.  
       [0201] By way of example, the polypeptides of the invention may be used as a receptor for a ligand(s) thereby transmitting the biological activity of that ligand(s). Ligands may be identified through binding assays, affinity chromatography, dihybrid screening assays, BlAcore assays, gel overlay assays, or other methods known in the art.  
       [0202] Studies characterizing drugs or proteins as agonist or antagonist or partial agonists or a partial antagonist require the use of other proteins as competing ligands. The polypeptides of the present invention or ligand(s) thereof may be labeled by being coupled to radioisotopes, calorimetric molecules or a toxin molecules by conventional methods. (“Guide to Protein Purification” Murray P. Deutscher (ed) Methods in Enzymology Vol. 182 (1990) Academic Press, Inc. San Diego). Examples of radioisotopes include, but are not limited to, tritium and carbon-14. Examples of colorimetric molecules include, but are not limited to, fluorescent molecules such as fluorescamine, or rhodamine or other calorimetric molecules. Examples of toxins include, but are not limited, to ricin.  
       4.7.13 DRUG SCREENING  
       [0203] This invention is particularly useful for screening chemical compounds by using the novel polypeptides or binding fragments thereof in any of a variety of drug screening techniques. The polypeptides or fragments employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or a fragment thereof. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between polypeptides of the invention or fragments and the agent being tested or examine the diminution in complex formation between the novel polypeptides and an appropriate cell line, which are well known in the art.  
       [0204] Sources for test compounds that may be screened for ability to bind to or modulate (i.e., increase or decrease) the activity of polypeptides of the invention include (1) inorganic and organic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of either random or mimetic peptides, oligonucleotides or organic molecules.  
       [0205] Chemical libraries may be readily synthesized or purchased from a number of commercial sources, and may include structural analogs of known compounds or compounds that are identified as “hits” or “leads” via natural product screening.  
       [0206] The sources of natural product libraries are microorganisms (including bacteria and fungi), animals, plants or other vegetation, or marine organisms, and libraries of mixtures for screening may be created by: (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of the organisms themselves. Natural product libraries include polyketides, non-ribosomal peptides, and (non-naturally occurring) variants thereof. For a review, see  Science  282:63-68 (1998).  
       [0207] Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds and can be readily prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods. Of particular interest are peptide and oligonucleotide combinatorial libraries. Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries. For a review of combinatorial chemistry and libraries created therefrom, see Myers,  Curr. Opin. Biotechnol.  8:701-707 (1997). For reviews and examples of peptidomimetic libraries, see Al-Obeidi et al.,  Mol. Biotechnol,  9(3):205-23 (1998); Hruby et al.,  Curr Opin Chem Biol,  1(1):114-19 (1997); Dorner et al.,  Bioorg Med Chem,  4(5):709-15 (1996) (alkylated dipeptides).  
       [0208] Identification of modulators through use of the various libraries described herein permits modification of the candidate “hit” (or “lead”) to optimize the capacity of the “hit” to bind a polypeptide of the invention. The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.  
       [0209] The binding molecules thus identified may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells such as radioisotopes. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for a polypeptide of the invention. Alternatively, the binding molecules may be complexed with imaging agents for targeting and imaging purposes.  
       4.7.14 ASSAY FOR RECEPTOR ACTIVITY  
       [0210] The invention also provides methods to detect specific binding of a polypeptide e.g. a ligand or a receptor. The art provides numerous assays particularly useful for identifying previously unknown binding partners for receptor polypeptides of the invention. For example, expression cloning using mammalian or bacterial cells, or dihybrid screening assays can be used to identify polynucleotides encoding binding partners. As another example, affinity chromatography with the appropriate immobilized polypeptide of the invention can be used to isolate polypeptides that recognize and bind polypeptides of the invention. There are a number of different libraries used for the identification of compounds, and in particular small molecules, that modulate (i.e., increase or decrease) biological activity of a polypeptide of the invention. Ligands for receptor polypeptides of the invention can also be identified by adding exogenous ligands, or cocktails of ligands to two cells populations that are genetically identical except for the expression of the receptor of the invention: one cell population expresses the receptor of the invention whereas the other does not. The response of the two cell populations to the addition of ligands(s) are then compared. Alternatively, an expression library can be co-expressed with the polypeptide of the invention in cells and assayed for an autocrine response to identify potential ligand(s). As still another example, BlAcore assays, gel overlay assays, or other methods known in the art can be used to identify binding partner polypeptides, including, (1) organic and inorganic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of random peptides, oligonucleotides or organic molecules.  
       [0211] The role of downstream intracellular signaling molecules in the signaling cascade of the polypeptide of the invention can be determined. For example, a chimeric protein in which the cytoplasmic domain of the polypeptide of the invention is fused to the extracellular portion of a protein, whose ligand has been identified, is produced in a host cell. The cell is then incubated with the ligand specific for the extracellular portion of the chimeric protein, thereby activating the chimeric receptor. Known downstream proteins involved in intracellular signaling can then be assayed for expected modifications i.e. phosphorylation. Other methods known to those in the art can also be used to identify signaling molecules involved in receptor activity.  
       4.7.15 ANTI-INFLAMMATORY ACTIVITY  
       [0212] Compositions of the present invention may also exhibit 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. Compositions with such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation intimation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, 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. Compositions of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material. Compositions of this invention may be utilized to prevent or treat conditions such as, but not limited to, sepsis, acute pancreatitis, endotoxin shock, cytokine induced shock, rheumatoid arthritis, chronic inflammatory arthritis, pancreatic cell damage from diabetes mellitus type 1, graft versus host disease, inflammatory bowel disease, inflamation associated with pulmonary disease, other autoimmune disease or inflammatory disease, an antiproliferative agent such as for acute or chronic mylegenous leukemia or in the prevention of premature labor secondary to intrauterine infections.  
       4.7.16 LEUKEMIAS  
       [0213] Leukemias and related disorders may be treated or prevented by administration of a therapeutic that promotes or inhibits function of the polynucleotides and/or polypeptides of the invention. Such leukemias and related disorders include but are not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyclocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia).  
       4.7.17 NERVOUS SYSTEM DISORDERS  
       [0214] Nervous system disorders, involving cell types which can be tested for efficacy of intervention with compounds that modulate the activity of the polynucleotides and/or polypeptides of the invention, and which can be treated upon thus observing an indication of therapeutic utility, include but are not limited to nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems:  
       [0215] (i) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries;  
       [0216] (ii) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia;  
       [0217] (iii) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis;  
       [0218] (iv) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkinson&#39;s disease, Alzheimer&#39;s disease, Huntington&#39;s chorea, or amyotrophic lateral sclerosis;  
       [0219] (v) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration;  
       [0220] (vi) neurological lesions associated with systemic diseases including but not limited to diabetes (diabetic neuropathy, Bell&#39;s palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis;  
       [0221] (vii) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and  
       [0222] (viii) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.  
       [0223] Therapeutics which are useful according to the invention for treatment of a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, therapeutics which elicit any of the following effects may be useful according to the invention:  
       [0224] (i) increased survival time of neurons in culture;  
       [0225] (ii) increased sprouting of neurons in culture or in vivo;  
       [0226] (iii) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (iv) decreased symptoms of neuron dysfunction in vivo.  
       [0227] Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased survival of neurons may be measured by the method set forth in Arakawa et al. (1990, J. Neurosci. 10:3507-3515); increased sprouting of neurons may be detected by methods set forth in Pestronk et al. (1980, Exp. Neurol. 70:65-82) or Brown et al. (1981, Ann. Rev. Neurosci. 4:17-42); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.  
       [0228] In specific embodiments, motor neuron disorders that may be treated according to the invention include but are not limited to disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including but not limited to progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis. infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).  
       4.7.18 OTHER ACTIVITIES  
       [0229] A polypeptide 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, co-factors 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.  
       4.7.19 IDENTIFICATION OF POLYMORPHISMS  
       [0230] The demonstration of polymorphisms makes possible the identification of such polymorphisms in human subjects and the phannacogenetic use of this information for diagnosis and treatment. Such polymorphisms may be associated with, e.g., differential predisposition or susceptibility to various disease states (such as disorders involving inflammation or immune response) or a differential response to drug administration, and this genetic information can be used to tailor preventive or therapeutic treatment appropriately. For example, the existence of a polymorphism associated with a predisposition to inflammation or autoimmune disease makes possible the diagnosis of this condition in humans by identifying the presence of the polymorphism.  
       [0231] Polymorphisms can be identified in a variety of ways known in the art which all generally involve obtaining a sample from a patient, analyzing DNA from the sample, optionally involving isolation or amplification of the DNA, and identifying the presence of the polymorphism in the DNA. For example, PCR may be used to amplify an appropriate fragment of genomic DNA which may then be sequenced. Alternatively, the DNA may be subjected to allele-specific oligonucleotide hybridization (in which appropriate oligonucleotides are hybridized to the DNA under conditions permitting detection of a single base mismatch) or to a single nucleotide extension assay (in which an oligonucleotide that hybridizes immediately adjacent to the position of the polymorphism is extended with one or more labeled nucleotides). In addition, traditional restriction fragment length polymorphism analysis (using restriction enzymes that provide differential digestion of the genomic DNA depending on the presence or absence of the polymorphism) may be performed. Arrays with nucleotide sequences of the present invention can be used to detect polymorphisms. The array can comprise modified nucleotide sequences of the present invention in order to detect the nucleotide sequences of the present invention. In the alternative, any one of the nucleotide sequences of the present invention can be placed on the array to detect changes from those sequences.  
       [0232] Alternatively a polymorphism resulting in a change in the amino acid sequence could also be detected by detecting a corresponding change in amino acid sequence of the protein, e.g., by an antibody specific to the variant sequence.  
       4.7.20 ARTHRITIS AND INFLAMMATION  
       [0233] The immunosuppressive effects of the compositions of the invention against rheumatoid arthritis is determined in an experimental animal model system. The experimental model system is adjuvant induced arthritis in rats, and the protocol is described by J. Holoshitz, et at., 1983, Science, 219:56, or by B. Waksman et al., 1963, Int. Arch. Allergy Appl. Immunol., 23:129. Induction of the disease can be caused by a single injection, generally intradermally, of a suspension of killed Mycobacterium tuberculosis in complete Freund&#39;s adjuvant (CFA). The route of injection can vary, but rats may be injected at the base of the tail with an adjuvant mixture. The polypeptide is administered in phosphate buffered solution (PBS) at a dose of about 1-5 mg/kg. The control consists of administering PBS only.  
       [0234] The procedure for testing the effects of the test compound would consist of intradermally injecting killed Mycobacterium tuberculosis in CFA followed by immediately administering the test compound and subsequent treatment every other day until day 24. At 14, 15, 18, 20, 22, and 24 days after injection of Mycobacterium CFA, an overall arthritis score may be obtained as described by J. Holoskitz above. An analysis of the data would reveal that the test compound would have a dramatic affect on the swelling of the joints as measured by a decrease of the arthritis score.  
       4.8 THERAPEUTIC METHODS  
       [0235] The compositions (including polypeptide fragments, analogs, variants and antibodies or other binding partners or modulators including antisense polynucleotides) of the invention have numerous applications in a variety of therapeutic methods. Examples of therapeutic applications include, but are not limited to, those exemplified herein.  
       4.8.1 EXAMPLE  
       [0236] One embodiment of the invention is the administration of an effective amount of the polypeptides or other composition of the invention to individuals affected by a disease or disorder that can be modulated by regulating the peptides of the invention. While the mode of administration is not particularly important, parenteral administration is preferred. An exemplary mode of administration is to deliver an intravenous bolus. The dosage of the polypeptides or other composition of the invention will normally be determined by the prescribing physician. It is to be expected that the dosage will vary according to the age, weight, condition and response of the individual patient. Typically, the amount of polypeptide administered per dose will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight, with the preferred dose being about 0.1 μg/kg to 10 mg/kg of patient body weight. For parenteral administration, polypeptides of the invention will be formulated in an injectable form combined with a pharmaceutically acceptable parenteral vehicle. Such vehicles are well known in the art and examples include water, saline, Ringer&#39;s solution, dextrose solution, and solutions consisting of small amounts of the human serum albumin. The vehicle may contain minor amounts of additives that maintain the isotonicity and stability of the polypeptide or other active ingredient. The preparation of such solutions is within the skill of the art.  
       4.9 PHARMACEUTICAL FORMULATIONS AND ROUTES OF ADMINISTRATION  
       [0237] A protein or other composition of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources and including antibodies and other binding partners of the polypeptides of the invention) may be administered to a patient in need, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a variety of disorders. Such a composition may optionally contain (in addition to protein or other active ingredient and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNF0, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin. In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the disease or disorder in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), insulin-like growth factor (IGF), as well as cytokines described herein.  
       [0238] The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or other active ingredient or complement its activity or use in treatment. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein or other active ingredient of the invention, or to minimize side effects. Conversely, protein or other active ingredient of the present invention may be included in formulations of the particular clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent (such as IL-1Ra, IL-1 Hy1, IL-1 Hy2, anti-TNF, corticosteroids, immunosuppressive agents). A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins. As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.  
       [0239] As an alternative to being included in a pharmaceutical composition of the invention including a first protein, a second protein or a therapeutic agent may be concurrently administered with the first protein (e.g., at the same time, or at differing times provided that therapeutic concentrations of the combination of agents is achieved at the treatment site). Techniques for formulation and administration of the compounds of the instant application may be found in “Remington&#39;s Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa. latest edition. A therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.  
       [0240] In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein or other active ingredient of the present invention is administered to a mammal having a condition to be treated. Protein or other active ingredient of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein or other active ingredient of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein or other active ingredient of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.  
       4.9.1 ROUTES OF ADMINISTRATION  
       [0241] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Administration of protein or other active ingredient of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection. Intravenous administration to the patient is preferred.  
       [0242] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a arthritic joints or in fibrotic tissue, often in a depot or sustained release formulation. In order to prevent the scarring process frequently occurring as complication of glaucoma surgery, the compounds may be administered topically, for example, as eye drops. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a specific antibody, targeting, for example, arthritic or fibrotic tissue. The liposomes will be targeted to and taken up selectively by the afflicted tissue.  
       [0243] The polypeptides of the invention are administered by any route that delivers an effective dosage to the desired site of action. The determination of a suitable route of administration and an effective dosage for a particular indication is within the level of skill in the art. Preferably for wound treatment, one administers the therapeutic compound directly to the site. Suitable dosage ranges for the polypeptides of the invention can be extrapolated from these dosages or from similar studies in appropriate animal models. Dosages can then be adjusted as necessary by the clinician to provide maximal therapeutic benefit.  
       4.9.2 COMPOSITIONS/FORMULATIONS  
       [0244] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. These pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of protein or other active ingredient of the present invention is administered orally, protein or other active ingredient of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% protein or other active ingredient of the present invention, and preferably from about 25 to 90% protein or other active ingredient ofthe present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein or other active ingredient of the present invention, and preferably from about 1 to 50% protein or other active ingredient of the present invention.  
       [0245] When a therapeutically effective amount of protein or other active ingredient of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein or other active ingredient of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein or other active ingredient solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein or other active ingredient of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer&#39;s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer&#39;s Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks&#39;s solution, Ringer&#39;s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.  
       [0246] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained from a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.  
       [0247] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.  
       [0248] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.  
       [0249] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.  
       [0250] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.  
       [0251] A pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various types of sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein or other active ingredient stabilization may be employed.  
       [0252] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the active ingredients of the invention may be provided as salts with pharmaceutically compatible counter ions. Such pharmaceutically acceptable base addition salts are those salts which retain the biological effectiveness and properties of the free acids and which are obtained by reaction with inorganic or organic bases such as sodium hydroxide, magnesium hydroxide, ammonia, trialkylamine, dialkylamine, monoalkylamine, dibasic amino acids, sodium acetate, potassium benzoate, triethanol amine and the like.  
       [0253] The pharmaceutical composition of the invention may be in the form of a complex of the protein(s) or other active ingredient(s) of present invention along with protein or peptide antigens. The protein and/or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes. B lymphocytes will respond to antigen through their surface immunoglobulin receptor. T lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigen(s) to T lymphocytes. The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells. Alternatively antibodies able to bind surface immunoglobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.  
       [0254] The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat. Nos. 4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference.  
       [0255] The amount of protein or other active ingredient of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of protein or other active ingredient of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein or other active ingredient of the present invention and observe the patient&#39;s response. Larger doses of protein or other active ingredient of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 μg to about 100 mg (preferably about 0.1 μg to about 10 mg, more preferably about 0.1 μg to about 1 mg) of protein or other active ingredient of the present invention per kg body weight. For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device. When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form. Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage. Topical administration may be suitable for wound healing and tissue repair. Therapeutically useful agents other than a protein or other active ingredient of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing or other active ingredient-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body. Such matrices may be formed of materials presently in use for other implanted medical applications.  
       [0256] The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the compositions will define the appropriate formulation. Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides. Other potential materials are biodegradable and biologically well-defined, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other ceramics. Matrices may be comprised of combinations of any of the above mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate. The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability. Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 150 to 800 microns. In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.  
       [0257] A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol). The amount of sequestering agent useful herein is 0.5-20 wt %, preferably 1-10 wt % based on total formulation weight, which represents the amount necessary to prevent desorption of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells. In further compositions, proteins or other active ingredients of the invention may be combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), and insulin-like growth factor (IGF).  
       [0258] The therapeutic compositions are also presently valuable for veterinary applications. Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins or other active ingredients of the present invention. The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient&#39;s age, sex, and diet, the severity of any infection, time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition. For example, the addition of other known growth factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage. Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations and tetracycline labeling.  
       [0259] Polynucleotides of the present invention can also be used for gene therapy. Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA). Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes.  
       4.9.3 EFFECTIVE DOSAGE  
       [0260] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from appropriate in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that can be used to more accurately determine useful doses in humans. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 50  as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of the protein&#39;s biological activity). Such information can be used to more accurately determine useful doses in humans.  
       [0261] A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50  (the dose lethal to 50% of the population) and the ED 50  (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50  and ED 50 . Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50  with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient&#39;s condition. See, e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p.1. Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.  
       [0262] Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.  
       [0263] An exemplary dosage regimen for polypeptides or other compositions of the invention will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight daily, with the preferred dose being about 0.1 μg/kg to 25 mg/kg of patient body weight daily, varying in adults and children. Dosing may be once daily, or equivalent doses may be delivered at longer or shorter intervals.  
       [0264] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject&#39;s age and weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.  
       4.9.4 PACKAGING  
       [0265] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.  
       4.10 ANTIBODIES  
       [0266] Another aspect of the invention is an antibody that specifically binds the polypeptide of the invention. Such antibodies include monoclonal and polyclonal antibodies, single chain antibodies, chimeric antibodies, bifunctional/bispecific antibodies, humanized antibodies, human antibodies, and complementary determining region (CDR)-grafted antibodies, including compounds which include CDR and/or antigen-binding sequences, which specifically recognize a polypeptide of the invention. Preferred antibodies of the invention are human antibodies which are produced and identified according to methods described in WO93/11236, published Jun. 20, 1993, which is incorporated herein by reference in its entirety. Antibody fragments, including Fab, Fab′, F(ab′) 2 , and Fv, are also provided by the invention. The term “specific for” indicates that the variable regions of the antibodies of the invention recognize and bind polypeptides of the invention exclusively (i.e., able to distinguish the polypeptide of the invention from other similar polypeptides despite sequence identity, homology, or similarity found in the family of polypeptides), but may also interact with other proteins (for example,  S. aureus  protein A or other antibodies in ELISA techniques) through interactions with sequences outside the variable region of the antibodies, and in particular, in the constant region of the molecule. Screening assays to determine binding specificity of an antibody of the invention are well known and routinely practiced in the art. For a comprehensive discussion of such assays, see Harlow et al. (Eds), Antibodies A Laboratory Manual; Cold Spring Harbor Laboratory; Cold Spring Harbor, N.Y. (1988), Chapter 6. Antibodies that recognize and bind fragments of the polypeptides of the invention are also contemplated, provided that the antibodies are first and foremost specific for, as defined above, full length polypeptides of the invention. As with antibodies that are specific for full length polypeptides of the invention, antibodies of the invention that recognize fragments are those which can distinguish polypeptides from the same family of polypeptides despite inherent sequence identity, homology, or similarity found in the family of proteins. Antibodies of the invention can be produced using any method well known and routinely practiced in the art.  
       [0267] Non-human antibodies may be humanized by any methods known in the art. In one method, the non-human CDRs are inserted into a human antibody or consensus antibody framework sequence. Further changes can then be introduced into the antibody framework to modulate affinity or immunogenicity.  
       [0268] Antibodies of the invention are useful for, for example, therapeutic purposes (by modulating activity of a polypeptide of the invention), diagnostic purposes to detect or quantitate a polypeptide of the invention, as well as purification of a polypeptide of the invention. Kits comprising an antibody of the invention for any of the purposes described herein are also comprehended. In general, a kit of the invention also includes a control antigen for which the antibody is immunospecific. The invention further provides a hybridoma that produces an antibody according to the invention. Antibodies of the invention are useful for detection and/or purification of the polypeptides of the invention.  
       [0269] Polypeptides of the invention may also be used to immunize animals to obtain polyclonal and monoclonal antibodies which specifically react with the protein. Such antibodies may be obtained using either the entire protein or fragments thereof as an immunogen. The peptide immunogens additionally may contain a cysteine residue at the carboxyl terminus, and are conjugated to a hapten such as keyhole limpet hemocyanin (KLH). Methods for synthesizing such peptides are known in the art, for example, as in R. P. Merrifield, J. Amer. Chem. Soc. 85, 2149-2154 (1963); J. L. Krstenansky, et al., FEBS Lett. 211, 10 (1987).  
       [0270] Monoclonal antibodies binding to the protein of the invention may be useful diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal antibodies binding to the protein may also be useful therapeutics for both conditions associated with the protein and also in the treatment of some forms of cancer where abnormal expression of the protein is involved. In the case of cancerous cells or leukemic cells, neutralizing monoclonal antibodies against the protein may be useful in detecting and preventing the metastatic spread of the cancerous cells, which may be mediated by the protein. In general, techniques for preparing polyclonal and monoclonal antibodies as well as hybridomas capable of producing the desired antibody are well known in the art (Campbell, A. M., Monoclonal Antibodies Technology: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1984); St. Groth et al., J. Immunol. 35:1-21 (1990); Kohler and Milstein, Nature 256:495-497 (1975)), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., Immunology Today 4:72 (1983); Cole et al., in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985), pp. 77-96).  
       [0271] Any animal (mouse, rabbit, etc.) which is known to produce antibodies can be immunized with a peptide or polypeptide of the invention. Methods for immunization are well known in the art. Such methods include subcutaneous or intraperitoneal injection of the polypeptide. One skilled in the art will recognize that the amount of the protein encoded by the ORF of the present invention used for immunization will vary based on the animal which is immunized, the antigenicity of the peptide and the site of injection. The protein that is used as an immunogen may be modified or administered in an adjuvant in order to increase the protein&#39;s antigenicity. Methods of increasing the antigenicity of a protein are well known in the art and include, but are not limited to, coupling the antigen with a heterologous protein (such as globulin or β-galactosidase) or through the inclusion of an adjuvant during immunization.  
       [0272] For monoclonal antibodies, spleen cells from the immunized animals are removed, fused with myeloma cells, such as SP2/0-Ag14 myeloma cells, and allowed to become monoclonal antibody producing hybridoma cells. Any one of a number of methods well known in the art can be used to identify the hybridoma cell which produces an antibody with the desired characteristics. These include screening the hybridomas with an ELISA assay, Western blot analysis, or radioimmunoassay (Lutz et al., Exp. Cell Research. 175:109-124 (1988)). Hybridomas secreting the desired antibodies are cloned and the class and subclass is determined using procedures known in the art (Campbell, A. M., Monoclonal Antibody Technology: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1984)). Techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce single chain antibodies to proteins of the present invention.  
       [0273] For polyclonal antibodies, antibody-containing antiserum is isolated from the immunized animal and is screened for the presence of antibodies with the desired specificity using one of the above-described procedures. The present invention further provides the above-described antibodies in delectably labeled form. Antibodies can be delectably labeled through the use of radioisotopes, affinity labels (such as biotin, avidin, etc.), enzymatic labels (such as horseradish peroxidase, alkaline phosphatase, etc.) fluorescent labels (such as FITC or rhodamine, etc.), paramagnetic atoms, etc. Procedures for accomplishing such labeling are well-known in the art, for example, see (Sternberger, L. A. et al., J. Histochem. Cytochem. 18:315 (1970); Bayer, E. A. et al., Meth. Enzym. 62:308 (1979); Engval, E. et al., Immunol. 109:129 (1972); Goding, J. W. J. Immunol. Meth. 13:215 (1976)).  
       [0274] The labeled antibodies of the present invention can be used for in vitro, in vivo, and in situ assays to identify cells or tissues in which a fragment of the polypeptide of interest is expressed. The antibodies may also be used directly in therapies or other diagnostics. The present invention further provides the above-described antibodies immobilized on a solid support. Examples of such solid supports include plastics such as polycarbonate, complex carbohydrates such as agarose and Sepharose®, acrylic resins and such as polyacrylamide and latex beads. Techniques for coupling antibodies to such solid supports are well known in the art (Weir, D. M. et al., “Handbook of Experimental Immunology” 4th Ed., Blackwell Scientific Publications, Oxford, England, Chapter 10 (1986); Jacoby, W. D. et al., Meth. Enzym. 34 Academic Press, N.Y. (1974)). The immobilized antibodies of the present invention can be used for in vitro, in vivo, and in situ assays as well as for immuno-affinity purification of the proteins of the present invention.  
       4.11 COMPUTER READABLE SEQUENCES  
       [0275] In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media. As used herein, “computer readable media” refers to any medium which can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. A skilled artisan can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention. As used herein, “recorded” refers to a process for storing information on computer readable medium. A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.  
       [0276] A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like. A skilled artisan can readily adapt any number of data processor structuring formats (e.g. text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.  
       [0277] By providing any of the nucleotide sequences SEQ ID NOs: 1-14 or a representative fragment thereof; or a nucleotide sequence at least 95% identical to any of the nucleotide sequences of SEQ ID NOs: 1-14 in computer readable form, a skilled artisan can routinely access the sequence information for a variety of purposes. Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium. The examples which follow demonstrate how software which implements the BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) and BLAZE (Brutlag et al., Comp. Chem. 17:203-207 (1993)) search algorithms on a Sybase system is used to identify open reading frames (ORFs) within a nucleic acid sequence. Such ORFs may be protein encoding fragments and may be useful in producing commercially important proteins such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.  
       [0278] As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention. As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means. As used herein, “data storage means” refers to memory which can store nucleotide sequence information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.  
       [0279] As used herein, “search means” refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means. Search means are used to identify fragments or regions of a known sequence which match a particular target sequence or target motif. A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention. Examples of such software includes, but is not limited to. Smith-Waterman, MacPattern (EMBL), BLASTN and BLASTA (NPOLYPEPTIDEIA). A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems. As used herein, a “target sequence” can be any nucleic acid or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. The most preferred sequence length of a target sequence is from about 10 to 300 amino acids, more preferably from about 30 to 100 nucleotide residues. However, it is well recognized that searches for commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.  
       [0280] As used herein, “a target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).  
       4.12 TRIPLE HELIX FORMATION  
       [0281] In addition, the fragments of the present invention, as broadly described, can be used to control gene expression through triple helix formation or antisense DNA or RNA, both of which methods are based on the binding of a polynucleotide sequence to DNA or RNA. Polynucleotides suitable for use in these methods are preferably 20 to 40 bases in length and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 15241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Olmno, J. Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide.  
       4.13 DIAGNOSTIC ASSAYS AND KITS  
       [0282] The present invention further provides methods to identify the presence or expression of one of the ORFs of the present invention, or homolog thereof, in a test sample, using a nucleic acid probe or antibodies of the present invention, optionally conjugated or otherwise associated with a suitable label.  
       [0283] In general, methods for detecting a polynucleotide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polynucleotide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polynucleotide of the invention is detected in the sample. Such methods can also comprise contacting a sample under stringent hybridization conditions with nucleic acid primers that anneal to a polynucleotide of the invention under such conditions, and amplifying annealed polynucleotides, so that if a polynucleotide is amplified, a polynucleotide of the invention is detected in the sample.  
       [0284] In general, methods for detecting a polypeptide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polypeptide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polypeptide of the invention is detected in the sample.  
       [0285] In detail, such methods comprise incubating a test sample with one or more of the antibodies or one or more of the nucleic acid probes of the present invention and assaying for binding of the nucleic acid probes or antibodies to components within the test sample.  
       [0286] Conditions for incubating a nucleic acid probe or antibody with a test sample vary. Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid probe or antibody used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification or immunological assay formats can readily be adapted to employ the nucleic acid probes or antibodies of the present invention. Examples of such assays can be found in Chard, T., An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G. R. et al., Techniques in Immunocytochemistry, Academic Press, Orlando, Fla. Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985). The test samples ofthe present invention include cells, protein or membrane extracts of cells, or biological fluids such as sputum, blood, serum, plasma, or urine. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is compatible with the system utilized.  
       [0287] In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention. Specifically, the invention provides a compartment kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the probes or antibodies of the present invention; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound probe or antibody.  
       [0288] In detail, a compartment kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers or strips of plastic or paper. Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the antibodies used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and containers which contain the reagents used to detect the bound antibody or probe. Types of detection reagents include labeled nucleic acid probes, labeled secondary antibodies. or in the alternative, if the primary antibody is labeled, the enzymatic, or antibody binding reagents which are capable of reacting with the labeled antibody. One skilled in the art will readily recognize that the disclosed probes and antibodies of the present invention can be readily incorporated into one of the established kit formats which are well known in the art.  
       4.14 MEDICAL IMAGING  
       [0289] The novel polypeptides and binding partners of the invention are useful in medical imaging of sites expressing the molecules of the invention (e.g., where the polypeptide of the invention is involved in the immune response, for imaging sites of inflammation or infection). See, e.g., Kunkel et al., U.S. Pat. No. 5,413,778. Such methods involve chemical attachment of a labeling or imaging agent, administration of the labeled polypeptide to a subject in a pharmaceutically acceptable carrier, and imaging the labeled polypeptide in vivo at the target site.  
       4.15 SCREENING ASSAYS  
       [0290] Using the isolated proteins and polynucleotides of the invention, the present invention further provides methods of obtaining and identifying agents which bind to a polypeptide encoded by an ORF corresponding to any of the nucleotide sequences set forth in SEQ ID NOs: 1-14, or bind to a specific domain of the polypeptide encoded by the nucleic acid. In detail, said method comprises the steps of:  
       [0291] (a) contacting an agent with an isolated protein encoded by an ORF of the present invention, or nucleic acid of the invention; and  
       [0292] (b) determining whether the agent binds to said protein or said nucleic acid.  
       [0293] In general, therefore, such methods for identifying compounds that bind to a polynucleotide of the invention can comprise contacting a compound with a polynucleotide of the invention for a time sufficient to form a polynucleotide/compound complex, and detecting the complex, so that if a polynucleotide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.  
       [0294] Likewise, in general, therefore, such methods for identifying compounds that bind to a polypeptide of the invention can comprise contacting a compound with a polypeptide of the invention for a time sufficient to form a polypeptide/compound complex, and detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.  
       [0295] Methods for identifying compounds that bind to a polypeptide of the invention can also comprise contacting a compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a receptor gene sequence in the cell, and detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds a polypeptide of the invention is identified.  
       [0296] Compounds identified via such methods can include compounds which modulate the activity of a polypeptide of the invention (that is, increase or decrease its activity, relative to activity observed in the absence of the compound). Alternatively, compounds identified via such methods can include compounds which modulate the expression of a polynucleotide of the invention (that is, increase or decrease expression relative to expression levels observed in the absence of the compound). Compounds, such as compounds identified via the methods of the invention, can be tested using standard assays well known to those of skill in the art for their ability to modulate activity/expression.  
       [0297] The agents screened in the above assay can be, but are not limited to, peptides, carbohydrates, vitamin derivatives, or other pharmaceutical agents. The agents can be selected and screened at random or rationally selected or designed using protein modeling techniques.  
       [0298] For random screening, agents such as peptides, carbohydrates, pharmaceutical agents and the like are selected at random and are assayed for their ability to bind to the protein encoded by the ORF of the present invention. Alternatively, agents may be rationally selected or designed. As used herein, an agent is said to be “rationally selected or designed” when the agent is chosen based on the configuration of the particular protein. For example, one skilled in the art can readily adapt currently available procedures to generate peptides, pharmaceutical agents and the like, capable of binding to a specific peptide sequence, in order to generate rationally designed antipeptide peptides, for example see Hurby et al., Application of Synthetic Peptides: Antisense Peptides,” In Synthetic Peptides, A User&#39;s Guide, W. H. Freeman, N.Y. (1992), pp. 289-307, and Kaspczak et al., Biochemistry 28:9230-8 (1989), or pharmaceutical agents, or the like.  
       [0299] In addition to the foregoing, one class of agents of the present invention, as broadly described, can be used to control gene expression through binding to one of the ORFs or EMFs of the present invention. As described above, such agents can be randomly screened or rationally designed/selected. Targeting the ORF or EMF allows a skilled artisan to design sequence specific or element specific agents, modulating the expression of either a single ORF or multiple ORFs which rely on the same EMF for expression control. One class of DNA binding agents are agents which contain base residues which hybridize or form a triple helix formation by binding to DNA or RNA. Such agents can be based on the classic phosphodiester, ribonucleic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base attachment capacity.  
       [0300] Agents suitable for use in these methods preferably contain 20 to 40 bases and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J. Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide and other DNA binding agents.  
       [0301] Agents which bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent. Agents which bind to a protein encoded by one of the ORFs of the present invention can be formulated using known techniques to generate a pharmaceutical composition.  
       4.16 USE OF NUCLEIC ACIDS AS PROBES  
       [0302] Another aspect of the subject invention is to provide for polypeptide-specific nucleic acid hybridization probes capable of hybridizing with naturally occurring nucleotide sequences. The hybridization probes of the subject invention may be derived from any of the nucleotide sequences SEQ ID NOs: 1-14. Because the corresponding gene is only expressed in a limited number of tissues, a hybridization probe derived from of any of the nucleotide sequences SEQ ID NOs: 1-14 can be used as an indicator of the presence of RNA of cell type of such a tissue in a sample.  
       [0303] Any suitable hybridization technique can be employed, such as, for example, in situ hybridization. PCR as described in U.S. Pat. Nos. 4,683,195 and 4,965,188 provides additional uses for oligonucleotides based upon the nucleotide sequences. Such probes used in PCR may be of recombinant origin, may be chemically synthesized, or a mixture of both. The probe will comprise a discrete nucleotide sequence for the detection of identical sequences or a degenerate pool of possible sequences for identification of closely related genomic sequences.  
       [0304] Other means for producing specific hybridization probes for nucleic acids include the cloning of nucleic acid sequences into vectors for the production of mRNA probes. Such vectors are known in the art and are commercially available and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerase as T7 or SP6 RNA polymerase and the appropriate radioactively labeled nucleotides. The nucleotide sequences may be used to construct hybridization probes for mapping their respective genomic sequences. The nucleotide sequence provided herein may be mapped to a chromosome or specific regions of a chromosome using well known genetic and/or chromosomal mapping techniques. These techniques include in situ hybridization, linkage analysis against known chromosomal markers, hybridization screening with libraries or flow-sorted chromosomal preparations specific to known chromosomes, and the like. The technique of fluorescent in situ hybridization of chromosome spreads has been described, among other places, in Verma et al (1988) Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York N.Y.  
       [0305] Fluorescent in situ hybridization of chromosomal preparations and other physical chromosome mapping techniques may be correlated with additional genetic map data. Examples of genetic map data can be found in the 1994 Genome Issue of Science (265:1981f). Correlation between the location of a nucleic acid on a physical chromosomal map and a specific disease (or predisposition to a specific disease) may help delimit the region of DNA associated with that genetic disease. The nucleotide sequences of the subject invention may be used to detect differences in gene sequences between normal, carrier or affected individuals.  
       4.17 PREPARATION OF SUPPORT BOUND OLIGONUCLEOTIDES  
       [0306] Oligonucleotides, i.e., small nucleic acid segments, may be readily prepared by, for example, directly synthesizing the oligonucleotide by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer.  
       [0307] Support bound oligonucleotides may be prepared by any of the methods known to those of skill in the art using any suitable support such as glass, polystyrene or Teflon. One strategy is to precisely spot oligonucleotides synthesized by standard synthesizers. Immobilization can be achieved using passive adsorption (Inouye &amp; Hondo, (1990) J. Clin. Microbiol. 28(6) 1469-72); using UV light (Nagata et al., 1985; Dahlen et al., 1987; Morrissey &amp;Collins, (1989) Mol. Cell Probes 3(2) 189-207) or by covalent binding of base modified DNA (Keller et al., 1988; 1989); all references being specifically incorporated herein.  
       [0308] Another strategy that may be employed is the use of the strong biotin-streptavidin interaction as a linker. For example, Broude et al. (1994) Proc. Natl. Acad. Sci. USA 91(8) 3072-6, describe the use of biotinylated probes, although these are duplex probes, that are immobilized on streptavidin-coated magnetic beads. Streptavidin-coated beads may be purchased from Dynal, Oslo. Of course, this same linking chemistry is applicable to coating any surface with streptavidin. Biotinylated probes may be purchased from various sources, such as, e.g., Operon Technologies (Alameda, Calif.).  
       [0309] Nunc Laboratories (Naperville, Ill.) is also selling suitable material that could be used. Nunc Laboratories have developed a method by which DNA can be covalently bound to the microwell surface termed Covalink NH. CovaLink NH is a polystyrene surface grafted with secondary amino groups (&gt;NH) that serve as bridge-heads for further covalent coupling. CovaLink Modules may be purchased from Nunc Laboratories. DNA molecules may be bound to CovaLink exclusively at the 5′-end by a phosphoramidate bond, allowing immobilization of more than 1 pmol of DNA (Rasmussen et al., (1991) Anal. Biochem. 198(1) 138-42).  
       [0310] The use of CovaLink NH strips for covalent binding of DNA molecules at the 5′-end has been described (Rasmussen et al., (1991). In this technology, a phosphoramidate bond is employed (Chu et al., (1983) Nucleic Acids Res. 11(8) 6513-29). This is beneficial as immobilization using only a single covalent bond is preferred. The phosphoramidate bond joins the DNA to the CovaLink NH secondary amino groups that are positioned at the end of spacer arms covalently grafted onto the polystyrene surface through a 2 nm long spacer arm. To link an oligonucleotide to CovaLink NH via an phosphoramidate bond, the oligonucleotide terminus must have a 5′-end phosphate group. It is, perhaps, even possible for biotin to be covalently bound to CovaLink and then streptavidin used to bind the probes.  
       [0311] More specifically, the linkage method includes dissolving DNA in water (7.5 ng/ul) and denaturing for 10 min. at 95° C. and cooling on ice for 10 min. Ice-cold 0.1 M 1-methyl imidazole, pH 7.0 (1-MeIm 7 ), is then added to a final concentration of 10 mM 1-MeIm 7 . A ss DNA solution is then dispensed into CovaLink NH strips (75 ul/well) standing on ice.  
       [0312] Carbodiimide 0.2 M 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), dissolved in 10 mM 1-MeIm 7 , is made fresh and 25 ul added per well. The strips are incubated for 5 hours at 50° C. After incubation the strips are washed using, e.g., Nunc-Immuno Wash; first the wells are washed 3 times, then they are soaked with washing solution for 5 min., and finally they are washed 3 times (where in the washing solution is 0.4 N NaOH, 0.25% SDS heated to 50° C.).  
       [0313] It is contemplated that a further suitable method for use with the present invention is that described in PCT Patent Application WO 90/03382 (Southern &amp; Maskos), incorporated herein by reference. This method of preparing an oligonucleotide bound to a support involves attaching a nucleoside 3′-reagent through the phosphate group by a covalent phosphodiester link to aliphatic hydroxyl groups carried by the support. The oligonucleotide is then synthesized on the supported nucleoside and protecting groups removed from the synthetic oligonucleotide chain under standard conditions that do not cleave the oligonucleotide from the support. Suitable reagents include nucleoside phosphoramidite and nucleoside hydrogen phosphorate.  
       [0314] An on-chip strategy for the preparation of DNA probe for the preparation of DNA probe arrays may be employed. For example, addressable laser-activated photodeprotection may be employed in the chemical synthesis of oligonucleotides directly on a glass surface, as described by Fodor et al. (1991) Science 251(4995) 767-73, incorporated herein by reference. Probes may also be immobilized on nylon supports as described by Van Ness et al. (1991) Nucleic Acids Res. 19(12) 3345-50; or linked to Teflon using the method of Duncan &amp; Cavalier (1988) Anal. Biochem. 169(1) 104-8; all references being specifically incorporated herein.  
       [0315] To link an oligonucleotide to a nylon support, as described by Van Ness et al. (1991), requires activation of the nylon surface via alkylation and selective activation of the 5′-amine of oligonucleotides with cyanuric chloride.  
       [0316] One particular way to prepare support bound oligonucleotides is to utilize the light-generated synthesis described by Pease et al., (1994) PNAS USA 91(11) 5022-6, incorporated herein by reference). These authors used current photolithographic techniques to generate arrays of immobilized oligonucleotide probes (DNA chips). These methods, in which light is used to direct the synthesis of oligonucleotide probes in high-density, miniaturized arrays, utilize photolabile 5′-protected N-acyl-deoxynucleoside phosphoramidites, surface linker chemistry and versatile combinatorial synthesis strategies. A matrix of 256 spatially defined oligonucleotide probes may be generated in this manner.  
       4.18 PREPARATION OF NUCLEIC ACID FRAGMENTS  
       [0317] The nucleic acids may be obtained from any appropriate source, such as cDNAs, genomic DNA, chromosomal DNA, microdissected chromosome bands, cosmid or YAC inserts, and RNA, including mRNA without any amplification steps. For example, Sambrook et al. (1989) describes three protocols for the isolation of high molecular weight DNA from mammalian cells (p. 9.14-9.23).  
       [0318] DNA fragments may be prepared as clones in M13, plasmid or lambda vectors and/or prepared directly from genomic DNA or cDNA by PCR or other amplification methods. Samples may be prepared or dispensed in multiwell plates. About 100-1000 ng of DNA samples may be prepared in 2-500 ml of final volume.  
       [0319] The nucleic acids would then be fragmented by any of the methods known to those of skill in the art including, for example, using restriction enzymes as described at 9.24-9.28 of Sambrook et al. (1989), shearing by ultrasound and NaOH treatment.  
       [0320] Low pressure shearing is also appropriate, as described by Schriefer et al. (1990) Nucleic Acids Res. 18(24) 7455-6, incorporated herein by reference). In this method, DNA samples are passed through a small French pressure cell at a variety of low to intermediate pressures. A lever device allows controlled application of low to intermediate pressures to the cell. The results of these studies indicate that low-pressure shearing is a useful alternative to sonic and enzymatic DNA fragmentation methods.  
       [0321] One particularly suitable way for fragmenting DNA is contemplated to be that using the two base recognition endonuclease, CviJI, described by Fitzgerald et al. (1992) Nucleic Acids Res. 20(14) 3753-62. These authors described an approach for the rapid fragmentation and fractionation of DNA into particular sizes that they contemplated to be suitable for shotgun cloning and sequencing.  
       [0322] The restriction endonuclease CviJI normally cleaves the recognition sequence PuGCPy between the G and C to leave blunt ends. Atypical reaction conditions, which alter the specificity of this enzyme (CviJI**), yield a quasi-random distribution of DNA fragments form the small molecule pUC19 (2688 base pairs). Fitzgerald et al. (1992) quantitatively evaluated the randomness of this fragmentation strategy, using a CviJI** digest of pUC19 that was size fractionated by a rapid gel filtration method and directly ligated, without end repair, to a lac Z minus M13 cloning vector. Sequence analysis of 76 clones showed that CviJl** restricts pyGCPy and PuGCPu, in addition to PuGCPy sites, and that new sequence data is accumulated at a rate consistent with random fragmentation.  
       [0323] As reported in the literature, advantages of this approach compared to sonication and agarose gel fractionation include: smaller amounts of DNA are required (0.2-0.5 ug instead of 2-5 ug); and fewer steps are involved (no preligation, end repair, chemical extraction, or agarose gel electrophoresis and elution are needed  
       [0324] Irrespective of the manner in which the nucleic acid fragments are obtained or prepared, it is important to denature the DNA to give single stranded pieces available for hybridization. This is achieved by incubating the DNA solution for 2-5 minutes at 80-90° C. The solution is then cooled quickly to 2° C. to prevent renaturation of the DNA fragments before they are contacted with the chip. Phosphate groups must also be removed from genomic DNA by methods known in the art.  
       4.19 PREPARATION OF DNA ARRAYS  
       [0325] Arrays may be prepared by spotting DNA samples on a support such as a nylon membrane. Spotting may be performed by using arrays of metal pins (the positions of which correspond to an array of wells in a microtiter plate) to repeated by transfer of about 20 nl of a DNA solution to a nylon membrane. By offset printing, a density of dots higher than the density of the wells is achieved. One to 25 dots may be accommodated in 1 mm 2 , depending on the type of label used. By avoiding spotting in some preselected number of rows and columns, separate subsets (subarrays) may be formed. Samples in one subarray may be the same genomic segment of DNA (or the same gene) from different individuals, or may be different, overlapped genomic clones. Each of the subarrays may represent replica spotting of the same samples. In one example, a selected gene segment may be amplified from 64 patients. For each patient, the amplified gene segment may be in one 96-well plate (all 96 wells containing the same sample). A plate for each of the 64 patients is prepared. By using a 96-pin device, all samples may be spotted on one 8×12 cm membrane. Subarrays may contain 64 samples, one from each patient. Where the 96 subarrays are identical, the dot span may be 1 mm 2  and there may be a 1 mm space between subarrays.  
       [0326] Another approach is to use membranes or plates (available from NUNC, Naperville, Ill.) which may be partitioned by physical spacers e.g. a plastic grid molded over the membrane, the grid being similar to the sort of membrane applied to the bottom of multiwell plates, or hydrophobic strips. A fixed physical spacer is not preferred for imaging by exposure to flat phosphor-storage screens or x-ray films.  
       [0327] The present invention is illustrated in the following examples. Upon consideration of the present disclosure, one of skill in the art will appreciate that many other embodiments and variations may be made in the scope of the present invention. Accordingly, it is intended that the broader aspects of the present invention not be limited to the disclosure of the following examples. The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention, and compositions and methods which are functionally equivalent are within the scope of the invention. Indeed, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the present preferred embodiments. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.  
       [0328] All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.  
     
    
    
     5.0 EXAMPLES  
     5.1 Example 1  
     [0329] Novel Nucleic Acid Sequences Obtained From Various Libraries  
     [0330] A plurality of novel nucleic acids were obtained from cDNA libraries prepared from various human tissues and in some cases isolated from a genomic library derived from human chromosome using standard PCR, SBH sequence signature analysis and Sanger sequencing techniques. The inserts of the library were amplified with PCR using primers specific for the vector sequences which flank the inserts. Clones from cDNA libraries were spotted on nylon membrane filters and screened with oligonucleotide probes (e.g., 7-mers) to obtain signature sequences. The clones were clustered into groups of similar or identical sequences. Representative clones were selected for sequencing.  
     [0331] In some cases, the 5′ sequence of the amplified inserts was then deduced using a typical Sanger sequencing protocol. PCR products were purified and subjected to fluorescent dye terminator cycle sequencing. Single pass gel sequencing was done using a 377 Applied Biosystems (ABI) sequencer to obtain the novel nucleic acid sequences. In some cases RACE (Random Amplification of cDNA Ends) was performed to further extend the sequence in the 5′ direction.  
     5.2 Example 2  
     [0332] Novel Nucleic Acids  
     [0333] The novel nucleic acids of the present invention of the invention were assembled from sequences that were obtained from a cDNA library by methods described in Example 1 above, and in some cases sequences obtained from one or more public databases. The nucleic acids were assembled using an EST sequence as a seed. Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (i.e., Hyseq&#39;s database containing EST sequences, dbEST version 114, gb pri 114, and UniGene version 101) that belong to this assemblage. The algorithm terminated when there was no additional sequences from the above databases that would extend the assemblage. Inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95%.  
     [0334] Using PHRAP (Univ. of Washington) or CAP4 (Paracel), a full length gene cDNA sequence and its corresponding protein sequence were generated from the assemblage. Any frame shifts and incorrect stop codons were corrected by hand editing. During editing, the sequence was checked using FASTY and/or BLAST against Genbank (i.e., dbEST version 120, gb pri 120, UniGene version 120, Genpept release 120). Other computer programs which may have been used in the editing process were phredPhrap and Consed (University of Washington) and ed-ready, ed-ext and cg-zip-2 (Hyseq, Inc.). The full-length nucleotide and amino acid sequences, including splice variants resulting from these procedures are shown in the Sequence Listing as SEQ ID NOS: 1-14.  
     [0335] Table 1 shows the various tissue sources of SEQ ID NO: 1-14.  
     [0336] The homology for SEQ ID NO: 1-14 were obtained by a BLASTP version 2.0al 19MP-WashU search against Genpept release 120 and the amino acid version of Geneseq released on Oct. 26, 2000, using BLAST algorithm. The results showed homologues for SEQ ID NO: 1-14 from Genpept. The homologues with identifiable functions for SEQ ID NO: 1-14 are shown in Table 2 below.  
     [0337] Using eMatrix software package (Stanford University, Stanford, Calif.) (Wu et al., J. Comp. Biol., Vol. 6 pp.219-235 (1999) herein incorporated by reference), all the sequences were examined to determine whether they had identifiable signature regions. Table 3 shows the signature region found in the indicated polypeptide sequences, the description of the signature, the eMatrix p-value(s) and the position(s) of the signature within the polypeptide sequence.  
     [0338] Using the pFAM software program (Sonnhammer et al., Nucleic Acids Res., Vol.26(1) pp.320-322 (1998) herein incorporated by reference) all the polypeptide sequences were examined for domains with homology to certain peptide domains. Table 4 shows the name of the domain found, the description, the p-value and the pFAM score for the identified domain within the sequence.  
     [0339] The nucleotide sequence within the sequences that codes for signal peptide sequences and their cleavage sites can be determine from using Neural Network SignalP V1.1 program (from Center for Biological Sequence Analysis, The Technical University of Denmark). The process for identifying prokaryotic and eukaryotic signal peptides and their cleavage sites are also disclosed by Henrik Nielson, Jacob Engelbrecht, Soren Brunak, and Gunnar von Heijne in the publication “Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites” Protein Engineering, Vol.10, no. 1, pp. 1-6 (1997), incorporated herein by reference. A maximum S score and a mean S score, as described in the Nielson et as reference, was obtained for the polypeptide sequences. Table 5 shows the position of the signal peptide in each of the polypeptides and the maximum score and mean score associated with that signal peptide.  
                           TABLE 1                           LIBRARY/   HYSEQ LIBRARY           TISSUE ORIGIN   RNA SOURCE   NAME   SEQ ID NOS:                  adult brain   GIBCO   AB3001   7       adult brain   GIBCO   ABD003   5 13       adult brain   Clontech   ABR001   7       adult brain   Clontech   ABR006   4-5       adult brain   Clontech   ABR008   2-3 7 12       cultured   Strategene   ADP001   1       preadipocytes       adrenal gland   Clontech   ADR002   5 11-12       adult heart   GIBCO   AHR001   5 7 11 13       adult kidney   GIBCO   AKD001   5 8 11 13-14       adult kidney   Invitrogen   AKT002   5 8 13       lymph node   Clontech   ALN001   5 13       young liver   GIBCO   ALV001   13       adult liver   Invitrogen   ALV002   8 11       adult ovary   Invitrogen   AOV001   2 5 7 11 13       adult spleen   GIBCO   ASP001   7 13       testis   GIBCO   ATS001   13       bone marrow   Clontech   BMD001   2 6 11 13-14       bone marrow   Clontech   BMD002   2 5 8-9 11 14       adult cervix   BioChain   CVX001   13       endothelial   Strategene   EDT001   5 7 11 13       cells       fetal brain   Clontech   FBR006   7       fetal heart   Invitrogen   FHR001   13       fetal kidney   Clontech   FKD001   14       fetal liver-   Columbia   FLS001   2-11 13-14       spleen   University       fetal liver-   Columbia   FLS002   2 5 7-9 11       spleen   University       13-14       fetal liver   Invitrogen   FLV001   2 10-11       fetal liver   Clontech   FLV004   1 8       fetal skin   Invitrogen   FSK001   6-8       fetal skin   Invitrogen   FSK002   5       umbilical cord   BioChain   FUC001   1 8 11       fetal brain   GIBCO   HFB001   5 12       infant brain   Columbia   IB2002   3 5 13           University       infant brain   Columbia   IB2003   12           University       infant brain   Columbia   IBS001   12           University       lung,   Strategene   LFB001   11       fibroblast       lung tumor   Invitrogen   LGT002   7 13       lymphocytes   ATCC   LPC001   7       leukocyte   GIBCO   LUC001   2 5 7-8 12-13       leukocyte   Clontech   LUC003   14       mammary gland   Invitrogen   MMG001   2 5       induced neuron   Strategene   NTD001   5       cells       rectum   Invitrogen   REC001   5       salivary gland   Clontech   SAL001   5       small   Clontech   SIN001   7 12-13       intestine       spinal cord   Clontech   SPC001   7 13       stomach   Clontech   STO001   5       thalamus   Clontech   THA002   12       thymus   Clontech   THM001   9       thymus   Clontech   THMc02   6-7 13-14       thyroid gland   Clontech   THR001   5 7                  
 
     [0340]                                   TABLE 2                           COR-                           RES-           PON-           DING           SEQ ID           NO. IN           SMITH-       SEQ   U.S.S.N           WATER-   %       ID   09/552,   ACCESSION       MAN   IDEN-       NO:   929   NUMBER   DESCRIPTION   SCORE   TITY                                                         1   70   U32855   Drosophila   465   96                   melanogaster                   cytoplasmic                   dynein light                   chain 1        2   239   AF116630   Homo sapiens   508   98                   PRO1278        3   376   AB046628   Macaca fasci-   233   93                   cularis hypothe-                   tical protein        4   862   AL023494   Homo sapiens   669   100                   dJ366L4.2 (novel                   protein)        5   1753   AF285159   Homo sapiens   247   68                   topoisomerase II                   alpha-4        6   1820        7   2841   AF151363   Mus musculus   3204   78                   Cdc42 GTPase-                   activating                   protein        8   2904   AF116712   Homo sapiens   237   48                   PRO2738        9   3619   AK001575   Homo sapiens   1550   100           3620       unnamed protein           3621       product       10   4069       11   4503   AF083392   Synechococcus   303   56           4504       PCC7942 promo-                   ter active frag-                   ment E3       12   5083   AJ272268   Homo sapiens   5241   100                   calcium channel                   alpha2 -delta3                   subunit       13   5202   Z82083   Caenorhabditis   330   30                   elegans ZK1010.2       14   5436   AF155827   Homo sapiens   4300   99                   proliferation-                   associated SNF2-                   like protein                    
     [0341]                           TABLE 3                       SEQ   ACCES-               ID   SION       NO:   NO.   DESCRIPTION   RESULTS*                   1   DM01803   1 HERPESVIRUS   DM01803D 9.36               GLYCOPROTEIN H.   6.680e-06 37-53        2   DM00315   072 RIBONUCLEASE   DM00315E 7.99               INHIBITOR.   1.422e-07 24-34        3   DM01482   kw PRIMASE DNA.   DM01482F 9.17                   9.679e-06 108-123        4   PR00297   10 KD CHAPERONIN   PR00297A 13.91               SIGNATURE   9.868e-07 149-165        5   DM00522   499 kw TRYPSIN   DM00522B 9.43               KINASE KUNITZ   8.846e-06 33-47               PANCREATIC.        7   PR00916   2C ENDOPEPTIDASE   PR00916B 17.44               (C24) CYSTEINE   5.366e-06 789-806               PROTEASE FAMILY               SIGNATURE        8   DM01688   2 POLY-IG RECEPTOR.   DM01688D 13.44                   9.727e-06 128-151        9   BL00785   5′-nucleotidase   BL00785E 15.85               proteins.   2.714e-06 244-260       10   DM01803   1 HERPESVIRUS   DM01803C 7.00               GLYCOPROTEIN H.   9.816e-06 1-11       12   PR00517   5-HYDROXYTRYPTA-   PR00517H 6.05               MINE 2C RECEPTOR   7.348e-07 695-710               SIGNATURE       13   PF00602   Influenza RNA-   PF00602B 10.60               dependant RNA   5.761e-06 35-87               polymerase subunit               PB1.       14   DM00547   1 kw CHROMO   DM00547F 23.43               BROMODOMAIN   1.000e-40 686-733               SHADOW GLOBAL.   DM00547E 13.94                   2.452e-22 378-401                   DM00547B 11.28                   3.045e-17 244-258                   DM00547D 11.60                   9.526e-16 348-362                   DM00547C 17.30                   7.395e-15 272-294                   DM00547A 12.38                   7.511e-09 223-235                            
     [0342]                               TABLE 4                       SEQ ID   pFAM           pFAM       NO:   NAME   DESCRIPTION   p-value   SCORE                                                     1   Dynein_light   Dynein light chain type 1   3.5e-66   233.3        7   RhoGAP   RhoGAP domain   6.7e-49   175.9       14   helicase_C   Helicases conserved C-   5.8e-26   99.7               terminal domain                    
     [0343]                           TABLE 5                           POSITION OF SIGNAL       meanS       SEQ ID   IN AMINO ACID   maxS (MAXIMUM   (MEAN       NO:   SEQUENCE   SCORE)   SCORE)                  5   1-19   0.969   0.933                    
     [0344] 
    
     
       
         1 
         
           
             14  
           
           
             1  
             711  
             DNA  
             Homo sapiens  
             
               CDS  
               (258)..(527)  
             
           
            1 

ggaaaatctc attttactta tgataaaaac tgatgagtta ttatgtccta ttggccctgt     60 

atttcccagg gtgggaacaa tgtctctgcc aaagcttagg ggctccctct cctaatgctt    120 

cacatccgtg ttttctgttg ccctcacctt ctatactccc ctcttgcact gagaccccac    180 

acccagcagc taatgttcac tgcccagagc aaggagttgt cagccttacc tctctgctcc    240 

ttctgtagtg tcacacc   atg tct gac cgg aag gca gtg atc aag aac gca     290 
                     Met Ser Asp Arg Lys Ala Val Ile Lys Asn Ala 
                       1               5                  10 

gac atg tct gag gac atg caa cag gat gcc gtt gac tgc gcc acg cag      338 
Asp Met Ser Glu Asp Met Gln Gln Asp Ala Val Asp Cys Ala Thr Gln 
             15                  20                  25 

gcc atg gag aag tac aat ata gag aag gac att gct gcc tat atc aag      386 
Ala Met Glu Lys Tyr Asn Ile Glu Lys Asp Ile Ala Ala Tyr Ile Lys 
         30                  35                  40 

aag gaa ttt gac aag aaa tat aac cct acc tgg cat tgt atc gtg ggc      434 
Lys Glu Phe Asp Lys Lys Tyr Asn Pro Thr Trp His Cys Ile Val Gly 
     45                  50                  55 

cga aat ttt ggc agc tac gtc aca cac gag aca aag cac ttc atc tat      482 
Arg Asn Phe Gly Ser Tyr Val Thr His Glu Thr Lys His Phe Ile Tyr 
 60                  65                  70                  75 

ttt tac ttg ggt caa gtt gca atc ctc ctc ttc aag tca ggc tag gtg      530 
Phe Tyr Leu Gly Gln Val Ala Ile Leu Leu Phe Lys Ser Gly  * 
                 80                  85                  90 

gccatggtga aggtgtcagt ggcggcggca gcgatggcaa gcaggcggcg ttgctgggac    590 

tgttttgcac tggagccagc atcaggatgt cctctcgaat ggctgtgcta ctgcatggac    650 

tgtatactcg atttcatgtg tatgtcgcag taaacaaaac caaacctcaa aaaaaaaaaa    710 

a                                                                    711 

 
           
             2  
             1095  
             DNA  
             Homo sapiens  
             
               CDS  
               (654)..(938)  
             
           
            2 

ctggtacaac aggtctctac aacgccaaga tctaactaag ctttaaaagg tcaagaagtt     60 

ttatggctga caaaggactc gcgcaacgca gaaggccttt cccaccttaa gcttccgggg    120 

atctgggaat tttaccccca ttctcttctg tttgtctgag tctcatctct ctgcaagcaa    180 

gggctgaaat cattttgttt ggttgttttg agggagagag gcggggtggg ggggtgcaaa    240 

tctgccagca gctcttacgt aaggcatgtt ttattgggga gggctgagct tttattttct    300 

cctctccagt ggggttggct tttattgttt cttgtttggg tttggaatgg aaatatggat    360 

agcagcataa agtactttta ttttgacaaa attcattttt ttcaacaatg gagacataga    420 

tttgacccac aataacttct ccccctctct ttttactctg ctcaaaaagc atctctcctc    480 

ccattaccca accttggtca taagtgtgcc tggctggttt gcagatattt gttctgcttt    540 

gtaaaaattg gccattagtg catttattga gatgatctct aaagagctat gccctgacct    600 

acccctgatt ctatgacatt ggggcccttc ttttgctgaa actgccttac gta   atg     656 
                                                             Met 
                                                               1 

gtt tta ctc ctt gaa aga gat ttg acg gaa tcc att tta tgc caa gtg      704 
Val Leu Leu Leu Glu Arg Asp Leu Thr Glu Ser Ile Leu Cys Gln Val 
              5                  10                  15 

ctg ccc tgc act gtt tct gca ata tgt ggt gta tgc tgt ggt gat ctt      752 
Leu Pro Cys Thr Val Ser Ala Ile Cys Gly Val Cys Cys Gly Asp Leu 
         20                  25                  30 

gct ggg aat gat tat aag tgt gtg tgt ggt ggg gga gtg ggt att aca      800 
Ala Gly Asn Asp Tyr Lys Cys Val Cys Gly Gly Gly Val Gly Ile Thr 
     35                  40                  45 

tgc att gct gaa gag tca tcc tgg tgt tcc tca ttc ctc cca cct tcc      848 
Cys Ile Ala Glu Glu Ser Ser Trp Cys Ser Ser Phe Leu Pro Pro Ser 
 50                  55                  60                  65 

cgt ggt cat ttt aat tac ggg gca gtg tca ccg caa agg gag gaa act      896 
Arg Gly His Phe Asn Tyr Gly Ala Val Ser Pro Gln Arg Glu Glu Thr 
                 70                  75                  80 

caa agc cga aag caa aat tcc agg cct gat tct ggc ttt tga ggttcct      945 
Gln Ser Arg Lys Gln Asn Ser Arg Pro Asp Ser Gly Phe  * 
             85                  90                  95 

ggttcttgaa gccaggcctg acccgactct cagatggggt cagtcccgtc gctttgcaga   1005 

ctgaccctgg aaatctacaa aatgcagatt ttcctgattt cctcttctct tgcccagctc   1065 

gtgccgaatt cttggcctcg agggccaaat                                    1095 

 
           
             3  
             901  
             DNA  
             Homo sapiens  
             
               CDS  
               (76)..(699)  
             
           
            3 

tttcgtgctg gagcggctgt gcgggctgcg tagcggtgct gggtcgggcc gacgtgccac     60 

ccacccggag ccggg atg cca gaa ggg ccg ttg gtg agg aaa ttt cac cat     111 
                 Met Pro Glu Gly Pro Leu Val Arg Lys Phe His His 
                   1               5                  10 

ttg gtc tcc ccc ctt gtg ggt cag cag gtg gtc aag aca ggg ggc agc      159 
Leu Val Ser Pro Leu Val Gly Gln Gln Val Val Lys Thr Gly Gly Ser 
         15                  20                  25 

agt aag aag cta cag ccc gcc agc ctg cag tct ctg tgg ctc cag gac      207 
Ser Lys Lys Leu Gln Pro Ala Ser Leu Gln Ser Leu Trp Leu Gln Asp 
     30                  35                  40 

acc cag gtc cat gga aag aaa tta ttc ctt aga ttt gat cta gat gaa      255 
Thr Gln Val His Gly Lys Lys Leu Phe Leu Arg Phe Asp Leu Asp Glu 
 45                  50                  55                  60 

gaa atg ggg ccc cct ggc agc agc cca aca cca gag cct cca caa aaa      303 
Glu Met Gly Pro Pro Gly Ser Ser Pro Thr Pro Glu Pro Pro Gln Lys 
                 65                  70                  75 

gaa gtg cag aag gaa ggg gct gcg gac cca aag cag gtc ggg gag ccc      351 
Glu Val Gln Lys Glu Gly Ala Ala Asp Pro Lys Gln Val Gly Glu Pro 
             80                  85                  90 

agc ggg cag aag acc ctt gat gga tcc tca cgg tct gca gag ctc gtc      399 
Ser Gly Gln Lys Thr Leu Asp Gly Ser Ser Arg Ser Ala Glu Leu Val 
         95                 100                 105 

ccc cag ggc gag gat gat tct gag tat ttg gag aga gac gcc cct gca      447 
Pro Gln Gly Glu Asp Asp Ser Glu Tyr Leu Glu Arg Asp Ala Pro Ala 
    110                 115                 120 

gga gat gct ggg agg tgg ctg cgt gtc agc ttt ggt ttg ttt ggc agc      495 
Gly Asp Ala Gly Arg Trp Leu Arg Val Ser Phe Gly Leu Phe Gly Ser 
125                 130                 135                 140 

gtt tgg gtg aac gat ttc tcc aga gcc aag aaa gcc aac aag agg ggg      543 
Val Trp Val Asn Asp Phe Ser Arg Ala Lys Lys Ala Asn Lys Arg Gly 
                145                 150                 155 

gac tgg agg gac cct tcc ccg agg ttg gtc ctg cac ttt ggt ggt ggt      591 
Asp Trp Arg Asp Pro Ser Pro Arg Leu Val Leu His Phe Gly Gly Gly 
            160                 165                 170 

ggc ttc ctg gca ttt tat aat tgt cag ttg tct tgg agc tct tcc cca      639 
Gly Phe Leu Ala Phe Tyr Asn Cys Gln Leu Ser Trp Ser Ser Ser Pro 
        175                 180                 185 

gtg gtc aca ccc acc tgt gac atc ctg tct gag aag ttc cat cga gga      687 
Val Val Thr Pro Thr Cys Asp Ile Leu Ser Glu Lys Phe His Arg Gly 
    190                 195                 200 

caa gcc tta taa gct ctaggccagg ctcagcctgt ctgctataca ctgctggacc      742 
Gln Ala Leu  * 
205 

agagatactt ctcagggcta gggaacatca ttaagaatga agccttgtac agagctggga    802 

tccatcccct ttctctcggt tcagtcctga gtgcctcgcg tcgggaggtc ctggtggatc    862 

acgtggtgga gttcagtaca gcctggctgc atggcaagt                           901 

 
           
             4  
             986  
             DNA  
             Homo sapiens  
             
               CDS  
               (100)..(939)  
             
           
            4 

cccgaggctg gcgggttttg gcagtagctg tggctgcggc tgccgggcct ggggacgcgg     60 

gcggcgaggc cgcgtcgcag cctcctcgtc tcgccggct   atg gct gcg ctc ggc     114 
                                             Met Ala Ala Leu Gly 
                                               1               5 

cgg ccc ttc agc ggc ctc cct ctg agc ggc ggc tcg gac ttc ctg cag      162 
Arg Pro Phe Ser Gly Leu Pro Leu Ser Gly Gly Ser Asp Phe Leu Gln 
                 10                  15                  20 

ccg ccg cag ccg gcc ttc ccc ggc cgg gcc ttc ccg ccg ggg gct gac      210 
Pro Pro Gln Pro Ala Phe Pro Gly Arg Ala Phe Pro Pro Gly Ala Asp 
             25                  30                  35 

ggc gcc gag ttg gcc ccg cgg ccg gga cct cgc gca gtc cct agc agt      258 
Gly Ala Glu Leu Ala Pro Arg Pro Gly Pro Arg Ala Val Pro Ser Ser 
         40                  45                  50 

ccc gct ggg agt gcg gcg cgc gga cgt gtt tct gtt cac tgt aaa aag      306 
Pro Ala Gly Ser Ala Ala Arg Gly Arg Val Ser Val His Cys Lys Lys 
     55                  60                  65 

aaa cac aag cga gag gag gag gag gat gat gat tgt cca gta aga aag      354 
Lys His Lys Arg Glu Glu Glu Glu Asp Asp Asp Cys Pro Val Arg Lys 
 70                  75                  80                  85 

aaa agg ata act gaa gca gag ctc tgt gct ggt cct aat gac tgg att      402 
Lys Arg Ile Thr Glu Ala Glu Leu Cys Ala Gly Pro Asn Asp Trp Ile 
                 90                  95                 100 

ctt tgt gca cat cag gat gta gag ggg cat gga gta aat ccc agt gtt      450 
Leu Cys Ala His Gln Asp Val Glu Gly His Gly Val Asn Pro Ser Val 
            105                 110                 115 

agt ggc ctt tcc ata cct ggg ata tta gat gtt att tgt gaa gaa atg      498 
Ser Gly Leu Ser Ile Pro Gly Ile Leu Asp Val Ile Cys Glu Glu Met 
        120                 125                 130 

gat cag aca act gga gaa cca cag tgt gaa gtt gcc cga agg aag ctt      546 
Asp Gln Thr Thr Gly Glu Pro Gln Cys Glu Val Ala Arg Arg Lys Leu 
    135                 140                 145 

cag gag att gag gac agg ata att gat gaa gat gaa gaa gtt gaa gct      594 
Gln Glu Ile Glu Asp Arg Ile Ile Asp Glu Asp Glu Glu Val Glu Ala 
150                 155                 160                 165 

gac aga aat gtt aac cat ctc ccc agt ctt gtc ctt tct gat acc atg      642 
Asp Arg Asn Val Asn His Leu Pro Ser Leu Val Leu Ser Asp Thr Met 
                170                 175                 180 

aaa aca ggt ttg aag agg gaa ttt gat gaa gtt ttt aca aag aaa atg      690 
Lys Thr Gly Leu Lys Arg Glu Phe Asp Glu Val Phe Thr Lys Lys Met 
            185                 190                 195 

att gag tct atg agc cgt cct tcc atg gag ctt gtt ctc tgg aaa ccc      738 
Ile Glu Ser Met Ser Arg Pro Ser Met Glu Leu Val Leu Trp Lys Pro 
        200                 205                 210 

ctc cct gaa ctc ctt tct gat aag cca aag cca tcc tct aat act aag      786 
Leu Pro Glu Leu Leu Ser Asp Lys Pro Lys Pro Ser Ser Asn Thr Lys 
    215                 220                 225 

aac tat aca gga gag agc caa gct aag cat gta gct gct ggc act gcc      834 
Asn Tyr Thr Gly Glu Ser Gln Ala Lys His Val Ala Ala Gly Thr Ala 
230                 235                 240                 245 

ttc cct cag aga act gaa ctg ttt tcg gaa cct cgg cca aca ggg atg      882 
Phe Pro Gln Arg Thr Glu Leu Phe Ser Glu Pro Arg Pro Thr Gly Met 
                250                 255                 260 

tct ctt tat aat agt ttg gag aca gct act agc aca gaa gaa gag atg      930 
Ser Leu Tyr Asn Ser Leu Glu Thr Ala Thr Ser Thr Glu Glu Glu Met 
            265                 270                 275 

gaa ctc tag aaaccaa tttctacact aaagttgtca aatgttagaa aaaaaaaaaa      986 
Glu Leu  * 
        280 

 
           
             5  
             1893  
             DNA  
             Homo sapiens  
             
               CDS  
               (760)..(1185)  
             
           
            5 

tggtttaatc tggataagct gaaagataga ttgctatcaa aaaagttccc caagatgtgc     60 

atagccaaac tgggatagaa ggcaaactcc ccaaagctac ctgctggttt tgagaggggt    120 

ggtaagacat ggcaattccc aggagtagta gaaaataata tgcctgacta ccaacagctc    180 

aagtatgctt atttgcacat cctagacttg gtgtctgtaa gactcagtta ccacttttat    240 

tttcctgtag ctaggagtta gcaaaaggaa ctggggcctt ccagccgagc cactaaacct    300 

gtcttatttg gaatggggat tgtccagcaa agggagcaaa catgaattag atgttaagct    360 

attgagctga agaaaagaaa gcagttcaca tttaggtgaa atagatgatg ttatcaggaa    420 

gccaggttcc caccagagtc ggtgcttggt acctggtctc tccagtctca acagactcag    480 

gtcaggtctc tcacccagga agcaaccact caataaaata gagaacatct gagaattaca    540 

aatgtctatg cttgattgct cctctaaatc cagtgcatag gttaaccctg catgcccatt    600 

tcttcctggg cttcttgatg gcaatgtgtt cttaaataac tggtcttgtg ttcatgctaa    660 

agacaaactt acatgaagtt tttcagttta agacattcta gtgaatggct gctatgtgtt    720 

tctggcactc attcctaacc aagtctttag agatttcag   atg acc tta aag atg     774 
                                             Met Thr Leu Lys Met 
                                               1               5 

caa tat ctt ttt ctt tct ttc ttt ctt tct ttt ttt ctg aga caa gag      822 
Gln Tyr Leu Phe Leu Ser Phe Phe Leu Ser Phe Phe Leu Arg Gln Glu 
                 10                  15                  20 

ttg cgc cct gtc gcc cag gct ggg gtg ctg gag tgc agt ggt gcg atc      870 
Leu Arg Pro Val Ala Gln Ala Gly Val Leu Glu Cys Ser Gly Ala Ile 
             25                  30                  35 

tca gct cac tgc agc ctc tgc ttc cca ggt tca agt gtt tct cct gcc      918 
Ser Ala His Cys Ser Leu Cys Phe Pro Gly Ser Ser Val Ser Pro Ala 
         40                  45                  50 

tca gcc ttc cga gta gct ggg att aca ggc atg tac cac tat gcc tgg      966 
Ser Ala Phe Arg Val Ala Gly Ile Thr Gly Met Tyr His Tyr Ala Trp 
     55                  60                  65 

cta att ttt att tct ata ttt tta gta gag atg ggg ttt cat cat gtt     1014 
Leu Ile Phe Ile Ser Ile Phe Leu Val Glu Met Gly Phe His His Val 
 70                  75                  80                  85 

tgc cag gct ggt ctc gaa ctc ctg gcc tca agt gat ccg ccc acc tca     1062 
Cys Gln Ala Gly Leu Glu Leu Leu Ala Ser Ser Asp Pro Pro Thr Ser 
                 90                  95                 100 

gcc tcc caa agt gct ggg att aca ggc gcg agc cac cgc gcc tgg cca     1110 
Ala Ser Gln Ser Ala Gly Ile Thr Gly Ala Ser His Arg Ala Trp Pro 
            105                 110                 115 

aag atg caa att ctt gtt tgg att tat gct ctg cct ctt ccc agc att     1158 
Lys Met Gln Ile Leu Val Trp Ile Tyr Ala Leu Pro Leu Pro Ser Ile 
        120                 125                 130 

ttc tta tct gta gcc ctg ctt gct tga gagta tacttggata agaagtattg     1210 
Phe Leu Ser Val Ala Leu Leu Ala  * 
    135                 140 

ctgttgaggg agctataaga aaaggattct tcttccagaa gtaaagaact catctttaga   1270 

gtacctttaa atgaattttg tttttctttc ttattttgag gtggattggt cttctctttt   1330 

tttgggtttc cagctcactg ggactctcag accttacctt tccagctcaa acaccattag   1390 

ttaaattcct tcattctcat tagaatgcag cctgctgagt atgtgggttt cactgccgga   1450 

gtccatcatt tagccagtat acatagagga actgcttcga atcaaggcaa ctggtgaagg   1510 

gcttagcatg ttggcagcaa tatcccagag attgaatctg tttgcatttt cctcatctag   1570 

gataacagct gcttgaagcc agggctctta gccctttgca ttccccttga gcgaggaagc   1630 

cacactgcct ttctgtgtct ggttcagagc tcttccttct tggcatgttt tctggactac   1690 

atgcacatgg gcagctatag attaatctgc aaaacctagt cacttaccta cccataatat   1750 

ctgggaaggt gtggtatttg ttttaaagaa acattgtttc tttgggaggg cagtttctgt   1810 

ctggactttg aggtggactt agttatccct acagttcttt aactctcagc ttttaataaa   1870 

agatgaaatc agaaaaaaaa aaa                                           1893 

 
           
             6  
             783  
             DNA  
             Homo sapiens  
             
               CDS  
               (278)..(454)  
             
           
            6 

atgatgctct tggaaaacac acacaggaag gcggaagtta aatgtgtacc caactacgaa     60 

gtcagatgag gcaggatcac accctggctg cccctctggt cactagatgc cttgggcagg    120 

taagctcacc tcttctggcc tcagtttctc catctgtgaa atgagtgtaa catctcatag    180 

gctgtggtac ggactcatga attgatgcat ataaagcgtt cagtaagcct tttctcttaa    240 

taaaaaaccc acaaaaccat catcagctca agattct atg caa aga gaa gac ggc     295 
                                         Met Gln Arg Glu Asp Gly 
                                           1               5 

aca ccc agc atg ggg tgt ccc ttg acg ctg cca gac tca agt gac ttg      343 
Thr Pro Ser Met Gly Cys Pro Leu Thr Leu Pro Asp Ser Ser Asp Leu 
             10                  15                  20 

agg ttc ctg gcc ttt gag ccc gcc cct ccc act ctt ccc tcg gcc agg      391 
Arg Phe Leu Ala Phe Glu Pro Ala Pro Pro Thr Leu Pro Ser Ala Arg 
         25                  30                  35 

cca agg ctc ctc caa gcc tca gtt acc ctg tct tta aaa gag cgc gct      439 
Pro Arg Leu Leu Gln Ala Ser Val Thr Leu Ser Leu Lys Glu Arg Ala 
     40                  45                  50 

cct ctg att cta tag aatcctgagg ctcaaagcca aagatgaaca gcctggaagc      494 
Pro Leu Ile Leu  * 
 55 

agagccatca gagcggcaaa gctgcccagg gatccccgag aactcgctgg ggttagagat    554 

caggaccctg agattcaggc tctacacctg attcctcgtg cccccgtccg ctacggggct    614 

gagttatggg catcgtttga catgggccac tcggattccc ttccaggccc ttgcccgtgc    674 

cgttccctct gcctggccac cggatgaagc aggaagacgg actgcaagta gaccatttct    734 

agccctgcct agataaaggc agagggcgca gtgaggtcct gcgacgaaa                783 

 
           
             7  
             6339  
             DNA  
             Homo sapiens  
             
               CDS  
               (533)..(4867)  
             
           
            7 

ggaaaaaaag gaaggcgtga gggcgggcag cagcgacagg atgcttgttt ttcgctctac     60 

caaagtcgtc tgaaggcgag acagcgggcc cagggcgcag gacccaccgc agccccctgg    120 

gcagtctcct cgccccgcgt ccgcgtcgtc tccggggcac ttagtaaggg gtggggagag    180 

cttgccctcc ctcttaagct gaggagaaac acccgaagac accgcaggag cctgtgaaag    240 

tccctaggac tccaagtgag gaagtgacac tcccaggcga gccggcccgc ggctgccagt    300 

ctgcacggcc tcggcacggc ggccccggag cggcgcgggg tggatctcag gctctgccgg    360 

cccgcggccc gcggggtcca tgcgcagggc ccccagccca agttcttcca tcttccgatg    420 

cggcccccca gagccgcggg gcagccggtg atctagcccg ggagcccatc ttacagcggt    480 

gccaagcaga ggggcggcag agacggaggg gcagcctctt tgggactaac tc    atg     535 
                                                             Met 
                                                               1 

aag aac aag ggt gct aag cag aag ctg aaa cga aag gga gcc gcc agc      583 
Lys Asn Lys Gly Ala Lys Gln Lys Leu Lys Arg Lys Gly Ala Ala Ser 
              5                  10                  15 

gcg ttt ggc tgt gac ctg acg gag tat ctg gaa agc tcg gga cag gat      631 
Ala Phe Gly Cys Asp Leu Thr Glu Tyr Leu Glu Ser Ser Gly Gln Asp 
         20                  25                  30 

gtt cca tac gtt ttg aag agc tgt gca gaa ttt ata gag act cac ggc      679 
Val Pro Tyr Val Leu Lys Ser Cys Ala Glu Phe Ile Glu Thr His Gly 
     35                  40                  45 

atc gtg gat gga atc tat cgg ctt tca gga gtc acc tca aac ata caa      727 
Ile Val Asp Gly Ile Tyr Arg Leu Ser Gly Val Thr Ser Asn Ile Gln 
 50                  55                  60                  65 

cgg cta agg caa gag ttt ggc tca gat caa tgt cca gat ctg aca agg      775 
Arg Leu Arg Gln Glu Phe Gly Ser Asp Gln Cys Pro Asp Leu Thr Arg 
                 70                  75                  80 

gaa gtg tac ctc cag gac atc cac tgt gtg ggc tcg ctt tgc aag ctc      823 
Glu Val Tyr Leu Gln Asp Ile His Cys Val Gly Ser Leu Cys Lys Leu 
             85                  90                  95 

tac ttt agg gag ctg ccc aac ccc ctc ctg act tat gag ctc tat gag      871 
Tyr Phe Arg Glu Leu Pro Asn Pro Leu Leu Thr Tyr Glu Leu Tyr Glu 
        100                 105                 110 

aaa ttc acg gag gca gtg tcg cat tgc cct gaa gaa ggc caa ctg gcc      919 
Lys Phe Thr Glu Ala Val Ser His Cys Pro Glu Glu Gly Gln Leu Ala 
    115                 120                 125 

cga atc caa aat gtt atc cag gag ctt cct cca tcc cac tat agg acc      967 
Arg Ile Gln Asn Val Ile Gln Glu Leu Pro Pro Ser His Tyr Arg Thr 
130                 135                 140                 145 

ttg gaa tac ctg att cga cac ctg gcc cat atc gcc tcc ttc agc agc     1015 
Leu Glu Tyr Leu Ile Arg His Leu Ala His Ile Ala Ser Phe Ser Ser 
                150                 155                 160 

aag acc aac atg cac gcc cgg aac ctg gcc ctg gtg tgg gcg cca aac     1063 
Lys Thr Asn Met His Ala Arg Asn Leu Ala Leu Val Trp Ala Pro Asn 
            165                 170                 175 

ctc ctc agg tct aaa gaa att gaa gcc act ggt tgc aat gga gat gca     1111 
Leu Leu Arg Ser Lys Glu Ile Glu Ala Thr Gly Cys Asn Gly Asp Ala 
        180                 185                 190 

gcc ttc ctt gca gtc cgg gtc cag cag gtg gtg att gag ttc ata ttg     1159 
Ala Phe Leu Ala Val Arg Val Gln Gln Val Val Ile Glu Phe Ile Leu 
    195                 200                 205 

aat cat gta gat caa atc ttt aac aac ggt gca cct ggg tct ctg gag     1207 
Asn His Val Asp Gln Ile Phe Asn Asn Gly Ala Pro Gly Ser Leu Glu 
210                 215                 220                 225 

aat gat gaa aac cgg ccc atc atg aag agc ctg acc ttg cca gcc ctc     1255 
Asn Asp Glu Asn Arg Pro Ile Met Lys Ser Leu Thr Leu Pro Ala Leu 
                230                 235                 240 

tcc ctg ccc atg aag ctg gtg agc ctt gag gaa gct caa gcc cgc agc     1303 
Ser Leu Pro Met Lys Leu Val Ser Leu Glu Glu Ala Gln Ala Arg Ser 
            245                 250                 255 

ctg gcc act aac cat cct gct cgc aag gaa agg agg gag aac agc ctg     1351 
Leu Ala Thr Asn His Pro Ala Arg Lys Glu Arg Arg Glu Asn Ser Leu 
        260                 265                 270 

cct gag att gtc cct ccc atg ggc acc ctc ttc cac act gtc ctt gag     1399 
Pro Glu Ile Val Pro Pro Met Gly Thr Leu Phe His Thr Val Leu Glu 
    275                 280                 285 

tta cca gac aac aag cga aag ctc tcc agt aaa tca aag aag tgg aaa     1447 
Leu Pro Asp Asn Lys Arg Lys Leu Ser Ser Lys Ser Lys Lys Trp Lys 
290                 295                 300                 305 

tca ata ttt aac ctg gga cgt tct gga tca gac tcc aaa tca aaa ctg     1495 
Ser Ile Phe Asn Leu Gly Arg Ser Gly Ser Asp Ser Lys Ser Lys Leu 
                310                 315                 320 

agt aga aat ggg agt gta ttt gtg aga gga cag agg ctc tcg gtg gaa     1543 
Ser Arg Asn Gly Ser Val Phe Val Arg Gly Gln Arg Leu Ser Val Glu 
            325                 330                 335 

aag gct act atc cga cca gct aaa agc atg gac tca cta tgt tca gtg     1591 
Lys Ala Thr Ile Arg Pro Ala Lys Ser Met Asp Ser Leu Cys Ser Val 
        340                 345                 350 

cct gtg gaa gga aaa gaa acc aag gga aat ttc aat cga aca gtt acc     1639 
Pro Val Glu Gly Lys Glu Thr Lys Gly Asn Phe Asn Arg Thr Val Thr 
    355                 360                 365 

acc ggt gga ttt ttc att cca gca aca aag atg cac tcc acc ggc acc     1687 
Thr Gly Gly Phe Phe Ile Pro Ala Thr Lys Met His Ser Thr Gly Thr 
370                 375                 380                 385 

ggc agc tca tgt gac ctc acc aag cag gag ggc gaa tgg ggc cag gag     1735 
Gly Ser Ser Cys Asp Leu Thr Lys Gln Glu Gly Glu Trp Gly Gln Glu 
                390                 395                 400 

ggg atg cct ccc ggg gct gag ggt ggc ttt gat gtg agc agt gat cgc     1783 
Gly Met Pro Pro Gly Ala Glu Gly Gly Phe Asp Val Ser Ser Asp Arg 
            405                 410                 415 

agc cat ctc cag ggc gct cag gcc cgg ccc cca ccg gaa cag ctg aag     1831 
Ser His Leu Gln Gly Ala Gln Ala Arg Pro Pro Pro Glu Gln Leu Lys 
        420                 425                 430 

gtt ttc cgg cct gtt gag gat ccg gag agc gag caa aca gcc cca aag     1879 
Val Phe Arg Pro Val Glu Asp Pro Glu Ser Glu Gln Thr Ala Pro Lys 
    435                 440                 445 

atg ttg ggt atg ttc tac act tcg aac gac agc cct agc aaa tcc gtc     1927 
Met Leu Gly Met Phe Tyr Thr Ser Asn Asp Ser Pro Ser Lys Ser Val 
450                 455                 460                 465 

ttc acc agc agc ctc ttc ccg atg gag ccc tcg ccg cgt aac cag cgc     1975 
Phe Thr Ser Ser Leu Phe Pro Met Glu Pro Ser Pro Arg Asn Gln Arg 
                470                 475                 480 

aag gcg ctg aac atc tcc gag ccc ttt gcg gta tct gtg ccg ctc cgc     2023 
Lys Ala Leu Asn Ile Ser Glu Pro Phe Ala Val Ser Val Pro Leu Arg 
            485                 490                 495 

gtg tcc gca gtc atc agc acc aac agc acg ccg tgc aga aca ccc ccg     2071 
Val Ser Ala Val Ile Ser Thr Asn Ser Thr Pro Cys Arg Thr Pro Pro 
        500                 505                 510 

aag gag ctg cag tct ctt tcc agc ctg gaa gag ttt tct ttt cat gga     2119 
Lys Glu Leu Gln Ser Leu Ser Ser Leu Glu Glu Phe Ser Phe His Gly 
    515                 520                 525 

tca gag agc gga ggc tgg cca gaa gaa gag aaa ccg ctg gga gct gag     2167 
Ser Glu Ser Gly Gly Trp Pro Glu Glu Glu Lys Pro Leu Gly Ala Glu 
530                 535                 540                 545 

act tct gca gct tct gta cct aag aag gca ggt ctt gag gat gcc aag     2215 
Thr Ser Ala Ala Ser Val Pro Lys Lys Ala Gly Leu Glu Asp Ala Lys 
                550                 555                 560 

gca gta cct gaa gca cca ggg aca gtg gaa tgc agc aaa ggc ctg tcc     2263 
Ala Val Pro Glu Ala Pro Gly Thr Val Glu Cys Ser Lys Gly Leu Ser 
            565                 570                 575 

cag gag cca ggc gcc cac ctg gag gag aag aaa acc cca gaa agc tcc     2311 
Gln Glu Pro Gly Ala His Leu Glu Glu Lys Lys Thr Pro Glu Ser Ser 
        580                 585                 590 

ttg agc tct caa cat tta aat gaa tta gag aag agg cca aat ccg gag     2359 
Leu Ser Ser Gln His Leu Asn Glu Leu Glu Lys Arg Pro Asn Pro Glu 
    595                 600                 605 

aag gtg gtg gag gag gga cga gag gct ggt gag atg gag tcc agc acc     2407 
Lys Val Val Glu Glu Gly Arg Glu Ala Gly Glu Met Glu Ser Ser Thr 
610                 615                 620                 625 

ctg cag gag agc ccc agg gcc aga gcc gaa gct gtg ctt ctc cat gag     2455 
Leu Gln Glu Ser Pro Arg Ala Arg Ala Glu Ala Val Leu Leu His Glu 
                630                 635                 640 

atg gat gaa gat gat ctg gcc aat gcc ctg atc tgg cct gag att caa     2503 
Met Asp Glu Asp Asp Leu Ala Asn Ala Leu Ile Trp Pro Glu Ile Gln 
            645                 650                 655 

cag gag ctg aaa atc att gaa tct gag gag gag ctc tca tcg ttg cca     2551 
Gln Glu Leu Lys Ile Ile Glu Ser Glu Glu Glu Leu Ser Ser Leu Pro 
        660                 665                 670 

cct cct gct ctg aag acc agc cca att cag cct att ctc gag tcg agt     2599 
Pro Pro Ala Leu Lys Thr Ser Pro Ile Gln Pro Ile Leu Glu Ser Ser 
    675                 680                 685 

ctg ggg ccc ttt att ccc tca gag cct cct ggg agc ttg cct tgt ggc     2647 
Leu Gly Pro Phe Ile Pro Ser Glu Pro Pro Gly Ser Leu Pro Cys Gly 
690                 695                 700                 705 

tcc ttc cct gct cca gtc tcc acc cct ctg gag gtg tgg act agg gat     2695 
Ser Phe Pro Ala Pro Val Ser Thr Pro Leu Glu Val Trp Thr Arg Asp 
                710                 715                 720 

cca gcc aat cag agc aca cag ggg gct tcc aca gca gcc agc aga gag     2743 
Pro Ala Asn Gln Ser Thr Gln Gly Ala Ser Thr Ala Ala Ser Arg Glu 
            725                 730                 735 

aag ccg gaa cct gag cag ggc ctg cac cca gac ctc gcc agc ctg gct     2791 
Lys Pro Glu Pro Glu Gln Gly Leu His Pro Asp Leu Ala Ser Leu Ala 
        740                 745                 750 

cct ctg gaa ata gtt cct ttt gag aag gca tct cca caa gca aca gtg     2839 
Pro Leu Glu Ile Val Pro Phe Glu Lys Ala Ser Pro Gln Ala Thr Val 
    755                 760                 765 

gaa gta gga ggc cca ggc aat ctg tct cct cca ctc cca cct gct cct     2887 
Glu Val Gly Gly Pro Gly Asn Leu Ser Pro Pro Leu Pro Pro Ala Pro 
770                 775                 780                 785 

ccc cct cca act cct ctg gag gag tca act cca gtc ctg ctt tca aag     2935 
Pro Pro Pro Thr Pro Leu Glu Glu Ser Thr Pro Val Leu Leu Ser Lys 
                790                 795                 800 

ggc agc ccg gaa aga gaa gac tca tcc agg aaa ttg agg aca gat ctc     2983 
Gly Ser Pro Glu Arg Glu Asp Ser Ser Arg Lys Leu Arg Thr Asp Leu 
            805                 810                 815 

tac ata gac cag ctg aag tcc caa gac agc cct gag atc tct agc ctc     3031 
Tyr Ile Asp Gln Leu Lys Ser Gln Asp Ser Pro Glu Ile Ser Ser Leu 
        820                 825                 830 

tgt cag gga gag gag gca acc cca aga cac agt gac aag caa aat tca     3079 
Cys Gln Gly Glu Glu Ala Thr Pro Arg His Ser Asp Lys Gln Asn Ser 
    835                 840                 845 

aag aat gct gct tct gag ggg aaa ggc tgt ggt ttt cca agc cca acc     3127 
Lys Asn Ala Ala Ser Glu Gly Lys Gly Cys Gly Phe Pro Ser Pro Thr 
850                 855                 860                 865 

agg gag gtt gag atc gtc tca caa gaa gag gag gat gta acc cat tca     3175 
Arg Glu Val Glu Ile Val Ser Gln Glu Glu Glu Asp Val Thr His Ser 
                870                 875                 880 

gta cag gag cct tca gac tgt gac gaa gat gac act gtg aca gac att     3223 
Val Gln Glu Pro Ser Asp Cys Asp Glu Asp Asp Thr Val Thr Asp Ile 
            885                 890                 895 

gcc cag cat ggc ctg gag atg gtg gag ccc tgg gag gaa ccc cag tgg     3271 
Ala Gln His Gly Leu Glu Met Val Glu Pro Trp Glu Glu Pro Gln Trp 
        900                 905                 910 

gtg acg agt ccc ctt cac tct ccc acc ctg aaa gac gcg cac aag gcc     3319 
Val Thr Ser Pro Leu His Ser Pro Thr Leu Lys Asp Ala His Lys Ala 
    915                 920                 925 

cag gta cag ggc ctt cag ggt cac cag ttg gag aag agg ctt tcc cac     3367 
Gln Val Gln Gly Leu Gln Gly His Gln Leu Glu Lys Arg Leu Ser His 
930                 935                 940                 945 

agg ccc agc ctt cgc cag agc cat tct cta gat agc aaa ccc acg gtt     3415 
Arg Pro Ser Leu Arg Gln Ser His Ser Leu Asp Ser Lys Pro Thr Val 
                950                 955                 960 

aaa agc cag tgg act ctc gag gtt ccc tcc tcc agc agc tgt gct aat     3463 
Lys Ser Gln Trp Thr Leu Glu Val Pro Ser Ser Ser Ser Cys Ala Asn 
            965                 970                 975 

ctt gaa aca gag agg aat tct gac cct ctt cag ccc cag gca ccc agg     3511 
Leu Glu Thr Glu Arg Asn Ser Asp Pro Leu Gln Pro Gln Ala Pro Arg 
        980                 985                 990 

aga gag att act gga tgg gat gag aaa gcc ctg agg tcc ttc aga gag     3559 
Arg Glu Ile Thr Gly Trp Asp Glu Lys Ala Leu Arg Ser Phe Arg Glu 
    995                1000                1005 

ttc tct ggc ctg aaa ggg gca gag gct cct ccc aac cag aag gga cca     3607 
Phe Ser Gly Leu Lys Gly Ala Glu Ala Pro Pro Asn Gln Lys Gly Pro 
1010                1015                1020                1025 

agt ggt gtg caa ccc aac cca gca gaa acc agc ccc atc agc cta gca     3655 
Ser Gly Val Gln Pro Asn Pro Ala Glu Thr Ser Pro Ile Ser Leu Ala 
               1030                1035                1040 

gag gga aag gag cta ggg aca cac ctg ggg cac agc agt cca cag att     3703 
Glu Gly Lys Glu Leu Gly Thr His Leu Gly His Ser Ser Pro Gln Ile 
           1045                1050                1055 

agg caa ggt ggt gtt cct ggg cca gag agc agc aag gag agt tca ccc     3751 
Arg Gln Gly Gly Val Pro Gly Pro Glu Ser Ser Lys Glu Ser Ser Pro 
       1060                1065                1070 

agc gtg cag gac agc act tcg cct gga gag cac ccc gca aag tta cag     3799 
Ser Val Gln Asp Ser Thr Ser Pro Gly Glu His Pro Ala Lys Leu Gln 
   1075                1080                1085 

cta aag agc aca gag tgt ggg ccc cca aaa ggg aaa aac agg cct tct     3847 
Leu Lys Ser Thr Glu Cys Gly Pro Pro Lys Gly Lys Asn Arg Pro Ser 
1090                1095                1100                1105 

tcc ctc aac ttg gac cct gcc att ccc att gct gac ctc ttc tgg ttt     3895 
Ser Leu Asn Leu Asp Pro Ala Ile Pro Ile Ala Asp Leu Phe Trp Phe 
               1110                1115                1120 

gag aat gtg gcc tca ttt agt tca cct gga atg cag gtc tct gag cca     3943 
Glu Asn Val Ala Ser Phe Ser Ser Pro Gly Met Gln Val Ser Glu Pro 
           1125                1130                1135 

gga gac cca aag gtc aca tgg atg acc tca tct tac tgt aaa gca gac     3991 
Gly Asp Pro Lys Val Thr Trp Met Thr Ser Ser Tyr Cys Lys Ala Asp 
       1140                1145                1150 

ccc tgg agg gtt tac tcc cag gac ccc cag gac ctg gac att gtt gct     4039 
Pro Trp Arg Val Tyr Ser Gln Asp Pro Gln Asp Leu Asp Ile Val Ala 
   1155                1160                1165 

cat gca ctg aca ggc cgc cgt aac tca gct cct gtg agt gtg tca gct     4087 
His Ala Leu Thr Gly Arg Arg Asn Ser Ala Pro Val Ser Val Ser Ala 
1170                1175                1180                1185 

gtg aga acc tcc ttc atg gtc aaa atg tgc cag gcc agg gcg gtc cca     4135 
Val Arg Thr Ser Phe Met Val Lys Met Cys Gln Ala Arg Ala Val Pro 
               1190                1195                1200 

gtc atc cct ccc aag att cag tac acc cag atc cca cag ccc ctg ccc     4183 
Val Ile Pro Pro Lys Ile Gln Tyr Thr Gln Ile Pro Gln Pro Leu Pro 
           1205                1210                1215 

tct cag agc tca ggg gag aat ggg gtt cag cct ctg gag agg agc cag     4231 
Ser Gln Ser Ser Gly Glu Asn Gly Val Gln Pro Leu Glu Arg Ser Gln 
       1220                1225                1230 

gag gga ccc agc tca acc agt ggg acc act cag aaa cct gcc aaa gat     4279 
Glu Gly Pro Ser Ser Thr Ser Gly Thr Thr Gln Lys Pro Ala Lys Asp 
   1235                1240                1245 

gat tct ccc tcc tcc ctg gaa agc tca aag gaa gaa aaa cca aag caa     4327 
Asp Ser Pro Ser Ser Leu Glu Ser Ser Lys Glu Glu Lys Pro Lys Gln 
1250                1255                1260                1265 

gat ccc gga gcc att aag tcc tca cca gtg gat gcc act gca ccc tgc     4375 
Asp Pro Gly Ala Ile Lys Ser Ser Pro Val Asp Ala Thr Ala Pro Cys 
               1270                1275                1280 

atg tgc gag gga cct acc ctt tct cca gaa cca ggc tcg tct aac ctg     4423 
Met Cys Glu Gly Pro Thr Leu Ser Pro Glu Pro Gly Ser Ser Asn Leu 
           1285                1290                1295 

ctc tcc acc cag gat gca gta gtg caa tgc aga aag cgc atg tca gag     4471 
Leu Ser Thr Gln Asp Ala Val Val Gln Cys Arg Lys Arg Met Ser Glu 
       1300                1305                1310 

aca gag cca tct ggg gac aac ctt ctt tct tca aaa cta gag cga cca     4519 
Thr Glu Pro Ser Gly Asp Asn Leu Leu Ser Ser Lys Leu Glu Arg Pro 
   1315                1320                1325 

tct ggg ggt tct aag cct ttc cac agg tca agg cca gga aga cct cag     4567 
Ser Gly Gly Ser Lys Pro Phe His Arg Ser Arg Pro Gly Arg Pro Gln 
1330                1335                1340                1345 

agc cta atc tta ttc agt cct cct ttc ccc att atg gac cac ctg ccc     4615 
Ser Leu Ile Leu Phe Ser Pro Pro Phe Pro Ile Met Asp His Leu Pro 
               1350                1355                1360 

cct tca tcc aca gtg aca gat tcc aag gtc ctg ctg tcc cct atc aga     4663 
Pro Ser Ser Thr Val Thr Asp Ser Lys Val Leu Leu Ser Pro Ile Arg 
           1365                1370                1375 

agt ccc acc cag aca gtt tcc cct ggc ctt ctt tgt gga gag ttg gca     4711 
Ser Pro Thr Gln Thr Val Ser Pro Gly Leu Leu Cys Gly Glu Leu Ala 
       1380                1385                1390 

gaa aac aca tgg gtc aca cca gaa ggg gtt aca ctt agg aat aaa atg     4759 
Glu Asn Thr Trp Val Thr Pro Glu Gly Val Thr Leu Arg Asn Lys Met 
   1395                1400                1405 

acc atc cct aag aat ggc cag aga cta gag acc tca acc agc tgt ttt     4807 
Thr Ile Pro Lys Asn Gly Gln Arg Leu Glu Thr Ser Thr Ser Cys Phe 
1410                1415                1420                1425 

tac cag cct cag cgg aga tca gta att ctg gat gga aga agt ggg agg     4855 
Tyr Gln Pro Gln Arg Arg Ser Val Ile Leu Asp Gly Arg Ser Gly Arg 
               1430                1435                1440 

caa ata gaa tga ttt cggttcacct gctggtgtct gaaaaaaacc gtgattcatc     4910 
Gln Ile Glu  * 
           1445 

tggaagttat tacagggcca gcttgccata ttccaggcac acgttatcaa gtttgggcct   4970 

attgtggcct ctgacttctc tttcttcagc cttttgacca cttattaatt agtccatttg   5030 

ctagaagagt ggtcaaggga aaaacgagag atgaaattta gttaagtcta tgtgagcaag   5090 

tgagagaagg ttaggtaagg ggagaggatg gaatgcttgc ctccaatgaa ctttggagct   5150 

tgtatgtgag tcagattgct cccctattgc tattatctat tactcttgag agctggctgt   5210 

cctttgaaag aaagaagtaa tgttctttga aagaaagaaa aatctcttgc tgtgtcaaac   5270 

ctcaaaatgt tgctattggg gttagaaggc ctcctcttta tgctttttaa tgctctttca   5330 

aacgtgttct tttagaccag ttttctaata agctttgtaa aatgtactat ccaaattaga   5390 

agcggatttg gaaatgcaaa ctaacgtgca cttagatatc caagtgggtg agcttagcca   5450 

ctcttaccca tgctctttcc ctggaatccc tggagacctg tccaagatga tttccatata   5510 

ccagcataga aaatcagaat caagagcaaa ctctgagact ggcacaatcc aagaagattt   5570 

cctggctctg gcttttagta atttgggact ccaactgcca ctgtactgga ctgtaattta   5630 

taaatccagt agctacgcag ggtggaggct gggctgagga ttaccataat gaaatgtact   5690 

aaatcttcat ttaggtatgc aattgtgaag tgaaggcatc tgctttcttt acagtatcag   5750 

agtccaagaa caggatgtca ccatagataa aagcctcata caaaggcaga actacactcc   5810 

aaatttaatg tgtttaaatt ggtggggcac cagcagaaaa tacttctagc tcagctttac   5870 

tcttcttcca cactaggctg ggcccagcaa tacaggagag gatgaaggga ggagctccag   5930 

gaggcgaggg aagagcccta gcagggcggc catcacaacc actcactgag agttgccctt   5990 

cttaaaaatg tattttattt tagccagtgg gtcccttcct ttctcctttc ctctctactg   6050 

ctcaagaaca gatttgaggc caggtgcggt gcctcacatc tgtaatccca acactttggg   6110 

aggctgagat gggtggattg cttgagccca ggagttcaag accagcctgg gcaacacagc   6170 

gagaccccat ctcttaaaaa ataacagact tgaggaaccc ctctcccttc cataattccc   6230 

ctcatccacc gcccactcca ggcactcact caaacttgct cttcaactct gtatacaagc   6290 

agaagcaata aaccaatctg attttctttt caattaaaaa aaaaaaaaa               6339 

 
           
             8  
             6593  
             DNA  
             Homo sapiens  
             
               CDS  
               (3200)..(3703)  
             
           
            8 

ttttcgtcta tgtttctgat ctgctttcag gaagaattat tcatttttat cttcccaatc     60 

tgaatgtttt attgaatttt tattttccaa gttaataaaa cctttggtta ttatcctgtc    120 

tttgttttac agtgtcctgc tcttgatgcg tggatgcaga ttttgtctct ctgtggacgt    180 

taatgattgt ggtctgaggg gaagtctttt ctgctccctg tgttgccctc attttctctg    240 

agttctcttt attttggtgg tctcagtctc tatctttcac gttgtgaatt tttctcaaat    300 

atatggtgat cctatggatc tgttcatgtt ttaagagtga ggcatccaaa agctgattgg    360 

aagttgtgtg tgccaactgg tgagcttttc cactagggtc accaggtggg cacctggact    420 

catcattgga gaacactgcc tgtcagtatt tgcacgtgtt ttctctgggg ctcattctgt    480 

ttcttgagag atattcccac tactctcctt cctgggaaac gggcatacac agggctttta    540 

gcctatgctg agtactcatg tggtttcatc aaatgttgtc ccactctcgg cagaagtccc    600 

catgagcact tggcttgatc tggccacagg acaccttttg ccccttcctt cagacatacc    660 

cagctctgag cttggacaat gctcgaggaa caatgaaaag gctagatttt aactcctaat    720 

tgccctcttt agccaagtgc ctctgtgcaa tgcacaactg taggaccata tccagagacc    780 

ctggtctata ctcagtgtgc ccgagtcctg accgctgagc aggcagcctc atcacccgtg    840 

agtatttaga ctttcattaa gttgcttcaa cctttgctgt gcctggtgtc cctgagttgg    900 

agctgctctg atttctccat ggagtaggag cacagtggtc atctggctgc atgggaagga    960 

caggggacct cagagccaat aaatgccctg gtcttcagcc ccatgtctca ccccatccct   1020 

cctattccaa tccccaagcc tctcctggag gccacagggc atctctgctg accactctgt   1080 

ggcctcccct ctgcaggcat gtggttttag gatccccctc cctgctcact tttccatcag   1140 

ttccattcct gcataaatag gttgctagct cttgcttact gttctcttct gtattctgtg   1200 

ttcatggttg tattaatata actttcattc ctctgctcct attttcatgg ggtttcatga   1260 

gggaagaaac aggctcatgt gttcagtata ccatcttgat ccataaaccc catttgagtt   1320 

atctcacagg ttgcttaggg ggcttgctgc tctgactggt ttgtgaacgt gccctgagtc   1380 

cagctgggac tgcagcaaca tccatcctgt tgagctgtgg tctgctaagt gattttgtgt   1440 

aatgctgtgc caagtgcagg agagggatac atagcatggc taagctctgc ttgaatgcca   1500 

tgattagtta ttaccttcct tccttccccc tggttttgct gcctattgtc agtaaatgat   1560 

cttagatctc ctgcctcccc aaagatatag tctatgtggt ggtctgggtt ctaggttttc   1620 

tttaccaccc ttgcttcact taagaaacag aaaactggct aggcacagta gtggctcaca   1680 

cctataatcc cagccctttg ggaggccaag gcaggaggat cgcttgaggc caggaattca   1740 

agaccagcct gcacaacata gcaagactcc atctctacaa aaagttaaat ttaaattagt   1800 

ggtggcatgc acttatagtc ccagctactc gggaggatga ggcaggagaa ttgtttgagc   1860 

ccatgacttt gaggttactg tgagctgtga tcctgctatt ttactccacc tgagtgacag   1920 

agcgagacgc tgtctcaaaa ataaagaaac aagtagtcca cacaggtgtt tgccagcaaa   1980 

caaacagcgc ggattctctg ttgaacgtgg ccaacattgc ctcgtcgaag tttgtatctt   2040 

gccatagttg atgatcaggt ggtcggggct tcctggtcag acctgacctt tgtggggaga   2100 

tgttctccca ccaaggctca gaagcaggac actcttgctg cccctcgggc agccacccag   2160 

aacatgggcg tctccatttc tgaggttcag catagttccc cccaccctct tcccatgcag   2220 

tgcatgcctg ctctttatca ggatggaaca gagggaaggc agaggcactg ggggcagcct   2280 

gtgttgttga tctctgtaag tcacagactg ttcgaaaacc tcaggaatta tgtaagcgtt   2340 

cagtgcctca tttaagagat gaaaaactga agattagaaa gaggaaacga ctagtcgccc   2400 

tgctagttga tgacctccag atagccatct tcattcccag ttaagtttac tacaaaacca   2460 

cagcctcagc tgctgaagct aacctcccta cccaccatcg ctagggactc agaacaccat   2520 

ggagctcatc tctccaacaa aagtcagaat tagcaagtac agatgtgtct tacgaaaatg   2580 

tcagaatcca tcatggctgc tttggtgagg agctgttctc cttccgtggt catgccattg   2640 

gaaggcagtt gtatgacaag aatgctttca catgagctcc gattttctta actctccaga   2700 

aggacttcag aagcctctgg agttttgaga cacggcctct ctctcccttc tgcttggaga   2760 

caccttcctg ggggtctcca ctgcattccc cgccggtatt cctctgtgga gccttgcgcc   2820 

ctcaggtccc agaaatgggc tgtgtgggag cttccagtca gcctggtatc tcgggacctt   2880 

ctcagccagg aaatgagact gcacaaagcc ctgtgaggcc cagctgtgtt atttctcctt   2940 

ccccgacatt gcataatcac tgctgacaca gcatttgggg aagatttaac gtcttgggcc   3000 

agcagctgcc atctggaacc atcaccacat agcaggttgt tctgtcccat ccaactgatg   3060 

agggggctgc cctaatgaca aggtccagga cctgggttgg gtggtggaag gctgggagct   3120 

ggagtgggca ttattgtgct tctgtgctga aaattgctat ggctcttttc ccctaacagc   3180 

cagcgtggga gaaccaaac atg aga cac aag cat ccc ctt gag ctc cac aga    3232 
                     Met Arg His Lys His Pro Leu Glu Leu His Arg 
                       1               5                  10 

tct tgc gcc ttg ctc tca tca ggc att tcc ttg gag aac agc agt cag     3280 
Ser Cys Ala Leu Leu Ser Ser Gly Ile Ser Leu Glu Asn Ser Ser Gln 
             15                  20                  25 

cag ctc atg gaa gtg agc ccg gtg cac aga ctt tgc atg gac ttt gca     3328 
Gln Leu Met Glu Val Ser Pro Val His Arg Leu Cys Met Asp Phe Ala 
         30                  35                  40 

cag gtt cca ttt cca tcg tgt gca gac acc tgt atc ttt ggg ctc cac     3376 
Gln Val Pro Phe Pro Ser Cys Ala Asp Thr Cys Ile Phe Gly Leu His 
     45                  50                  55 

gtg agc acc tgc cct ctt cac tct gat ttt ttt ttt aag aga cag cat     3424 
Val Ser Thr Cys Pro Leu His Ser Asp Phe Phe Phe Lys Arg Gln His 
 60                  65                  70                  75 

ctt act ctg tca ccg agg ctg gag tac agt ggt gtg atc aca gct cac     3472 
Leu Thr Leu Ser Pro Arg Leu Glu Tyr Ser Gly Val Ile Thr Ala His 
                 80                  85                  90 

tgc agc ctg aaa ctc ctg ggc tca ggc aat cct cct gcc tca gcc tcc     3520 
Cys Ser Leu Lys Leu Leu Gly Ser Gly Asn Pro Pro Ala Ser Ala Ser 
             95                 100                 105 

cga gtg gct ggt agt aca ggt gca tgc cac cac gcc cac cta att ttt     3568 
Arg Val Ala Gly Ser Thr Gly Ala Cys His His Ala His Leu Ile Phe 
        110                 115                 120 

tta tct ttt ata gat aca ggt ctc act gtt gct cag gct ggt ctc gaa     3616 
Leu Ser Phe Ile Asp Thr Gly Leu Thr Val Ala Gln Ala Gly Leu Glu 
    125                 130                 135 

ctc ctg gcc tca agt gat cct cct gcc ttg gcc tac caa aat gct ggg     3664 
Leu Leu Ala Ser Ser Asp Pro Pro Ala Leu Ala Tyr Gln Asn Ala Gly 
140                 145                 150                 155 

att ata ggc atg aac cac tgt gcc tgg cct tca ctc tga tttttcttaa      3713 
Ile Ile Gly Met Asn His Cys Ala Trp Pro Ser Leu  * 
                160                 165 

gagtcctaca ggaccttcag gtcttgtcac ttctctacca ttgtgtgtga gacagggcat   3773 

ggggtgagct tggtcaggtg tgggtcaaaa gcctggagac tcagagctgc tggttcccca   3833 

agagcccaca aaagttatca gagtttctga gctgagtgtt ctgcagttgc cagaccccac   3893 

aatgctggga atactggctt ctttgtgttt agaacttgtt ctgagaacct tgatgagaac   3953 

acatcaagca agcagttcct cccagccagg gctggagcaa catgccaaaa aacattcttg   4013 

tctatgggaa aaagacaacc agtattttgt actgtttgac caagttgttt ttaaatatac   4073 

acatgcctca acaacccacg gcctcaatcg cactgctaat ttgtttaaat ccctgacact   4133 

cagatgtcaa gaatagcttc atctagcagt gttctcttta aaggaaccct tttttttgtt   4193 

ttcattttaa tcactgcctt cttctctggg aggtattgtg ggctagagaa agaagtcagg   4253 

tttgggagtc agccagattt agattggagt cccagctctg tcaccagatc tctgggtgat   4313 

cttggcaaac taacttctga gcttctgtgc attataggca ttcagcacat atttgttgga   4373 

tgaaaaatac ttttcttgaa agtttatgaa gttgtaggat gcccagcagc ccccttttct   4433 

ctatttcctt cctcttgaag caagcgttga ctatacctct ttccctaacc cttagtgtac   4493 

catagcttct tccaacctct ctccaatcca ttactttttt ctgagctacc ctgtctcaaa   4553 

tctaactcag gcctttttgc aagaggaagt ttaagccatt gtttactcat taactcactt   4613 

gacccttaga acaatcgtgg gaggtgttta tttcggaaag gaagctaaag cacaggacag   4673 

aaaaataagg tcatagcgtg aactagtaag tagcagaact gggaacatag gactgttatt   4733 

ttcaaacact ctaaacttca ctgcagttgc aaatttgcaa ccaaaatggc cgccttgaaa   4793 

gggtcttttg cagtaaaatc tcagtgtcca acatcaaaga cagttcttca gggcctccaa   4853 

ttaactatac atcctgcccc cagctgctca tctctgcacc tctaacacgt acttcacaga   4913 

gtaggaaatt gggctttctc cttcaaaaag aaaagtagag aaggcctgag ggcagtgtaa   4973 

ttaaaatgga gaagtagaga ccacgaatta cttggatgaa ttcataactg gttggtctct   5033 

gaggcaggga ttattatttt tcctgtattt taagcttaaa agtagtgatt tttgcattgt   5093 

tacaaaaaac aaaatagcaa aatatcattt gatacttgta ttctgtttgc aatagctacc   5153 

acttccttta gccccagcaa aaatcaatag gtgtgtattc tctacaagcc catgctgtgc   5213 

cagaatgcca gtattgctaa atgtcatgca aggatttaga cactttttta aaggaaactc   5273 

tgggagtgcc tgttgtctgg agagttgaca ttgtccaaag caggccaaca ctggtatggg   5333 

tatggagaac ccacgtccta gctgtggctc acctgcagat gccttgaatt tacctctctg   5393 

ggttggaagt gggaagactt cttttaaaag tcctttctaa gtttaaaaat ccaaaggtta   5453 

cgaaggtagt ttttatttat ctcaataagt ggcctatttg cttaaagcaa gtgtacctct   5513 

gtatatcagc ccaaagctta gggcagtgct tcttggcttt agtatctgag aaaggtgcct   5573 

ttgggaagag tttggtcaga cagaaggtag tctgaatctt aaaggtttca gatgaatgtt   5633 

tgaagtagaa cctgggaaat ctgcttccta gggctgttag aaggaaattg gtctccttaa   5693 

attacgtcag catctgaggc agtttcctaa gggaatttct tttaaattca aaagttcaac   5753 

tgcaggaata aatagctgta caggactaga tcttcccatc cctcatcttt tccccttccc   5813 

cgagtaacga ctcaaaaagg cttctgaaat tctactcaga atcggagccg tttgcattcc   5873 

aacaaggatc ccttaagcca aatgctggtg tgtttgtgta gaatgtccct ggggtagggg   5933 

cggtagctgt ggggagggaa tgtggtgcag gggacacctg ccctctgccc ttgaaattgc   5993 

accataagat gctgcctatg tcactcacag tggtgctgat actatccgcc aaagacaaat   6053 

tgtgaacacg gaaaaatggt cgttccctac tgtacatcct caggacagac ttaactaaac   6113 

ttggagacag gagattgttc agaccatatt gtagtgggtg gtgatcattg ttttattttg   6173 

ggggagtctg gtctattgag cagattgaat gtttccttat tgtgcagggc ttaattgact   6233 

atgtctgaaa gtttttactg agagctctaa gaaaactatt gaggaaaatg aaatgttatt   6293 

ttgtagtaca aggattattt ttgtctattt aggatataca tagctgtagc tttgtaaaaa   6353 

aaaagatctt tataaacaat atatgaatgt gccgtcttat ttattgatta ctgtaaatta   6413 

agatataaat ggctatttgc ataatttata cctgtgggaa ttaactggag tatttgttat   6473 

ttgactgttt tctattaagg aatattaggc ttggtgctat gatgaatgat cttgtaaaat   6533 

catgtgtatt cttaagaaaa tttttgaata taaatttctt gaactgaaaa aaaaaaaaaa   6593  
           
             9  
             2994  
             DNA  
             Homo sapiens  
             
               CDS  
               (27)..(911)  
             
           
            9 

tgcgaggctc cgcttcttct acaagt atg gag aag gca aaa ggc aag gag tgg      53 
                             Met Glu Lys Ala Lys Gly Lys Glu Trp 
                               1               5 

acc tcc aca gag aag tcg agg gaa gag gat cag cag gct tct aat caa      101 
Thr Ser Thr Glu Lys Ser Arg Glu Glu Asp Gln Gln Ala Ser Asn Gln 
 10                  15                  20                  25 

cca aat tca att gct ttg cca gga aca tca gca aag aga acc aaa gaa      149 
Pro Asn Ser Ile Ala Leu Pro Gly Thr Ser Ala Lys Arg Thr Lys Glu 
                 30                  35                  40 

aaa atg tct gtc aaa ggc agt aaa gtg ctc tgc cct aag aaa aag gca      197 
Lys Met Ser Val Lys Gly Ser Lys Val Leu Cys Pro Lys Lys Lys Ala 
             45                  50                  55 

gag cac act gac aac ccc aga cct cag aag aag ata cca atc cct cca      245 
Glu His Thr Asp Asn Pro Arg Pro Gln Lys Lys Ile Pro Ile Pro Pro 
         60                  65                  70 

tta cct tct aaa ctg cca cct gtt aat ctg att cac cgg gac att ctg      293 
Leu Pro Ser Lys Leu Pro Pro Val Asn Leu Ile His Arg Asp Ile Leu 
     75                  80                  85 

cgg gcc tgg tgc caa caa ttg aag ctg agc tcc aaa ggc cag aaa ttg      341 
Arg Ala Trp Cys Gln Gln Leu Lys Leu Ser Ser Lys Gly Gln Lys Leu 
 90                  95                 100                 105 

gat gca tat aag cgc ctg tgt gcc ttt gcc tac cca aat caa aag gat      389 
Asp Ala Tyr Lys Arg Leu Cys Ala Phe Ala Tyr Pro Asn Gln Lys Asp 
                110                 115                 120 

ttt cct agc aca gca aaa gag gcc aaa atc cgg aaa tca ttg caa aaa      437 
Phe Pro Ser Thr Ala Lys Glu Ala Lys Ile Arg Lys Ser Leu Gln Lys 
            125                 130                 135 

aaa tta aag gtg gaa aag ggg gaa acg tcc ctg caa agt tct gag aca      485 
Lys Leu Lys Val Glu Lys Gly Glu Thr Ser Leu Gln Ser Ser Glu Thr 
        140                 145                 150 

cat cct cct gaa gtg gct ctt cct cct gtg ggg gag ccg cct gcc ctg      533 
His Pro Pro Glu Val Ala Leu Pro Pro Val Gly Glu Pro Pro Ala Leu 
    155                 160                 165 

gaa aat tcc act gct ctc ctt gag gga gtt aat aca gtt gtg gtg aca      581 
Glu Asn Ser Thr Ala Leu Leu Glu Gly Val Asn Thr Val Val Val Thr 
170                 175                 180                 185 

act tct gcc cca gag gct ttg ctg gcc tcc tgg gcg aga att tca gcc      629 
Thr Ser Ala Pro Glu Ala Leu Leu Ala Ser Trp Ala Arg Ile Ser Ala 
                190                 195                 200 

agg gcg agg aca cca gag gca gtg gaa tct cca caa gag gcc tct ggt      677 
Arg Ala Arg Thr Pro Glu Ala Val Glu Ser Pro Gln Glu Ala Ser Gly 
            205                 210                 215 

gtc agg tgg tgt gtg gtc cat ggg aaa agt ctc cct gca gac aca gat      725 
Val Arg Trp Cys Val Val His Gly Lys Ser Leu Pro Ala Asp Thr Asp 
        220                 225                 230 

ggt tgg gtt cac ctg cag ttt cat gct ggt caa gcc tgg gtt cca gaa      773 
Gly Trp Val His Leu Gln Phe His Ala Gly Gln Ala Trp Val Pro Glu 
    235                 240                 245 

aag caa gaa ggg aga gtg agt gca ctc ttc ttg ctt cct gcc tcc aat      821 
Lys Gln Glu Gly Arg Val Ser Ala Leu Phe Leu Leu Pro Ala Ser Asn 
250                 255                 260                 265 

ttt cca ccc ccg cac ctt gaa gac aat atg ttg tgc ccc aaa tgt gtt      869 
Phe Pro Pro Pro His Leu Glu Asp Asn Met Leu Cys Pro Lys Cys Val 
                270                 275                 280 

cac agg aac aag gtc tta ata aaa agc ctc caa tgg gaa tag aatatca      918 
His Arg Asn Lys Val Leu Ile Lys Ser Leu Gln Trp Glu  * 
            285                 290                 295 

ggaaaaaggc cacatctatg gtaattaatg gcagaaaagc tggagagttg gattctgcgg    978 

tgctgctgac aggtgaactc tggtcctctg cacctgttta tgggccatgc agactggtgg   1038 

ggtggcagat gttagcctaa gacccctagc agtgcctgtt gctttgtgag tggagataga   1098 

gactcttaca tttaaaaatg gaaaaacatt tcacaaatta ccataaattg tagttaatat   1158 

gtagaaaaac tcattcatac tacttttcta aaatagacat gacttcagca gcagcttttt   1218 

tttgttgtat tttgagacag tgtctcactg ttgcccaggc tggagtgcag tggtgcaatc   1278 

tcagttcagt gcaatctccg cctcctgggt tcaaatgatt ctcctgcctc agcctcttga   1338 

gtagctaggt acaggcacct gccaccacac ccagctaatt ttttgtattt ttagtagaga   1398 

tggggtttca ccatgttggc caggttggtc tcaaactcct ggactcaagt gatcaccctc   1458 

ctcagcctcc caaaatgctg ggactatggg catgagcccc tgcgcctgac cttcaacagc   1518 

tcttttaagt gagttcttca gctaagcatt gtgatggact tgagtaaaat ggtagttggc   1578 

tcttgtgctc aattttctct tcctctgaac actgactact ttaggagctg cttcattcca   1638 

attgcaattt cataaaacgt aaagtatttt aaggcaaaga aaggctgtta attccctccc   1698 

tcccccaaac acatgatttt taatattcta aacaatattt ttcaaagttc tcttaataac   1758 

ctgagatttc tatggtttga ctccaggatc aaaacacaag ggactttgta ttatttcact   1818 

tataattgtt ttgtatattt ctggagttta aaatgtttaa ggttgcttcc cgctcataaa   1878 

tacataatat attgaattta aaatgtgttt attaaccgat tctccataaa taaaaataag   1938 

atgtgtatgt aaaataattc atctgttgta tttagagaac catattcatt gcatgcaaat   1998 

cttattgtta gtgttcttaa ctcaagtagg agtaaaccaa aaagtgtgat ttttcttttg   2058 

tatgactcgt ttgttcttta ttagttggtg gtatgggttg gatcatttgt ttttaaaact   2118 

acttaggtat gattcacata caaaaagctg cacatattta atgtatccta ttgtgtaatt   2178 

aatttttaat tttttttgtg tacttcctaa acttatagtc ctgcgagtct gggaacagat   2238 

ctgtttttca cttatcctga tttaatgaca gtttccaaca ttgttttgtt attacaagta   2298 

ggggatcttt ttttttgccc gtttaatgaa gatactaaaa ataatgcact ggaaggagtg   2358 

gaagagttgg aaaatttgta accatcataa tacaggtgta ataggtttgg gaaagaatcc   2418 

tcaaaaatgt taaagcaagg gaggaaagtt tgttgagaag caagatgttc ttctctcctg   2478 

cccgcccccg ccgttggttg ttggtggtca gaattattgt gtaataaata atagacattt   2538 

tttcttatac tatgtgtatt gttccttttg tttccttttt aaacttctcc cctgctttat   2598 

ttggatgggt caagtttctg ttctgtttcc ttcctttcta ttaatttgga aatgtccttg   2658 

gctttacgat tctgcttgta gatacttccc ctgtttctaa cacatttcaa taaacttaaa   2718 

tttctctata tacaaaataa attaataatt ggagtctacc agtaagacag tttatttact   2778 

catcttcctg ccccagcaag ataaaaccta aggttacata cttgccaaat caccctaatt   2838 

ttcacaggcc tcccccaaag ttcctatcaa tcacattcag tcccccactc cctgtctccc   2898 

tgctatgctc ccagaatgct aagaggaaga cagttggagc tataaactcc ctgtgtctca   2958 

gatgagttcc ctggcagagg catgacatcc tcgtgc                             2994 

 
           
             10  
             813  
             DNA  
             Homo sapiens  
             
               CDS  
               (303)..(449)  
             
           
            10 

gcagggagga gggagagctg ctgatggcct gagaggtcca accgggccct ggctgcagag     60 

ctcaggtggt ggggcttgca gggcagggct gtggccaggg caaagagcgg ccatcacagc    120 

ttacgcatga ctcgaaggtg tttatgagga cctactgtgt gccatgtgcc tactgaggct    180 

tacacattca aggcgttatc ggaccctgac cagtgctccc aggtgccctg taacacagtc    240 

tgctggcctc tgggagggca gtctcctaag ttctttatgg ggtctgagca gggattgcag    300 

gg   atg atg cct cca gga gac caa ggt gga cca gga gct cct gcc ttc     347 
     Met Met Pro Pro Gly Asp Gln Gly Gly Pro Gly Ala Pro Ala Phe 
       1               5                  10                  15 

tgt gag aac cac ctt ggg cag tct ttc cga ggt ggt ggc aag agc ctg      395 
Cys Glu Asn His Leu Gly Gln Ser Phe Arg Gly Gly Gly Lys Ser Leu 
                 20                  25                  30 

ggg ccc agc ctc cca ggg tcc cct ctc caa ggc cat ggc ttt act aac      443 
Gly Pro Ser Leu Pro Gly Ser Pro Leu Gln Gly His Gly Phe Thr Asn 
             35                  40                  45 

atg taa agtgaccaag gcctttgtag tgtctgagtg caggcaccac aggcctgtgt       499 
Met  * 

gctctgcctg tctggctttg gtggtggcca gccctgcctc tgtgaactca tctctctttg    559 

tttgggagac actgccgtgt cctggttctc atcctctgcc cgtggcccag gcccttacgt    619 

ggctctacca ggagtctgtc cttggcactt tcccatctca cttctaccaa gtctgttctt    679 

tccagaagcc agactcgtgg gtgagccatg tcacctcgcc gagcctcagt ttttccttct    739 

gtaaaatggg gtacagcctt catttagtgg ggtgagtaag cctcatgtct cttctgctgg    799 

ggcactgatg tgct                                                      813 

 
           
             11  
             1113  
             DNA  
             Homo sapiens  
             
               CDS  
               (35)..(508)  
             
           
            11 

ccgggccgtc gtgggctccg gcttgcgtgc ggag    atg agc ggg tcc ctc ggc      52 
                                         Met Ser Gly Ser Leu Gly 
                                           1               5 

cga gct gcg gcg gct ctg ctc cgc tgg ggg cgc ggc gcg ggc ggc ggt      100 
Arg Ala Ala Ala Ala Leu Leu Arg Trp Gly Arg Gly Ala Gly Gly Gly 
             10                  15                  20 

ggc ctt tgg ggt ccg ggc gtg cgg gcg gcg ggc tcg ggc gcg ggc ggc      148 
Gly Leu Trp Gly Pro Gly Val Arg Ala Ala Gly Ser Gly Ala Gly Gly 
         25                  30                  35 

ggc ggc tcg gcg gag cag ttg gac gcg ctg gtg aag aag gac aag gtg      196 
Gly Gly Ser Ala Glu Gln Leu Asp Ala Leu Val Lys Lys Asp Lys Val 
     40                  45                  50 

gtg gtc ttc ctc aag ggg acg ccg gag cag ccc cag tgc ggc ttc agc      244 
Val Val Phe Leu Lys Gly Thr Pro Glu Gln Pro Gln Cys Gly Phe Ser 
 55                  60                  65                  70 

aac gcc gtg gtg cag atc ctg cgg ctg cac ggc gtc cgc gat tac gcg      292 
Asn Ala Val Val Gln Ile Leu Arg Leu His Gly Val Arg Asp Tyr Ala 
                 75                  80                  85 

gcc tac aac gtg ctg gac gac ccg gag ctc cga caa ggc att aaa gac      340 
Ala Tyr Asn Val Leu Asp Asp Pro Glu Leu Arg Gln Gly Ile Lys Asp 
             90                  95                 100 

tat tcc aac tgg ccc acc atc ccg caa gtg tac ctc aat ggc gag ttt      388 
Tyr Ser Asn Trp Pro Thr Ile Pro Gln Val Tyr Leu Asn Gly Glu Phe 
        105                 110                 115 

gta ggg ggc tgt gac att ctt ctg cag atg cac cag aat ggg gac ttg      436 
Val Gly Gly Cys Asp Ile Leu Leu Gln Met His Gln Asn Gly Asp Leu 
    120                 125                 130 

gtg gaa gaa ctg aaa aag ctg ggg atc cac tcc gcc ctt tta gat gaa      484 
Val Glu Glu Leu Lys Lys Leu Gly Ile His Ser Ala Leu Leu Asp Glu 
135                 140                 145                 150 

aag aaa gac caa gac tcc aag tga gggcggccaa gtcctcgctg agcagagagg     538 
Lys Lys Asp Gln Asp Ser Lys  * 
                155 

gagccgttca tgtcagagac tcactgccag aaaagcctta cccattttgg ttttcactat    598 

tgagaccgca actgcttgca ctgatcattt tggttcgtga gcagttggtg attttagttg    658 

gtctggtgtt cgggctaaga atattttatt gtggacttaa ttacaaccac tgcactgtaa    718 

tgattcaatg ctgtattatg atattgctgt aaacaaaatt cattcttata ttgtcactta    778 

ttctttgcct gattcagaag ttaaatagga gctttggaat cattattcat gacccctctg    838 

caaatgtgtc agtctccaaa gagagtatct ccccccaaat tttgtgtagc ttcttttgtt    898 

atggaaaatg gtggacaaaa aaagaaactg tgataactgg ggcgttgttt tttaaaataa    958 

actccagcac agggatgctg tgcatgcctg agttgattcc gaagtgcata tgtctgtaag   1018 

gatttggagt gcctgcagtg ttttatgtgt gggaagtaag ggtgagtctc atattcttct   1078 

attaaatttg ccacaagaat tgcaaaaaaa aaaaa                              1113 

 
           
             12  
             3528  
             DNA  
             Homo sapiens  
             
               CDS  
               (213)..(3206)  
             
           
            12 

gttgactgtg acacgggtgt tacatatctt cctgtgcccc ttctccctgt agggtgaagc     60 

tctgggcctc ggcttttggt ggggagataa aatccattgc tgctaagtac tccggttccc    120 

agcttctgca aaagaaatac aaagagtatg agaaagacgt tgccatagaa gaaatcgatg    180 

gcctccaact ggtaaagaag ctggcaaaga ac  atg gaa gag atg ttt cac aag     233 
                                     Met Glu Glu Met Phe His Lys 
                                       1               5 

aag tct gag gcc gtc agg cgt ctg gtg gag gct gca gaa gaa gca cac      281 
Lys Ser Glu Ala Val Arg Arg Leu Val Glu Ala Ala Glu Glu Ala His 
         10                  15                  20 

ctg aaa cat gaa ttt gat gca gac tta cag tat gaa tac ttc aat gct      329 
Leu Lys His Glu Phe Asp Ala Asp Leu Gln Tyr Glu Tyr Phe Asn Ala 
     25                  30                  35 

gtg ctg ata aat gaa agg gac aaa gac ggg aat ttt ttg gag ctg gga      377 
Val Leu Ile Asn Glu Arg Asp Lys Asp Gly Asn Phe Leu Glu Leu Gly 
 40                  45                  50                  55 

aag gaa ttc atc tta gcc cca aat gac cat ttt aat aat ttg cct gtg      425 
Lys Glu Phe Ile Leu Ala Pro Asn Asp His Phe Asn Asn Leu Pro Val 
                 60                  65                  70 

aac atc agt cta agt gac gtc caa gta cca acg aac atg tac aac aaa      473 
Asn Ile Ser Leu Ser Asp Val Gln Val Pro Thr Asn Met Tyr Asn Lys 
             75                  80                  85 

gac cct gca att gtc aat ggg gtt tat tgg tct gaa tct cta aac aaa      521 
Asp Pro Ala Ile Val Asn Gly Val Tyr Trp Ser Glu Ser Leu Asn Lys 
         90                  95                 100 

gtt ttt gta gat aac ttt gac cgt gac cca tct ctc ata tgg cag tac      569 
Val Phe Val Asp Asn Phe Asp Arg Asp Pro Ser Leu Ile Trp Gln Tyr 
    105                 110                 115 

ttt gga agt gca aag ggc ttt ttt agg cag tat ccg ggg att aaa tgg      617 
Phe Gly Ser Ala Lys Gly Phe Phe Arg Gln Tyr Pro Gly Ile Lys Trp 
120                 125                 130                 135 

gaa cca gat gag aat gga gtc att gcc ttc gac tgc agg aac cga aaa      665 
Glu Pro Asp Glu Asn Gly Val Ile Ala Phe Asp Cys Arg Asn Arg Lys 
                140                 145                 150 

tgg tac atc cag gca gca act tct ccg aaa gac gtg gtc att tta gtt      713 
Trp Tyr Ile Gln Ala Ala Thr Ser Pro Lys Asp Val Val Ile Leu Val 
            155                 160                 165 

gac gtc agt ggc agc atg aaa gga ctc cgt ctg act atc gcg aag caa      761 
Asp Val Ser Gly Ser Met Lys Gly Leu Arg Leu Thr Ile Ala Lys Gln 
        170                 175                 180 

aca gtc tca tcc att ttg gat aca ctt ggg gat gat gac ttc ttc aac      809 
Thr Val Ser Ser Ile Leu Asp Thr Leu Gly Asp Asp Asp Phe Phe Asn 
    185                 190                 195 

ata att gct tat aat gag gag ctt cac tat gtg gaa cct tgc ctg aat      857 
Ile Ile Ala Tyr Asn Glu Glu Leu His Tyr Val Glu Pro Cys Leu Asn 
200                 205                 210                 215 

gga act ttg gtg caa gcc gac agg aca aac aaa gag cac ttc agg gag      905 
Gly Thr Leu Val Gln Ala Asp Arg Thr Asn Lys Glu His Phe Arg Glu 
                220                 225                 230 

cat ctg gac aaa ctt ttc gcc aaa gga att gga atg ttg gat ata gct      953 
His Leu Asp Lys Leu Phe Ala Lys Gly Ile Gly Met Leu Asp Ile Ala 
            235                 240                 245 

ctg aat gag gcc ttc aac att ctg agt gat ttc aac cac acg gga caa     1001 
Leu Asn Glu Ala Phe Asn Ile Leu Ser Asp Phe Asn His Thr Gly Gln 
        250                 255                 260 

gga agt atc tgc agt cag gcc atc atg ctc ata act gat ggg gcg gtg     1049 
Gly Ser Ile Cys Ser Gln Ala Ile Met Leu Ile Thr Asp Gly Ala Val 
    265                 270                 275 

gac acc tat gat aca atc ttt gca aaa tac aat tgg cca gat cga aag     1097 
Asp Thr Tyr Asp Thr Ile Phe Ala Lys Tyr Asn Trp Pro Asp Arg Lys 
280                 285                 290                 295 

gtt cgc atc ttc aca tac ctc att gga cga gag gct gcg ttt gca gac     1145 
Val Arg Ile Phe Thr Tyr Leu Ile Gly Arg Glu Ala Ala Phe Ala Asp 
                300                 305                 310 

aat cta aag tgg atg gcc tgt gcc aac aaa gga ttt ttt acc caa atc     1193 
Asn Leu Lys Trp Met Ala Cys Ala Asn Lys Gly Phe Phe Thr Gln Ile 
            315                 320                 325 

tcc acc ttg gct gat gtg cag gag aat gtc atg gaa tac ctt cac gtg     1241 
Ser Thr Leu Ala Asp Val Gln Glu Asn Val Met Glu Tyr Leu His Val 
        330                 335                 340 

ctt agc cgg ccc aaa gtc atc gac cag gag cat gat gtg gtg tgg acc     1289 
Leu Ser Arg Pro Lys Val Ile Asp Gln Glu His Asp Val Val Trp Thr 
    345                 350                 355 

gaa gct tac att gac agc act ctc cct cag gca caa aag ctg act gat     1337 
Glu Ala Tyr Ile Asp Ser Thr Leu Pro Gln Ala Gln Lys Leu Thr Asp 
360                 365                 370                 375 

gat cag ggc ccc gtc ctg atg acc act gta gcc atg cct gtg ttt agt     1385 
Asp Gln Gly Pro Val Leu Met Thr Thr Val Ala Met Pro Val Phe Ser 
                380                 385                 390 

aag cag aac gaa acc aga tcg aag ggc att ctt ctg gga gtg gtt ggc     1433 
Lys Gln Asn Glu Thr Arg Ser Lys Gly Ile Leu Leu Gly Val Val Gly 
            395                 400                 405 

aca gat gtc cca gtg aaa gaa ctt ctg aag acc atc ccc aaa tac aag     1481 
Thr Asp Val Pro Val Lys Glu Leu Leu Lys Thr Ile Pro Lys Tyr Lys 
        410                 415                 420 

tta ggg att cac ggt tat gcc ttt gca atc aca aat aat gga tat atc     1529 
Leu Gly Ile His Gly Tyr Ala Phe Ala Ile Thr Asn Asn Gly Tyr Ile 
    425                 430                 435 

ctg acg cat ccg gaa ctc agg ctg ctg tac gaa gaa gga aaa aag cga     1577 
Leu Thr His Pro Glu Leu Arg Leu Leu Tyr Glu Glu Gly Lys Lys Arg 
440                 445                 450                 455 

agg aaa cct aac tat agt agc gtt gac ctc tct gag gtg gag tgg gaa     1625 
Arg Lys Pro Asn Tyr Ser Ser Val Asp Leu Ser Glu Val Glu Trp Glu 
                460                 465                 470 

gac cga gat gac gtg ttg aga aat gct atg gtg aat cga aag acg ggg     1673 
Asp Arg Asp Asp Val Leu Arg Asn Ala Met Val Asn Arg Lys Thr Gly 
            475                 480                 485 

aag ttt tcc atg gag gtg aag aag aca gtg gac aaa ggg aaa cgg gtt     1721 
Lys Phe Ser Met Glu Val Lys Lys Thr Val Asp Lys Gly Lys Arg Val 
        490                 495                 500 

ttg gtg atg aca aat gac tac tat tat aca gac atc aag ggt act cct     1769 
Leu Val Met Thr Asn Asp Tyr Tyr Tyr Thr Asp Ile Lys Gly Thr Pro 
    505                 510                 515 

ttc agt tta ggt gtg gcg ctt tcc aga ggt cat ggg aaa tat ttc ttc     1817 
Phe Ser Leu Gly Val Ala Leu Ser Arg Gly His Gly Lys Tyr Phe Phe 
520                 525                 530                 535 

cga ggg aat gta acc atc gaa gaa ggc ctg cat gac tta gaa cat ccc     1865 
Arg Gly Asn Val Thr Ile Glu Glu Gly Leu His Asp Leu Glu His Pro 
                540                 545                 550 

gat gtg tcc ttg gca gat gaa tgg tcc tac tgc aac act gac cta cac     1913 
Asp Val Ser Leu Ala Asp Glu Trp Ser Tyr Cys Asn Thr Asp Leu His 
            555                 560                 565 

cct gag cac cgc cat ctg tct cag tta gaa gcg att aag ctc tac cta     1961 
Pro Glu His Arg His Leu Ser Gln Leu Glu Ala Ile Lys Leu Tyr Leu 
        570                 575                 580 

aaa ggc aaa gaa cct ctg ctc cag tgt gat aaa gaa ttg atc caa gaa     2009 
Lys Gly Lys Glu Pro Leu Leu Gln Cys Asp Lys Glu Leu Ile Gln Glu 
    585                 590                 595 

gtc ctt ttt gac gcg gtg gtg agt gcc ccc att gaa gcg tat tgg acc     2057 
Val Leu Phe Asp Ala Val Val Ser Ala Pro Ile Glu Ala Tyr Trp Thr 
600                 605                 610                 615 

agc ctg gcc ctc aac aaa tct gaa aat tct gac aag ggc gtg gag gtt     2105 
Ser Leu Ala Leu Asn Lys Ser Glu Asn Ser Asp Lys Gly Val Glu Val 
                620                 625                 630 

gcc ttc ctc ggc act cgc acg ggc ctc tcc aga atc aac ctg ttt gtc     2153 
Ala Phe Leu Gly Thr Arg Thr Gly Leu Ser Arg Ile Asn Leu Phe Val 
            635                 640                 645 

ggg gct gag cag ctc acc aat cag gac ttc ctg aaa gct ggt gac aag     2201 
Gly Ala Glu Gln Leu Thr Asn Gln Asp Phe Leu Lys Ala Gly Asp Lys 
        650                 655                 660 

gag aac att ttt aac gca gac cat ttc cct ctc tgg tac cga aga gcc     2249 
Glu Asn Ile Phe Asn Ala Asp His Phe Pro Leu Trp Tyr Arg Arg Ala 
    665                 670                 675 

gct gag cag att cca ggg agc ttc gtc tac tcg atc cca ttc agc act     2297 
Ala Glu Gln Ile Pro Gly Ser Phe Val Tyr Ser Ile Pro Phe Ser Thr 
680                 685                 690                 695 

gga cca gtc aat aaa agc aat gtg gtg aca gca agt aca tcc atc cag     2345 
Gly Pro Val Asn Lys Ser Asn Val Val Thr Ala Ser Thr Ser Ile Gln 
                700                 705                 710 

ctc ctg gat gaa cgg aaa tct cct gtg gtg gca gct gta ggc att cag     2393 
Leu Leu Asp Glu Arg Lys Ser Pro Val Val Ala Ala Val Gly Ile Gln 
            715                 720                 725 

atg aaa ctt gaa ttt ttc caa agg aag ttc tgg act gcc agc aga cag     2441 
Met Lys Leu Glu Phe Phe Gln Arg Lys Phe Trp Thr Ala Ser Arg Gln 
        730                 735                 740 

tgt gct tcc ctg gat ggc aaa tgc tcc atc agc tgt gat gat gag act     2489 
Cys Ala Ser Leu Asp Gly Lys Cys Ser Ile Ser Cys Asp Asp Glu Thr 
    745                 750                 755 

gtg aat tgt tac ctc ata gac aat aat gga ttt att ttg gtg tct gaa     2537 
Val Asn Cys Tyr Leu Ile Asp Asn Asn Gly Phe Ile Leu Val Ser Glu 
760                 765                 770                 775 

gac tac aca cag act gga gac ttt ttt ggt gag atc gag gga gct gtg     2585 
Asp Tyr Thr Gln Thr Gly Asp Phe Phe Gly Glu Ile Glu Gly Ala Val 
                780                 785                 790 

atg aac aaa ttg cta aca atg ggc tcc ttt aaa aga att acc ctt tat     2633 
Met Asn Lys Leu Leu Thr Met Gly Ser Phe Lys Arg Ile Thr Leu Tyr 
            795                 800                 805 

gac tac caa gcc atg tgt aga gcc aac aag gaa agc agc gat ggc gcc     2681 
Asp Tyr Gln Ala Met Cys Arg Ala Asn Lys Glu Ser Ser Asp Gly Ala 
        810                 815                 820 

cat ggc ctc ctg gat cct tat aat gcc ttc ctc tct gca gta aaa tgg     2729 
His Gly Leu Leu Asp Pro Tyr Asn Ala Phe Leu Ser Ala Val Lys Trp 
    825                 830                 835 

atc atg aca gaa ctt gtc ttg ttc ctg gtg gaa ttt aac ctc tgc agt     2777 
Ile Met Thr Glu Leu Val Leu Phe Leu Val Glu Phe Asn Leu Cys Ser 
840                 845                 850                 855 

tgg tgg cac tcc gat atg aca gct aaa gcc cag aaa ttg aaa cag acc     2825 
Trp Trp His Ser Asp Met Thr Ala Lys Ala Gln Lys Leu Lys Gln Thr 
                860                 865                 870 

ctg gag cct tgt gat act gaa tat cca gca ttc gtc tct gag cgc acc     2873 
Leu Glu Pro Cys Asp Thr Glu Tyr Pro Ala Phe Val Ser Glu Arg Thr 
            875                 880                 885 

atc aag gag act aca ggg aat att gct tgt gaa gac tgc tcc aag tcc     2921 
Ile Lys Glu Thr Thr Gly Asn Ile Ala Cys Glu Asp Cys Ser Lys Ser 
        890                 895                 900 

ttt gtc atc cag caa atc cca agc agc aac ctg ttc atg gtg gtg gtg     2969 
Phe Val Ile Gln Gln Ile Pro Ser Ser Asn Leu Phe Met Val Val Val 
    905                 910                 915 

gac agc agc tgc ctc tgt gaa tct gtg gcc ccc atc acc atg gca ccc     3017 
Asp Ser Ser Cys Leu Cys Glu Ser Val Ala Pro Ile Thr Met Ala Pro 
920                 925                 930                 935 

att gaa atc agg tat aat gaa tcc ctt aag tgt gaa cgt cta aag gcc     3065 
Ile Glu Ile Arg Tyr Asn Glu Ser Leu Lys Cys Glu Arg Leu Lys Ala 
                940                 945                 950 

cag aag atc aga agg cgc cca gaa tct tgt cat ggc ttc cat cct gag     3113 
Gln Lys Ile Arg Arg Arg Pro Glu Ser Cys His Gly Phe His Pro Glu 
            955                 960                 965 

gag aat gca agg gag tgt ggg ggt gcg ccg agt ctc caa gcc cag aca     3161 
Glu Asn Ala Arg Glu Cys Gly Gly Ala Pro Ser Leu Gln Ala Gln Thr 
        970                 975                 980 

gtc ctc ctt ctg ctc cct ctg ctt ttg atg ctc ttc tca agg tga cac     3209 
Val Leu Leu Leu Leu Pro Leu Leu Leu Met Leu Phe Ser Arg  * 
    985                 990                 995 

tgactgagat gttctcttgg catgctaaat catggataaa ctgtgaacca aaatatggtg   3269 

caacatacga gacatgaata tagtccaacc atcagcatct catcatgatt ttaaactgtg   3329 

cgtgatataa actcttaaag atatgttgac aaaaagttat ctttttactt tgccagtcat   3389 

gcaaatgtga gtttgccaca tgataatcac ccttcatcag aaatgggacc gcaagtggta   3449 

ggcagtgtcc cttctgcttg aaacctattg aaaccaattt aaaactgtgt actttttaaa   3509 

taaagtatat taaaatcat                                                3528 

 
           
             13  
             1957  
             DNA  
             Homo sapiens  
             
               CDS  
               (124)..(1473)  
             
           
            13 

gagatgggtt ggctgcagta gtgagaggct gggggtgcgg ctctttccct gcagtcctgc     60 

cgaggaagcg tgcgtccctg gcgcttcctt cttctcttcc ggcggagagc ttgggatgtg    120 

gta  atg cca gcc aca ctc ctc aga gcc gtg gcc aga tct cat cat ata     168 
     Met Pro Ala Thr Leu Leu Arg Ala Val Ala Arg Ser His His Ile 
       1               5                  10                  15 

tta tca aaa gca cat cag tgc cga aga atc ggt cat cta atg tta aaa      216 
Leu Ser Lys Ala His Gln Cys Arg Arg Ile Gly His Leu Met Leu Lys 
                 20                  25                  30 

cca ctt aag gaa ttt gaa aat aca aca tgc agc aca ctg aca ata cgt      264 
Pro Leu Lys Glu Phe Glu Asn Thr Thr Cys Ser Thr Leu Thr Ile Arg 
             35                  40                  45 

caa agc ttg gat ttg ttc ctt cct gat aaa aca gct agt ggt ttg aat      312 
Gln Ser Leu Asp Leu Phe Leu Pro Asp Lys Thr Ala Ser Gly Leu Asn 
         50                  55                  60 

aag tct cag atc ctg gaa atg aac caa aaa aag tca gat acc agc atg      360 
Lys Ser Gln Ile Leu Glu Met Asn Gln Lys Lys Ser Asp Thr Ser Met 
     65                  70                  75 

ctg tct cca tta aat gct gct cgt tgc caa gat gaa aag gca cac ctt      408 
Leu Ser Pro Leu Asn Ala Ala Arg Cys Gln Asp Glu Lys Ala His Leu 
 80                  85                  90                  95 

cca acc atg aaa tcc ttt ggt act cac agg aga gtg acc cac aaa cca      456 
Pro Thr Met Lys Ser Phe Gly Thr His Arg Arg Val Thr His Lys Pro 
                100                 105                 110 

aat ctg ttg ggt tct aaa tgg ttt ata aaa ata tta aag agg cat ttc      504 
Asn Leu Leu Gly Ser Lys Trp Phe Ile Lys Ile Leu Lys Arg His Phe 
            115                 120                 125 

tca tct gta tca acg gaa aca ttt gtt cca aaa caa gac ttc cca cag      552 
Ser Ser Val Ser Thr Glu Thr Phe Val Pro Lys Gln Asp Phe Pro Gln 
        130                 135                 140 

gtg aag aga cca cta aaa gca tcc agg acc aga cag cca tcc agg acc      600 
Val Lys Arg Pro Leu Lys Ala Ser Arg Thr Arg Gln Pro Ser Arg Thr 
    145                 150                 155 

aac ctt cca gtt ctg tct gtg aac gag gac cca atg cac tgc aca gca      648 
Asn Leu Pro Val Leu Ser Val Asn Glu Asp Pro Met His Cys Thr Ala 
160                 165                 170                 175 

ttt gca acg gca gat gag tat cat ctg gga aat ctg tct caa gat ctg      696 
Phe Ala Thr Ala Asp Glu Tyr His Leu Gly Asn Leu Ser Gln Asp Leu 
                180                 185                 190 

gcc tcc cac gga tat gtt gaa gta aca agc ttg cct aga gat gca gca      744 
Ala Ser His Gly Tyr Val Glu Val Thr Ser Leu Pro Arg Asp Ala Ala 
            195                 200                 205 

aat att ttg gtg atg ggt gtg gaa aat tct gca aaa gaa ggt gat cct      792 
Asn Ile Leu Val Met Gly Val Glu Asn Ser Ala Lys Glu Gly Asp Pro 
        210                 215                 220 

gga aca ata ttc ttc ttc agg gaa gga gct gct gtg ttt tgg aat gtg      840 
Gly Thr Ile Phe Phe Phe Arg Glu Gly Ala Ala Val Phe Trp Asn Val 
    225                 230                 235 

aaa gac aaa act atg aag cat gtg atg aaa gtt cta gaa aaa cat gaa      888 
Lys Asp Lys Thr Met Lys His Val Met Lys Val Leu Glu Lys His Glu 
240                 245                 250                 255 

att cag ccc tat gaa atc gca ctg gta cac tgg gaa aat gaa gaa ctt      936 
Ile Gln Pro Tyr Glu Ile Ala Leu Val His Trp Glu Asn Glu Glu Leu 
                260                 265                 270 

aac tac ata aaa ata gag gga cag tca aaa ctt cac agg ggg gaa atc      984 
Asn Tyr Ile Lys Ile Glu Gly Gln Ser Lys Leu His Arg Gly Glu Ile 
            275                 280                 285 

aag tta aat tca gag ctg gat tta gat gat gcc att cta gag aag ttt     1032 
Lys Leu Asn Ser Glu Leu Asp Leu Asp Asp Ala Ile Leu Glu Lys Phe 
        290                 295                 300 

gct ttc tcc aat gct cta tgc ctt tct gta aaa ctg gca att tgg gaa     1080 
Ala Phe Ser Asn Ala Leu Cys Leu Ser Val Lys Leu Ala Ile Trp Glu 
    305                 310                 315 

gca tca ctg gat aaa ttt att gaa tct att cag tca att cct gag gct     1128 
Ala Ser Leu Asp Lys Phe Ile Glu Ser Ile Gln Ser Ile Pro Glu Ala 
320                 325                 330                 335 

tta aaa gct ggg aag aaa gtg aaa cta tct cat gaa gaa gtt atg cag     1176 
Leu Lys Ala Gly Lys Lys Val Lys Leu Ser His Glu Glu Val Met Gln 
                340                 345                 350 

aaa atc ggt gaa ctc ttt gct cta agg cac cgt ata aac ttg agt tca     1224 
Lys Ile Gly Glu Leu Phe Ala Leu Arg His Arg Ile Asn Leu Ser Ser 
            355                 360                 365 

gac ttc ctg att act cct gat ttc tac tgg gac aga gaa aac ctg gaa     1272 
Asp Phe Leu Ile Thr Pro Asp Phe Tyr Trp Asp Arg Glu Asn Leu Glu 
        370                 375                 380 

gga ctt tac gat aaa acg tgt caa ttc ctt agc att ggc cga aga gtt     1320 
Gly Leu Tyr Asp Lys Thr Cys Gln Phe Leu Ser Ile Gly Arg Arg Val 
    385                 390                 395 

aag gtc atg aat gaa aaa ctt cag cac tgc atg gaa cta aca gat cta     1368 
Lys Val Met Asn Glu Lys Leu Gln His Cys Met Glu Leu Thr Asp Leu 
400                 405                 410                 415 

atg cgg aat cac ctg aat gag aag agg gca ctc cgc ttg gag tgg atg     1416 
Met Arg Asn His Leu Asn Glu Lys Arg Ala Leu Arg Leu Glu Trp Met 
                420                 425                 430 

att gtc atc ctc att acc ata gag gta atg ttt gag ctg gga cga gta     1464 
Ile Val Ile Leu Ile Thr Ile Glu Val Met Phe Glu Leu Gly Arg Val 
            435                 440                 445 

ttt ttc tga tcaagtg ataaccaaag tgtcactgca agagatattc aagttctaca     1520 
Phe Phe  * 
        450 

atcaaaaatt aaatgttcgg cccggcgcgg tgcctcatgc ctgtaatccc agcactttcg   1580 

gaggccaaga agggtggctt gagatgagat caggagctca agacaagcct ggccaacatg   1640 

gtgaaacccc atctctacta aaaataccaa aattagccag gtgtgttggc acacgcccgt   1700 

catctcagct actcaggagg ctgaggcagg agaatctctt gaacttggga ggcggaggtt   1760 

gcagtgagct aagatcacac cactgcactc cagccagggc aacagtgaga ctcagtctca   1820 

aaaataaaca ataaaataaa taaataaatg ttcactactg ggtgatcatt taataggtgt   1880 

ttttttaatc aagaaattat ctttttcagc ccagtatatc gtgtgaataa aattatgaag   1940 

aatctaaaaa aaaaaaa                                                  1957 

 
           
             14  
             3094  
             DNA  
             Homo sapiens  
             
               CDS  
               (95)..(2611)  
             
           
            14 

gcacgagctg ggccggcagc ggttgtgagg agttagctcg cggcattgca ggctctgaga     60 

ggaggggacc cggttcccgg gtgagtgtcc aggc    atg cca gcg gaa cgg ccc     112 
                                         Met Pro Ala Glu Arg Pro 
                                           1               5 

gcg ggc agc ggc ggc tcg gag gct cca gca atg gtt gaa caa ctg gac      160 
Ala Gly Ser Gly Gly Ser Glu Ala Pro Ala Met Val Glu Gln Leu Asp 
             10                  15                  20 

act gct gtg att acc ccg gcc atg cta gaa gag gaa gaa cag ctt gaa      208 
Thr Ala Val Ile Thr Pro Ala Met Leu Glu Glu Glu Glu Gln Leu Glu 
         25                  30                  35 

gct gct gga cta gag aga gag cgg aag atg ctg gaa aag gct cgc atg      256 
Ala Ala Gly Leu Glu Arg Glu Arg Lys Met Leu Glu Lys Ala Arg Met 
     40                  45                  50 

tct tgg gat aga gag tcg aca gaa att cgg tac cgt aga ctt caa cat      304 
Ser Trp Asp Arg Glu Ser Thr Glu Ile Arg Tyr Arg Arg Leu Gln His 
 55                  60                  65                  70 

ttg ctt gaa aaa agc aat atc tac tcc aaa ttt tta ttg acg aaa atg      352 
Leu Leu Glu Lys Ser Asn Ile Tyr Ser Lys Phe Leu Leu Thr Lys Met 
                 75                  80                  85 

gaa cag caa caa tta gag gaa cag aag aag aaa gaa aaa ttg gag aga      400 
Glu Gln Gln Gln Leu Glu Glu Gln Lys Lys Lys Glu Lys Leu Glu Arg 
             90                  95                 100 

aaa aag gag tct tta aaa gtt aaa aag ggt aaa aat tca att gat gca      448 
Lys Lys Glu Ser Leu Lys Val Lys Lys Gly Lys Asn Ser Ile Asp Ala 
        105                 110                 115 

agt gaa gag aag cca gtt atg agg aaa aaa aga gga aga gaa gat gaa      496 
Ser Glu Glu Lys Pro Val Met Arg Lys Lys Arg Gly Arg Glu Asp Glu 
    120                 125                 130 

tca tac aat att tca gag gtc atg tca aaa gag gaa att ttg tct gtg      544 
Ser Tyr Asn Ile Ser Glu Val Met Ser Lys Glu Glu Ile Leu Ser Val 
135                 140                 145                 150 

gct aaa aaa aat aaa aag gag aat gag gat gaa aac tcc tcc tct act      592 
Ala Lys Lys Asn Lys Lys Glu Asn Glu Asp Glu Asn Ser Ser Ser Thr 
                155                 160                 165 

aat ctc tgt gtg gaa gat ctt cag aaa aat aaa gat tcg aat agt ata      640 
Asn Leu Cys Val Glu Asp Leu Gln Lys Asn Lys Asp Ser Asn Ser Ile 
            170                 175                 180 

att aaa gat aga ttg tct gaa acg gtt agg cag aat act aaa ttc ttt      688 
Ile Lys Asp Arg Leu Ser Glu Thr Val Arg Gln Asn Thr Lys Phe Phe 
        185                 190                 195 

ttt gac cca gtc cgg aag tgt aat ggt cag cca gta cct ttt caa caa      736 
Phe Asp Pro Val Arg Lys Cys Asn Gly Gln Pro Val Pro Phe Gln Gln 
    200                 205                 210 

cca aag cac ttc act gga gga gtg atg cga tgg tac caa gta gaa ggc      784 
Pro Lys His Phe Thr Gly Gly Val Met Arg Trp Tyr Gln Val Glu Gly 
215                 220                 225                 230 

atg gaa tgg ctt agg atg ctt tgg gaa aat gga att aat ggc att tta      832 
Met Glu Trp Leu Arg Met Leu Trp Glu Asn Gly Ile Asn Gly Ile Leu 
                235                 240                 245 

gca gat gaa atg gga ttg ggt aag aca gtt cag tgc att gct act att      880 
Ala Asp Glu Met Gly Leu Gly Lys Thr Val Gln Cys Ile Ala Thr Ile 
            250                 255                 260 

gca ttg atg att cag aga gga gta cca gga cct ttt ctt gtc tgt ggc      928 
Ala Leu Met Ile Gln Arg Gly Val Pro Gly Pro Phe Leu Val Cys Gly 
        265                 270                 275 

cct ttg tct aca ctt cct aac tgg atg gct gaa ttc aaa aga ttt aca      976 
Pro Leu Ser Thr Leu Pro Asn Trp Met Ala Glu Phe Lys Arg Phe Thr 
    280                 285                 290 

cca gat atc cct aca atg tta tat cat gga acc cag gag gaa cgt caa     1024 
Pro Asp Ile Pro Thr Met Leu Tyr His Gly Thr Gln Glu Glu Arg Gln 
295                 300                 305                 310 

aaa ttg gta aga aat att tac aaa cgg aaa ggg act ttg cag att cat     1072 
Lys Leu Val Arg Asn Ile Tyr Lys Arg Lys Gly Thr Leu Gln Ile His 
                315                 320                 325 

cct gtg gta atc acg tca ttt gaa ata gcc atg aga gac cga aat gcg     1120 
Pro Val Val Ile Thr Ser Phe Glu Ile Ala Met Arg Asp Arg Asn Ala 
            330                 335                 340 

tta cag cat tgc tat tgg aaa tac tta ata gta gat gaa gga cac agg     1168 
Leu Gln His Cys Tyr Trp Lys Tyr Leu Ile Val Asp Glu Gly His Arg 
        345                 350                 355 

att aag aat atg aag tgc cgt cta atc agg gag tta aaa cga ttc aat     1216 
Ile Lys Asn Met Lys Cys Arg Leu Ile Arg Glu Leu Lys Arg Phe Asn 
    360                 365                 370 

gct gat aac aaa ctt ctt ttg act ggt act ccc ttg caa aac aat tta     1264 
Ala Asp Asn Lys Leu Leu Leu Thr Gly Thr Pro Leu Gln Asn Asn Leu 
375                 380                 385                 390 

tca gaa ctt tgg tca ttg cta aac ttt ttg ttg cca gat gta ttt gat     1312 
Ser Glu Leu Trp Ser Leu Leu Asn Phe Leu Leu Pro Asp Val Phe Asp 
                395                 400                 405 

gac ttg aaa agc ttt gag tct tgg ttt gac atc act agt ctt tct gaa     1360 
Asp Leu Lys Ser Phe Glu Ser Trp Phe Asp Ile Thr Ser Leu Ser Glu 
            410                 415                 420 

act gct gaa gat att att gct aaa gaa aga gaa cag aat gta ttg cat     1408 
Thr Ala Glu Asp Ile Ile Ala Lys Glu Arg Glu Gln Asn Val Leu His 
        425                 430                 435 

atg ctg cac cag att tta aca cct ttc tta ttg aga aga ctg aag tct     1456 
Met Leu His Gln Ile Leu Thr Pro Phe Leu Leu Arg Arg Leu Lys Ser 
    440                 445                 450 

gat gtt gct ctt gaa gtt cct cct aaa cga gaa gta gtc gtt tat gct     1504 
Asp Val Ala Leu Glu Val Pro Pro Lys Arg Glu Val Val Val Tyr Ala 
455                 460                 465                 470 

cca ctt tca aag aag cag gag atc ttt tat aca gcc att gtg aac cgt     1552 
Pro Leu Ser Lys Lys Gln Glu Ile Phe Tyr Thr Ala Ile Val Asn Arg 
                475                 480                 485 

aca att gca aac atg tat gga tcc agt gag aaa gaa aca att gag tta     1600 
Thr Ile Ala Asn Met Tyr Gly Ser Ser Glu Lys Glu Thr Ile Glu Leu 
            490                 495                 500 

agt cct act ggt aga cca aaa cga cga act aga aaa tca ata aat aac     1648 
Ser Pro Thr Gly Arg Pro Lys Arg Arg Thr Arg Lys Ser Ile Asn Asn 
        505                 510                 515 

agc aaa ata gat gaa ttc cct aat gaa ttg gaa aaa ctg atc agt caa     1696 
Ser Lys Ile Asp Glu Phe Pro Asn Glu Leu Glu Lys Leu Ile Ser Gln 
    520                 525                 530 

ata cag cca gag gtg gac cga gaa aga gct gtt gtg gaa gtg aat atc     1744 
Ile Gln Pro Glu Val Asp Arg Glu Arg Ala Val Val Glu Val Asn Ile 
535                 540                 545                 550 

cct gta gaa tct gaa gtt aat ctg aag ctg cag aat ata atg atg cta     1792 
Pro Val Glu Ser Glu Val Asn Leu Lys Leu Gln Asn Ile Met Met Leu 
                555                 560                 565 

ctt cgt aaa tgt tgt aat cat cca tat ttg att gaa tat cct ata gac     1840 
Leu Arg Lys Cys Cys Asn His Pro Tyr Leu Ile Glu Tyr Pro Ile Asp 
            570                 575                 580 

cct gtt aca caa gaa ttt aag atc gat gaa gaa ttg gta aca aat tct     1888 
Pro Val Thr Gln Glu Phe Lys Ile Asp Glu Glu Leu Val Thr Asn Ser 
        585                 590                 595 

ggg aag ttc ttg att ttg gat cga atg ctg cca gaa cta aaa aaa aga     1936 
Gly Lys Phe Leu Ile Leu Asp Arg Met Leu Pro Glu Leu Lys Lys Arg 
    600                 605                 610 

ggt cac aag gtg ctg ctt ttt tca caa atg aca agc atg ttg gac att     1984 
Gly His Lys Val Leu Leu Phe Ser Gln Met Thr Ser Met Leu Asp Ile 
615                 620                 625                 630 

ttg atg gat tac tgc cat ctc aga gat ttc aac ttc agc agg ctt gat     2032 
Leu Met Asp Tyr Cys His Leu Arg Asp Phe Asn Phe Ser Arg Leu Asp 
                635                 640                 645 

ggg tcc atg tct tac tca gag aga gaa aaa aac atg cac agc ttc aac     2080 
Gly Ser Met Ser Tyr Ser Glu Arg Glu Lys Asn Met His Ser Phe Asn 
            650                 655                 660 

acg gat cca gag gtg ttt atc ttc tta gtg agt aca cga gct ggt ggc     2128 
Thr Asp Pro Glu Val Phe Ile Phe Leu Val Ser Thr Arg Ala Gly Gly 
        665                 670                 675 

ctg ggc att aat ctg act gca gca gat aca gtt atc att tat gat agt     2176 
Leu Gly Ile Asn Leu Thr Ala Ala Asp Thr Val Ile Ile Tyr Asp Ser 
    680                 685                 690 

gat tgg aac ccc cag tcg gat ctt cag gcc cag gat aga tgt cat aga     2224 
Asp Trp Asn Pro Gln Ser Asp Leu Gln Ala Gln Asp Arg Cys His Arg 
695                 700                 705                 710 

att ggt cag aca aag cca gtt gtt gtt tat cgc ctt gtt aca gca aat     2272 
Ile Gly Gln Thr Lys Pro Val Val Val Tyr Arg Leu Val Thr Ala Asn 
                715                 720                 725 

act atc gat cag aaa att gtg gaa aga gca gct gct aaa agg aaa ctg     2320 
Thr Ile Asp Gln Lys Ile Val Glu Arg Ala Ala Ala Lys Arg Lys Leu 
            730                 735                 740 

gaa aag ttg atc atc cat aaa aat cat ttc aaa ggt ggt cag tct gga     2368 
Glu Lys Leu Ile Ile His Lys Asn His Phe Lys Gly Gly Gln Ser Gly 
        745                 750                 755 

tta aat ctg tct aag aat ttc tta gat cct aag gaa tta atg gaa tta     2416 
Leu Asn Leu Ser Lys Asn Phe Leu Asp Pro Lys Glu Leu Met Glu Leu 
    760                 765                 770 

tta aaa tct aga gat tat gaa agg gaa ata aaa gga tca aga gag aag     2464 
Leu Lys Ser Arg Asp Tyr Glu Arg Glu Ile Lys Gly Ser Arg Glu Lys 
775                 780                 785                 790 

gtc att agt gat aaa gat cta gag ttg ttg tta gat cga agt gat ctt     2512 
Val Ile Ser Asp Lys Asp Leu Glu Leu Leu Leu Asp Arg Ser Asp Leu 
                795                 800                 805 

att gat caa atg aat gct tca gga cca att aaa gag aag atg ggg ata     2560 
Ile Asp Gln Met Asn Ala Ser Gly Pro Ile Lys Glu Lys Met Gly Ile 
            810                 815                 820 

ttc aag ata tta gaa aat tct gaa gat tcc agt cct gaa tgt ttg ttt     2608 
Phe Lys Ile Leu Glu Asn Ser Glu Asp Ser Ser Pro Glu Cys Leu Phe 
        825                 830                 835 

taa agtg gagctcaaga atagctttta aaagttctta tttacatcta gtgatttccc     2665 
 * 

tgtattgggt ttgaaatact gattgtccac ttcacctttt ttattatatc agttgacatg   2725 

taactagtac catgcgtact taaatagatg gtaattttct gagccttacc aagaacaaag   2785 

aagtatccat attaagttta gattttcagt taatttttga gactgagtag tattcttgga   2845 

tacaggctga tgtgtactta accacttcca gatttataca gtcttcctgt ggaagtttag   2905 

taaatgtctt tttccctcct ttcttctagt aatgcagttc atgggcttta ggtacttcag   2965 

ttatgaagta ggcttttcat ggggagagat tgggattatg ctctctgttg tttaagaaac   3025 

tgtttgattt tagagtctat ttctatgaga tagtttacca aataaatgtt ccttataaaa   3085 

aaaaaaaaa                                                           3094