Patent Publication Number: US-2003224406-A1

Title: MBCATs as modifiers of the beta-catenin pathway and methods of use

Description:
REFERENCE TO RELATED APPLICATIONS  
     [0001] This application claims priority to U.S. provisional patent application No. 60/361,242 filed Mar. 1, 2002. The content of the prior application is hereby incorporated in its entirety. 
    
    
     
       BACKGROUND OF THE INVENTION  
       [0002] Beta-catenin is an adherens junction protein. Adherens junctions (AJs; also called the zonula adherens) are critical for the establishment and maintenance of epithelial layers, such as those lining organ surfaces. AJs mediate adhesion between cells, communicate a signal that neighboring cells are present, and anchor the actin cytoskeleton. In serving these roles, AJs regulate normal cell growth and behavior. At several stages of embryogenesis, wound healing, and tumor cell metastasis, cells form and leave epithelia. This process, which involves the disruption and reestablishment of epithelial cell-cell contacts, may be regulated by the disassembly and assembly of AJs. AJs may also function in the transmission of the ‘contact inhibition’ signal, which instructs cells to stop dividing once an epithelial sheet is complete.  
       [0003] The AJ is a multiprotein complex assembled around calcium-regulated cell adhesion molecules called cadherins (Peifer, M.(1993) Science 262: 1667-1668). Cadherins are transmembrane proteins: the extracellular domain mediates homotypic adhesion with cadherins on neighboring cells, and the intracellular domain interacts with cytoplasmic proteins that transmit the adhesion signal and anchor the AJ to the actin cytoskeleton. These cytoplasmic proteins include the alpha-, beta-, and gamma-catenins. The beta-catenin protein shares 70% amino acid identity with both plakoglobin, which is found in desmosomes (another type of intracellular junction), and the product of the Drosophila segment polarity gene ‘armadillo’. Armadillo is part of a multiprotein AJ complex in Drosophila that also includes some homologs of alpha-catenin and cadherin, and genetic studies indicate that it is required for cell adhesion and cytoskeletal integrity.  
       [0004] Beta-catenin, in addition to its role as a cell adhesion component, also functions as a transcriptional co-activator in the Wnt signaling pathway through its interactions with the family of Tcf and Lef transcription factors (for a review see Polakis, (1999) Current Opinion in Genetics &amp; Development, 9:15-21 and Gat U., et al., (1998) Cell 95:605-614).  
       [0005] The APC gene, which is mutant in adenomatous polyposis of the colon, is a negative regulator of beta-catenin signaling (Korinek, V. et al., (1997) Science 275: 1784-1787; Morin, P. J., et al., (1997) Science 275: 1787-1790). The APC protein normally binds to beta-catenin and, in combination with other proteins (including glycogen synthase kinase-3b and axin, is required for the efficient degradation of b-catenin. The regulation of beta-catenin is critical to the tumor suppressive effect of APC and that this regulation can be circumvented by mutations in either APC or beta-catenin.  
       [0006] While mammals contain only a single beta-catenin gene,  C. elegans  contains three (Korswagen H C, et al., (2000) Nature 406:527-32). Each worm beta-catenin appears to carry out unique functions (Korswagen H C, et al., (2000) Nature 406:527-32, Nartarajan L et al. (2001) Genetics 159: 159-72). Because of the divergence of function in  C. elegans,  it is possible to specifically study beta-catenin role in cell adhesion, which is mediated by the  C. elegans  beta-catenin HMP-2.  
       [0007] MAST205 is a protein with strong similarity to microtubule associated testis specific serine/threonine protein kinase (mouse Mtssk), which may act in spermatid maturation and microtubule organization. SAST, KIAA0561, and KIAA0303 are similar to MAST205 (Nagase T et al (1998) DNA Res 5:277-286; Walden P D and Millette C F (1996) Biol Reprod 55:1039-1044; Walden P D and Cowan N J (1993) mol Cell Biol 13:7625-7635).  
       [0008] The ability to manipulate the genomes of model organisms such as  C. elegans  provides a powerful means to analyze biochemical processes that, due to significant evolutionary conservation, have direct relevance to more complex vertebrate organisms. Due to a high level of gene and pathway conservation, the strong similarity of cellular processes, and the functional conservation of genes between these model organisms and mammals, identification of the involvement of novel genes in particular pathways and their functions in such model organisms can directly contribute to the understanding of the correlative pathways and methods of modulating them in mammals (see, for example, Dulubova I, et al, J Neurochem 2001 April;77(1):229-38; Cai T, et al., Diabetologia 2001 January;44(1):81-8; Pasquinelli A E, et al., Nature. Nov. 2, 2000;408(6808):37-8; Ivanov I P, et al., EMBO J Apr. 17, 2000;19(8):1907-17; Vajo Z et al., Mamm Genome 1999 October;10(10):1000-4). For example, a genetic screen can be carried out in an invertebrate model organism having underexpression (e.g. knockout) or overexpression of a gene (referred to as a “genetic entry point”) that yields a visible phenotype. Additional genes are mutated in a random or targeted manner. When a gene mutation changes the original phenotype caused by the mutation in the genetic entry point, the gene is identified as a “modifier” involved in the same or overlapping pathway as the genetic entry point. When the genetic entry point is an ortholog of a human gene implicated in a disease pathway, such as beta-catenin, modifier genes can be identified that may be attractive candidate targets for novel therapeutics.  
       [0009] All references cited herein, including patents, patent applications, publications, and sequence information in referenced Genbank identifier numbers, are incorporated herein in their entireties.  
       SUMMARY OF THE INVENTION  
       [0010] We have discovered genes that modify the beta-catenin pathway in  C. elegans , and identified their human orthologs, hereinafter referred to as modifier of beta-catenin (MBCAT). The invention provides methods for utilizing these beta-catenin modifier genes and polypeptides to identify MBCAT-modulating agents that are candidate therapeutic agents that can be used in the treatment of disorders associated with defective or impaired beta-catenin function and/or MBCAT function. Preferred MBCAT-modulating agents specifically bind to MBCAT polypeptides and restore beta-catenin function. Other preferred MBCAT-modulating agents are nucleic acid modulators such as antisense oligomers and RNAi that repress MBCAT gene expression or product activity by, for example, binding to and inhibiting the respective nucleic acid (i.e. DNA or mRNA).  
       [0011] MBCAT modulating agents may be evaluated by any convenient in vitro or in vivo assay for molecular interaction with an MBCAT polypeptide or nucleic acid. In one embodiment, candidate MBCAT modulating agents are tested with an assay system comprising a MBCAT polypeptide or nucleic acid. Agents that produce a change in the activity of the assay system relative to controls are identified as candidate beta-catenin modulating agents. The assay system may be cell-based or cell-free. MBCAT-modulating agents include MBCAT related proteins (e.g. dominant negative mutants, and biotherapeutics); MBCAT-specific antibodies; MBCAT-specific antisense oligomers and other nucleic acid modulators; and chemical agents that specifically bind to or interact with MBCAT or compete with MBCAT binding partner (e.g. by binding to an MBCAT binding partner). In one specific embodiment, a small molecule modulator is identified using a kinase assay. In specific embodiments, the screening assay system is selected from a binding assay, an apoptosis assay, a cell proliferation assay, an angiogenesis assay, and a hypoxic induction assay.  
       [0012] In another embodiment, candidate beta-catenin pathway modulating agents are further tested using a second assay system that detects changes in the beta-catenin pathway, such as angiogenic, apoptotic, or cell proliferation changes produced by the originally identified candidate agent or an agent derived from the original agent. The second assay system may use cultured cells or non-human animals. In specific embodiments, the secondary assay system uses non-human animals, including animals predetermined to have a disease or disorder implicating the beta-catenin pathway, such as an angiogenic, apoptotic, or cell proliferation disorder (e.g. cancer).  
       [0013] The invention further provides methods for modulating the MBCAT function and/or the beta-catenin pathway in a mammalian cell by contacting the mammalian cell with an agent that specifically binds a MBCAT polypeptide or nucleic acid. The agent may be a small molecule modulator, a nucleic acid modulator, or an antibody and may be administered to a mammalian animal predetermined to have a pathology associated the beta-catenin pathway.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0014] Genetic screens were designed to identify modifiers of the beta-catenin pathway in  C. elegans . A weak allele of beta-catenin was used in our screen (a homozygous viable mutant of beta-catenin, allele qm39). The hmp-2 (qm-39) strain produces larval worms with a highly penetrant lumpy body phenotype in first stage larval worms (L1s). Various specific genes were silenced by RNA inhibition (RNAi). Methods for using RNAi to silence genes in  C. elegans  are known in the art (Fire A, et al., 1998 Nature 391:806-811; Fire, A. Trends Genet. 15, 358-363 (1999); WO9932619). The C10C6.1 gene was identified as a modifier of the beta-catenin pathway. Accordingly, vertebrate orthologs of the modifier, and preferably the human orthologs, MBCAT genes (i.e., nucleic acids and polypeptides) are attractive drug targets for the treatment of pathologies associated with a defective beta-catenin signaling pathway, such as cancer.  
       [0015] In vitro and in vivo methods of assessing MBCAT function are provided herein. Modulation of the MBCAT or their respective binding partners is useful for understanding the association of the beta-catenin pathway and its members in normal and disease conditions and for developing diagnostics and therapeutic modalities for beta-catenin related pathologies. MBCAT-modulating agents that act by inhibiting or enhancing MBCAT expression, directly or indirectly, for example, by affecting an MBCAT function such as enzymatic (e.g., catalytic) or binding activity, can be identified using methods provided herein. MBCAT modulating agents are useful in diagnosis, therapy and pharmaceutical development.  
       [0016] Nucleic Acids and Polypeptides of the Invention  
       [0017] Sequences related to MBCAT nucleic acids and polypeptides that can be used in the invention are disclosed in Genbank (referenced by Genbank identifier (GI) number) as GI#s 14149670 (SEQ ID NO: 1), 3882334 (SEQ ID NO:2), 10440171 (SEQ ID NO:3), 16198348 (SEQ ID NO:4), 16549992 (SEQ ID NO:5), 21756034 (SEQ ID NO:6), 18600993 (SEQ ID NO:7), 22051641 (SEQ ID NO:9), 17455843 (SEQ ID NO: 10), 18561839 (SEQ ID NO:11), 13177744 (SEQ ID NO:12), and 2224546 (SEQ ID NO:13) for nucleic acid, and GI#s 14149671 (SEQ ID NO: 14), 14759411 (SEQ ID NO: 15), 17455844 (SEQ ID NO: 16), 18561840 (SEQ ID NO: 17), and 27498257 (SEQ ID NO:18) for polypeptides. Additionally, nucleic acid sequence of SEQ ID NO:8 may also be used in the invention.  
       [0018] MBCATs are kinase proteins with protein kinase domains. The term “MBCAT polypeptide” refers to a full-length MBCAT protein or a functionally active fragment or derivative thereof. A “functionally active” MBCAT fragment or derivative exhibits one or more functional activities associated with a full-length, wild-type MBCAT protein, such as antigenic or immunogenic activity, enzymatic activity, ability to bind natural cellular substrates, etc. The functional activity of MBCAT proteins, derivatives and fragments can be assayed by various methods known to one skilled in the art (Current Protocols in Protein Science (1998) Coligan et al., eds., John Wiley &amp; Sons, Inc., Somerset, N.J.) and as further discussed below. In one embodiment, a functionally active MBCAT polypeptide is a MBCAT derivative capable of rescuing defective endogenous MBCAT activity, such as in cell based or animal assays; the rescuing derivative may be from the same or a different species. For purposes herein, functionally active fragments also include those fragments that comprise one or more structural domains of an MBCAT, such as a kinase domain or a binding domain. Protein domains can be identified using the PFAM program (Bateman A., et al., Nucleic Acids Res, 1999, 27:260-2). For example, the kinase domain of MBCAT from GI#s 14149671, 14759411, 17455844, and 27498257 (SEQ ID NOs: 14, 15, 16, and 18, respectively) are located respectively at approximately amino acid residues 512 to 785, 460 to 547, 197 to 470, and 39 to 312 (PFAM 00069). Methods for obtaining MBCAT polypeptides are also further described below. In some embodiments, preferred fragments are functionally active, domain-containing fragments comprising at least 25 contiguous amino acids, preferably at least 50, more preferably 75, and most preferably at least 100 contiguous amino acids of any one of SEQ ID NOs: 14-18 (an MBCAT). In further preferred embodiments, the fragment comprises the entire kinase (functionally active) domain.  
       [0019] The term “MBCAT nucleic acid” refers to a DNA or RNA molecule that encodes a MBCAT polypeptide. Preferably, the MBCAT polypeptide or nucleic acid or fragment thereof is from a human, but can also be an ortholog, or derivative thereof with at least 70% sequence identity, preferably at least 80%, more preferably 85%, still more preferably 90%, and most preferably at least 95% sequence identity with human MBCAT. Methods of identifying orthlogs are known in the art. Normally, orthologs in different species retain the same function, due to presence of one or more protein motifs and/or 3-dimensional structures. Orthologs are generally identified by sequence homology analysis, such as BLAST analysis, usually using protein bait sequences. Sequences are assigned as a potential ortholog if the best hit sequence from the forward BLAST result retrieves the original query sequence in the reverse BLAST (Huynen M A and Bork P, Proc Natl Acad Sci (1998) 95:5849-5856; Huynen M A et al., Genome Research (2000) 10:1204-1210). Programs for multiple sequence alignment, such as CLUSTAL (Thompson J D et al, 1994, Nucleic Acids Res 22:4673-4680) may be used to highlight conserved regions and/or residues of orthologous proteins and to generate phylogenetic trees. In a phylogenetic tree representing multiple homologous sequences from diverse species (e.g., retrieved through BLAST analysis), orthologous sequences from two species generally appear closest on the tree with respect to all other sequences from these two species. Structural threading or other analysis of protein folding (e.g., using software by ProCeryon, Biosciences, Salzburg, Austria) may also identify potential orthologs. In evolution, when a gene duplication event follows speciation, a single gene in one species, such as  C. elegans , may correspond to multiple genes (paralogs) in another, such as human. As used herein, the term “orthologs” encompasses paralogs. As used herein, “percent (%) sequence identity” with respect to a subject sequence, or a specified portion of a subject sequence, is defined as the percentage of nucleotides or amino acids in the candidate derivative sequence identical with the nucleotides or amino acids in the subject sequence (or specified portion thereof), after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent sequence identity, as generated by the program WU-BLAST-2.0a19 (Altschul et al., J. Mol. Biol. (1997) 215:403-410) with all the search parameters set to default values. The HSP S and HSP S2 parameters are dynamic values and are established by the program itself depending upon the composition of the particular sequence and composition of the particular database against which the sequence of interest is being searched. A % identity value is determined by the number of matching identical nucleotides or amino acids divided by the sequence length for which the percent identity is being reported. “Percent (%) amino acid sequence similarity” is determined by doing the same calculation as for determining % amino acid sequence identity, but including conservative amino acid substitutions in addition to identical amino acids in the computation.  
       [0020] A conservative amino acid substitution is one in which an amino acid is substituted for another amino acid having similar properties such that the folding or activity of the protein is not significantly affected. Aromatic amino acids that can be substituted for each other are phenylalanine, tryptophan, and tyrosine; interchangeable hydrophobic amino acids are leucine, isoleucine, methionine, and valine; interchangeable polar amino acids are glutamine and asparagine; interchangeable basic amino acids are arginine, lysine and histidine; interchangeable acidic amino acids are aspartic acid and glutamic acid; and interchangeable small amino acids are alanine, serine, threonine, cysteine and glycine.  
       [0021] Alternatively, an alignment for nucleic acid sequences is provided by the local homology algorithm of Smith and Waterman (Smith and Waterman, 1981, Advances in Applied Mathematics 2:482-489; database: European Bioinformatics Institute; Smith and Waterman, 1981, J. of Molec. Biol., 147:195-197; Nicholas et al., 1998, “A Tutorial on Searching Sequence Databases and Sequence Scoring Methods” (www.psc.edu) and references cited therein.; W. R. Pearson, 1991, Genomics 11:635-650). This algorithm can be applied to amino acid sequences by using the scoring matrix developed by Dayhoff (Dayhoff: Atlas of Protein Sequences and Structure, M. 0. Dayhoff ed., 5 suppl. 3:353-358, National Biomedical Research Foundation, Washington, D.C., USA), and normalized by Gribskov (Gribskov 1986 Nucl. Acids Res. 14(6):6745-6763). The Smith-Waterman algorithm may be employed where default parameters are used for scoring (for example, gap open penalty of 12, gap extension penalty of two). From the data generated, the “Match” value reflects “sequence identity.” 
       [0022] Derivative nucleic acid molecules of the subject nucleic acid molecules include sequences that hybridize to the nucleic acid sequence of any of SEQ ID NOs: 14-18. The stringency of hybridization can be controlled by temperature, ionic strength, pH, and the presence of denaturing agents such as formamide during hybridization and washing. Conditions routinely used are set out in readily available procedure texts (e.g., Current Protocol in Molecular Biology, Vol. 1, Chap. 2.10, John Wiley &amp; Sons, Publishers (1994); Sambrook et al., Molecular Cloning, Cold Spring Harbor (1989)). In some embodiments, a nucleic acid molecule of the invention is capable of hybridizing to a nucleic acid molecule containing the nucleotide sequence of any one of SEQ ID NOs: 1-13 under high stringency hybridization conditions that are: prehybridization of filters containing nucleic acid for 8 hours to overnight at 65° C. in a solution comprising 6× single strength citrate (SSC) (1×SSC is 0.15 M NaCl, 0.015 M Na citrate; pH 7.0), 5× Denhardt&#39;s solution, 0.05% sodium pyrophosphate and 100 μg/ml herring sperm DNA; hybridization for 18-20 hours at 65° C. in a solution containing 6×SSC, 1× Denhardt&#39;s solution, 100 μg/ml yeast tRNA and 0.05% sodium pyrophosphate; and washing of filters at 65° C. for 1 h in a solution containing 0.1×SSC and 0.1% SDS (sodium dodecyl sulfate).  
       [0023] In other embodiments, moderately stringent hybridization conditions are used that are: pretreatment of filters containing nucleic acid for 6 h at 40° C. in a solution containing 35% formamide, 5×SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 μg/ml denatured salmon sperm DNA; hybridization for 18-20 h at 40° C. in a solution containing 35% formamide, 5×SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 μg/ml salmon sperm DNA, and 10% (wt/vol) dextran sulfate; followed by washing twice for 1 hour at 55° C. in a solution containing 2×SSC and 0.1% SDS.  
       [0024] Alternatively, low stringency conditions can be used that are: incubation for 8 hours to overnight at 37° C. in a solution comprising 20% formamide, 5×SSC, 50 mM sodium phosphate (pH 7.6), 5× Denhardt&#39;s solution, 10% dextran sulfate, and 20 μg/ml denatured sheared salmon sperm DNA; hybridization in the same buffer for 18 to 20 hours; and washing of filters in 1×SSC at about 37° C. for 1 hour.  
       [0025] Isolation, Production, Expression, and Mis-Expression of MBCAT Nucleic Acids and Polypeptides  
       [0026] MBCAT nucleic acids and polypeptides, useful for identifying and testing agents that modulate MBCAT function and for other applications related to the involvement of MBCAT in the beta-catenin pathway. MBCAT nucleic acids and derivatives and orthologs thereof may be obtained using any available method. For instance, techniques for isolating cDNA or genomic DNA sequences of interest by screening DNA libraries or by using polymerase chain reaction (PCR) are well known in the art. In general, the particular use for the protein will dictate the particulars of expression, production, and purification methods. For instance, production of proteins for use in screening for modulating agents may require methods that preserve specific biological activities of these proteins, whereas production of proteins for antibody generation may require structural integrity of particular epitopes. Expression of proteins to be purified for screening or antibody production may require the addition of specific tags (e.g., generation of fusion proteins). Overexpression of an MBCAT protein for assays used to assess MBCAT function, such as involvement in cell cycle regulation or hypoxic response, may require expression in eukaryotic cell lines capable of these cellular activities. Techniques for the expression, production, and purification of proteins are well known in the art; any suitable means therefore may be used (e.g., Higgins S J and Hames B D (eds.) Protein Expression: A Practical Approach, Oxford University Press Inc., New York 1999; Stanbury P F et al., Principles of Fermentation Technology, 2 nd  edition, Elsevier Science, New York, 1995; Doonan S (ed.) Protein Purification Protocols, Humana Press, N.J., 1996; Coligan J E et al, Current Protocols in Protein Science (eds.), 1999, John Wiley &amp; Sons, New York). In particular embodiments, recombinant MBCAT is expressed in a cell line known to have defective beta-catenin function. The recombinant cells are used in cell-based screening assay systems of the invention, as described further below.  
       [0027] The nucleotide sequence encoding an MBCAT polypeptide can be inserted into any appropriate expression vector. The necessary transcriptional and translational signals, including promoter/enhancer element, can derive from the native MBCAT gene and/or its flanking regions or can be heterologous. A variety of host-vector expression systems may be utilized, such as mammalian cell systems infected with virus (e.g. vaccinia virus, adenovirus, etc.); insect cell systems infected with virus (e.g. baculovirus); microorganisms such as yeast containing yeast vectors, or bacteria transformed with bacteriophage, plasmid, or cosmid DNA. An isolated host cell strain that modulates the expression of, modifies, and/or specifically processes the gene product may be used.  
       [0028] To detect expression of the MBCAT gene product, the expression vector can comprise a promoter operably linked to an MBCAT gene nucleic acid, one or more origins of replication, and, one or more selectable markers (e.g. thymidine kinase activity, resistance to antibiotics, etc.). Alternatively, recombinant expression vectors can be identified by assaying for the expression of the MBCAT gene product based on the physical or functional properties of the MBCAT protein in in vitro assay systems (e.g. immunoassays).  
       [0029] The MBCAT protein, fragment, or derivative may be optionally expressed as a fusion, or chimeric protein product (i.e. it is joined via a peptide bond to a heterologous protein sequence of a different protein), for example to facilitate purification or detection. A chimeric product can be made by ligating the appropriate nucleic acid sequences encoding the desired amino acid sequences to each other using standard methods and expressing the chimeric product. A chimeric product may also be made by protein synthetic techniques, e.g. by use of a peptide synthesizer (Hunkapiller et al., Nature (1984) 310:105-111).  
       [0030] Once a recombinant cell that expresses the MBCAT gene sequence is identified, the gene product can be isolated and purified using standard methods (e.g. ion exchange, affinity, and gel exclusion chromatography; centrifugation; differential solubility; electrophoresis). Alternatively, native MBCAT proteins can be purified from natural sources, by standard methods (e.g. immunoaffinity purification). Once a protein is obtained, it may be quantified and its activity measured by appropriate methods, such as immunoassay, bioassay, or other measurements of physical properties, such as crystallography.  
       [0031] The methods of this invention may also use cells that have been engineered for altered expression (mis-expression) of MBCAT or other genes associated with the beta-catenin pathway. As used herein, mis-expression encompasses ectopic expression, over-expression, under-expression, and non-expression (e.g. by gene knock-out or blocking expression that would otherwise normally occur).  
       [0032] Genetically Modified Animals  
       [0033] Animal models that have been genetically modified to alter MBCAT expression may be used in in vivo assays to test for activity of a candidate beta-catenin modulating agent, or to further assess the role of MBCAT in a beta-catenin pathway process such as apoptosis or cell proliferation. Preferably, the altered MBCAT expression results in a detectable phenotype, such as decreased or increased levels of cell proliferation, angiogenesis, or apoptosis compared to control animals having normal MBCAT expression. The genetically modified animal may additionally have altered beta-catenin expression (e.g. beta-catenin knockout). Preferred genetically modified animals are mammals such as primates, rodents (preferably mice or rats), among others. Preferred non-mammalian species include zebrafish,  C. elegans , and Drosophila. Preferred genetically modified animals are transgenic animals having a heterologous nucleic acid sequence present as an extrachromosomal element in a portion of its cells, i.e. mosaic animals (see, for example, techniques described by Jakobovits, 1994, Curr. Biol. 4:761-763.) or stably integrated into its germ line DNA (i.e., in the genomic sequence of most or all of its cells). Heterologous nucleic acid is introduced into the germ line of such transgenic animals by genetic manipulation of, for example, embryos or embryonic stem cells of the host animal.  
       [0034] Methods of making transgenic animals are well-known in the art (for transgenic mice see Brinster et al., Proc. Nat. Acad. Sci. USA 82: 4438-4442 (1985), U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No. 4,873,191 by Wagner et al., and Hogan, B., Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1986); for particle bombardment see U.S. Pat. No., 4,945,050, by Sandford et al.; for transgenic Drosophila see Rubin and Spradling, Science (1982) 218:348-53 and U.S. Pat. No. 4,670,388; for transgenic insects see Berghammer A. J. et al., A Universal Marker for Transgenic Insects (1999) Nature 402:370-371; for transgenic Zebrafish see Lin S., Transgenic Zebrafish, Methods Mol Biol. (2000);136:375-3830); for microinjection procedures for fish, amphibian eggs and birds see Houdebine and Chourrout, Experientia (1991) 47:897-905; for transgenic rats see Hammer et al., Cell (1990) 63:1099-1112; and for culturing of embryonic stem (ES) cells and the subsequent production of transgenic animals by the introduction of DNA into ES cells using methods such as electroporation, calcium phosphate/DNA precipitation and direct injection see, e.g., Teratocarcinomas and Embryonic Stem Cells, A Practical Approach, E. J. Robertson, ed., IRL Press (1987)). Clones of the nonhuman transgenic animals can be produced according to available methods (see Wilmut, I. et al. (1997) Nature 385:810-813; and PCT International Publication Nos. WO 97/07668 and WO 97/07669).  
       [0035] In one embodiment, the transgenic animal is a “knock-out” animal having a heterozygous or homozygous alteration in the sequence of an endogenous MBCAT gene that results in a decrease of MBCAT function, preferably such that MBCAT expression is undetectable or insignificant. Knock-out animals are typically generated by homologous recombination with a vector comprising a transgene having at least a portion of the gene to be knocked out. Typically a deletion, addition or substitution has been introduced into the transgene to functionally disrupt it. The transgene can be a human gene (e.g., from a human genomic clone) but more preferably is an ortholog of the human gene derived from the transgenic host species. For example, a mouse MBCAT gene is used to construct a homologous recombination vector suitable for altering an endogenous MBCAT gene in the mouse genome. Detailed methodologies for homologous recombination in mice are available (see Capecchi, Science (1989) 244:1288-1292; Joyner et al., Nature (1989) 338:153-156). Procedures for the production of non-rodent transgenic mammals and other animals are also available (Houdebine and Chourrout, supra; Pursel et al., Science (1989) 244:1281-1288; Simms et al., Bio/Technology (1988) 6:179-183). In a preferred embodiment, knock-out animals, such as mice harboring a knockout of a specific gene, may be used to produce antibodies against the human counterpart of the gene that has been knocked out (Claesson M H et al., (1994) Scan J Immunol 40:257-264; Declerck P J et al., (1995) J Biol Chem. 270:8397-400).  
       [0036] In another embodiment, the transgenic animal is a “knock-in” animal having an alteration in its genome that results in altered expression (e.g., increased (including ectopic) or decreased expression) of the MBCAT gene, e.g., by introduction of additional copies of MBCAT, or by operatively inserting a regulatory sequence that provides for altered expression of an endogenous copy of the MBCAT gene. Such regulatory sequences include inducible, tissue-specific, and constitutive promoters and enhancer elements. The knock-in can be homozygous or heterozygous.  
       [0037] Transgenic nonhuman animals can also be produced that contain selected systems allowing for regulated expression of the transgene. One example of such a system that may be produced is the cre/loxP recombinase system of bacteriophage P1 (Lakso et al., PNAS (1992) 89:6232-6236; U.S. Pat. No. 4,959,317). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae (O&#39;Gorman et al. (1991) Science 251:1351-1355; U.S. Pat. No. 5,654,182). In a preferred embodiment, both Cre-LoxP and Flp-Frt are used in the same system to regulate expression of the transgene, and for sequential deletion of vector sequences in the same cell (Sun X et al (2000) Nat Genet 25:83-6).  
       [0038] The genetically modified animals can be used in genetic studies to further elucidate the beta-catenin pathway, as animal models of disease and disorders implicating defective beta-catenin function, and for in vivo testing of candidate therapeutic agents, such as those identified in screens described below. The candidate therapeutic agents are administered to a genetically modified animal having altered MBCAT function and phenotypic changes are compared with appropriate control animals such as genetically modified animals that receive placebo treatment, and/or animals with unaltered MBCAT expression that receive candidate therapeutic agent.  
       [0039] In addition to the above-described genetically modified animals having altered MBCAT function, animal models having defective beta-catenin function (and otherwise normal MBCAT function), can be used in the methods of the present invention. Preferably, the candidate beta-catenin modulating agent when administered to a model system with cells defective in beta-catenin function, produces a detectable phenotypic change in the model system indicating that the beta-catenin function is restored, i.e., the cells exhibit normal cell cycle progression.  
       [0040] Modulating Agents  
       [0041] The invention provides methods to identify agents that interact with and/or modulate the function of MBCAT and/or the beta-catenin pathway. Modulating agents identified by the methods are also part of the invention. Such agents are useful in a variety of diagnostic and therapeutic applications associated with the beta-catenin pathway, as well as in further analysis of the MBCAT protein and its contribution to the beta-catenin pathway. Accordingly, the invention also provides methods for modulating the beta-catenin pathway comprising the step of specifically modulating MBCAT activity by administering a MBCAT-interacting or -modulating agent.  
       [0042] As used herein, an “MBCAT-modulating agent” is any agent that modulates MBCAT function, for example, an agent that interacts with MBCAT to inhibit or enhance MBCAT activity or otherwise affect normal MBCAT function. MBCAT function can be affected at any level, including transcription, protein expression, protein localization, and cellular or extra-cellular activity. In a preferred embodiment, the MBCAT-modulating agent specifically modulates the function of the MBCAT. The phrases “specific modulating agent”, “specifically modulates”, etc., are used herein to refer to modulating agents that directly bind to the MBCAT polypeptide or nucleic acid, and preferably inhibit, enhance, or otherwise alter, the function of the MBCAT. These phrases also encompass modulating agents that alter the interaction of the MBCAT with a binding partner, substrate, or cofactor (e.g. by binding to a binding partner of an MBCAT, or to a protein/binding partner complex, and altering MBCAT function). In a further preferred embodiment, the MBCAT-modulating agent is a modulator of the beta-catenin pathway (e.g. it restores and/or upregulates beta-catenin function) and thus is also a beta-catenin-modulating agent.  
       [0043] Preferred MBCAT-modulating agents include small molecule compounds; MBCAT-interacting proteins, including antibodies and other biotherapeutics; and nucleic acid modulators such as antisense and RNA inhibitors. The modulating agents may be formulated in pharmaceutical compositions, for example, as compositions that may comprise other active ingredients, as in combination therapy, and/or suitable carriers or excipients. Techniques for formulation and administration of the compounds may be found in “Remington&#39;s Pharmaceutical Sciences” Mack Publishing Co., Easton, Pa., 19 th  edition.  
       [0044] Small Molecule Modulators  
       [0045] Small molecules are often preferred to modulate function of proteins with enzymatic function, and/or containing protein interaction domains. Chemical agents, referred to in the art as “small molecule” compounds are typically organic, non-peptide molecules, having a molecular weight less than 10,000, preferably less than 5,000, more preferably less than 1,000, and most preferably less than 500. This class of modulators includes chemically synthesized molecules, for instance, compounds from combinatorial chemical libraries. Synthetic compounds may be rationally designed or identified based on known or inferred properties of the MBCAT protein or may be identified by screening compound libraries. Alternative appropriate modulators of this class are natural products, particularly secondary metabolites from organisms such as plants or fungi, which can also be identified by screening compound libraries for MBCAT-modulating activity. Methods for generating and obtaining compounds are well known in the art (Schreiber S L, Science (2000) 151: 1964-1969; Radmann J and Gunther J, Science (2000) 151:1947-1948).  
       [0046] Small molecule modulators identified from screening assays, as described below, can be used as lead compounds from which candidate clinical compounds may be designed, optimized, and synthesized. Such clinical compounds may have utility in treating pathologies associated with the beta-catenin pathway. The activity of candidate small molecule modulating agents may be improved several-fold through iterative secondary functional validation, as further described below, structure determination, and candidate modulator modification and testing. Additionally, candidate clinical compounds are generated with specific regard to clinical and pharmacological properties. For example, the reagents may be derivatized and re-screened using in vitro and in vivo assays to optimize activity and minimize toxicity for pharmaceutical development.  
       [0047] Protein Modulators  
       [0048] Specific MBCAT-interacting proteins are useful in a variety of diagnostic and therapeutic applications related to the beta-catenin pathway and related disorders, as well as in validation assays for other MBCAT-modulating agents. In a preferred embodiment, MBCAT-interacting proteins affect normal MBCAT function, including transcription, protein expression, protein localization, and cellular or extra-cellular activity. In another embodiment, MBCAT-interacting proteins are useful in detecting and providing information about the function of MBCAT proteins, as is relevant to beta-catenin related disorders, such as cancer (e.g., for diagnostic means).  
       [0049] An MBCAT-interacting protein may be endogenous, i.e. one that naturally interacts genetically or biochemically with an MBCAT, such as a member of the MBCAT pathway that modulates MBCAT expression, localization, and/or activity. MBCAT-modulators include dominant negative forms of MBCAT-interacting proteins and of MBCAT proteins themselves. Yeast two-hybrid and variant screens offer preferred methods for identifying endogenous MBCAT-interacting proteins (Finley, R. L. et al. (1996) in DNA Cloning-Expression Systems: A Practical Approach, eds. Glover D. &amp; Hames B. D (Oxford University Press, Oxford, England), pp. 169-203; Fashema SF et al., Gene (2000) 250:1-14; Drees B L Curr Opin Chem Biol (1999) 3:64-70; Vidal M and Legrain P Nucleic Acids Res (1999) 27:919-29; and U.S. Pat. No. 5,928,868). Mass spectrometry is an alternative preferred method for the elucidation of protein complexes (reviewed in, e.g., Pandley A and Mann M, Nature (2000) 405:837-846; Yates JR 3 rd , Trends Genet (2000) 16:5-8).  
       [0050] An MBCAT-interacting protein may be an exogenous protein, such as an MBCAT-specific antibody or a T-cell antigen receptor (see, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory; Harlow and Lane (1999) Using antibodies: a laboratory manual. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press). MBCAT antibodies are further discussed below.  
       [0051] In preferred embodiments, an MBCAT-interacting protein specifically binds an MBCAT protein. In alternative preferred embodiments, an MBCAT-modulating agent binds an MBCAT substrate, binding partner, or cofactor.  
       [0052] Antibodies  
       [0053] In another embodiment, the protein modulator is an MBCAT specific antibody agonist or antagonist. The antibodies have therapeutic and diagnostic utilities, and can be used in screening assays to identify MBCAT modulators. The antibodies can also be used in dissecting the portions of the MBCAT pathway responsible for various cellular responses and in the general processing and maturation of the MBCAT.  
       [0054] Antibodies that specifically bind MBCAT polypeptides can be generated using known methods. Preferably the antibody is specific to a mammalian ortholog of MBCAT polypeptide, and more preferably, to human MBCAT. Antibodies may be polyclonal, monoclonal (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′).sub.2 fragments, fragments produced by a FAb expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above. Epitopes of M1BCAT which are particularly antigenic can be selected, for example, by routine screening of MBCAT polypeptides for antigenicity or by applying a theoretical method for selecting antigenic regions of a protein (Hopp and Wood (1981), Proc. Natl. Acad. Sci. U.S.A. 78:3824-28; Hopp and Wood, (1983) Mol. Immunol. 20:483-89; Sutcliffe et al., (1983) Science 219:660-66) to the amino acid sequence of any of SEQ ID NOs: 14-18. Monoclonal antibodies with affinities of 10 8  M −1  preferably 10 9  M −1  to 10 10  M −1 , or stronger can be made by standard procedures as described (Harlow and Lane, supra; Goding (1986) Monoclonal Antibodies: Principles and Practice (2d ed) Academic Press, New York; and U.S. Pat. Nos. 4,381,292; 4,451,570; and 4,618,577). Antibodies may be generated against crude cell extracts of MBCAT or substantially purified fragments thereof. If MBCAT fragments are used, they preferably comprise at least 10, and more preferably, at least 20 contiguous amino acids of an MBCAT protein. In a particular embodiment, MBCAT-specific antigens and/or immunogens are coupled to carrier proteins that stimulate the immune response. For example, the subject polypeptides are covalently coupled to the keyhole limpet hemocyanin (KLH) carrier, and the conjugate is emulsified in Freund&#39;s complete adjuvant, which enhances the immune response. An appropriate immune system such as a laboratory rabbit or mouse is immunized according to conventional protocols.  
       [0055] The presence of MBCAT-specific antibodies is assayed by an appropriate assay such as a solid phase enzyme-linked immunosorbant assay (ELISA) using immobilized corresponding MBCAT polypeptides. Other assays, such as radioimmunoassays or fluorescent assays might also be used.  
       [0056] Chimeric antibodies specific to MBCAT polypeptides can be made that contain different portions from different animal species. For instance, a human immunoglobulin constant region may be linked to a variable region of a murine mAb, such that the antibody derives its biological activity from the human antibody, and its binding specificity from the murine fragment. Chimeric antibodies are produced by splicing together genes that encode the appropriate regions from each species (Morrison et al., Proc. Natl. Acad. Sci. (1984) 81:6851-6855; Neuberger et al., Nature (1984) 312:604-608; Takeda et al., Nature (1985) 31:452-454). Humanized antibodies, which are a form of chimeric antibodies, can be generated by grafting complementary-determining regions (CDRs) (Carlos, T. M., J. M. Harlan. 1994. Blood 84:2068-2101) of mouse antibodies into a background of human framework regions and constant regions by recombinant DNA technology (Riechmann L M, et al., 1988 Nature 323: 323-327). Humanized antibodies contain ˜10% murine sequences and ˜90% human sequences, and thus further reduce or eliminate immunogenicity, while retaining the antibody specificities (Co MS, and Queen C. 1991 Nature 351: 501-501; Morrison S L. 1992 Ann. Rev. Immun. 10:239-265). Humanized antibodies and methods of their production are well-known in the art (U.S. Pat. Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370).  
       [0057] MBCAT-specific single chain antibodies which are recombinant, single chain polypeptides formed by linking the heavy and light chain fragments of the Fv regions via an amino acid bridge, can be produced by methods known in the art (U.S. Pat. No. 4,946,778; Bird, Science (1988) 242:423-426; Huston et al., Proc. Natl. Acad. Sci. USA (1988) 85:5879-5883; and Ward et al., Nature (1989) 334:544-546).  
       [0058] Other suitable techniques for antibody production involve in vitro exposure of lymphocytes to the antigenic polypeptides or alternatively to selection of libraries of antibodies in phage or similar vectors (Huse et al., Science (1989) 246:1275-1281). As used herein, T-cell antigen receptors are included within the scope of antibody modulators (Harlow and Lane, 1988, supra).  
       [0059] The polypeptides and antibodies of the present invention may be used with or without modification. Frequently, antibodies will be labeled by joining, either covalently or non-covalently, a substance that provides for a detectable signal, or that is toxic to cells that express the targeted protein (Menard S, et al., Int J. Biol Markers (1989) 4:131-134). A wide variety of labels and conjugation techniques are known and are reported extensively in both the scientific and patent literature. Suitable labels include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, fluorescent emitting lanthanide metals, chemiluminescent moieties, bioluminescent moieties, magnetic particles, and the like (U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241). Also, recombinant immunoglobulins may be produced (U.S. Pat. No. 4,816,567). Antibodies to cytoplasmic polypeptides may be delivered and reach their targets by conjugation with membrane-penetrating toxin proteins (U.S. Pat. No. 6,086,900).  
       [0060] When used therapeutically in a patient, the antibodies of the subject invention are typically administered parenterally, when possible at the target site, or intravenously. The therapeutically effective dose and dosage regimen is determined by clinical studies. Typically, the amount of antibody administered is in the range of about 0.1 mg/kg-to about 10 mg/kg of patient weight. For parenteral administration, the antibodies are formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable vehicle. Such vehicles are inherently nontoxic and non-therapeutic. Examples are water, saline, Ringer&#39;s solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils, ethyl oleate, or liposome carriers may also be used. The vehicle may contain minor amounts of additives, such as buffers and preservatives, which enhance isotonicity and chemical stability or otherwise enhance therapeutic potential. The antibodies&#39; concentrations in such vehicles are typically in the range of about 1 mg/ml to about 10 mg/ml. Immunotherapeutic methods are further described in the literature (U.S. Pat. No. 5,859,206; WO0073469).  
       [0061] Nucleic Acid Modulators  
       [0062] Other preferred MBCAT-modulating agents comprise nucleic acid molecules, such as antisense oligomers or double stranded RNA (dsRNA), which generally inhibit MBCAT activity. Preferred nucleic acid modulators interfere with the function of the MBCAT nucleic acid such as DNA replication, transcription, translocation of the MBCAT RNA to the site of protein translation, translation of protein from the MBCAT RNA, splicing of the MBCAT RNA to yield one or more mRNA species, or catalytic activity which may be engaged in or facilitated by the MBCAT RNA.  
       [0063] In one embodiment, the antisense oligomer is an oligonucleotide that is sufficiently complementary to an MBCAT mRNA to bind to and prevent translation, preferably by binding to the 5′ untranslated region. MBCAT-specific antisense oligonucleotides, preferably range from at least 6 to about 200 nucleotides. In some embodiments the oligonucleotide is preferably at least 10, 15, or 20 nucleotides in length. In other embodiments, the oligonucleotide is preferably less than 50, 40, or 30 nucleotides in length. The oligonucleotide can be DNA or RNA or a chimeric mixture or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone. The oligonucleotide may include other appending groups such as peptides, agents that facilitate transport across the cell membrane, hybridization-triggered cleavage agents, and intercalating agents.  
       [0064] In another embodiment, the antisense oligomer is a phosphothioate morpholino oligomer (PMO). PMOs are assembled from four different morpholino subunits, each of which contain one of four genetic bases (A, C, G, or T) linked to a six-membered morpholine ring. Polymers of these subunits are joined by non-ionic phosphodiamidate intersubunit linkages. Details of how to make and use PMOs and other antisense oligomers are well known in the art (e.g. see WO99/18193; Probst J C, Antisense Oligodeoxynucleotide and Ribozyme Design, Methods. (2000) 22(3):271-281; Summerton J, and Weller D. 1997 Antisense Nucleic Acid Drug Dev.:7:187-95; U.S. Pat. No. 5,235,033; and U.S. Pat. No. 5,378,841).  
       [0065] Alternative preferred MBCAT nucleic acid modulators are double-stranded RNA species mediating RNA interference (RNAi). RNAi is the process of sequence-specific, post-transcriptional gene silencing in animals and plants, initiated by double-stranded RNA (dsRNA) that is homologous in sequence to the silenced gene. Methods relating to the use of RNAi to silence genes in  C. elegans , Drosophila, plants, and humans are known in the art (Fire A, et al., 1998 Nature 391:806-811; Fire, A. Trends Genet. 15, 358-363 (1999); Sharp, P. A. RNA interference 2001. Genes Dev. 15, 485-490 (2001); Hammond, S. M., et al., Nature Rev. Genet. 2, 110-1119 (2001); Tuschl, T. Chem. Biochem. 2, 239-245 (2001); Hamilton, A. et al., Science 286, 950-952 (1999); Hammond, S. M., et al., Nature 404, 293-296 (2000); Zamore, P. D., et al., Cell 101, 25-33 (2000); Bernstein, E., et al., Nature 409, 363-366 (2001); Elbashir, S. M., et al., Genes Dev. 15, 188-200 (2001); WO0129058; WO9932619; Elbashir S M, et al., 2001 Nature 411:494-498).  
       [0066] Nucleic acid modulators are commonly used as research reagents, diagnostics, and therapeutics. For example, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used to elucidate the function of particular genes (see, for example, U.S. Pat. No. 6,165,790). Nucleic acid modulators are also used, for example, to distinguish between functions of various members of a biological pathway. For example, antisense oligomers have been employed as therapeutic moieties in the treatment of disease states in animals and man and have been demonstrated in numerous clinical trials to be safe and effective (Milligan J F, et al, Current Concepts in Antisense Drug Design, J Med Chem. (1993) 36:1923-1937; Tonkinson J L et al., Antisense Oligodeoxynucleotides as Clinical Therapeutic Agents, Cancer Invest. (1996) 14:54-65). Accordingly, in one aspect of the invention, an MBCAT-specific nucleic acid modulator is used in an assay to further elucidate the role of the MBCAT in the beta-catenin pathway, and/or its relationship to other members of the pathway. In another aspect of the invention, an MBCAT-specific antisense oligomer is used as a therapeutic agent for treatment of beta-catenin-related disease states.  
       [0067] Assay Systems  
       [0068] The invention provides assay systems and screening methods for identifying specific modulators of MBCAT activity. As used herein, an “assay system” encompasses all the components required for performing and analyzing results of an assay that detects and/or measures a particular event. In general, primary assays are used to identify or confirm a modulator&#39;s specific biochemical or molecular effect with respect to the MBCAT nucleic acid or protein. In general, secondary assays further assess the activity of a MBCAT modulating agent identified by a primary assay and may confirm that the modulating agent affects MBCAT in a manner relevant to the beta-catenin pathway. In some cases, MBCAT modulators will be directly tested in a secondary assay.  
       [0069] In a preferred embodiment, the screening method comprises contacting a suitable assay system comprising an MBCAT polypeptide or nucleic acid with a candidate agent under conditions whereby, but for the presence of the agent, the system provides a reference activity (e.g. kinase activity), which is based on the particular molecular event the screening method detects. A statistically significant difference between the agent-biased activity and the reference activity indicates that the candidate agent modulates MBCAT activity, and hence the beta-catenin pathway. The MBCAT polypeptide or nucleic acid used in the assay may comprise any of the nucleic acids or polypeptides described above.  
       [0070] Primary Assays  
       [0071] The type of modulator tested generally determines the type of primary assay.  
       [0072] Primary Assays for Small Molecule Modulators  
       [0073] For small molecule modulators, screening assays are used to identify candidate modulators. Screening assays may be cell-based or may use a cell-free system that recreates or retains the relevant biochemical reaction of the target protein (reviewed in Sittampalam G S et al., Curr Opin Chem Biol (1997) 1:384-91 and accompanying references). As used herein the term “cell-based” refers to assays using live cells, dead cells, or a particular cellular fraction, such as a membrane, endoplasmic reticulum, or mitochondrial fraction. The term “cell free” encompasses assays using substantially purified protein (either endogenous or recombinantly produced), partially purified or crude cellular extracts. Screening assays may detect a variety of molecular events, including protein-DNA interactions, protein-protein interactions (e.g., receptor-ligand binding), transcriptional activity (e.g., using a reporter gene), enzymatic activity (e.g., via a property of the substrate), activity of second messengers, immunogenicty and changes in cellular morphology or other cellular characteristics. Appropriate screening assays may use a wide range of detection methods including fluorescent, radioactive, colorimetric, spectrophotometric, and amperometric methods, to provide a read-out for the particular molecular event detected.  
       [0074] Cell-based screening assays usually require systems for recombinant expression of MBCAT and any auxiliary proteins demanded by the particular assay. Appropriate methods for generating recombinant proteins produce sufficient quantities of proteins that retain their relevant biological activities and are of sufficient purity to optimize activity and assure assay reproducibility. Yeast two-hybrid and variant screens, and mass spectrometry provide preferred methods for determining protein-protein interactions and elucidation of protein complexes. In certain applications, when MBCAT-interacting proteins are used in screens to identify small molecule modulators, the binding specificity of the interacting protein to the MBCAT protein may be assayed by various known methods such as substrate processing (e.g. ability of the candidate MBCAT-specific binding agents to function as negative effectors in MBCAT-expressing cells), binding equilibrium constants (usually at least about 10 7  M −1 , preferably at least about 10 8  M −1 , more preferably at least about 10 9  M −1 ), and immunogenicity (e.g. ability to elicit MBCAT specific antibody in a heterologous host such as a mouse, rat, goat or rabbit). For enzymes and receptors, binding may be assayed by, respectively, substrate and ligand processing.  
       [0075] The screening assay may measure a candidate agent&#39;s ability to specifically bind to or modulate activity of a MBCAT polypeptide, a fusion protein thereof, or to cells or membranes bearing the polypeptide or fusion protein. The MBCAT polypeptide can be full length or a fragment thereof that retains functional MBCAT activity. The MBCAT polypeptide may be fused to another polypeptide, such as a peptide tag for detection or anchoring, or to another tag. The MBCAT polypeptide is preferably human MBCAT, or is an ortholog or derivative thereof as described above. In a preferred embodiment, the screening assay detects candidate agent-based modulation of MBCAT interaction with a binding target, such as an endogenous or exogenous protein or other substrate that has MBCAT-specific binding activity, and can be used to assess normal MBCAT gene function.  
       [0076] Suitable assay formats that may be adapted to screen for MBCAT modulators are known in the art. Preferred screening assays are high throughput or ultra high throughput and thus provide automated, cost-effective means of screening compound libraries for lead compounds (Fernandes P B, Curr Opin Chem Biol (1998) 2:597-603; Sundberg S A, Curr Opin Biotechnol 2000, 11:47-53). In one preferred embodiment, screening assays uses fluorescence technologies, including fluorescence polarization, time-resolved fluorescence, and fluorescence resonance energy transfer. These systems offer means to monitor protein-protein or DNA-protein interactions in which the intensity of the signal emitted from dye-labeled molecules depends upon their interactions with partner molecules (e.g., Selvin P R, Nat Struct Biol (2000) 7:730-4; Fernandes P B, supra; Hertzberg R P and Pope A J, Curr Opin Chem Biol (2000) 4:445-451).  
       [0077] A variety of suitable assay systems may be used to identify candidate MBCAT and beta-catenin pathway modulators (e.g. U.S. Pat. No. 6,165,992 (kinase assays); U.S. Pat. Nos. 5,550,019 and 6,133,437 (apoptosis assays); and U.S. Pat. Nos. 5,976,782, 6,225,118 and 6,444,434 (angiogenesis assays), among others). Specific preferred assays are described in more detail below.  
       [0078] Kinase assays. In some preferred embodiments the screening assay detects the ability of the test agent to modulate the kinase activity of an MBCAT polypeptide. In further embodiments, a cell-free kinase assay system is used to identify a candidate beta-catenin modulating agent, and a secondary, cell-based assay, such as an apoptosis or hypoxic induction assay (described below), may be used to further characterize the candidate beta-catenin modulating agent. Many different assays for kinases have been reported in the literature and are well known to those skilled in the art (e.g. U.S. Pat. No. 6,165,992; Zhu et al., Nature Genetics (2000) 26:283-289; and WO0073469). Radioassays, which monitor the transfer of a gamma phosphate are frequently used. For instance, a scintillation assay for p56 (lck) kinase activity monitors the transfer of the gamma phosphate from gamma- 33 P ATP to a biotinylated peptide substrate; the substrate is captured on a streptavidin coated bead that transmits the signal (Beveridge M et al., J Biomol Screen (2000) 5:205-212). This assay uses the scintillation proximity assay (SPA), in which only radio-ligand bound to receptors tethered to the surface of an SPA bead are detected by the scintillant immobilized within it, allowing binding to be measured without separation of bound from free ligand.  
       [0079] Other assays for protein kinase activity may use antibodies that specifically recognize phosphorylated substrates. For instance, the kinase receptor activation (KIRA) assay measures receptor tyrosine kinase activity by ligand stimulating the intact receptor in cultured cells, then capturing solubilized receptor with specific antibodies and quantifying phosphorylation via phosphotyrosine ELISA (Sadick M D, Dev Biol Stand (1999) 97:121-133).  
       [0080] Another example of antibody based assays for protein kinase activity is TRF (time-resolved fluorometry). This method utilizes europium chelate-labeled anti-phosphotyrosine antibodies to detect phosphate transfer to a polymeric substrate coated onto microtiter plate wells. The amount of phosphorylation is then detected using time-resolved, dissociation-enhanced fluorescence (Braunwalder A F, et al., Anal Biochem Jul. 1, 1996;238(2):159-64).  
       [0081] Apoptosis assays. Assays for apoptosis may be performed by terminal deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nick end labeling (TUNEL) assay. The TUNEL assay is used to measure nuclear DNA fragmentation characteristic of apoptosis (Lazebnik et al., 1994, Nature 371, 346), by following the incorporation of fluorescein-dUTP (Yonehara et al., 1989, J. Exp. Med. 169, 1747). Apoptosis may further be assayed by acridine orange staining of tissue culture cells (Lucas, R., et al., 1998, Blood 15:4730-41). An apoptosis assay system may comprise a cell that expresses an MBCAT, and that optionally has defective beta-catenin function (e.g. beta-catenin is over-expressed or under-expressed relative to wild-type cells). A test agent can be added to the apoptosis assay system and changes in induction of apoptosis relative to controls where no test agent is added, identify candidate beta-catenin modulating agents. In some embodiments of the invention, an apoptosis assay may be used as a secondary assay to test a candidate beta-catenin modulating agents that is initially identified using a cell-free assay system. An apoptosis assay may also be used to test whether MBCAT function plays a direct role in apoptosis. For example, an apoptosis assay may be performed on cells that over- or under-express MBCAT relative to wild type cells. Differences in apoptotic response compared to wild type cells suggests that the MBCAT plays a direct role in the apoptotic response. Apoptosis assays are described further in U.S. Pat. No. 6,133,437.  
       [0082] Cell proliferation and cell cycle assays. Cell proliferation may be assayed via bromodeoxyuridine (BRDU) incorporation. This assay identifies a cell population undergoing DNA synthesis by incorporation of BRDU into newly-synthesized DNA. Newly-synthesized DNA may then be detected using an anti-BRDU antibody (Hoshino et al., 1986, Int. J. Cancer 38, 369; Campana et al., 1988, J. Immunol. Meth. 107, 79), or by other means.  
       [0083] Cell proliferation is also assayed via phospho-histone H3 staining, which identifies a cell population undergoing mitosis by phosphorylation of histone H3. Phosphorylation of histone H3 at serine 10 is detected using an antibody specific to the phosphorylated form of the serine 10 residue of histone H3. (Chadlee, D. N. 1995, J. Biol. Chem 270:20098-105). Cell Proliferation may also be examined using [ 3 H]-thymidine incorporation (Chen, J., 1996, Oncogene 13:1395-403; Jeoung, J., 1995, J. Biol. Chem. 270:18367-73). This assay allows for quantitative characterization of S-phase DNA syntheses. In this assay, cells synthesizing DNA will incorporate [ 3 H]-thymidine into newly synthesized DNA. Incorporation can then be measured by standard techniques such as by counting of radioisotope in a scintillation counter (e.g., Beckman LS 3800 Liquid Scintillation Counter). Another proliferation assay uses the dye Alamar Blue (available from Biosource International), which fluoresces when reduced in living cells and provides an indirect measurement of cell number (Voytik-Harbin S L et al., 1998, In Vitro Cell Dev Biol Anim 34:239-46).  
       [0084] Cell proliferation may also be assayed by colony formation in soft agar (Sambrook et al., Molecular Cloning, Cold Spring Harbor (1989)). For example, cells transformed with MBCAT are seeded in soft agar plates, and colonies are measured and counted after two weeks incubation.  
       [0085] Involvement of a gene in the cell cycle may be assayed by flow cytometry (Gray J W et al. (1986) Int J Radiat Biol Relat Stud Phys Chem Med 49:237-55). Cells transfected with an MBCAT may be stained with propidium iodide and evaluated in a flow cytometer (available from Becton Dickinson), which indicates accumulation of cells in different stages of the cell cycle.  
       [0086] Accordingly, a cell proliferation or cell cycle assay system may comprise a cell that expresses an MBCAT, and that optionally has defective beta-catenin function (e.g. beta-catenin is over-expressed or under-expressed relative to wild-type cells). A test agent can be added to the assay system and changes in cell proliferation or cell cycle relative to controls where no test agent is added, identify candidate beta-catenin modulating agents. In some embodiments of the invention, the cell proliferation or cell cycle assay may be used as a secondary assay to test a candidate beta-catenin modulating agents that is initially identified using another assay system such as a cell-free assay system. A cell proliferation assay may also be used to test whether MBCAT function plays a direct role in cell proliferation or cell cycle. For example, a cell proliferation or cell cycle assay may be performed on cells that over- or under-express MBCAT relative to wild type cells. Differences in proliferation or cell cycle compared to wild type cells suggests that the MBCAT plays a direct role in cell proliferation or cell cycle.  
       [0087] Angiogenesis. Angiogenesis may be assayed using various human endothelial cell systems, such as umbilical vein, coronary artery, or dermal cells. Suitable assays include Alamar Blue based assays (available from Biosource International) to measure proliferation; migration assays using fluorescent molecules, such as the use of Becton Dickinson Falcon HTS FluoroBlock cell culture inserts to measure migration of cells through membranes in presence or absence of angiogenesis enhancer or suppressors; and tubule formation assays based on the formation of tubular structures by endothelial cells on Matrigel® (Becton Dickinson). Accordingly, an angiogenesis assay system may comprise a cell that expresses an MBCAT, and that optionally has defective beta-catenin function (e.g. beta-catenin is over-expressed or under-expressed relative to wild-type cells). A test agent can be added to the angiogenesis assay system and changes in angiogenesis relative to controls where no test agent is added, identify candidate beta-catenin modulating agents. In some embodiments of the invention, the angiogenesis assay may be used as a secondary assay to test a candidate beta-catenin modulating agents that is initially identified using another assay system. An angiogenesis assay may also be used to test whether MBCAT function plays a direct role in cell proliferation. For example, an angiogenesis assay may be performed on cells that over- or under-express MBCAT relative to wild type cells. Differences in angiogenesis compared to wild type cells suggests that the MBCAT plays a direct role in angiogenesis. U.S. Pat. Nos. 5,976,782, 6,225,118 and 6,444,434, among others, describe various angiogenesis assays.  
       [0088] Hypoxic induction. The alpha subunit of the transcription factor, hypoxia inducible factor-1 (HIF-1), is upregulated in tumor cells following exposure to hypoxia in vitro. Under hypoxic conditions, HIF-1 stimulates the expression of genes known to be important in tumour cell survival, such as those encoding glyolytic enzymes and VEGF. Induction of such genes by hypoxic conditions may be assayed by growing cells transfected with MBCAT in hypoxic conditions (such as with 0.1% O2, 5% CO2, and balance N2, generated in a Napco 7001 incubator (Precision Scientific)) and normoxic conditions, followed by assessment of gene activity or expression by Taqman®. For example, a hypoxic induction assay system may comprise a cell that expresses an MBCAT, and that optionally has defective beta-catenin function (e.g. beta-catenin is over-expressed or under-expressed relative to wild-type cells). A test agent can be added to the hypoxic induction assay system and changes in hypoxic response relative to controls where no test agent is added, identify candidate beta-catenin modulating agents. In some embodiments of the invention, the hypoxic induction assay may be used as a secondary assay to test a candidate beta-catenin modulating agents that is initially identified using another assay system. A hypoxic induction assay may also be used to test whether MBCAT function plays a direct role in the hypoxic response. For example, a hypoxic induction assay may be performed on cells that over- or under-express MBCAT relative to wild type cells. Differences in hypoxic response compared to wild type cells suggests that the MBCAT plays a direct role in hypoxic induction.  
       [0089] Cell adhesion. Cell adhesion assays measure adhesion of cells to purified adhesion proteins, or adhesion of cells to each other, in presence or absence of candidate modulating agents. Cell-protein adhesion assays measure the ability of agents to modulate the adhesion of cells to purified proteins. For example, recombinant proteins are produced, diluted to 2.5 g/mL in PBS, and used to coat the wells of a microtiter plate. The wells used for negative control are not coated. Coated wells are then washed, blocked with 1% BSA, and washed again. Compounds are diluted to 2× final test concentration and added to the blocked, coated wells. Cells are then added to the wells, and the unbound cells are washed off. Retained cells are labeled directly on the plate by adding a membrane-permeable fluorescent dye, such as calcein-AM, and the signal is quantified in a fluorescent microplate reader.  
       [0090] Cell-cell adhesion assays measure the ability of agents to modulate binding of cell adhesion proteins with their native ligands. These assays use cells that naturally or recombinantly express the adhesion protein of choice. In an exemplary assay, cells expressing the cell adhesion protein are plated in wells of a multiwell plate. Cells expressing the ligand are labeled with a membrane-permeable fluorescent dye, such as BCECF, and allowed to adhere to the monolayers in the presence of candidate agents. Unbound cells are washed off, and bound cells are detected using a fluorescence plate reader.  
       [0091] High-throughput cell adhesion assays have also been described. In one such assay, small molecule ligands and peptides are bound to the surface of microscope slides using a microarray spotter, intact cells are then contacted with the slides, and unbound cells are washed off. In this assay, not only the binding specificity of the peptides and modulators against cell lines are determined, but also the functional cell signaling of attached cells using immunofluorescence techniques in situ on the microchip is measured (Falsey J R et al., Bioconjug Chem. 2001 May-June;12(3):346-53).  
       [0092] Tubulogenesis. Tubulogenesis assays monitor the ability of cultured cells, generally endothelial cells, to form tubular structures on a matrix substrate, which generally simulates the environment of the extracellular matrix. Exemplary substrates include Matrigel™ (Becton Dickinson), an extract of basement membrane proteins containing laminin, collagen IV, and heparin sulfate proteoglycan, which is liquid at 4° C. and forms a solid gel at 37° C. Other suitable matrices comprise extracellular components such as collagen, fibronectin, and/or fibrin. Cells are stimulated with a pro-angiogenic stimulant, and their ability to form tubules is detected by imaging. Tubules can generally be detected after an overnight incubation with stimuli, but longer or shorter time frames may also be used. Tube formation assays are well known in the art (e.g., Jones M K et al., 1999, Nature Medicine 5:1418-1423). These assays have traditionally involved stimulation with serum or with the growth factors FGF or VEGF. Serum represents an undefined source of growth factors. In a preferred embodiment, the assay is performed with cells cultured in serum free medium, in order to control which process or pathway a candidate agent modulates. Moreover, we have found that different target genes respond differently to stimulation with different pro-angiogenic agents, including inflammatory angiogenic factors such as TNF-alpa. Thus, in a further preferred embodiment, a tubulogenesis assay system comprises testing an MBCAT&#39;s response to a variety of factors, such as FGF, VEGF, phorbol myristate acetate (PMA), TNF-alpha, ephrin, etc.  
       [0093] Cell Migration. An invasion/migration assay (also called a migration assay) tests the ability of cells to overcome a physical barrier and to migrate towards pro-angiogenic signals. Migration assays are known in the art (e.g., Paik J H et al., 2001, J Biol Chem 276:11830-11837). In a typical experimental set-up, cultured endothelial cells are seeded onto a matrix-coated porous lamina, with pore sizes generally smaller than typical cell size. The matrix generally simulates the environment of the extracellular matrix, as described above. The lamina is typically a membrane, such as the transwell polycarbonate membrane (Corning Costar Corporation, Cambridge, Mass.), and is generally part of an upper chamber that is in fluid contact with a lower chamber containing pro-angiogenic stimuli. Migration is generally assayed after an overnight incubation with stimuli, but longer or shorter time frames may also be used. Migration is assessed as the number of cells that crossed the lamina, and may be detected by staining cells with hemotoxylin solution (VWR Scientific, South San Francisco, Calif.), or by any other method for determining cell number. In another exemplary set up, cells are fluorescently labeled and migration is detected using fluorescent readings, for instance using the Falcon HTS FluoroBlok (Becton Dickinson). While some migration is observed in the absence of stimulus, migration is greatly increased in response to pro-angiogenic factors. As described above, a preferred assay system for migration/invasion assays comprises testing an MBCAT&#39;s response to a variety of pro-angiogenic factors, including tumor angiogenic and inflammatory angiogenic agents, and culturing the cells in serum free medium.  
       [0094] Sprouting assay. A sprouting assay is a three-dimensional in vitro angiogenesis assay that uses a cell-number defined spheroid aggregation of endothelial cells (“spheroid”), embedded in a collagen gel-based matrix. The spheroid can serve as a starting point for the sprouting of capillary-like structures by invasion into the extracellular matrix (termed “cell sprouting”) and the subsequent formation of complex anastomosing networks (Korff and Augustin, 1999, J Cell Sci 112:3249-58). In an exemplary experimental set-up, spheroids are prepared by pipetting 400 human umbilical vein endothelial cells into individual wells of a nonadhesive 96-well plates to allow overnight spheroidal aggregation (Korff and Augustin: J Cell Biol 143: 1341-52, 1998). Spheroids are harvested and seeded in 900 μl of methocel-collagen solution and pipetted into individual wells of a 24 well plate to allow collagen gel polymerization. Test agents are added after 30 min by pipetting 100 μl of 10-fold concentrated working dilution of the test substances on top of the gel. Plates are incubated at 37° C. for 24 h. Dishes are fixed at the end of the experimental incubation period by addition of paraformaldehyde. Sprouting intensity of endothelial cells can be quantitated by an automated image analysis system to determine the cumulative sprout length per spheroid.  
       [0095] Primary Assays for Antibody Modulators  
       [0096] For antibody modulators, appropriate primary assays test is a binding assay that tests the antibody&#39;s affinity to and specificity for the MBCAT protein. Methods for testing antibody affinity and specificity are well known in the art (Harlow and Lane, 1988, 1999, supra). The enzyme-linked immunosorbant assay (ELISA) is a preferred method for detecting MBCAT-specific antibodies; others include FACS assays, radioimmunoassays, and fluorescent assays.  
       [0097] In some cases, screening assays described for small molecule modulators may also be used to test antibody modulators.  
       [0098] Primary Assays for Nucleic Acid Modulators  
       [0099] For nucleic acid modulators, primary assays may test the ability of the nucleic acid modulator to inhibit or enhance MBCAT gene expression, preferably mRNA expression. In general, expression analysis comprises comparing MBCAT expression in like populations of cells (e.g., two pools of cells that endogenously or recombinantly express MBCAT) in the presence and absence of the nucleic acid modulator. Methods for analyzing mRNA and protein expression are well known in the art. For instance, Northern blotting, slot blotting, ribonuclease protection, quantitative RT-PCR (e.g., using the TaqMan®, PE Applied Biosystems), or microarray analysis may be used to confirm that MBCAT mRNA expression is reduced in cells treated with the nucleic acid modulator (e.g., Current Protocols in Molecular Biology (1994) Ausubel FM et al., eds., John Wiley &amp; Sons, Inc., chapter 4; Freeman W M et al., Biotechniques (1999) 26:112-125; Kallioniemi O P, Ann Med 2001, 33:142-147; Blohm D H and Guiseppi-Elie, A Curr Opin Biotechnol 2001, 12:41-47). Protein expression may also be monitored. Proteins are most commonly detected with specific antibodies or antisera directed against either the MBCAT protein or specific peptides. A variety of means including Western blotting, ELISA, or in situ detection, are available (Harlow E and Lane D, 1988 and 1999, supra).  
       [0100] In some cases, screening assays described for small molecule modulators, particularly in assay systems that involve MBCAT mRNA expression, may also be used to test nucleic acid modulators.  
       [0101] Secondary Assays  
       [0102] Secondary assays may be used to further assess the activity of MBCAT-modulating agent identified by any of the above methods to confirm that the modulating agent affects MBCAT in a manner relevant to the beta-catenin pathway. As used herein, MBCAT-modulating agents encompass candidate clinical compounds or other agents derived from previously identified modulating agent. Secondary assays can also be used to test the activity of a modulating agent on a particular genetic or biochemical pathway or to test the specificity of the modulating agent&#39;s interaction with MBCAT.  
       [0103] Secondary assays generally compare like populations of cells or animals (e.g., two pools of cells or animals that endogenously or recombinantly express MBCAT) in the presence and absence of the candidate modulator. In general, such assays test whether treatment of cells or animals with a candidate MBCAT-modulating agent results in changes in the beta-catenin pathway in comparison to untreated (or mock- or placebo-treated) cells or animals. Certain assays use “sensitized genetic backgrounds”, which, as used herein, describe cells or animals engineered for altered expression of genes in the beta-catenin or interacting pathways.  
       [0104] Cell-Based Assays  
       [0105] Cell based assays may use a variety of mammalian cell lines known to have defective beta-catenin function. Cell based assays may detect endogenous beta-catenin pathway activity or may rely on recombinant expression of beta-catenin pathway components. Any of the aforementioned assays may be used in this cell-based format. Candidate modulators are typically added to the cell media but may also be injected into cells or delivered by any other efficacious means.  
       [0106] Animal Assays  
       [0107] A variety of non-human animal models of normal or defective beta-catenin pathway may be used to test candidate MBCAT modulators. Models for defective beta-catenin pathway typically use genetically modified animals that have been engineered to mis-express (e.g., over-express or lack expression in) genes involved in the beta-catenin pathway. Assays generally require systemic delivery of the candidate modulators, such as by oral administration, injection, etc.  
       [0108] In a preferred embodiment, beta-catenin pathway activity is assessed by monitoring neovascularization and angiogenesis. Animal models with defective and normal beta-catenin are used to test the candidate modulator&#39;s affect on MBCAT in Matrigel® assays. Matrigel® is an extract of basement membrane proteins, and is composed primarily of laminin, collagen IV, and heparin sulfate proteoglycan. It is provided as a sterile liquid at 4° C., but rapidly forms a solid gel at 37° C. Liquid Matrigel® is mixed with various angiogenic agents, such as bFGF and VEGF, or with human tumor cells which over-express the MBCAT. The mixture is then injected subcutaneously (SC) into female athymic nude mice (Taconic, Germantown, N.Y.) to support an intense vascular response. Mice with Matrigel® pellets may be dosed via oral (PO), intraperitoneal (IP), or intravenous (IV) routes with the candidate modulator. Mice are euthanized 5-12 days post-injection, and the Matrigel® pellet is harvested for hemoglobin analysis (Sigma plasma hemoglobin kit). Hemoglobin content of the gel is found to correlate the degree of neovascularization in the gel.  
       [0109] In another preferred embodiment, the effect of the candidate modulator on MBCAT is assessed via tumorigenicity assays. Tumor xenograft assays are known in the art (see, e.g., Ogawa K et al., 2000, Oncogene 19:6043-6052). Xenografts are typically implanted SC into female athymic mice, 6-7 week old, as single cell suspensions either from a pre-existing tumor or from in vitro culture. The tumors which express the MBCAT endogenously are injected in the flank, 1×10 5  to 1×10 7  cells per mouse in a volume of 100 μL using a 27 gauge needle. Mice are then ear tagged and tumors are measured twice weekly. Candidate modulator treatment is initiated on the day the mean tumor weight reaches 100 mg. Candidate modulator is delivered IV, SC, IP, or PO by bolus administration. Depending upon the pharmacokinetics of each unique candidate modulator, dosing can be performed multiple times per day. The tumor weight is assessed by measuring perpendicular diameters with a caliper and calculated by multiplying the measurements of diameters in two dimensions. At the end of the experiment, the excised tumors maybe utilized for biomarker identification or further analyses. For immunohistochemistry staining, xenograft tumors are fixed in 4% paraformaldehyde, 0.1M phosphate, pH 7.2, for 6 hours at 4° C., immersed in 30% sucrose in PBS, and rapidly frozen in isopentane cooled with liquid nitrogen.  
       [0110] In another preferred embodiment, tumorogenicity is monitored using a hollow fiber assay, which is described in U.S. Pat No. U.S. Pat. No. 5,698,413. Briefly, the method comprises implanting into a laboratory animal a biocompatible, semi-permeable encapsulation device containing target cells, treating the laboratory animal with a candidate modulating agent, and evaluating the target cells for reaction to the candidate modulator. Implanted cells are generally human cells from a pre-existing tumor or a tumor cell line. After an appropriate period of time, generally around six days, the implanted samples are harvested for evaluation of the candidate modulator. Tumorogenicity and modulator efficacy may be evaluated by assaying the quantity of viable cells present in the macrocapsule, which can be determined by tests known in the art, for example, MTT dye conversion assay, neutral red dye uptake, trypan blue staining, viable cell counts, the number of colonies formed in soft agar, the capacity of the cells to recover and replicate in vitro, etc.  
       [0111] In another preferred embodiment, a tumorogenicity assay use a transgenic animal, usually a mouse, carrying a dominant oncogene or tumor suppressor gene knockout under the control of tissue specific regulatory sequences; these assays are generally referred to as transgenic tumor assays. In a preferred application, tumor development in the transgenic model is well characterized or is controlled. In an exemplary model, the “RIP1-Tag2” transgene, comprising the SV40 large T-antigen oncogene under control of the insulin gene regulatory regions is expressed in pancreatic beta cells and results in islet cell carcinomas (Hanahan D, 1985, Nature 315:115-122; Parangi S et al, 1996, Proc Natl Acad Sci USA 93: 2002-2007; Bergers G et al, 1999, Science 284:808-812). An “angiogenic switch,” occurs at approximately five weeks, as normally quiescent capillaries in a subset of hyperproliferative islets become angiogenic. The RIP1-TAG2 mice die by age 14 weeks. Candidate modulators may be administered at a variety of stages, including just prior to the angiogenic switch (e.g., for a model of tumor prevention), during the growth of small tumors (e.g., for a model of intervention), or during the growth of large and/or invasive tumors (e.g., for a model of regression). Tumorogenicity and modulator efficacy can be evaluating life-span extension and/or tumor characteristics, including number of tumors, tumor size, tumor morphology, vessel density, apoptotic index, etc.  
       [0112] Diagnostic and Therapeutic Uses  
       [0113] Specific MBCAT-modulating agents are useful in a variety of diagnostic and therapeutic applications where disease or disease prognosis is related to defects in the beta-catenin pathway, such as angiogenic, apoptotic, or cell proliferation disorders. Accordingly, the invention also provides methods for modulating the beta-catenin pathway in a cell, preferably a cell pre-determined to have defective or impaired beta-catenin function (e.g. due to overexpression, underexpression, or misexpression of beta-catenin, or due to gene mutations), comprising the step of administering an agent to the cell that specifically modulates MBCAT activity. Preferably, the modulating agent produces a detectable phenotypic change in the cell indicating that the beta-catenin function is restored. The phrase “function is restored”, and equivalents, as used herein, means that the desired phenotype is achieved, or is brought closer to normal compared to untreated cells. For example, with restored beta-catenin function, cell proliferation and/or progression through cell cycle may normalize, or be brought closer to normal relative to untreated cells. The invention also provides methods for treating disorders or disease associated with impaired beta-catenin function by administering a therapeutically effective amount of an MBCAT-modulating agent that modulates the beta-catenin pathway. The invention further provides methods for modulating MBCAT function in a cell, preferably a cell pre-determined to have defective or impaired MBCAT function, by administering an MBCAT-modulating agent. Additionally, the invention provides a method for treating disorders or disease associated with impaired MBCAT function by administering a therapeutically effective amount of an MBCAT-modulating agent.  
       [0114] The discovery that MBCAT is implicated in beta-catenin pathway provides for a variety of methods that can be employed for the diagnostic and prognostic evaluation of diseases and disorders involving defects in the beta-catenin pathway and for the identification of subjects having a predisposition to such diseases and disorders.  
       [0115] Various expression analysis methods can be used to diagnose whether MBCAT expression occurs in a particular sample, including Northern blotting, slot blotting, ribonuclease protection, quantitative RT-PCR, and microarray analysis. (e.g., Current Protocols in Molecular Biology (1994) Ausubel F M et al., eds., John Wiley &amp; Sons, Inc., chapter 4; Freeman W M et al., Biotechniques (1999) 26:112-125; Kallioniemi O P, Ann Med 2001, 33:142-147; Blohm and Guiseppi-Elie, Curr Opin Biotechnol 2001, 12:41-47). Tissues having a disease or disorder implicating defective beta-catenin signaling that express an MBCAT, are identified as amenable to treatment with an MBCAT modulating agent. In a preferred application, the beta-catenin defective tissue overexpresses an MBCAT relative to normal tissue. For example, a Northern blot analysis of mRNA from tumor and normal cell lines, or from tumor and matching normal tissue samples from the same patient, using full or partial MBCAT cDNA sequences as probes, can determine whether particular tumors express or overexpress MBCAT. Alternatively, the TaqMan® is used for quantitative RT-PCR analysis of MBCAT expression in cell lines, normal tissues and tumor samples (PE Applied Biosystems).  
       [0116] Various other diagnostic methods may be performed, for example, utilizing reagents such as the MBCAT oligonucleotides, and antibodies directed against an MBCAT, as described above for: (1) the detection of the presence of MBCAT gene mutations, or the detection of either over- or under-expression of MBCAT mRNA relative to the non-disorder state; (2) the detection of either an over- or an under-abundance of MBCAT gene product relative to the non-disorder state; and (3) the detection of perturbations or abnormalities in the signal transduction pathway mediated by MBCAT.  
       [0117] Thus, in a specific embodiment, the invention is drawn to a method for diagnosing a disease or disorder in a patient that is associated with alterations in MBCAT expression, the method comprising: a) obtaining a biological sample from the patient; b) contacting the sample with a probe for MBCAT expression; c) comparing results from step (b) with a control; and d) determining whether step (c) indicates a likelihood of the disease or disorder. Preferably, the disease is cancer, most preferably a cancer as shown in TABLE 1. The probe may be either DNA or protein, including an antibody. 
     
    
    
     EXAMPLES  
     [0118] The following experimental section and examples are offered by way of illustration and not by way of limitation.  
     [0119] I.  C. elegans  Beta-Catenin Screen  
     [0120] The identification of mutants that suppress the cell adhesion defect of beta-catenin may lead to unique therapeutic targets that inhibit cell migration or metastasis. hmp-2 was initially identified in an EMS screen for defects in body elongation during embryonic morphogenesis (see Costa et al., (1998) The Journal of Cell Biology 1998, 141: 297-308). The loss of function allele hmp-2 (zu364) exhibits 99% embryonic lethality, with mutant embryos arresting during elongation and abnormal bulges forming on the dorsal side. About 1% of these embryos hatch to form viable lumpy larvae. The reduction of function allele hmp-2 (qm39) yields viable larvae with a characteristic lumpy appearance. When grown at 15° C., approximately 92% (SD 3.9) of the L1 larvae show this lumpy phenotype, with the penetrance of the phenotype decreasing as the animals molt and move through successive larval stages. For this screen, hmp-2 (qm39) worms were soaked at 15° C. in double stranded RNA (dsRNA) at the L4 larval stage and the progeny were scored as L1 larvae for modification of the adhesion defect. The screen protocol is described below.  
     [0121] 1) hmp-2 (qm39) animals were bleached and hatched on peptone free agarose plates to produce a synchronous population. Starved L1s were transferred to 10× peptone plates seeded with 750 μl OP50 (25% w/v in TB) and allowed to develop to the L4 larval stage.  
     [0122] 2) dsRNA was dispensed in 6 μl aliquots into 96 well round bottom plates (Nunc #262162). L4 animals were collected by suspension in M9 buffer, washed 2× with M9 to remove any excess OP50, and dispensed in 2 μl aliquots into the RNA to a total worm density of 75-100 worms per well. As a control, multiple wells contained only RNA resuspension buffer (lx IM buffer).  
     [0123] 3) Animals were soaked in dsRNA at 15° C. for 24 hours.  
     [0124] 4) Following dsRNA soaking, the animals were fed in the wells by addition of 25 μl liquid NGM+3% OP50. The animals were kept at 15° C. and allowed to become gravid and lay progeny in the wells, which took approximately 72 hours. Food levels were monitored visually during maturation and more was added as needed.  
     [0125] 5) Following maturation, animals from each well were plated onto individual 6 cm peptone free agarose plates and placed at 15° C. overnight.  
     [0126] 6) Animals on each plate were scored visually under the dissecting microscope for modification of the lumpy phenotype. Scoring was performed qualitatively, with an increase in dead embryos scored as enhancement and an increase in wild type appearing animals scored as suppression of the defect.  
     [0127] 7) Retests of interesting suppressor candidates followed the same protocol as the primary screen with certain modifications: several retests were performed for each suppressor, retested candidates were encoded so that they could be scored blindly, and retested candidates were scored quantitatively. Each plate was scored by counting 100 total objects. An object was defined as either an embryo or an L1 stage larva. Each object was scored as one of the following: a wildtype appearing animal, a lumpy appearing animal, or an unhatched embryo. Scores were represented as the percentage of wildtype appearing animals relative to all objects scored. Wildtype animals were defined as L1 larvae with smooth cuticles that did not have any sort of lumpy body morphology.  
     [0128] 8) A confirmed suppressor was one that was ≧2 standard deviations away from the mean of the controls for at least 3 of the four retest experiments.  
     [0129] We identified C 10C6.1 as a suppressor from this screen. Human orthologs of the modifier are referred to herein as MBCAT.  
     [0130] BLAST analysis (Altschul et al., supra) was employed to identify orthologs of  C. elegans  modifier. For example, representative sequences from MBCAT, GI#s 14149671, 14759411, 17455844, and 27498257 (SEQ ID NOs:14, 15, 16, and 18, respectively) share 41%, 36%, 43% and 41% amino acid identity, respectively, with the  C. elegnas  C10C6.1.  
     [0131] Various domains, signals, and functional subunits in proteins were analyzed using the PSORT (Nakai K., and Horton P., Trends Biochem Sci, 1999, 24:34-6; Kenta Nakai, Protein sorting signals and prediction of subcellular localization, Adv. Protein Chem. 54, 277-344 (2000)), PFAM (Bateman A., et al., Nucleic Acids Res, 1999, 27:260-2), SMART (Ponting C P, et al., SMART: identification, and annotation of domains from signaling and extracellular protein sequences. Nucleic Acids Res. Jan. 1, 1999;27(1):229-32), TM-HMM (Erik L. L. Sonnhammer, Gunnar von Heijne, and Anders Krogh: A hidden Markov model for predicting transmembrane helices in protein sequences. In Proc. of Sixth Int. Conf. on Intelligent Systems for Molecular Biology, p 175-182 Ed J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D. Sankoff, and C. Sensen Menlo Park, Calif.: AAAI Press, 1998), and dust (Remm M, and Sonnhammer E. Classification of transmembrane protein families in the Caenorhabditis elegans genome and identification of human orthologs. Genome Res. 2000 November;10(11):1679-89) programs. For example, the kinase domain of MBCAT from GI#s 14149671, 14759411, 17455844, and 27498257 (SEQ ID NOs: 14, 15, 16, and 18, respectively) are located respectively at approximately amino acid residues 512 to 785, 460 to 547, 197 to 470, and 39 to 312 (PFAM 00069).  
     [0132] II. High-Throughput In Vitro Fluorescence Polarization Assay  
     [0133] Fluorescently-labeled MBCAT peptide/substrate are added to each well of a 96-well microtiter plate, along with a test agent in a test buffer (10 mM HEPES, 10 mM NaCl, 6 mM magnesium chloride, pH 7.6). Changes in fluorescence polarization, determined by using a Fluorolite FPM-2 Fluorescence Polarization Microtiter System (Dynatech Laboratories, Inc), relative to control values indicates the test compound is a candidate modifier of MBCAT activity.  
     [0134] III. High-Throuphput in Vitro Binding Assay.  
     [0135] 33 P-labeled MBCAT peptide is added in an assay buffer (100 mM KCl, 20 mM HEPES pH 7.6, 1 mM MgCl 2 , 1% glycerol, 0.5% NP-40, 50 mM beta-mercaptoethanol, 1 mg/ml BSA, cocktail of protease inhibitors) along with a test agent to the wells of a Neutralite-avidin coated assay plate and incubated at 25° C. for 1 hour. Biotinylated substrate is then added to each well and incubated for 1 hour. Reactions are stopped by washing with PBS, and counted in a scintillation counter. Test agents that cause a difference in activity relative to control without test agent are identified as candidate beta-catenin modulating agents.  
     [0136] IV. Immunoprecipitations and Immunoblotting  
     [0137] For coprecipitation of transfected proteins, 3×10 6  appropriate recombinant cells containing the MBCAT proteins are plated on 10-cm dishes and transfected on the following day with expression constructs. The total amount of DNA is kept constant in each transfection by adding empty vector. After 24 h, cells are collected, washed once with phosphate-buffered saline and lysed for 20 min on ice in 1 ml of lysis buffer containing 50 mM Hepes, pH 7.9, 250 mM NaCl, 20 mM-glycerophosphate, 1 mM sodium orthovanadate, 5 mM p-nitrophenyl phosphate, 2 mM dithiothreitol, protease inhibitors (complete, Roche Molecular Biochemicals), and 1% Nonidet P-40. Cellular debris is removed by centrifugation twice at 15,000×g for 15 min. The cell lysate is incubated with 25 μl of M2 beads (Sigma) for 2 h at 4° C. with gentle rocking.  
     [0138] After extensive washing with lysis buffer, proteins bound to the beads are solubilized by boiling in SDS sample buffer, fractionated by SDS-polyacrylamide gel electrophoresis, transferred to polyvinylidene difluoride membrane and blotted with the indicated antibodies. The reactive bands are visualized with horseradish peroxidase coupled to the appropriate secondary antibodies and the enhanced chemiluminescence (ECL) Western blotting detection system (Amersham Pharmacia Biotech).  
     [0139] V. Kinase Assay  
     [0140] A purified or partially purified MBCAT is diluted in a suitable reaction buffer, e.g., 50 mM Hepes, pH 7.5, containing magnesium chloride or manganese chloride (1-20 mM) and a peptide or polypeptide substrate, such as myelin basic protein or casein (1-10 μg/ml). The final concentration of the kinase is 1-20 nM. The enzyme reaction is conducted in microtiter plates to facilitate optimization of reaction conditions by increasing assay throughput. A 96-well microtiter plate is employed using a final volume 30-100 μl. The reaction is initiated by the addition of  33 P-gamma-ATP (0.5 μCl/ml) and incubated for 0.5 to 3 hours at room temperature. Negative controls are provided by the addition of EDTA, which chelates the divalent cation (Mg2 +  or Mn 2+ ) required for enzymatic activity. Following the incubation, the enzyme reaction is quenched using EDTA. Samples of the reaction are transferred to a 96-well glass fiber filter plate (MultiScreen, Millipore). The filters are subsequently washed with phosphate-buffered saline, dilute phosphoric acid (0.5%) or other suitable medium to remove excess radiolabeled ATP. Scintillation cocktail is added to the filter plate and the incorporated radioactivity is quantitated by scintillation counting (Wallac/Perkin Elmer). Activity is defined by the amount of radioactivity detected following subtraction of the negative control reaction value (EDTA quench).  
     [0141] VI. Expression Analysis  
     [0142] All cell lines used in the following experiments are NCI (National Cancer Institute) lines, and are available from ATCC (American Type Culture Collection, Manassas, Va. 20110-2209). Normal and tumor tissues were obtained from Impath, U C Davis, Clontech, Stratagene, Ardais, Genome Collaborative, and Ambion.  
     [0143] TaqMan analysis was used to assess expression levels of the disclosed genes in various samples.  
     [0144] RNA was extracted from each tissue sample using Qiagen (Valencia, Calif.) RNeasy kits, following manufacturer&#39;s protocols, to a final concentration of 50 ng/μl. Single stranded cDNA was then synthesized by reverse transcribing the RNA samples using random hexamers and 500 ng of total RNA per reaction, following protocol 4304965 of Applied Biosystems (Foster City, Calif.).  
     [0145] Primers for expression analysis using TaqMan assay (Applied Biosystems, Foster City, Calif.) were prepared according to the TaqMan protocols, and the following criteria: a) primer pairs were designed to span introns to eliminate genomic contamination, and b) each primer pair produced only one product. Expression analysis was performed using a 7900HT instrument.  
     [0146] Taqman reactions were carried out following manufacturer&#39;s protocols, in 25 μl total volume for 96-well plates and 10 μl total volume for 384-well plates, using 300 nM primer and 250 nM probe, and approximately 25 ng of cDNA. The standard curve for result analysis was prepared using a universal pool of human cDNA samples, which is a mixture of cDNAs from a wide variety of tissues so that the chance that a target will be present in appreciable amounts is good. The raw data were normalized using 18S rRNA (universally expressed in all tissues and cells).  
     [0147] For each expression analysis, tumor tissue samples were compared with matched normal tissues from the same patient. A gene was considered overexpressed in a tumor when the level of expression of the gene was 2 fold or higher in the tumor compared with its matched normal sample. In cases where normal tissue was not available, a universal pool of cDNA samples was used instead. In these cases, a gene was considered overexpressed in a tumor sample when the difference of expression levels between a tumor sample and the average of all normal samples from the same tissue type was greater than 2 times the standard deviation of all normal samples (i.e., Tumor−average (all normal samples)&gt;2×STDEV (all normal samples)).  
     [0148] Results are shown in Table 1. Number of pairs of tumor samples and matched normal tissue from the same patient are shown for each tumor type. Percentage of the samples with at least two-fold overexpression for each tumor type is provided. A modulator identified by an assay described herein can be further validated for therapeutic effect by administration to a tumor in which the gene is overexpressed. A decrease in tumor growth confirms therapeutic utility of the modulator. Prior to treating a patient with the modulator, the likelihood that the patient will respond to treatment can be diagnosed by obtaining a tumor sample from the patient, and assaying for expression of the gene targeted by the modulator. The expression data for the gene(s) can also be used as a diagnostic marker for disease progression. The assay can be performed by expression analysis as described above, by antibody directed to the gene target, or by any other available detection method.  
                                                                                           TABLE 1                           SEQ                   Head                                                               ID       # of   Col-   # of   and   # of   Kid-   # of       # of   Ov-   # of   Pro-   # of       # of   Uter-   # of       GI#   NO:   Breast   Pairs   on   Pairs   Neck   Pairs   ney   Pairs   Lung   Pairs   ary   Pairs   state   Pairs   Skin   Pairs   us   Pairs                                                                                                                18561839   11   0%   21   15%   33   12%   8   25%   24   5%   21   0%   11   8%   12   0%   3   16%   19       17455843   10   5%   21   6%   33   25%   8   12%   24   5%   21   0%   11   8%   12   33%   3   5%   19       10440171   3   38%   21   9%   33   12%   8   8%   24   19%   21   27%   11   8%   12   67%   3   11%   19       16198348   4   38%   21   9%   33   12%   8   8%   24   19%   21   27%   11   8%   12   67%   3   11%   19       10440171   3   38%   21   9%   33   12%   8   8%   24   19%   21   27%   11   8%   12   67%   3   11%   19       &amp;   &amp;       16198348   4       18600993   7   14%   21   6%   33   12%   8   8%   24   14%   21   27%   11   8%   12   33%   3   5%   19                  
 
     [0149] 
    
     
       
         1 
         
           
             18  
           
           
             1  
             5737  
             DNA  
             Homo sapiens  
           
            1 

taggcaggcg gctgagccgg cggcgggtgg cctgcccaac gtgtgctggg tgggagaagg     60 

cgaggcggca gcgatgctgt ctcttccgtg aggagcgcag aggaggtcgc ggcgccggag    120 

gccccagaag gctcgaaggc gccgcgggct ggggtcggtg gcttagggag cccgtccggc    180 

catggtggcc gcgggtggtg gttggcgcgg ctgcgctgcg gcccggggca gtgcggagcc    240 

gggacagtcg cggcgctgac gcccgcgggc cccagctgca gatatgaagc ggagccgctg    300 

ccgcgaccga ccgcagccgc cgccgcccga ccgccgggag gatggagttc agcgggcagc    360 

ggagctgtct cagtctttgc cgccgcgccg gcgagcgccg cccgggaggc agcggctgga    420 

ggagcggacg ggccccgcgg ggcccgaggg caaggagcag gatgtagtaa ctggagttag    480 

tcccctgctc ttcaggaaac tcagtaatcc tgacatattt tcatccactg gaaaagttaa    540 

acttcagcga caactgagtc aggatgattg taagttatgg agaggaaacc tggccagctc    600 

tctatcgggt aagcagctgc tccctttgtc cagcagtgta catagcagtg tgggacaggt    660 

gacttggcag tcgtcaggag aagcatcaaa cctggttcga atgagaaacc agtcccttgg    720 

acagtctgca ccttctctta ctgctggcct gaaggagttg agccttccaa gaagaggcag    780 

cttttgtcgg acaagtaacc gcaagagctt gattgtgacc tctagcacat cacctacact    840 

accacggcca cactcaccac tccatggcca cacaggtaac agtcctttgg acagcccccg    900 

gaatttctct ccaaatgcac ctgctcactt ttcttttgtt cctgcccgta ggactgatgg    960 

gcggcgctgg tctttggcct ctttgccctc ttcaggatat ggaactaaca ctcctagctc   1020 

cactgtctca tcatcatgct cctcacagga aaagctgcat cagttgcctt tccagcctac   1080 

agctgatgag ctgcactttt tgacgaagca tttcagcaca gagagcgtac cagatgagga   1140 

aggacggcag tccccagcca tgcggcctcg ctcccggagc ctcagtcccg gacgatcccc   1200 

agtatccttt gacagtgaaa taataatgat gaatcacgtt tacaaagaaa gattcccaaa   1260 

ggccaccgca caaatggaag agcgactagc agagtttatt tcctccaaca ctccagacag   1320 

cgtgctgccc ttggcagatg gagccctgag ctttattcat catcaggtga ttgagatggc   1380 

ccgagactgc ctggataaat ctcggagtgg cctcattaca tcacaatact tctacgaact   1440 

tcaagagaat ttggagaaac ttttacaaga tgctcatgag cgctcagaga gctcagaagt   1500 

ggcttttgtg atgcagctgg tgaaaaagct gatgattatc attgcccgcc cagcacgtct   1560 

cctggaatgc ctggagtttg accctgaaga gttctaccac cttttagaag cagctgaggg   1620 

ccacgccaaa gagggacaag ggattaaatg tgacattccc cgctacatcg ttagccagct   1680 

gggcctcacc cgggatcccc tagaagaaat ggcccagttg agcagctgtg acagtcctga   1740 

cactccagag acagatgatt ctattgaggg ccatggggca tctctgccat ctaaaaagac   1800 

accctctgaa gaggacttcg agaccattaa gctcatcagc aatggcgcct atggggctgt   1860 

atttctggtg cggcacaagt ccacccggca gcgctttgcc atgaagaaga tcaacaagca   1920 

gaacctgatc ctacggaacc agatccagca ggccttcgtg gagcgtgaca tactgacttt   1980 

cgctgagaac ccctttgtgg tcagcatgtt ctgctccttt gataccaagc gccacttgtg   2040 

catggtgatg gagtacgttg aagggggaga ctgtgccact ctgctgaaga atattggggc   2100 

cctgcctgtg gacatggtgc gtctatactt tgcggaaact gtgctggccc tggagtactt   2160 

acacaactat ggcatcgtgc accgtgacct caagcctgac aacctcctaa ttacatccat   2220 

ggggcacatc aagctcacgg actttggact gtccaaaatg ggcctcatga gtctgacaac   2280 

gaacttgtat gagggtcata ttgaaaagga tgcccgggaa ttcctggaca agcaggtatg   2340 

cgggacccca gaatacattg cgcctgaggt gatcctgcgc cagggctatg ggaagccagt   2400 

ggactggtgg gccatgggca ttatcctgta tgagttcctg gtgggctgcg tccctttttt   2460 

tggagatact ccggaggagc tctttgggca ggtgatcagt gatgagattg tgtggcctga   2520 

gggtgatgag gcactgcccc cagacgccca ggacctcacc tccaaactgc tccaccagaa   2580 

ccctctggag agacttggca caggcagtgc ctatgaggtg aagcagcacc cattctttac   2640 

tggtctggac tggacaggac ttctccgcca gaaggctgaa tttattcctc agttggagtc   2700 

agaggatgat actagctatt ttgacacccg ctcagagcga taccaccaca tggactcgga   2760 

ggatgaggaa gaagtgagtg aggatggctg ccttgagatc cgccagttct cttcctgctc   2820 

tccaaggttc aacaaggtgt acagcagcat ggagcggctc tcactgctcg aggagcgccg   2880 

gacaccaccc ccgaccaagc gcagcctgag tgaggagaag gaggaccatt cagatggcct   2940 

ggcagggctc aaaggccgag accggagctg ggtgattggc tcccctgaga tattacggaa   3000 

gcggctgtcg gtgtctgagt cgtcccacac agagagtgac tcaagccctc caatgacagt   3060 

gcgacgccgc tgctcaggcc tcctggatgc gcctcggttc ccggagggcc ctgaggaggc   3120 

cagcagcacc ctcaggaggc aaccacagga gggtatatgg gtcctgacac ccccatctgg   3180 

agagggggta tctgggcctg tcactgaaca ctcaggggag cagcggccaa agctggatga   3240 

ggaagctgtt ggccggagca gtggttccag tccagctatg gagacccgag gccgtgggac   3300 

ctcacagctg gctgagggag ccacagccaa ggccatcagt gacctggctg tgcgtagggc   3360 

ccgccaccgg ctgctctctg gggactcaac agagaagcgc actgctcgcc ctgtcaacaa   3420 

agtgatcaag tccgcctcag ccacagccct ctcactcctc attccttcgg aacaccacac   3480 

ctgctccccg ttggccagcc ccatgtcccc acattctcag tcgtccaacc catcatcccg   3540 

ggactcttct ccaagcaggg acttcttgcc agcccttggc agcatgaggc ctcccatcat   3600 

catccaccga gctggcaaga agtatggctt caccctgcgg gccattcgcg tctacatggg   3660 

tgactccgat gtctacaccg tgcaccatat ggtgtggcac gtggaggatg gaggtccggc   3720 

cagtgaggca gggcttcgtc aaggtgacct catcacccat gtcaatgggg aacctgtgca   3780 

tggcctggtg cacacggagg tggtggagct gatcctgaag agtggaaaca aggtggccat   3840 

ttcaacaact cccctggaga acacatccat taaagtgggg ccagctcgga agggcagcta   3900 

caaggccaag atggcccgaa ggagcaagag gagccgcggc aaggatgggc aagaaagcag   3960 

aaaaaggagc tccctgttcc gcaagatcac caagcaagca tccctgctcc acaccagccg   4020 

cagcctttct tcccttaacc gctccttgtc atcaggggag agtgggccag gctctcccac   4080 

acacagccac agcctttccc cccgatctcc cactcaaggc taccgggtga cccccgatgc   4140 

tgtgcattca gtgggaggga attcatcaca gagcagctcc cccagctcca gcgtgcccag   4200 

ttccccagcc ggctctgggc acacacggcc cagctccctc cacggtctgg cacccaagct   4260 

ccaacgccag taccgctctc cacggcgcaa gtcagcaggc agcatcccac tgtcaccact   4320 

ggcccacacc ccttctcccc cacccccaac agcttcacct cagcggtccc catcgcccct   4380 

gtctggccat gtagcccagg cctttcccac aaagcttcac ttgtcacctc ccctgggcag   4440 

gcaactctca cggcccaaga gtgcggagcc accccgttca ccactactca agagggtgca   4500 

gtcggctgag aaactggcag cagcacttgc cgcctctgag aagaagctag ccacttctcg   4560 

caagcacagc cttgacctgc cccactctga actaaagaag gaactgccgc ccagggaagt   4620 

gagccctctg gaggtagttg gagccaggag tgtgctgtct ggcaaggggg ccctgccagg   4680 

gaagggggtg ctgcagcctg ctccctcacg ggccctaggc accctccggc aggaccgagc   4740 

cgaacgacgg gagtcgctgc agaagcaaga agccattcgt gaggtggact cctcagagga   4800 

cgacaccgag gaagggcctg agaacagcca gggtgcacag gagctgagct tggcacctca   4860 

cccagaagtg agccagagtg tggcccctaa aggagcagga gagagtgggg aagaggatcc   4920 

tttcccgtcc agaggcccta ggagcctggg cccaatggtc ccaagcctat tgacagggat   4980 

cacactgggg cctcccagaa tggaaagtcc cagtggtccc cacaggaggc tcgggagccc   5040 

acaagccatt gaggaggctg ccagctcctc ctcagcaggc cccaacctag gtcagtctgg   5100 

agccacagac cccatccctc ctgaaggttg ctggaaggcc cagcacctcc acacccaggc   5160 

actaacagca ctttctccca gcacttcggg actcaccccc accagcagtt gctctcctcc   5220 

cagctccacc tctgggaagc tgagcatgtg gtcctggaaa tcccttattg agggcccaga   5280 

cagggcatcc ccaagcagaa aggcaaccat ggcaggtggg ctagccaacc tccaggattt   5340 

ggaaacacaa ctccagccca gcctaagaac ctgtctccca gggagcaggg gaagacacag   5400 

ccacctagtg cccccagact ggcccatcca tcttatgagg atcccagcca gggctggcta   5460 

tgggagtctg agtgtgcaca agcagtgaaa gaggatccag ccctgagcat cacccaagtg   5520 

cctgatgcct caggtgacag aaggcaggac gttccatgcc gaggctgccc cctcacccag   5580 

aagtctgagc ccagcctcag gaggggccaa gaaccagggg gccatcaaaa gcatcgggat   5640 

ttggcattgg ttccagatga gcttttaaag caaacatagc agttgtttgc catttcttgc   5700 

actcagacct gtgtaatata tgctcctgga aaccatc                            5737 

 
           
             2  
             4049  
             DNA  
             Homo sapiens  
           
            2 

cccgggatcc cctagaagaa atggcccagt tgagcagctg tgacagtcct gacactccag     60 

agacagatga ttctattgag ggccatgggg catctctgcc atctaaaaag acaccctctg    120 

aagaggactt cgagaccatt aagctcatca gcaatggcgc ctatggggct gtatttctgg    180 

tgcggcacaa gtccacccgg cagcgctttg ccatgaagaa gatcaacaag cagaacctga    240 

tcctacggaa ccagatccag caggccttcg tggagcgtga catactgact ttcgctgaga    300 

acccctttgt ggtcagcatg ttctgctcct ttgataccaa gcgccacttg tgcatggtga    360 

tggagtacgt tgaaggggga gactgtgcca ctctgctgaa gaatattggg gccctgcctg    420 

tggacatggt gcgtctatac tttgcggaaa ctgtgctggc cctggagtac ttacacaact    480 

atggcatcgt gcaccgtgac ctcaagcctg acaacctcct aattacatcc atggggcaca    540 

tcaagctcac ggactttgga ctgtccaaaa tgggcctcat gagtctgaca acgaacttgt    600 

atgagggtca tattgaaaag gatgcccggg aattcctgga caagcaggta tgcgggaccc    660 

cagaatacat tgcgcctgag gtgatcctgc gccagggcta tgggaagcca gtggactggt    720 

gggccatggg cattatcctg tatgagttcc tggtgggctg cgtccctttt tttggagata    780 

ctccggagga gctctttggg caggtgatca gtgatgagat tgtgtggcct gagggtgatg    840 

aggcactgcc cccagacgcc caggacctca cctccaaact gctccaccag aaccctctgg    900 

agagacttgg cacaggcagt gcctatgagg tgaagcagca cccattcttt actggtctgg    960 

actggacagg acttctccgc cagaaggctg aatttattcc tcagttggag tcagaggatg   1020 

atactagcta ttttgacacc cgctcagagc gataccacca catggactcg gaggatgagg   1080 

aagaagtgag tgaggatggc tgccttgaga tccgccagtt ctcttcctgc tctccaaggt   1140 

tcaacaaggt gtacagcagc atggagcggc tctcactgct cgaggagcgc cggacaccac   1200 

ccccgaccaa gcgcagcctg agtgaggaga aggaggacca ttcagatggc ctggcagggc   1260 

tcaaaggccg agaccggagc tgggtgattg gctcccctga gatattacgg aagcggctgt   1320 

cggtgtctga gtcgtcccac acagagagtg actcaagccc tccaatgaca gtgcgacgcc   1380 

gctgctcagg cctcctggat gcgcctcggt tcccggaggg ccctgaggag gccagcagca   1440 

ccctcaggag gcaaccacag gagggtatat gggtcctgac acccccatct ggagaggggg   1500 

tatctgggcc tgtcactgaa cactcagggg agcagcggcc aaagctggat gaggaagctg   1560 

ttggccggag cagtggttcc agtccagcta tggagacccg aggccgtggg acctcacagc   1620 

tggctgaggg agccacagcc aaggccatca gtgacctggc tgtgcgtagg gcccgccacc   1680 

ggctgctctc tggggactca acagagaagc gcactgctcg ccctgtcaac aaagtgatca   1740 

agtccgcctc agccacagcc ctctcactcc tcattccttc ggaacaccac acctgctccc   1800 

cgttggccag ccccatgtcc ccacattctc agtcgtccaa cccatcatcc cgggactctt   1860 

ctccaagcag ggacttcttg ccagcccttg gcagcatgag gcctcccatc atcatccacc   1920 

gagctggcaa gaagtatggc ttcaccctgc gggccattcg cgtctacatg ggtgactccg   1980 

atgtctacac cgtgcaccat atggtgtggc acgtggagga tggaggtccg gccagtgagg   2040 

cagggcttcg tcaaggtgac ctcatcaccc atgtcaatgg ggaacctgtg catggcctgg   2100 

tgcacacgga ggtggtggag ctgatcctga agagtggaaa caaggtggcc atttcaacaa   2160 

ctcccctgga gaacacatcc attaaagtgg ggccagctcg gaagggcagc tacaaggcca   2220 

agatggcccg aaggagcaag aggagccgcg gcaaggatgg gcaagaaagc agaaaaagga   2280 

gctccctgtt ccgcaagatc accaagcaag catccctgct ccacaccagc cgcagccttt   2340 

cttcccttaa ccgctccttg tcatcagggg agagtgggcc aggctctccc acacacagcc   2400 

acagcctttc cccccgatct cccactcaag gctaccgggt gacccccgat gctgtgcatt   2460 

cagtgggagg gaattcatca cagagcagct cccccagctc cagcgtgccc agttccccag   2520 

ccggctctgg gcacacacgg cccagctccc tccacggtct ggcacccaag ctccaacgcc   2580 

agtaccgctc tccacggcgc aagtcagcag gcagcatccc actgtcacca ctggcccaca   2640 

ccccttctcc cccaccccca acagcttcac ctcagcggtc cccatcgccc ctgtctggcc   2700 

atgtagccca ggcctttccc acaaagcttc acttgtcacc tcccctgggc aggcaactct   2760 

cacggcccaa gagtgcggag ccaccccgtt caccactact caagagggtg cagtcggctg   2820 

agaaactggc agcagcactt gccgcctctg agaagaagct agccacttct cgcaagcaca   2880 

gccttgacct gccccactct gaactaaaga aggaactgcc gcccagggaa gtgagccctc   2940 

tggaggtagt tggagccagg agtgtgctgt ctggcaaggg ggccctgcca gggaaggggg   3000 

tgctgcagcc tgctccctca cgggccctag gcaccctccg gcaggaccga gccgaacgac   3060 

gggagtcgct gcagaagcaa gaagccattc gtgaggtgga ctcctcagag gacgacaccg   3120 

aggaagggcc tgagaacagc cagggtgcac aggagctgag cttggcacct cacccagaag   3180 

tgagccagag tgtggcccct aaaggagcag gagagagtgg ggaagaggat cctttcccgt   3240 

ccagaggccc taggagcctg ggcccaatgg tcccaagcct attgacaggg atcacactgg   3300 

ggcctcccag aatggaaagt cccagtggtc cccacaggag gctcgggagc ccacaagcca   3360 

ttgaggaggc tgccagctcc tcctcagcag gccccaacct aggtcagtct ggagccacag   3420 

accccatccc tcctgaaggt tgctggaagg cccagcacct ccacacccag gcactaacag   3480 

cactttctcc cagcacttcg ggactcaccc ccaccagcag ttgctctcct cccagctcca   3540 

cctctgggaa gctgagcatg tggtcctgga aatcccttat tgagggccca gacagggcat   3600 

ccccaagcag aaaggcaacc atggcaggtg ggctagccaa cctccaggat ttggaaacac   3660 

aactccagcc cagcctaaga acctgtctcc cagggagcag gggaagacac agccacctag   3720 

tgcccccaga ctggcccatc catcttatga ggatcccagc cagggctggc tatgggagtc   3780 

tgagtgtgca caagcagtga aagaggatcc agccctgagc atcacccaag tgcctgatgc   3840 

ctcaggtgac agaaggcagg acgttccatg ccgaggctgc cccctcaccc agaagtctga   3900 

gcccagcctc aggaggggcc aagaaccagg gggccatcaa aagcatcggg atttggcatt   3960 

ggttccagat gagcttttaa agcaaacata gcagttgttt gccatttctt gcactcagac   4020 

ctgtgtaata tatgctcctg gaaaccatc                                     4049 

 
           
             3  
             2776  
             DNA  
             Homo sapiens  
           
            3 

attcatttgg gatctggaac ttgtcactgt cccactgctg cctcgtgggc tcttaggtct     60 

tttgtggggg gatgggaggg gtgttctgaa gatcatgttt ttgaagaaaa gtactttaat    120 

ttttgccaat ctctaccctt tgccgaggag ctgaagtaaa ccagcacatg ttttcaccca    180 

catctgctcc agccctcttc ctcactaaag tcccatttag tgctgattgt gctttggcta    240 

cttctcctct tgccattttc ctgaacccac gagcccacag cagtcctggc actccttgtt    300 

ccagccgccc actgccgtgg agttgtcgga caagtaaccg caagagcttg attgtgacct    360 

ctagcacatc acctacacta ccacggccac actcaccact ccatggccac acaggtaaca    420 

gtcctttgga cagcccccgg aatttctctc caaatgcacc tgctcacttt tcttttgttc    480 

ctgcccgtag gactgatggg cggcgctggt ctttggcctc tttgccctct tcaggatatg    540 

gaactaacac tcctagctcc actgtctcat catcatgctc ctcacaggaa aagctgcatc    600 

agttgccttt ccagcctaca gctgatgagc tgcacttttt gacgaagcat ttcagcacag    660 

agagcgtacc agatgaggaa ggacggcagt ccccagccat gcggcctcgc tcccggagcc    720 

tcagtcccgg acgatcccca gtatcctttg acagtgaaat aataatgatg aatcatgttt    780 

acaaagaaag attcccaaag gccaccgcac aaatggaaga gcgactagca gagtttattt    840 

cctccaacac tccagacagc gtgctgccct tggcagatgg agccctgagc tttattcatc    900 

atcaggtgat tgagatggcc cgagactgcc tggataaatc tcggagtggc ctcattacat    960 

cacaatactt ctacgaactt caagagaatt tggagaaact tttacaagat gctcatgagc   1020 

gctcagagag ctcagaagtg gcttttgtga tgcagctggt gaaaaagctg atgattatca   1080 

ttgcccgccc agcacgtctc ctggaatgcc tggagtttga ccctgaagag ttctaccacc   1140 

ttttagaagc agctgagggc cacgccaaag agggacaagg gattaaatgt gacattcccc   1200 

gctacatcgt tagccagctg ggcctcaccc gggatcccct agaagaaatg gcccagttga   1260 

gcagctgtga cagtcctgac actccagaga cagatgattc tattgagggc catggggcat   1320 

ctctgccatc taaaaagaca ccctctgaag aggacttcga gaccattaag ctcatcagca   1380 

atggcgccta tggggctgta tttctggtgc ggcacaagtc cacccggcag cgctttgcca   1440 

tgaagaagat caacaagcag aacctgatcc tacggaacca gatccagcag gccttcgtgg   1500 

agcgtgacat actgactttc gctgagaacc cctttgtggt cagcatgttc tgctcctttg   1560 

ataccaagcg ccacttgtgc atggtgatgg agtacgttga agggggagac tgtgccactc   1620 

tgctgaagaa tattggggcc ctgcctgtgg acatggtgcg tctatacttt gcggaaactg   1680 

tgctggccct ggagtactta cacaactatg gcatcgtgca ccgtgacctc aagcctgaca   1740 

acctcctaat tacatccatg gggcacatca agctcacgga ctttggactg tccaaaatgg   1800 

gcctcatgag tctgacaacg aacttgtatg agggtcatat tgaaaaggat gcccgggaat   1860 

tcctggacaa gcaggtatgc gggaccccag aatacattgc gcctgaggtg atcctgcgcc   1920 

agggctatgg gaagccagtg gactggtggg ccatgggcat tatcctgtat gagttcctgg   1980 

tgggctgcgt cccttttttt ggagatactc cggaggagct ctttgggcag gtgatcagtg   2040 

atgagattgt gtggcctgag ggtgatgagg cactgccccc agacgcccag gacctcacct   2100 

ccaaactgct ccaccagaac cctctggaga gacttggcac aggcagtgcc tatgaggtga   2160 

agcagcaccc attctttact ggtctggact ggacaggact tctccgccag aaggctgaat   2220 

ttattcctca gttggagtca gaggatgata ctagctattt tgacacccgc tcagagcgat   2280 

accaccacat ggactcggag gatgaggaag aagtgagtga ggatggctgc cttgagatcc   2340 

gccagttctc ttcctgctct ccaaggttca acaaggtgta cagcagcatg gagcggctct   2400 

cactgctcga ggagcgccgg acaccacccc cgaccaagcg cagcctgagt gaggagaagg   2460 

aggaccattc agatggcctg gcagggctca aaggccgaga ccggagctgg gtgattggct   2520 

cccctgagca tcacccaagt gcctgatgcc tcaggtgaca gaaggcagga cgttccatgc   2580 

cgaggctgcc ccctcaccca gaagtctgag cccagcctca ggaggggcca agaaccaggg   2640 

ggccatcaaa agcatcggga tttggcattg gttccagatg agcttttaaa gcaaacatag   2700 

cagttgtttg ccatttcttg cactcagacc tgtgtaatat atgctcctgg aaaccataaa   2760 

aaaaaaaaaa aaaaaa                                                   2776 

 
           
             4  
             4087  
             DNA  
             Homo sapiens  
           
            4 

ggcacgaggg agcgtaccag atgaggaagg acggcagtcc ccagccatgc ggcctcgctc     60 

ccggagcctc agtcccggac gatccccagt atcctttgac agtgaaataa taatgatgaa    120 

tcatgtttac aaagaaagat tcccaaaggc tcatgagcgc tcagagagct cagaagtggc    180 

ttttgtgatg cagctggtga aaaagctgat gattatcatt gcccgcccag cacgtctcct    240 

ggaatgcctg gagtttgacc ctgaagagtt ctaccacctt ttagaagcag ctgagggcca    300 

cgccaaagag ggacaaggga ttaaatgtga cattccccgc tacatcgtta gccagctggg    360 

cctcacccgg gatcccctag aagaaatggc ccagttgagc agctgtgaca gtcctgacac    420 

tccagagaca gatgattcta ttgagggcca tggggcatct ctgccatcta aaaagacacc    480 

ctctgaagag gacttcgaga ccattaagct catcagcaat ggcgcctatg gggctgtatt    540 

tctggtgcgg cacaagtcca cccggcagcg ctttgccatg aagaagatca acaagcagaa    600 

cctgatccta cggaaccaga tccagcaggc cttcgtggag cgtgacatac tgactttcgc    660 

tgagaacccc tttgtggtca gcatgttctg ctcctttgat accaagcgcc acttgtgcat    720 

ggtgatggag tacgttgaag ggggagactg tgccactctg ctgaagaata ttggggccct    780 

gcctgtggac atggtgcgtc tatactttgc ggaaactgtg ctggccctgg agtacttaca    840 

caactatggc atcgtgcacc gtgacctcaa gcctgacaac ctcctaatta catccatggg    900 

gcacatcaag ctcacggact ttggactgtc caaaatgggc ctcatgagtc tgacaacgaa    960 

cttgtatgag ggtcatattg aaaaggatgc ccgggaattc ctggacaagc aggtatgcgg   1020 

gaccccagaa tacattgcgc ctgaggtgat cctgcgccag ggctatggga agccagtgga   1080 

ctggtgggcc atgggcatta tcctgtatga gttcctggtg ggctgcgtcc ctttttttgg   1140 

agatactccg gaggagctct ttgggcaggt gatcagtgat gagattgtgt ggcctgaggg   1200 

tgatgaggca ctgcccccag acgcccagga cctcacctcc aaactgctcc accagaaccc   1260 

tctggagaga cttggcacag gcagtgccta tgaggtgaag cagcacccat tctttactgg   1320 

tctggactgg acaggacttc tccgccagaa ggctgaattt attcctcagt tggagtcaga   1380 

ggatgatact agctattttg acacccgctc agagcgatac caccacatgg actcggagga   1440 

tgaggaagaa gtgagtgagg atggctgcct tgagatccgc cagttctctt cctgctctcc   1500 

aaggttcaac aaggtgtaca gcagcatgga gcggctctca ctgctcgagg agcgccggac   1560 

accacccccg accaagcgca gcctgagtga ggagaaggag gaccattcag atggcctggc   1620 

agggctcaaa ggccgagacc ggagctgggt gattggctcc cctgagatat tacggaagcg   1680 

gctgtcggtg tctgagtcgt cccacacaga gagtgactca agccctccaa tgacagtgcg   1740 

acgccgctgc tcaggcctcc tggatgcgcc tcggttcccg gagggccctg aggaggccag   1800 

cagcaccctc aggaggcaac cacaggaggg tatatgggtc ctgacacccc catctggaga   1860 

gggggtatct gggcctgtca ctgaacactc aggggagcag cggccaaagc tggatgagga   1920 

agctgttggc cggagcagtg gttccagtcc agctatggag acccgaggcc gtgggacctc   1980 

acagctggct gagggagcca cagccaaggc catcagtgac ctggctgtgc gtagggcccg   2040 

ccaccggctg ctctctgggg actcaacaga gaagcgcact gctcgccctg tcaacaaagt   2100 

gatcaagtcc gcctcagcca cagccctctc actcctcatt ccttcggaac accacacctg   2160 

ctccccgttg gccagcccca tgtccccaca ttctcagtcg tccaacccat catcccggga   2220 

ctcttctcca agaagtatgg cttcaccctg cgggccattc gcgtctacat gggtgactcc   2280 

gatgtctaca ccgtgcacca tatggtgtgg cacgtggagg atggaggtcc ggccagtgag   2340 

gcagggcttc gtcaaggtga cctcatcacc catgtcaatg gggaacctgt gcatggcctg   2400 

gtgcacacgg aggtggtgga gctgatcctg aagagtggaa acaaggtggc catttcaaca   2460 

actcccctgg agaacacatc cattaaagtg gggccagctc ggaagggcag ctacaaggcc   2520 

aagatggccc gaaggagcaa gaggagccgc ggcaaggatg ggcaagaaag cagaaaaagg   2580 

agctccctgt tccgcaagat caccaagcaa gcatccctgc tccacaccag ccgcagcctt   2640 

tcttccctta accgctcctt gtcatcaggg gagagtgggc caggctctcc cacacacagc   2700 

cacagccttt ccccccgatc tcccactcaa ggctaccggg tgacccccga tgctgtgcat   2760 

tcaggcaact ctcacggccc aagagtgcgg agccaccccg ttcaccacta ctcaagaggg   2820 

tgcagtcggc tgagaaactg gcagcagcac ttgccgcctc tgagaagaag ctagccactt   2880 

ctcgcaagca cagccttgac ctgccccact ctgaactaaa gaaggaactg ccgcccaggg   2940 

aagtgagccc tctggaggta gttggagcca ggagtgtgct gtctggcaag ggggccctgc   3000 

cagggaaggg ggtgctgcag cctgctccct cacgggccct aggcaccctc cggcaggacc   3060 

gagccgaacg acgggagtcg ctgcagaagc aagaagccat tcgtgaggtg gactcctcag   3120 

aggacgacac cgaggaaggg cctgagaaca gccagggtgc acaggagctg agcttggcac   3180 

ctcacccaga agtgagccag agtgtggccc ctaaaggagc aggagagagt ggggaagagg   3240 

atcctttccc gtccagagac cctaggagcc tgggcccaat ggtcccaagc ctattgacag   3300 

ggatcacact ggggcctccc agaatggaaa gtcccagtgg tccccacagg aggctcggga   3360 

gcccacaagc cattgaggag gctgccagct cctcctcagc aggccccaac ctaggtcagt   3420 

ctggagccac agaccccatc cctcctgaag gttgctggaa ggcccagcac ctccacaccc   3480 

aggcactaac agcactttct cccagcactt cgggactcac ccccaccagc agttgctctc   3540 

ctcccagctc cacctctggg aagctgagca tgtggtcctg gaaatccctt attgagggcc   3600 

cagacagggc atccccaagc agaaaggcaa ccatggcagg tgggctagcc aacctccagg   3660 

atttggaaaa cacaactcca gcccagccta agaacctgtc tcccagggag caggggaaga   3720 

cacagccacc tagtgccccc agactggccc atccatctta tgaggatccc agccagggct   3780 

ggctatggga gtctgagtgt gcacaagcag tgaaagagga tccagccctg agcatcaccc   3840 

aagtgcctga tgcctcaggt gacagaaggc aggacgttcc atgccgaggc tgccccctca   3900 

cccagaagtc tgagcccagc ctcaggaggg gccaagaacc agggggccat caaaagcatc   3960 

gggatttggc attggttcca gatgagcttt taaagcaaac atagcagttg tttgccattt   4020 

cttgcactca gacctgtgta atatatgctc ctggaaccca aaaaaaaaaa aaaaaaaaaa   4080 

aaaaaaa                                                             4087 

 
           
             5  
             2113  
             DNA  
             Homo sapiens  
           
            5 

aatgatctag ctcctgaaga aagaggcttt cgttactgtc caagaagtga agaccagtga     60 

gtctagcgat aaagaaacaa aagagcccct gacagtatcg aaagaatctg acatttgctt    120 

tgtctgtaca aaggatgaaa ggaattttgc cgacttagtc aaaacaataa ctggttttat    180 

atcattttga gtctaaaata caggcatcag aatcgtatgt ttttctttgt atttctgaag    240 

aattgtcatc tttttaaaaa cgtatgtgga gtggttttgt ttctggaaag gaaaacgtga    300 

catggatttt ataagcttag tagctgtagg tggagactct tgttttgttt gctaaacctt    360 

tttaataagc agcaaagtca ggatatcaaa gattggaatt tttcccccgg aaccttttgt    420 

tcttttctta gtacttcaaa taatttcaac caaaggggta tgcatggaaa atgaaaacaa    480 

atatgaagtc tttccgctat ttggcagtgc ttcagatgag atgtatctat acttctgtga    540 

agaaagacgt gattctgata tgaggcagtg attgtatact tacgctggac agagggataa    600 

ctggtttagt ggaacagtgg gttagtggtg tgctgaaagg attgtttgcc tctttatcca    660 

gcagtaagta ggcactagta gttgactgtc tggggagtgg cttttttttg tctgatatct    720 

attatggatg attccagtat tctgagaagg agagggttac agaaggagtt gagccttcca    780 

agaagaggca gcttttgtcg gacaagtaac cgcaagagct tgattgtgac ctctagcaca    840 

tcacctacac taccacggcc acactcacca ctccatggcc acacaggtaa cagtcctttg    900 

gacagccccc ggaatttctc tccaaatgca cctgctcact tttcttttgt tcctgcccgt    960 

agccatagcc acagagctga caggactgat gggcggcgct ggtctttggc ctctttgccc   1020 

tcttcaggat atggaactaa cactcctagc tccactgtct catcatcatg ctcctcacag   1080 

gaaaagctgc atcagttgcc tttccagcct acagctgatg agctgcactt tttgacgaag   1140 

catttcagca cagagagcgt accagatgag gaaggacggc agtccccagc catgcagcct   1200 

gctccctcac gggccctagg caccctccgg caggaccgag ccgaacgacg ggagtcgctg   1260 

cagaagcaag aagccattcg tgaggtggac tcctcagagg acgacaccga ggaagggcct   1320 

gagaacagcc agggtgcaca ggagctgagc ttggcacctc acccagaagt gagccagagt   1380 

gtggccccta aaggagcagg agagagtggg gaagaggatc ctttcccgtc cagagaccct   1440 

aggagcctgg gcccaatggt cccaagccta ttgacaggga tcacactggg gcctcccaga   1500 

atggaaagtc ccagtggtcc ccacaggagg ctcgggagcc cacaagccat tgaggaggct   1560 

gccagctcct cctcagcagg ccccaaccta ggtcagtctg gagccacaga ccctatccct   1620 

cctgaaggtt gctggaaggc ccagcacctc cacacccagg cactaacagc actttctccc   1680 

agcacttcgg gactcacccc catccatctt atgaggatcc cagccagggc tggctatggg   1740 

agtctgagtg tgcacaagca gtgaaagagg atccagccct gagcatcacc caagtgcctg   1800 

atgcctcagg tgacagaagg caggacgttc catgccgagg ctgccccctc acccagaagt   1860 

ctgagcccag cctcaggagg ggccaagaac cagggggcca tcaaaagcat cgggatttgg   1920 

cattggttcc agatgagctt ttaaagcaaa catagcagtt gtttgccatt tcttgcactc   1980 

agacctgtgt aatatatgct cctggaaacc atctttatgt cttttgcttg cttgttttcc   2040 

ttcggtcaac ccacatgtaa ctaggtcctg tgttgctgct gggaatatag tggtgaataa   2100 

aacagtttcc acc                                                      2113 

 
           
             6  
             2945  
             DNA  
             Homo sapiens  
           
            6 

tatggatgat tccagtattc tgagaaggag agggttacag aaggagttga gccttccaag     60 

aagaggcagt ttatttcttt tcccggccca gcgcgatggc ttacacctgt aatcccagca    120 

ctttactttg ggaggctgag gcaagtggat cacaaggtca ggagttcaag aacagcctgg    180 

ccaacatgtt gtcggacaag taaccgcaag agcttgattg tgacctctag cacatcacct    240 

acactaccac ggccacactc accactccat ggccacacag gtaacagtcc tttggacagc    300 

ccccggaatt tctctccaaa tgcacctgct cacttttctt ttgttcctgc ccgtagccat    360 

agccacagag ctgacaggac tgatgggcgg cgctggtctt tggcctcttt gccctcttca    420 

ggatatggaa ctaacactcc tagctccact gtctcatcat catgctcctc acaggaaaag    480 

ctgcatcagt tgcctttcca gcctacagct gatgagctgc actttttgac gaagcatttc    540 

agcacagaga gcgtaccaga tgaggaagga cggcagtccc cagccatgcg gcctcgctcc    600 

cggagcctca gtcccggacg atccccagta tcctttgaca gtgaaataat aatgatgaat    660 

catgtttaca aagaaagatt cccaaaggcc accgcacaaa tggaagagcg actagcagag    720 

tttatttcct ccaacactcc agacagcgtg ctgcccttgg cagatggagc cctgagcttt    780 

attcatcatc aggtgattga gatggcccga gactgcctgg ataaatctcg gagtggcctc    840 

attacatcac aatacttcta cgaacttcaa gagaatttgg agaaactttt acaagatgag    900 

tttgaccctg aagagttcta ccacctttta gaagcagctg agggccacgc caaagaggga    960 

caagggatta aatgtgacat tccccgctac atcgttagcc agctgggcct cacccgggat   1020 

cccctagaag aaatggccca gttgagcagc tgtgacagtc ctgacactcc agagacagat   1080 

gattctattg agggccatgg ggcatctctg ccatctaaaa agacaccctc tgaagaggac   1140 

ttcgagacca ttaagctcat cagcaatggc gcctatgggg ctgtatttct ggtgcggcac   1200 

aagtccaccc ggcagcgctt tgccatgaag aagatcaaca agcagaacct gatcctacgg   1260 

aaccagatcc agcaggcctt cgtggagcgt gacatactga ctttcgctga gaaccccttt   1320 

gtggtcagca tgttctgctc ctttgatacc aagcgccact tgtgcatggt gatggagtac   1380 

gttgaagggg gagactgtgc cactctgctg aagaatattg gggccctgcc tgtggacatg   1440 

gtgcgtctat actttgcgga aactgtgctg gccctggagt acttacacaa ctatggcatc   1500 

gtgcaccgtg acctcaagcc tgacaacctc ctaattacat ccatggggca catcaagctc   1560 

acggactttg gactgtccaa aattggcctc atgagtctga caacgaactt gtatgagggt   1620 

catattgaaa aggatgcccg ggaattcctg gacaagcagg tatgcgggac cccagaatac   1680 

attgcgcctg aggtgatcct gcgccagggc tatgggaagc cagtggactg gtgggccatg   1740 

ggcattatcc tgtatgagtt cctggtgggc tgcgtccctt tttttggaga tactccggag   1800 

gagctctttg ggcaggtgat cagtgatgag attgtgtggc ctgagggtga tgaggcactg   1860 

cccccagacg cccaggacct cacctccaaa ctgctccacc agaaccctct ggagagactt   1920 

ggcacaggca gtgcctatga ggtgaagcag cacccattct ttactggtct ggactggaca   1980 

ggacttctcc gccagaaggc tgaatttatt cctcagttgg agtcagagga tgatactagc   2040 

tattttgaca cccgctcaga gcgataccac cacatggact cggaggatga ggaagaagtg   2100 

agtgaggatg gctgccttga gatccgccag ttctcttcct gctctccaag gttcaacaag   2160 

gtgtacagca gcatggagcg gctctcactg ctcgaggagc gccggacacc acccccgacc   2220 

aagcgcagcc tgagtgagga gaaggaggac cattcagatg gcctggcagg gctcaaaggc   2280 

cgagaccgga gctgggtgat tggctcccct gagatattac ggaagcggct gtcggtgtct   2340 

gagtcatccc tcctgaaggt tgctggaagg cccagcactt tctcccagca cttcgggact   2400 

cacccccacc agcagttgct ctcctcccag ctccacctct gggaagctga gcatgtggtc   2460 

ctggaaatcc cttattgagg gcccagacag ggcatcccca agcagaaagg caaccatggc   2520 

aggtgggcta gccaacctcc aggatttgga aaacacaact ccagcccagc ctaagaacct   2580 

gtctcccagg gagcagggga agacacagcc acctagtgcc cccagactgg cccatccatc   2640 

ttatgaggat cccagccagg gctggctatg ggagtctgag tgtgcacaag cagtgaaaga   2700 

ggatccagcc ctgagcatca cccaagtgcc tgatgcctca ggtgacagaa ggcaggacgt   2760 

tccatgccga ggctgccccc tcacccagaa gtctgagccc agcctcagga ggggccaaga   2820 

accagggggc catcaaaagc atcgggattt ggcattggtt ccagatgagc ttttaaagca   2880 

aacatagcag ttgtttgcca tttcttgcac tcagacctgt gtaatatatg ctcctggaaa   2940 

ccatc                                                               2945 

 
           
             7  
             4865  
             DNA  
             Homo sapiens  
           
            7 

tgctccccgc gccgccgccg ccgccgcctc cgccgctgct gccgcacctg ccaccatgtc     60 

gccgccgccg ggtcatgtct gactctctct ggaccgcgct ttctaatttc tcgatgccct    120 

ccttccccgg cggcagtatg ttccgccgca ccaagagctg ccgcaccagt aatcggaaaa    180 

gcctcatcct gaccagcact tcacccacgc taccgagacc ccactccccg ctgccaggtc    240 

acctaggcag cagtcccctg gacagccccc gaaacttctc ccccaacacc cccgcccact    300 

tctcgtttgc ctcctcccga agggcggacg gacgccggtg gtctctggcc tcgctccctt    360 

catctggcta tggcaccaac acgcccagtt ccaccgtctc gtcctcctgc tcctcccagg    420 

agcgccttca ccagctgccc taccagccca cggtggacga gctccacttc ctctccaaac    480 

acttcgggag caccgagagc atcacagacg aggatggtgg ccgtcgctcc ccagccgtgc    540 

ggccccgctc acggagcctc agccccgggc gctccccctc ctcctacgac aacgagatcg    600 

tgatgatgaa tcacgtctac aaggagaggt tcccgaaggc cactgcgcag atggaggaga    660 

agctgcgcga ctttacccgc gcctacgaac ccgacagcgt tctgcctctg gccgatggcg    720 

tgctcagctt catccaccac cagatcatcg agctggcccg ggactgcctg accaagtccc    780 

gtgacggcct catcaccacg gtctacttct atgaattgca ggagaacctg gagaagctcc    840 

ttcaagacgc ctatgaacgc tctgagagct tggaggtggc cttcgttact cagctggtga    900 

agaagttgct tattatcatc tcacgccctg cgaggctgct ggagtgcctg gaattcaacc    960 

ccgaggagtt ctaccacctg ctggaggcgg ccgaaggaca cgccaaggag ggccaccttg   1020 

tgaagacgga catcccccgc tacatcatcc gccagctggg cctcacccgt gacccctttc   1080 

cagatgtggt gcatctggag gaacaggaca gtggtggttc caacacccct gagcaagacg   1140 

atctctctga gggccgcagc agcaaggcca agaaaccgcc gggggagaat gacttcgata   1200 

ccatcaagct cataagcaac ggtgcctacg gcgctgtcta cctggtgcgg caccgcgaca   1260 

cgcggcagcg ctttgccatg aaaaagatca acaagcagaa cttgatcctc cgcaaccaga   1320 

tccagcaggc ctttgtggag cgcgatatcc tcaccttcgc cgagaacccg tttgtggtcg   1380 

gcatgttctg ctcctttgag actcggcgcc acctctgcat ggtcatggaa tatgtggaag   1440 

gcggcgactg tgccaccctg ctgaagaata ttggagcgct gcccgtagag atggcccgca   1500 

tgtactttgc tgagacggtg ctagccctgg agtatttgca caactatggc atcgtgcacc   1560 

gcgacctcaa gcctacagcc tccttatcac ctccatgggt cacatcaagc tcacagattt   1620 

cggcctctcc aagatggggc tcatgagcct caccaccaac ttatatgaag gccacatcga   1680 

gaaggacgcc cgagagttcc tggacaaaca ggtgtgtggg accccagagt acatcgcgcc   1740 

cgaggtcatc ctgcgtcaag gctacggcaa gccagtggac tggtgggcta tggggatcat   1800 

cctctacgag ttcctggtgg gctgtgtgcc cttcttcgga gacacaccag aggagctatt   1860 

tggacaggtc atcagtgatg acatcctgtg gcccgagggg gatgaggccc tacctacgga   1920 

ggcccaactc ctcatatcca gcctcctgca gaccaaccct ctggtcaggc ttggggcagg   1980 

cggcgctttt gaggtgaagc agcacagttt ctttcgagac ctggactgga cagggctgct   2040 

gaggcagaag gccgagttca tcccccacct agagtcggaa gatgacacta gctactttga   2100 

cacccgctca gacaggtatc accacgtgaa ctcctatgac gaggatgaca cgacggagga   2160 

ggagcccgtg gaaatccgcc agttctcttc ctgctctccg cgcttcagca aggtgtatag   2220 

cagcatggag cagctgtcgc agcacgagcc caagacccca gtagcagctg cagggagcag   2280 

caagcgggag ccgagcacca agggccccga ggagaaggtg gccggcaagc gggaggggct   2340 

gggcggcctg accctgcgtg agaagacctg gagagggggc tctccggaga tcaagcgatt   2400 

ctccgcgtcc gaggccagtt tcctggaggg agaggccagt ccccctttgg gcgcccgccg   2460 

ccgtttctcg gcgctgctgg agcccagccg cttcagcgcc ccccaagagg acgaggatga   2520 

ggcccggctg cgcaggcctc cccggcccag ctccgacccc gcgggatccc tggatgcacg   2580 

ggcccccaaa gaggagactc aaggggaagg cacctccagc gccggggact ccgaggccac   2640 

tgaccgtcca cgcccaggtg acctctgccc accctcgaag gatggggatg catcaggccc   2700 

aagggctacc aatgacttgg ttctgcgccg ggcgcggcac cagcagatgt caggggatgt   2760 

ggcagtagag aagaggcctt ctcgaactgg gggcaaagtc atcaaatcag cctcagccac   2820 

tgccttatct gtcatgattc ctgcagtgga cccacatgga agttcacccc ttgctagtcc   2880 

catgtctcca cgatctctgt cctccaaccc atcctcacgg gactcctcac ccagccggga   2940 

ctactcacca gctgtcagtg ggctccgctc ccccatcacc atccagcgct cgggcaagaa   3000 

gtatggcttc acactgcgtg ccatccgtgt ctacatgggt gacacggatg tctatagtgt   3060 

ccaccacatt gtctggcatg tggaggaagg aggcccagcc caggaggcag gactctgtgc   3120 

tggggacctc atcacccacg tgaatgggga gcctgtgcat ggcatggtgc atcctgaggt   3180 

cgtggagctg atccttaaga gtggcaacaa ggtagcagtg accacaacgc ccttcgaaaa   3240 

tacctctatc cgcattggtc ccgcaaggcg cagcagctac aaggctaaaa tggctcggag   3300 

gaacaagcga ccctccgcca aggagggcca ggagagcaag aagcgcagct ccctcttccg   3360 

gaagatcacg aagcagtcga acctgctgca tactagccgc tcgctgtcgt cgctgaaccg   3420 

ctcgctgtca tccagcgata gtctcccggg ctcgcctacg cacgggctgc cggcgcgctc   3480 

gcccacgcac agctaccgct ccacgcctga ctccgcctac ctaggcgcct catcccagag   3540 

cagctcccca gcctcgagca cgcccaactc gcctgcgtcg tcggcgtcgc accacattcg   3600 

gcccagcacg ctgcacggac tgtcgccaaa gctccatcgc cagtaccgct ctgcgcgatg   3660 

caagtcggcc ggcaacatcc ctctatcgcc gctggcacac acgccgtccc ccacgcaggc   3720 

gtcaccgccg ccactgccgg gccacacggt gggcagctcg cacactactc agagcttccc   3780 

ggccaaactg cactcatcgc ctcccgtcgt gcgcccgcgc cccaagagtg ccgagccccc   3840 

tcgctcgccg ctcctcaagc gcgtgcagtc ggccgagaag ctgggagcct ctttgagtgc   3900 

ggacaagaag ggcgcgctgc gcaaacacag cctcgaggtg ggccacccgg atttccgcaa   3960 

ggacttccat ggcgagctgg cgctgcatag ccttgccgag tccgacggtg agacgccccc   4020 

agtcgagggc cttggcgcgc cccggcaggt cgccgtccgc cgcctgggcc gacaggagtc   4080 

acctttgagc ctgggcgcgg acccgttgct gcccgagggt gcctccaggc caccagtgtc   4140 

gagcaaggag aaggaatccc cggggggcgc cgaggcgtgc accccacccc gcgcgacgac   4200 

ccccggtggc cggaccctgg agcgggacgt cggctgcacg cggcatcaga gcgtgcagac   4260 

ggaggatggc actggcggga tggccagggc tgtggccaag gcggcgctga gcccggtgca   4320 

ggaacacgag acaggccggc gcagcagctc tggcgaggcg ggcacacccc tggtacccat   4380 

tgtcgtagag cctgcgcggc ccggggctaa ggctgtggtg cctcagcctc tgggcgcgga   4440 

ctccaagggg ttgcaggaac ccgcacccct ggcgccttcc gtgcccgagg ccccccgggg   4500 

ccgggagcgc tgggtgttgg aggtggtgga ggagcgcacc acgctgagcg gtcctcgctc   4560 

caagcccgcc tccccaaagc tctccccgga gccccagaca ccctccctag ccccagcgaa   4620 

gtgcagtgca cccagcagtg cagtgacccc agtcccaccc gcatccctct tgggctcagg   4680 

caccaagcct caagtggggc tgacctcccg gtgccctgct gaagctgtgc ccccagcagg   4740 

cctgaccaaa aaaggagtgt ccagtcccgc acccccggga ccatagccaa gggggtcatc   4800 

ggccccgcgc tgtacagcct ccgtatacat atgtacacat ataaataaag tgcgtccgtg   4860 

ctgcg                                                               4865 

 
           
             8  
             4740  
             DNA  
             Homo sapiens  
           
            8 

ccgccgggtc atgtctgact ctctctggac cgcgctttct aatttctcga tgccctcctt     60 

ccccggcggc agtatgttcc gccgcaccaa gagctgccgc accagtaatc ggaaaagcct    120 

catcctgacc agcacttcac ccacgctacc gagaccccac tccccgctgc caggtcacct    180 

aggcagcagt cccctggaca gcccccgaaa cttctccccc aacacccccg cccacttctc    240 

gtttgcctcc tcccgaaggg cggacggacg ccggtggtct ctggcctcgc tcccttcatc    300 

tggctatggc accaacacgc ccagttccac cgtctcgtcc tcctgctcct cccaggagcg    360 

ccttcaccag ctgccctacc agcccacggt ggacgagctc cacttcctct ccaaacactt    420 

cgggagcacc gagagcatca cagacgagga tggtggccgt cgctccccag ccgtgcggcc    480 

ccgctcacgg agcctcagcc ccgggcgctc cccctcctcc tacgacaacg agatcgtgat    540 

gatgaatcac gtctacaagg agaggttccc gaaggccact gcgcagatgg aggagaagct    600 

gcgcgacttt acccgcgcct acgaacccga cagcgttctg cctctggccg atggcgtgct    660 

cagcttcatc caccaccaga tcatcgagct ggcccgggac tgcctgacca agtcccgtga    720 

cggcctcatc accacggtct acttctatga attgcaggag aacctggaga agctccttca    780 

agacgcctat gaacgctctg agagcttgga ggtggccttc gttactcagc tggtgaagaa    840 

gttgcttatt atcatctcac gccctgcgag gctgctggag tgcctggaat tcaaccccga    900 

ggagttctac cacctgctgg aggcggccga aggacacgcc aaggagggcc accttgtgaa    960 

gacggacatc ccccgctaca tcatccgcca gctgggcctc acccgtgacc cctttccaga   1020 

tgtggtgcat ctggaggaac aggacagtgg tggttccaac acccctgagc aagacgatct   1080 

ctctgagggc cgcagcagca aggccaagaa accgccgggg gagaatgact tcgataccat   1140 

caagctcata agcaacggtg cctacggcgc tgtctacctg gtgcggcacc gcgacacgcg   1200 

gcagcgcttt gccatgaaaa agatcaacaa gcagaacttg atcctccgca accagatcca   1260 

gcaggccttt gtggagcgcg atatcctcac cttcgccgag aacccgtttg tggtcggcat   1320 

gttctgctcc tttgagactc ggcgccacct ctgcatggtc atggaatatg tggaaggcgg   1380 

cgactgtgcc accctgctga agaatattgg agcgctgccc gtagagatgg cccgcatgta   1440 

ctttgctgag acggtgctag ccctggagta tttgcacaac tatggcatcg tgcaccgcga   1500 

cctcaagcct gacaacctcc ttatcacctc catgggtcac atcaagctca cagatttcgg   1560 

cctctccaag atggggctca tgagcctcac caccaactta tatgaaggcc acatcgagaa   1620 

ggacgcccga gagttcctgg acaaacaggt gtgtgggacc ccagagtaca tcgcgcccga   1680 

ggtcatcctg cgtcaaggct acggcaagcc agtggactgg tgggctatgg ggatcatcct   1740 

ctacgagttc ctggtgggct gtgtgccctt cttcggagac acaccagagg agctatttgg   1800 

acaggtcatc agtgatgaca tcctgtggcc cgagggggat gaggccctac ctacggaggc   1860 

ccaactcctc atatccagcc tcctgcagac caaccctctg gtcaggcttg gggcaggcgg   1920 

cgcttttgag gtgaagcagc acagtttctt tcgagacctg gactggacag ggctgctgag   1980 

gcagaaggcc gagttcatcc cccacctaga gtcggaagat gacactagct actttgacac   2040 

ccgctcagac aggtatcacc acgtgaactc ctatgacgag gatgacacga cggaggagga   2100 

gcccgtggaa atccgccagt tctcttcctg ctctccgcgc ttcagcaagg tgtatagcag   2160 

catggagcag ctgtcgcagc acgagcccaa gaccccagta gcagctgcag ggagcagcaa   2220 

gcgggagccg agcaccaagg gccccgagga gaaggtggcc ggcaagcggg aggggctggg   2280 

cggcctgacc ctgcgtgaga agacctggag agggggctct ccggagatca agcgattctc   2340 

cgcgtccgag gccagtttcc tggagggaga ggccagtccc cctttgggcg cccgccgccg   2400 

tttctcggcg ctgctggagc ccagccgctt cagcgccccc caagaggacg aggatgaggc   2460 

ccggctgcgc aggcctcccc ggcccagctc cgaccccgcg ggatccctgg atgcacgggc   2520 

ccccaaagag gagactcaag gggaaggcac ctccagcgcc ggggactccg aggccactga   2580 

ccgtccacgc ccaggtgacc tctgcccacc ctcgaaggat ggggatgcat caggcccaag   2640 

ggctaccaat gacttggttc tgcgccgggc gcggcaccag cagatgtcag gggatgtggc   2700 

agtagagaag aggccttctc gaactggggg caaagtcatc aaatcagcct cagccactgc   2760 

cttatctgtc atgattcctg cagtggaccc acatggaagt tcaccccttg ctagtcccat   2820 

gtctccacga tctctgtcct ccaacccatc ctcacgggac tcctcaccca gccgggacta   2880 

ctcaccagct gtcagtgggc tccgctcccc catcaccatc cagcgctcgg gcaagaagta   2940 

tggcttcaca ctgcgtgcca tccgtgtcta catgggtgac acggatgtct atagtgtcca   3000 

ccacattgtc tggcatgtgg aggaaggagg cccagcccag gaggcaggac tctgtgctgg   3060 

ggacctcatc acccacgtga atggggagcc tgtgcatggc atggtgcatc ctgaggtcgt   3120 

ggagctgatc cttaagagtg gcaacaaggt agcagtgacc acaacgccct tcgaaaatac   3180 

ctctatccgc attggtcccg caaggcgcag cagctacaag gctaaaatgg ctcggaggaa   3240 

caagcgaccc tccgccaagg agggccagga gagcaagaag cgcagctccc tcttccggaa   3300 

gatcacgaag cagtcgaacc tgctgcatac tagccgctcg ctgtcgtcgc tgaaccgctc   3360 

gctgtcatcc agcgatagtc tcccgggctc gcctacgcac gggctgccgg cgcgctcgcc   3420 

cacgcacagc taccgctcca cgcctgactc cgcctaccta ggcgcctcat cccagagcag   3480 

ctccccagcc tcgagcacgc ccaactcgcc tgcgtcgtcg gcgtcgcacc acattcggcc   3540 

cagcacgctg cacggactgt cgccaaagct ccatcgccag taccgctctg cgcgatgcaa   3600 

gtcggccggc aacatccctc tatcgccgct ggcacacacg ccgtccccca cgcaggcgtc   3660 

accgccgcca ctgccgggcc acacggtggg cagctcgcac actactcaga gcttcccggc   3720 

caaactgcac tcatcgcctc ccgtcgtgcg cccgcgcccc aagagtgccg agccccctcg   3780 

ctcgccgctc ctcaagcgcg tgcagtcggc cgagaagctg ggagcctctt tgagtgcgga   3840 

caagaagggc gcgctgcgca aacacagcct cgaggtgggc cacccggatt tccgcaagga   3900 

cttccatggc gagctggcgc tgcatagcct tgccgagtcc gacggtgaga cgcccccagt   3960 

cgagggcgtt ggcgcgcccc ggcaggtcgc cgtccgccgc ctgggccgac aggagtcacc   4020 

tttgagcctg ggcgcggacc cgttgctgcc cgagggtgcc tccaggccac cagtgtcgag   4080 

caaggagaag gaatccccgg ggggcgccga ggcgtgcacc ccaccccgcg cgacgacccc   4140 

cggtggccgg accctggagc gggacgtcgg ctgcacgcgg catcagagcg tgcagacgga   4200 

ggatggcact ggcgggatgg ccagggctgt ggccaaggcg gcgctgagcc cggtgcagga   4260 

acacgagaca ggccggcgca gcagctctgg cgaggcgggc acacccctgg tacccattgt   4320 

cgtagagcct gcgcggcccg gggctaaggc tgtggtgcct cagcctctgg gcgcggactc   4380 

caaggggttg caggaacccg cacccctggc gccttccgtg cccgaggccc cccggggccg   4440 

ggagcgctgg gtgttggagg tggtggagga gcgcaccacg ctgagcggtc ctcgctccaa   4500 

gcccgcctcc ccaaagctct ccccggagcc ccagacaccc tccctagccc cagcgaagtg   4560 

cagtgcaccc agcagtgcag tgaccccagt cccacccgca tccctcttgg gctcaggcac   4620 

caagcctcaa gtggggctga cctcccggtg ccctgctgaa gctgtgcccc cagcaggcct   4680 

gaccaaaaaa ggagtgtcca gtcccgcacc cccgggacca tagccaaggg ggtcatcggc   4740 

 
           
             9  
             4867  
             DNA  
             Homo sapiens  
           
            9 

tgctccccgc gccgccgccg ccgccgcctc cgccgctgct gccgcacctg ccaccatgtc     60 

gccgccgccg ggtcatgtct gactctctct ggaccgcgct ttctaatttc tcgatgccct    120 

ccttccccgg cggcagtatg ttccgccgca ccaagagctg ccgcaccagt aatcggaaaa    180 

gcctcatcct gaccagcact tcacccacgc taccgagacc ccactccccg ctgccaggtc    240 

acctaggcag cagtcccctg gacagccccc gaaacttctc ccccaacacc cccgcccact    300 

tctcgtttgc ctcctcccga agggcggacg gacgccggtg gtctctggcc tcgctccctt    360 

catctggcta tggcaccaac acgcccagtt ccaccgtctc gtcctcctgc tcctcccagg    420 

agcgccttca ccagctgccc taccagccca cggtggacga gctccacttc ctctccaaac    480 

acttcgggag caccgagagc atcacagacg aggatggtgg ccgtcgctcc ccagccgtgc    540 

ggccccgctc acggagcctc agccccgggc gctccccctc ctcctacgac aacgagatcg    600 

tgatgatgaa tcacgtctac aaggagaggt tcccgaaggc cactgcgcag atggaggaga    660 

agctgcgcga ctttacccgc gcctacgaac ccgacagcgt tctgcctctg gccgatggcg    720 

tgctcagctt catccaccac cagatcatcg agctggcccg ggactgcctg accaagtccc    780 

gtgacggcct catcaccacg gtctacttct atgaattgca ggagaacctg gagaagctcc    840 

ttcaagacgc ctatgaacgc tctgagagct tggaggtggc cttcgttact cagctggtga    900 

agaagttgct tattatcatc tcacgccctg cgaggctgct ggagtgcctg gaattcaacc    960 

ccgaggagtt ctaccacctg ctggaggcgg ccgaaggaca cgccaaggag ggccaccttg   1020 

tgaagacgga catcccccgc tacatcatcc gccagctggg cctcacccgt gacccctttc   1080 

cagatgtggt gcatctggag gaacaggaca gtggtggttc caacacccct gagcaagacg   1140 

atctctctga gggccgcagc agcaaggcca agaaaccgcc gggggagaat gacttcgata   1200 

ccatcaagct cataagcaac ggtgcctacg gcgctgtcta cctggtgcgg caccgcgaca   1260 

cgcggcagcg ctttgccatg aaaaagatca acaagcagaa cttgatcctc cgcaaccaga   1320 

tccagcaggc ctttgtggag cgcgatatcc tcaccttcgc cgagaacccg tttgtggtcg   1380 

gcatgttctg ctcctttgag actcggcgcc acctctgcat ggtcatggaa tatgtggaag   1440 

gcggcgactg tgccaccctg ctgaagaata ttggagcgct gcccgtagag atggcccgca   1500 

tgtactttgc tgagacggtg ctagccctgg agtatttgca caactatggc atcgtgcacc   1560 

gcgacctcaa gcctacagcc tccttatcac ctccatgggt cacatcaagc tcacagattt   1620 

cggcctctcc aagatggggc tcatgagcct caccaccaac ttatatgaag gccacatcga   1680 

gaaggacgcc cgagagttcc tggacaaaca ggtgtgtggg accccagagt acatcgcgcc   1740 

cgaggtcatc ctgcgtcaag gctacggcaa gccagtggac tggtgggcta tggggatcat   1800 

cctctacgag ttcctggtgg gctgtgtgcc cttcttcgga gacacaccag aggagctatt   1860 

tggacaggtc atcagtgatg acatcctgtg gcccgagggg gatgaggccc tacctacgga   1920 

ggcccaactc ctcatatcca gcctcctgca gaccaaccct ctggtcaggc ttggggcagg   1980 

cggcgctttt gaggtgaagc agcacagttt ctttcgagac ctggactgga cagggctgct   2040 

gaggcagaag gccgagttca tcccccacct agagtcggaa gatgacacta gctactttga   2100 

cacccgctca gacaggtatc accacgtgaa ctcctatgac gaggatgaca cgacggagga   2160 

ggagcccgtg gaaatccgcc agttctcttc ctgctctccg cgcttcagca aggtgtatag   2220 

cagcatggag cagctgtcgc agcacgagcc caagacccca gtagcagctg cagggagcag   2280 

caagcgggag ccgagcacca agggccccga ggagaaggtg gccggcaagc gggaggggct   2340 

gggcggcctg accctgcgtg agaagacctg gagagggggc tctccggaga tcaagcgatt   2400 

ctccgcgtcc gaggccagtt tcctggaggg agaggccagt ccccctttgg gcgcccgccg   2460 

ccgtttctcg gcgctgctgg agcccagccg cttcagcgcc ccccaagagg acgaggatga   2520 

ggcccggctg cgcaggcctc cccggcccag ctccgacccc gcgggatccc tggatgcacg   2580 

ggcccccaaa gaggagactc aaggggaagg cacctccagc gccggggact ccgaggccac   2640 

tgaccgtcca cgcccaggtg acctctgccc accctcgaag gatggggatg catcaggccc   2700 

aagggctacc aatgacttgg ttctgcgccg ggcgcggcac cagcagatgt caggggatgt   2760 

ggcagtagag aagaggcctt ctcgaactgg gggcaaagtc atcaaatcag cctcagccac   2820 

tgccttatct gtcatgattc ctgcagtgga cccacatgga agttcacccc ttgctagtcc   2880 

catgtctcca cgatctctgt cctccaaccc atcctcacgg gactcctcac ccagccggga   2940 

ctactcacca gctgtcagtg ggctccgctc ccccatcacc atccagcgct cgggcaagaa   3000 

gtatggcttc acactgcgtg ccatccgtgt ctacatgggt gacacggatg tctatagtgt   3060 

ccaccacatt gtctggcatg tggaggaagg aggcccagcc caggaggcag gactctgtgc   3120 

tggggacctc atcacccacg tgaatgggga gcctgtgcat ggcatggtgc atcctgaggt   3180 

cgtggagctg atccttaaga gtggcaacaa ggtagcagtg accacaacgc ccttcgaaaa   3240 

tacctctatc cgcattggtc ccgcaaggcg cagcagctac aaggctaaaa tggctcggag   3300 

gaacaagcga ccctccgcca aggagggcca ggagagcaag aagcgcagct ccctcttccg   3360 

gaagatcacg aagcagtcga acctgctgca tactagccgc tcgctgtcgt cgctgaaccg   3420 

ctcgctgtca tccagcgata gtctcccggg ctcgcctacg cacgggctgc cggcgcgctc   3480 

gcccacgcac agctaccgct ccacgcctga ctccgcctac ctaggcgcct catcccagag   3540 

cagctcccca gcctcgagca cgcccaactc gcctgcgtcg tcggcgtcgc accacattcg   3600 

gcccagcacg ctgcacggac tgtcgccaaa gctccatcgc cagtaccgct ctgcgcgatg   3660 

caagtcggcc ggcaacatcc ctctatcgcc gctggcacac acgccgtccc ccacgcaggc   3720 

gtcaccgccg ccactgccgg gccacacggt gggcagctcg cacactactc agagcttccc   3780 

ggccaaactg cactcatcgc ctcccgtcgt gcgcccgcgc cccaagagtg ccgagccccc   3840 

tcgctcgccg ctcctcaagc gcgtgcagtc ggccgagaag ctgggagcct ctttgagtgc   3900 

ggacaagaag ggcgcgctgc gcaaacacag cctcgaggtg ggccacccgg atttccgcaa   3960 

ggacttccat ggcgagctgg cgctgcatag ccttgccgag tccgacggtg agacgccccc   4020 

agtcgagggc cttggcgcgc cccggcaggt cgccgtccgc cgcctgggcc gacaggagtc   4080 

acctttgagc ctgggcgcgg acccgttgct gcccgagggt gcctccaggc caccagtgtc   4140 

gagcaaggag aaggaatccc cggggggcgc cgaggcgtgc accccacccc gcgcgacgac   4200 

ccccggtggc cggaccctgg agcgggacgt cggctgcacg cggcatcaga gcgtgcagac   4260 

ggaggatggc actggcggga tggccagggc tgtggccaag gcggcgctga gcccggtgca   4320 

ggaacacgag acaggccggc gcagcagctc tggcgaggcg ggcacacccc tggtacccat   4380 

tgtcgtagag cctgcgcggc ccggggctaa ggctgtggtg cctcagcctc tgggcgcgga   4440 

ctccaagggg ttgcaggaac ccgcacccct ggcgccttcc gtgcccgagg ccccccgggg   4500 

ccgggagcgc tgggtgttgg aggtggtgga ggagcgcacc acgctgagcg gtcctcgctc   4560 

caagcccgcc tccccaaagc tctccccgga gccccagaca ccctccctag ccccagcgaa   4620 

gtgcagtgca cccagcagtg cagtgacccc agtcccaccc gcatccctct tgggctcagg   4680 

caccaagcct caagtggggc tgacctcccg gtgccctgct gaagctgtgc ccccagcagg   4740 

cctgaccaaa aaaggagtgt ccagtcccgc acccccggga ccatagccaa gggggtcatc   4800 

ggccccgcgc tgtacagcct ccgtatacat atgtacacat ataaataaag tgcgtccgtg   4860 

ctgcgtg                                                             4867 

 
           
             10  
             5886  
             DNA  
             Homo sapiens  
           
            10 

ggacgagtcg agcctcctgc ggcgccgcgg gctccagaag gagctgagcc tgccacgccg     60 

aggacgtggc tgccgcagcg ggaaccgcaa gagcttggtg gtaggaacgc cctccccgac    120 

cctctcccgg cccctgtcgc cattgtcggt cccaacggca ggcagcagcc ccttggatag    180 

tcctcggaat ttctcggctg cctctgccct aaatttcccc tttgcccgga gggcagacgg    240 

cagaagatgg tccctcgcgt ctctcccatc ttccggctat ggaaccaaca cacccagctc    300 

caccctctcg tcaagctcat cctcccggga acgtctccac cagcttccct tccagccgac    360 

gccggacgag ctgcacttcc tgtccaagca cttccgcagc tcagagaatg tgcttgatga    420 

ggaaggcggc cggtcacccc gcctccgacc ccgctctcgc agtctcagcc cgggccgtgc    480 

aacggggacc ttcgacaatg agattgtcat gatgaatcac gtgtaccggg agaggttccc    540 

caaggccaca gcacagatgg agggccgtct gcaggagttc ctgacggcct acgcgcccgg    600 

cgcccggctg gcgctggctg atggcgtctt gggcttcatc caccaccaga tcgtcgagct    660 

ggcccgagac tgcttggcca agtctggcga gaacctcgtc acctcccgct acttcctaga    720 

gatgcaggag aagctggagc ggcttctgca ggatgcccat gagcgttcgg acagtgagga    780 

ggtcagcttc atcgtccagc ttgtccggaa actgctgatc atcatctcac ggccagctcg    840 

gctgctggag tgtctggagt ttgaccctga ggaattttac cacctgctgg aggcggctga    900 

gggccatgcg cgggagggcc aaggcattaa gactgacctt ccacagtaca tcattgggca    960 

gctgggcctg gccaaggacc ccctggagga gatggtgcca ctgagtcacc tcgaagaaga   1020 

acagccccca gcacctgagt ccccagagag ccgcgccctg gtcggccagt cacggaggaa   1080 

gccatgcgaa agcgactttg agaccatcaa actcattagc aacggagcct atggggccgt   1140 

ctacctggtg cggcaccgtg acacacggca gcgctttgcc atcaagaaga tcaacaaaca   1200 

gaacttgatc ctgcgtaacc agatccagca ggtctttgtg gagcgtgaca ttctcacctt   1260 

tgccgagaac ccctttgtgg tcagcatgtt ctgctccttt gagacccggc gccacctatg   1320 

tatggtcatg gaatacgtgg aaggcggcga ctgcgccacg ctcctgaaga acatgggccc   1380 

gctgcccgtg gacatggccc gcctgtactt cgccgagacg gtgttggcgc tggagtacct   1440 

gcataactat ggcatcgtgc accgtgacct caaaccagac aatctgctca tcacctcgct   1500 

tggccacatc aagctcacgg acttcggcct gtccaagatc ggcctcatga gcatggccac   1560 

caacctctat gagggccaca tcgagaagga cgcccgagag ttcatcgaca agcaggtgtg   1620 

tgggacgccg gagtacatag cccccgaggt gatcttccgc cagggctatg ggaagccagt   1680 

ggactggtgg gccatgggcg tcgtcctcta tgagtttctg gtgggctgcg tgcctttctt   1740 

tggagatacc cccgaggaac tcttcggtca ggtggtcagc gatgagatca tgtggccaga   1800 

gggagatgag gcccttccag cagacgccca ggacctcatc accaggttgc tccggcagag   1860 

cccgctggac cgtctgggca ctggtggcac ccacgaagtg aagcagcacc cctttttcct   1920 

ggccctggac tgggcagggc ttctccgaca caaagccgag ttcgtgcccc agctcgaagc   1980 

tgaggatgat accagctact ttgacacacg ttcggaacgt taccgccatc tgggctccga   2040 

ggacgacgag accaatgatg aagaatcgtc cacagagatc ccccagttct cctcctgctc   2100 

ccaccggttc agcaaggtct acagcagctc tgagttcctg gccgtccagc ccactcctac   2160 

cttcgctgaa aggagcttca gtgaagaccg ggaggagggg tgggagcgca gcgaagtgga   2220 

ctatggccgc cggctgagtg ctgacatccg gctgaggtcc tggacatcct ctggatcctc   2280 

ctgtcagtca tcttcgtccc agcccgagcg gggtcccagc ccatctctcc tgaataccat   2340 

cagcctggac acaatgccca agtttgcctt ctcatcagag gatgaggggg taggcccagg   2400 

ccctgcaggc cccaagaggc ccgtcttcat tctaggggag cctgaccccc caccagcggc   2460 

caccccagtg atgcccaagc cctcgagcct ttctgccgac acagctgctc tcagccacgc   2520 

ccgcctacgg agcaatagca tcggcgcccg acactccaca ccaaggcctc tggatgccgg   2580 

ccggggccgc cgccttgggg gcccaagaga cccagcccct gagaagtcca gagcctcctc   2640 

cagcggtggc agtggtggcg gcagtggggg ccgcgtgccc aagtcagcct ctgtctctgc   2700 

cctgtccctc atcatcacgg cagatgatgg cagcggcggc cccctcatga gccccctttc   2760 

cccgcgctct ctgtcctcga acccgtcgtc ccgtgactct tcgccgagcc gagacccgtc   2820 

ccccgtgtgt ggcagcctgc ggccccccat cgttatccac agctctggca agaagtacgg   2880 

cttcagcctg cgggcgatcc gcgtctacat gggtgatagc gacgtctaca ctgtgcacca   2940 

cgtcgtctgg agtgtggagg acggaagccc cgcccaggag gcgggcctgc gggctgggga   3000 

cctcatcacc cacatcaacg gggagtcagt gctggggctg gtgcacatgg acgtcgtgga   3060 

gctgctgctg aagagcggca acaagatatc cctgcggacc acagccctgg agaacacctc   3120 

catcaaggtg ggccccgccc ggaagaatgt ggccaagggc cgcatggcac gcaggagcaa   3180 

gaggagccgt cggcgggaga cccaggatcg gcggaagtca cttttcaaga agatctccaa   3240 

gcagacctcc gtgctgcaca ccagccgcag cttctcctcc ggactccacc actcactgtc   3300 

atccagtgag agcctccccg gctcgcccac ccacagcctc tcccccagcc ccaccactcc   3360 

ctgccgaagc ccagcccctg atgtcccagc agataccact gcatccccac ccagcgcatc   3420 

cccgagctcc agcagccccg cctccccagc tgctgctggc cacacccgcc ccagctccct   3480 

gcacggcctg gctgccaagc ttgggccacc ccgccccaag actggccgcc gcaagtccac   3540 

cagcagcatc ccgccctccc cgctggcctg cccgcccatc tccgcgcccc caccccgctc   3600 

gccctcgccc ctgcccgggc acccgcccgc acctgcccga tccccgcggc tgcgccgggg   3660 

ccagtcagct gacaagctgg gcacagggga gcggctggat ggggaggcgg ggcggcgcac   3720 

tcgtgggcca gaggccgagc tcgtggtcat gcggcggctg cacctgtccg agcgccgaga   3780 

ctccttcaag aagcaggagg ccgtgcagga ggttagcttc gatgagccgc aggaggaggc   3840 

cactgggctg cccacctcag tgccacagat cgccgtggag ggcgaggaag ccgtgccagt   3900 

agctctcggg cccaccggaa gagactgatc ccctgccagg tctctccctg gcatcaaagt   3960 

tacgcgtttt cttgtgcaat gttttttccg taaagtcatg cctggatggg gactgagcca   4020 

ccagcctgac acccagaagg cgagaagcca tctcggtcct tgctggaagg tggagacatc   4080 

gcttgtgttc tggtgtcaat cggggctgga tggggcaaga atgggggaca agggtggctt   4140 

tgtaaatagc agcaaatccc tgcaactaat ttattacttt ttttttcttt tttttttttt   4200 

ttttttgaga cagagtctca ctctgttgcc cgggctggag tgcagcggcg tgatctcagc   4260 

tcactgcaac ctccgcctcc caagttcaag cgattgtcct gcctcagctt cccaagtggc   4320 

tgggattaca ggcgcccacc actatgccca gctaattttt tgtattttta gtacagacgg   4380 

ggtttcacca tgttggtcag gctggtctcg aactcctgac ctcatgattt gcctgccttt   4440 

gcctcccaaa gtgctgggat tacaggcgtg agccactggg cccagcctaa tttattactt   4500 

tttataagcg atagccgtac tgagccgccc cctgaaggcg gctgccaggt cttgccccag   4560 

gcacctggga ctctgtttgc aggccctgcc ctctgggctg agaaggatgc actttggaca   4620 

agtcatctgt gtttgtgttt tccagttttt ctgtactttt taagtgtttt gtgttacctg   4680 

gtctcattcc cctccccaca cctacccatt tgaggggatg gagttgaagt cacctggtca   4740 

cctgtaccgg cccagttcgg ctacaacctg gagtgtccgt aaacaattcc tctcacccac   4800 

aaaacaatgt aatcccagcg atggactgga ttctgaaggc cacttcccac catcatagct   4860 

gccatgccca ggcagtgcct gctctatata tagagtctgc ctccaatcct gctggcttca   4920 

gcctggagaa gggatatggg agctggagct ttgatggatg aataggtgtt caccggatct   4980 

gggcagaggg gtcatccgct ccccaggtgg gcactgataa aggaaggtac aggcctcacc   5040 

tggaactgcc aaggcagcct ccagaaatgc tcggctgtct cggggcacgc tccagtatgc   5100 

cagtcctgcg ggattacgtc cagctacttc cagaaacact cagtgtcccc tcccctcagg   5160 

ctctgccttg gcctggcctt gtccagtcta ccctggacaa gatgccgtgt gtttgaggcc   5220 

cagcagagta agcccttggc cgtgatgtgt ctgaaacacc tgttaggggt tccctccata   5280 

tgtcagagcc tctctgggat gaagttcaag ccagaaaacc cagtcgaggc tcaagtttga   5340 

atttcagctt cactgtgtgg ctctgggaaa atggctttcc cactctgtgc ctcagtttcc   5400 

ttgtgtttac aagactaatc ccattgactg tttattaagc acctactgtg tgccaagcgc   5460 

ttttacgtgg cttctccctc agccagcctt gagaaggctg gaggtggtgt catcacctcc   5520 

attttacaga caaagcagct gagaccccag cgaggggcgg agacctgtcc cacgatcacc   5580 

cagcaggagt cgtggcagaa cggagcatca gccagaccct gttgtgggcg ttgtcatcaa   5640 

gggagcttga atggagggtc tggtgtcaga tacagccgac tccagcccca gctcatcccc   5700 

catgatgctg tgtgacccac tgggcactct ggtgagggag ctttccagac atcaacagcc   5760 

cactctgctt ccctttctga gtcccctgtc cagcactgcc tagtgttgga gggtagacca   5820 

aggctgtgca tgattcaccc cctccttcca tcctggagct ggcagtgaat aaaagcccgt   5880 

atttac                                                              5886 

 
           
             11  
             7826  
             DNA  
             Homo sapiens  
           
            11 

agaacgcacg gctcaactca tgtaattact gtttatagct ggccgagcct gactaggaga     60 

gggcagaccc gagaggaaat cagtttcccg gacctttgag aggaggctgt gtgttaatta    120 

aaggctagga cgggacgggt acttctcaga catgctccaa gttgttcttg agatcacagt    180 

tcccatcaca ttttctctgg agggagtgag tagataattg ggattttttt tttatttttg    240 

gccttgtctt tcttcctttt ttttacctct ccccatttta gtcatatggc cttgaaccca    300 

cagtgaattg aagagagaaa gaaatggata tgtctgaccc caatttttgg actgtgctct    360 

caaactttac tttgcctcat ttgaggagtg ggaacaggct tcggcgaaca caaagttgcc    420 

gaacaagcaa ccggaaaagc ttaataggca atgggcagtc accagcattg cctcgaccac    480 

actcacctct ctctgctcat gcaggaaata gccctcaaga tagtccaaga aatttctccc    540 

ccagtgcctc agcccatttt tcatttgcac ggaggactga tggacgccgc tggtcgttgg    600 

cttctctccc ttcctctggc tatgggacaa acacacccag ctctacggtc tcttcatcct    660 

gttcctccca ggagaagttg catcagttac cataccaacc aacaccagac gagttacact    720 

tcttatcaaa acatttctgt accaccgaaa gcatcgccac tgagaacaga tgcaggaaca    780 

cgccgatgcg cccccgttcc cgaagtctga gccctggacg ttctcccgcc tgctgtgacc    840 

atgaaataat tatgatgaac catgtctaca aagaaaggtt cccaaaggct acagctcaga    900 

tggaagaacg tctaaaggaa attatcacca gctactctcc tgacaacgtt ctacccttag    960 

cagatggagt gcttagtttc actcaccacc agattattga actggctcga gattgcttgg   1020 

ataaatccca ccagggcctc atcacctcac gatacttcct tgaattacag cacaaattag   1080 

ataagttgct acaggaggct catgatcgtt cagaaagtgg agaattggca tttattaaac   1140 

aactagttcg aaagatccta attgttattg cccgccctgc tcggttatta gagtgcctgg   1200 

aatttgatcc ggaagaattt tactacctat tggaagcagc agaaggccat gccaaagaag   1260 

gacagggtat taaaaccgac attcccaggt acatcattag ccaactggga ctcaataagg   1320 

atcccttgga agaaatggct catttgggaa actacgatag tgggacagca gaaacaccag   1380 

aaacagatga atcagtgagt agctctaatg cctccctgaa acttcgaagg aaacctcggg   1440 

aaagtgattt tgaaacgatt aaattgatta gcaatggagc ctatggggca gtctactttg   1500 

ttcggcataa agaatcccgg cagaggtttg ccatgaagaa gattaataaa cagaacctca   1560 

tccttcgaaa ccagatccag caggcctttg tggagcggga tatcctgact tttgcagaaa   1620 

acccctttgt tgtcagcatg tattgctcct ttgaaacaag gcgccacttg tgcatggtca   1680 

tggaatatgt ggaaggggga gactgtgcta ctttaatgaa aaacatgggt cctctccctg   1740 

ttgatatggc cagaatgtac tttgctgaga cggtcttggc cttggaatat ttacataatt   1800 

atggaattgt acacagggat ttgaaaccag acaacttgtt ggttacctcc atggggcaca   1860 

taaagctgac agattttgga ttatctaagg tgggactaat gagcatgact accaaccttt   1920 

acgagggtca tattgagaag gatgctagag agttcctgga taaacaggtc tgtggcacac   1980 

ctgaatacat tgcaccagaa gtgattctga ggcagggtta tggaaagccg gtggactggt   2040 

gggccatggg gattatcctc tatgaatttc tggttggatg cgtgccattc tttggggata   2100 

ctccagagga gctatttgga caagtcatca gtgatgagat caactggcct gagaaggatg   2160 

aggcaccccc acctgatgcc caggatctga ttaccttact cctcaggcag aatcccctgg   2220 

agaggctggg aacaggtggt gcatatgaag tcaaacagca tcgattcttc cgttctttag   2280 

actggaacag tttgctgaga cagaaggcag aatttattcc ccaactggaa tctgaggatg   2340 

acacaagtta ttttgatact cggtctgaga agtatcatca tatggaaacg gaggaagaag   2400 

atgacacaaa tgatgaagac tttaatgtgg aaataaggca gttttcttca tgttcacaca   2460 

ggttttcaaa agttttcagc agtatagatc gaatcactca gaattcagca gaagagaagg   2520 

aagactctgt ggacaaaacc aaaagcacca ccttgccatc cacagaaaca ctgagctgga   2580 

gttcagaata ttctgaaatg caacagctat caacatccaa ctcttcagat actgaaagca   2640 

acagacataa actcagttct ggcctacttc ccaaactggc tatttcaaca gagggagagc   2700 

aagatgaagc tgcctcctgc cctggagacc cccatgagga gccaggaaag ccagcccttc   2760 

ctcctgaaga gtgtgcccag gaggagcctg aggtcaccac cccagccagc accatcagca   2820 

gctccaccct gtcagttggc agtttttcag agcacttgga tcagataaat ggacgaagcg   2880 

agtgtgtgga cagtacagat aattcctcaa agccatccag tgaacccgct tctcacatgg   2940 

ctcggcagcg attagaaagc acagaaaaaa agaaaatctc ggggaaagtc acaaagtccc   3000 

tctctgccag tgctctttcc ctcatgatcc caggagatat gtttgctgtt tcccctctgg   3060 

gaagtccaat gtctccccat tccctgtcct cggacccttc ttcttcacga gattcctctc   3120 

ccagccgaga ttcctcagca gcttctgcca gtccacatca gccgattgtg atccacagtt   3180 

cggggaagaa ctacggcttt accatccgag ccatccgggt gtatgtggga gacagtgaca   3240 

tctatacagt gcaccatatc gtctggaatg tagaagaagg aagtccggca tgccaggcag   3300 

gactgaaggc tggagatctt atcactcaca tcaatggaga accagtgcat ggacttgtcc   3360 

acacagaagt tatagaactc ctactgaaga gtgggaataa ggtgtcaatc actactaccc   3420 

catttgaaaa cacatcaatc aaaactggac cagccaggag aaacagctat aagagccgga   3480 

tggtgaggcg gagcaagaaa tccaagaaga aagaaagtct cgaaaggagg agatctcttt   3540 

tcaaaaagct agccaagcag ccttctcctt tactccacac cagccgaagt ttctcctgct   3600 

tgaacagatc cctgtcatcg ggtgagagcc tcccaggttc ccccactcat agcttgtctc   3660 

cccggtctcc aacaccaagc taccgctcca cccctgactt cccatctggt actaattcct   3720 

cccagagcag ctcccctagt tctagtgccc ccaattcccc agcagggtcc gggcacatcc   3780 

ggcccagcac tctccacggt cttgcaccca aactcggcgg gcagcggtac cggtccggaa   3840 

ggcgaaagtc cgccggcaac atcccactgt ccccgctggc ccggacgccc tctccaaccc   3900 

cgcaacccac ctccccgcag cggtcaccat cccctcttct gggacactca ctgggcaatt   3960 

ccaagatcgc gcaagccttt cccagcaaga tgcactcccc gcccaccatc gtcagacaca   4020 

tcgtgaggcc caagagtgcg gagcccccca ggtccccgct gctcaagcgc gtgcagtccg   4080 

aggagaagct gtcgccctct tacggcagtg acaagaagca cctgtgctcc cgcaagcaca   4140 

gcctggaggt gacccaagag gaggtgcagc gggagcagtc ccagcgggag gcgccgctgc   4200 

agagcctgga tgagaacgtg tgcgacgtgc cgccgctcag ccgcgcccgg ccagtggagc   4260 

aaggctgcct gaaacgccca gtctcccgga aggtgggccg ccaggagtct gtggacgacc   4320 

tggaccgcga caagctgaag gccaaggtgg tggtgaagaa agcagacggc ttcccagaga   4380 

aacaggaatc ccaccagaaa tcccatggac ccgggagtga tttggaaaac tttgctctgt   4440 

ttaagctgga agagagagag aagaaagtct atccgaaggc tgtggaaagg tcaagtactt   4500 

ttgaaaacaa agcgtctatg caggaggcgc caccgctggg cagcctgctg aaggatgctc   4560 

ttcacaagca ggccagcgtg cgcgccagcg agggtgcgat gtcggatggc ccggtgcctg   4620 

cggagcaccg ccagggtggc ggggacttca gacgggcccc cgctcctggc accctccagg   4680 

atggtctctg ccactccctc gacaggggca tctctgggaa gggggaaggc acggagaagt   4740 

cctcccaggc caaggagctt ctccgatgtg aaaagttaga cagcaagctg gccaacatcg   4800 

attacctccg aaagaaaatg tcacttgagg acaaagagga caacctctgc cctgtgctga   4860 

agcccaagat gacagctggc tcccacgaat gcctgccagg gaacccagtc cgacccacgg   4920 

gtgggcagca ggagcccccg ccggcttctg agagccgagc ttttgtcagc agcacccatg   4980 

cagctcagat gagtgccgtc tcttttgttc ccctcaaggc cttaacaggc cgggtggaca   5040 

gtggaacgga gaagcctggc ttggttgctc ctgagtcccc tgttaggaag agcccctccg   5100 

agtataagct ggaaggtagg tctgtctcat gcctgaagcc gatcgagggc actctggaca   5160 

ttgctctcct gtccggacct caggcctcca agacagaact gccttcccca gagtctgcac   5220 

agagccccag cccaagtggt gacgtgaggg cctctgtgcc accagttctc cccagcagca   5280 

gtgggaaaaa gaacgatacc accagtgcaa gagagctttc tccttccagc ttaaagatga   5340 

ataaatccta cctgctggag ccttggttcc tgccccccag ccgaggtctc cagaattcac   5400 

cagcagtttc cctgcctgac ccagagttca agagggacag gaaaggtccc catcctactg   5460 

ccaggagccc tggaacagtc atggaaagca atccccaaca gagagagggc agctccccta   5520 

aacaccaaga ccacaccact gaccccaagc ttctgacctg cctggggcag aacctccaca   5580 

gccctgacct ggccaggcca cgctgcccgc tcccacctga agcttccccc tcaagggaga   5640 

agccaggcct gagggaatcg tctgaaagag gccctcccac agccagaagc gagcgctctg   5700 

ctgcgagggc tgacacatgc agagagccct ccatggaact gtgctttcca gaaactgcga   5760 

aaaccagtga caactccaaa aatctcctct ctgtgggaag gacccaccca gatttctata   5820 

cacagaccca ggccatggag aaagcatggg cgccgggtgg gaaaacgaac cacaaagatg   5880 

gcccaggtga ggcgaggccc ccgcccagag acaactcctc tctgcactca gctggaattc   5940 

cctgtgagaa ggagctgggc aaggtgaggc gtggcgtgga acccaagccc gaagcgcttc   6000 

ttgccaggcg gtctctgcag ccacctggaa ttgagagtga gaagagtgaa aagctctcca   6060 

gtttcccatc tttgcagaaa gatggtgcca aggaacctga aaggaaggag cagcctctac   6120 

aaaggcatcc cagcagcatc cctccgcccc ctctgacggc caaagacctg tccagcccgg   6180 

ctgccaggca gcattgcagt tccccaagcc acgcttctgg cagagagccg ggggccaagc   6240 

ccagcactgc agagcccagc tcgagccccc aggaccctcc caagcctgtt gctgcgcaca   6300 

gtgaaagcag cagccacaag ccccggcctg gccctgaccc gggccctcca aagactaagc   6360 

accccgaccg gtccctctcc tctcagaaac caagtgtcgg ggccacaaag ggcaaagagc   6420 

ctgccactca gtccctcggt ggctctagca gagaggggaa gggccacagt aagagtgggc   6480 

cggatgtgtt tcctgctacc ccaggctccc agaacaaagc cagcgatggg attggccagg   6540 

gagaaggtgg gccctctgtc ccactgcaca ctgacagggc tcctctagac gccaagccac   6600 

aacccaccag tggtgggcgg cccctggagg tgctggagaa gcctgtgcat ttgccaaggc   6660 

cgggacaccc agggcctagt gagccagcgg accagaaact gtccgctgtt ggtgaaaagc   6720 

aaaccctgtc tccaaagcac cccaaaccat ccactgtgaa agattgcccc accctgtgca   6780 

aacagacaga caacagacag acagacaaaa gcccgagtca gccggccgcc aacaccgaca   6840 

gaagggcgga agggaagaaa tgcactgaag cactttatgc tccagcagag ggcgacaagc   6900 

tcgaggccgg cctttccttt gtgcatagcg agaaccggtt gaaaggcgcg gagcggccag   6960 

ccgcgggggt ggggaagggc ttccctgagg ccagagggaa agggcccggt ccccagaagc   7020 

caccgacgga ggcagacaag cccaatggca tgaaacggtc cccctcagcc actgggcaga   7080 

gttctttccg atccacggcc ctcccggaaa agtctctgag ctgctcctcc agcttccctg   7140 

aaaccagggc cggagttaga gaggcctctg cagccagcag cgacacctct tctgccaagg   7200 

ccgccggggg catgctggag cttccagccc ccagcaacag ggaccatagg aaggctcagc   7260 

ctgccgggga gggccgaacc cacatgacaa agagtgactc cctgccctcc ttccgggtct   7320 

ccaccctgcc tctggagtca caccaccccg acccaaacac catgggcggg gccagccacc   7380 

gggacagggc tctctcggtg actgccaccg taggggaaac caaagggaag gaccctgccc   7440 

cagcccagcc tcccccagct aggaaacaga acgtgggcag agacgtgacc aagccatccc   7500 

cagccccaaa cactgaccgc cccatctctc tttctaatga gaaggacttt gtggtacggc   7560 

agaggcgggg gaaagagagt ttgcgtagca gccctcacaa aaaggccttg taacggggag   7620 

ggcccagggg caggactgtg gagacccgtc ctgaacgggc gactgtgtct tgactacctt   7680 

tcaaaaccag cactgtgtgg gaatgtccgc caggcagagc tcggagcctc attgagacag   7740 

gggagagaga aagacaaaga ggggaccttc ttccagatgc cttcccagtt gtaaccggta   7800 

aaactgttac cagatagtgt ttgtac                                        7826 

 
           
             12  
             1005  
             DNA  
             Homo sapiens  
           
            12 

ggcacgaggg tccagcccgg ctgccaggca gcattgcagt tccccaagcc acgcttctgg     60 

cagagagccg ggggccaagc ccagcactgc agagcccagc tcgagccccc aggaccctcc    120 

caagcctgtt gctgcgcaca gtgaaagcag cagccacaaa gggcaaagag cctgccaccg    180 

acggaggcag acaagcccaa tggcatgaaa cggtccccct cagccactgg gcagagttct    240 

ttccgatcca cggccctccc ggaaaagtct ctgagctgct cctccagctt ccctgaaacc    300 

agggccggag ttagagaggc ctctgcagcc agcagcgaca cctcttctgc caaggccgcc    360 

gggggcatgc tggagcttcc agcccccagc aacagggacc ataggaaggc tcagcctgcc    420 

ggggagggcc gaacccacat gacaaagagt gactccctgc cctccttccg ggtctccacc    480 

ctgcctctgg agtcacacca ccccgaccca aacaccatgg gcggggccag ccaccgggac    540 

agggctctct cggtgactgc caccgtaggg gaaaccaaag ggaaggaccc tgccccagcc    600 

cagcctcccc cagctaggaa acagaacgtg ggcagagacg tgaccaagcc atccccagcc    660 

ccaaacactg accgccccat ctctctttct aatgagaagg actttgtggt acggcggagg    720 

cgggggaaag agagtttgcg tagcagccct cacaaaaagg ccttgtaacg gggagggccc    780 

aggggcagga ctgtggagac ccgtcctgaa cgggcgactg tgtcttgact acctttcaaa    840 

accagcactg tgtgggaatg tccgccaggc agagctcgga gcctcattga gacaggggag    900 

agagaaagac aaagagggga ccttcttcca gatgccttcc cagttgtaac cggtaaaact    960 

gttaccagat agtgtttgta caaaaaaaaa aaaaaaaaaa aaaaa                   1005 

 
           
             13  
             6629  
             DNA  
             Homo sapiens  
           
            13 

tggaatttga tccggaagaa ttttactacc tattggaagc agcagaaggc catgccaaag     60 

aaggacaggg tattaaaacc gacattccca ggtacatcat tagccaactg ggactcaata    120 

aggatccctt ggaagaaatg gctcatttgg gaaactacga tagtgggaca gcagaaacac    180 

cagaaacaga tgaatcagtg agtagctcta atgcctccct gaaacttcga aggaaacctc    240 

gggaaagtga ttttgaaacg attaaattga ttagcaatgg agcctatggg gcagtctact    300 

ttgttcggca taaagaatcc cggcagaggt ttgccatgaa gaagattaat aaacagaacc    360 

tcatccttcg aaaccagatc cagcaggcct ttgtggagcg ggatatcctg acttttgcag    420 

aaaacccctt tgttgtcagc atgtattgct cctttgaaac aaggcgccac ttgtgcatgg    480 

tcatggaata tgtggaaggg ggagactgtg ctactttaat gaaaaacatg ggtcctctcc    540 

ctgttgatat ggccagaatg tactttgctg agacggtctt ggccttggaa tatttacata    600 

attatggaat tgtacacagg gatttgaaac cagacaactt gttggttacc tccatggggc    660 

acataaagct gacagatttt ggattatcta aggtgggact aatgagcatg actaccaacc    720 

tttacgaggg tcatattgag aaggatgcta gagagttcct ggataaacag gtctgtggca    780 

cacctgaata cattgcacca gaagtgattc tgaggcaggg ttatggaaag ccggtggact    840 

ggtgggccat ggggattatc ctctatgaat ttctggttgg atgcgtgcca ttctttgggg    900 

atactccaga ggagctattt ggacaagtca tcagtgatga gatcaactgg cctgagaagg    960 

atgaggcacc cccacctgat gcccaggatc tgattacctt actcctcagg cagaatcccc   1020 

tggagaggct gggaacaggt ggtgcatatg aagtcaaaca gcatcgattc ttccgttctt   1080 

tagactggaa cagtttgctg agacagaagg cagaatttat tccccaactg gaatctgagg   1140 

atgacacaag ttattttgat actcggtctg agaagtatca tcatatggaa acggaggaag   1200 

aagatgacac aaatgatgaa gactttaatg tggaaataag gcagttttct tcatgttcac   1260 

acaggttttc aaaagttttc agcagtatag atcgaatcac tcagaattca gcagaagaga   1320 

aggaagactc tgtggacaaa accaaaagca ccaccttgcc atccacagaa acactgagct   1380 

ggagttcaga atattctgaa atgcaacagc tatcaacatc caactcttca gatactgaaa   1440 

gcaacagaca taaactcagt tctggcctac ttcccaaact ggctatttca acagagggag   1500 

agcaagatga agctgcctcc tgccctggag acccccatga ggagccagga aagccagccc   1560 

ttcctcctga agagtgtgcc caggaggagc ctgaggtcac caccccagcc agcaccatca   1620 

gcagctccac cctgtcagtt ggcagttttt cagagcactt ggatcagata aatggacgaa   1680 

gcgagtgtgt ggacagtaca gataattcct caaagccatc cagtgaaccc gcttctcaca   1740 

tggctcggca gcgattagaa agcacagaaa aaaagaaaat ctcggggaaa gtcacaaagt   1800 

ccctctctgc cagtgctctt tccctcatga tcccaggaga tatgtttgct gtttcccctc   1860 

tgggaagtcc aatgtctccc cattccctgt cctcggaccc ttcttcttca cgagattcct   1920 

ctcccagccg agattcctca gcagcttctg ccagtccaca tcagccgatt gtgatccaca   1980 

gttcggggaa gaactacggc tttaccatcc gagccatccg ggtgtatgtg ggagacagtg   2040 

acatctatac agtgcaccat atcgtctgga atgtagaaga aggaagtccg gcatgccagg   2100 

caggactgaa ggctggagat cttatcactc acatcaatgg agaaccagtg catggacttg   2160 

tccacacaga agttatagaa ctcctactga agagtgggaa taaggtgtca atcactacta   2220 

ccccatttga aaacacatca atcaaaactg gaccagccag gagaaacagc tataagagcc   2280 

ggatggtgag gcggagcaag aaatccaaga agaaagaaag tctcgaaagg aggagatctc   2340 

ttttcaaaaa gctagccaag cagccttctc ctttactcca caccagccga agtttctcct   2400 

gcttgaacag atccctgtca tcgggtgaga gcctcccagg ttcccccact catagcttgt   2460 

ctccccggtc tccaacacca agctaccgct ccacccctga cttcccatct ggtactaatt   2520 

cctcccagag cagctcccct agttctagtg cccccaattc cccagcaggg tccgggcaca   2580 

tccggcccag cactctccac ggtcttgcac ccaaactcgg cgggcagcgg taccggtccg   2640 

gaaggcgaaa gtccgccggc aacatcccac tgtccccgct ggcccggacg ccctctccaa   2700 

ccccgcaacc cacctccccg cagcggtcac catcccctct tctgggacac tcactgggca   2760 

attccaagat cgcgcaagcc tttcccagca agatgcactc cccgcccacc atcgtcagac   2820 

acatcgtgag gcccaagagt gcggagcccc ccaggtcccc gctgctcaag cgcgtgcagt   2880 

ccgaggagaa gctgtcgccc tcttacggca gtgacaagaa gcacctgtgc tcccgcaagc   2940 

acagcctgga ggtgacccaa gaggaggtgc agcgggagca gtcccagcgg gaggcgccgc   3000 

tgcagagcct ggatgagaac gtgtgcgacg tgccgccgct cagccgcgcc cggccagtgg   3060 

agcaaggctg cctgaaacgc ccagtctccc ggaaggtggg ccgccaggag tctgtggacg   3120 

acctggaccg cgacaagctg aaggccaagg tggtggtgaa gaaagcagac ggcttcccag   3180 

agaaacagga atcccaccag aaatcccatg gacccgggag tgatttggaa aactttgctc   3240 

tgtttaagct ggaagagaga gagaagaaag tctatccgaa ggctgtggaa aggtcaagta   3300 

cttttgaaaa caaagcgtct atgcaggagg cgccaccgct gggcagcctg ctgaaggatg   3360 

ctcttcacaa gcaggccagc gtgcgcgcca gcgagggtgc gatgtcggat ggcccggtgc   3420 

ctgcggagca ccgccagggt ggcggggact tcagacgggc ccccgctcct ggcaccctcc   3480 

aggatggtct ctgccactcc ctcgacaggg gcatctctgg gaagggggaa ggcacggaga   3540 

agtcctccca ggccaaggag cttctccgat gtgaaaagtt agacagcaag ctggccaaca   3600 

tcgattacct ccgaaagaaa atgtcacttg aggacaaaga ggacaacctc tgccctgtgc   3660 

tgaagcccaa gatgacagct ggctcccacg aatgcctgcc agggaaccca gtccgaccca   3720 

cgggtgggca gcaggagccc ccgccggctt ctgagagccg agcttttgtc agcagcaccc   3780 

atgcagctca gatgagtgcc gtctcttttg ttcccctcaa ggccttaaca ggccgggtgg   3840 

acagtggaac ggagaagcct ggcttggttg ctcctgagtc ccctgttagg aagagcccct   3900 

ccgagtataa gctggaaggt aggtctgtct catgcctgga gccgatcgag ggcactctgg   3960 

acattgctct cctgtccgga cctcaggcct ccaagacaga actgccttcc ccagagtctg   4020 

cacagagccc cagcccaagt ggtgacgtga gggcctctgt gccaccagtt ctccccagca   4080 

gcagtgggaa aaagaacgat accaccagtg caagagagct ttctccttcc agcttaaaga   4140 

tgaataaatc ctacctgctg gagccttggt tcctgccccc cagccgaggt ctccagaatt   4200 

caccagcagt ttccctgcct gacccagagt tcaagaggga caggaaaggt ccccatccta   4260 

ctgccaggag ccctggaaca gtcatggaaa gcaatcccca acagagagag ggcagctccc   4320 

ctaaacacca agaccacacc actgacccca agcttctgac ctgcctgggg cagaacctcc   4380 

acagccctga cctggccagg ccacgctgcc cgctcccacc tgaagcttcc ccctcaaggg   4440 

agaagccagg cctgagggaa tcgtctgaaa gaggccctcc cacagccaga agcgagcgct   4500 

ctgctgcgag ggctgacaca tgcagagagc cctccatgga actgtgcttt ccagaaactg   4560 

cgaaaaccag tgacaactcc aaaaatctcc tctctgtggg aaggacccac ccagatttct   4620 

atacacagac ccaggccatg gagaaagcat gggcgccggg tgggaaaacg aaccacaaag   4680 

atggcccagg tgaggcgagg cccccgccca gagacaactc ctctctgcac tcagctggaa   4740 

ttccctgtga gaaggagctg ggcaaggtga ggcgtggcgt ggaacccaag cccgaagcgc   4800 

ttcttgccag gcggtctctg cagccacctg gaattgagag tgagaagagt gaaaagctct   4860 

ccagtttccc atctttgcag aaagatggtg ccaaggaacc tgaaaggaag gagcagcctc   4920 

tacaaaggca tcccagcagc atccctccgc cccctctgac ggccaaagac ctgtccagcc   4980 

cggctgccag gcagcattgc agttccccaa gccacgcttc tggcagagag ccgggggcca   5040 

agcccagcac tgcagagccc agctcgagcc cccaggaccc tcccaagcct gttgctgcgc   5100 

acagtgaaag cagcagccac aagccccggc ctggccctga cccgggccct ccaaagacta   5160 

agcaccccga ccggtccctc tcctctcaga aaccaagtgt cggggccaca aagggcaaag   5220 

agcctgccac tcagtccctc ggtggctcta gcagagaggg gaagggccac agtaagagtg   5280 

ggccggatgt gtttcctgct accccaggct cccagaacaa agccagcgat gggattggcc   5340 

agggagaagg tgggccctct gtcccactgc acactgacag ggctcctcta gacgccaagc   5400 

cacaacccac cagtggtggg cggcccctgg aggtgctgga gaagcctgtg catttgccaa   5460 

ggccgggaca cccagggcct agtgagccag cggaccagaa actgtccgct gttggtgaaa   5520 

agcaaaccct gtctccaaag caccccaaac catccactgt gaaagattgc cccaccctgt   5580 

gcaaacagac agacaacaga cagacagaca aaagcccgag tcagccggcc gccaacaccg   5640 

acagaagggc ggaagggaag aaatgcactg aagcacttta tgctccagca gagggcgaca   5700 

agctcgaggc cggcctttcc tttgtgcata gcgagaaccg gttgaaaggc gcggagcggc   5760 

cagccgcggg ggtggggaag ggcttccctg aggccagagg gaaagggccc ggtccccaga   5820 

agccaccgac ggaggcagac aagcccaatg gcatgaaacg gtccccctca gccactgggc   5880 

agagttcttt ccgatccacg gccctcccgg aaaagtctct gagctgctcc tccagcttcc   5940 

ctgaaaccag ggccggagtt agagaggcct ctgcagccag cagcgacacc tcttctgcca   6000 

aggccgccgg gggcatgctg gagcttccag cccccagcaa cagggaccat aggaaggctc   6060 

agcctgccgg ggagggccga acccacatga caaagagtga ctccctgccc tccttccggg   6120 

tctccaccct gcctctggag tcacaccacc ccgacccaaa caccatgggc ggggccagcc   6180 

accgggacag ggctctctcg gtgactgcca ccgtagggga aaccaaaggg aaggaccctg   6240 

ccccagccca gcctccccca gctaggaaac agaacgtggg cagagacgtg accaagccat   6300 

ccccagcccc aaacactgac cgccccatct ctctttctaa tgagaaggac tttgtggtac   6360 

ggcagaggcg ggggaaagag agtttgcgta gcagccctca caaaaaggcc ttgtaacggg   6420 

gagggcccag gggcaggact gtggagaccc gtcctgaacg ggcgactgtg tcttgactac   6480 

ctttcaaaac cagcactgtg tgggaatgtc cgccaggcag agctcggagc ctcattgaga   6540 

caggggagag agaaagacaa agaggggacc ttcttccaga tgccttccca gttgtaaccg   6600 

gtaaaactgt taccagatag tgtttgtac                                     6629 

 
           
             14  
             1734  
             PRT  
             Homo sapiens  
           
            14 

Met Lys Arg Ser Arg Cys Arg Asp Arg Pro Gln Pro Pro Pro Pro Asp 
1               5                   10                  15 

Arg Arg Glu Asp Gly Val Gln Arg Ala Ala Glu Leu Ser Gln Ser Leu 
            20                  25                  30 

Pro Pro Arg Arg Arg Ala Pro Pro Gly Arg Gln Arg Leu Glu Glu Arg 
        35                  40                  45 

Thr Gly Pro Ala Gly Pro Glu Gly Lys Glu Gln Asp Val Val Thr Gly 
    50                  55                  60 

Val Ser Pro Leu Leu Phe Arg Lys Leu Ser Asn Pro Asp Ile Phe Ser 
65                  70                  75                  80 

Ser Thr Gly Lys Val Lys Leu Gln Arg Gln Leu Ser Gln Asp Asp Cys 
                85                  90                  95 

Lys Leu Trp Arg Gly Asn Leu Ala Ser Ser Leu Ser Gly Lys Gln Leu 
            100                 105                 110 

Leu Pro Leu Ser Ser Ser Val His Ser Ser Val Gly Gln Val Thr Trp 
        115                 120                 125 

Gln Ser Ser Gly Glu Ala Ser Asn Leu Val Arg Met Arg Asn Gln Ser 
    130                 135                 140 

Leu Gly Gln Ser Ala Pro Ser Leu Thr Ala Gly Leu Lys Glu Leu Ser 
145                 150                 155                 160 

Leu Pro Arg Arg Gly Ser Phe Cys Arg Thr Ser Asn Arg Lys Ser Leu 
                165                 170                 175 

Ile Val Thr Ser Ser Thr Ser Pro Thr Leu Pro Arg Pro His Ser Pro 
            180                 185                 190 

Leu His Gly His Thr Gly Asn Ser Pro Leu Asp Ser Pro Arg Asn Phe 
        195                 200                 205 

Ser Pro Asn Ala Pro Ala His Phe Ser Phe Val Pro Ala Arg Arg Thr 
    210                 215                 220 

Asp Gly Arg Arg Trp Ser Leu Ala Ser Leu Pro Ser Ser Gly Tyr Gly 
225                 230                 235                 240 

Thr Asn Thr Pro Ser Ser Thr Val Ser Ser Ser Cys Ser Ser Gln Glu 
                245                 250                 255 

Lys Leu His Gln Leu Pro Phe Gln Pro Thr Ala Asp Glu Leu His Phe 
            260                 265                 270 

Leu Thr Lys His Phe Ser Thr Glu Ser Val Pro Asp Glu Glu Gly Arg 
        275                 280                 285 

Gln Ser Pro Ala Met Arg Pro Arg Ser Arg Ser Leu Ser Pro Gly Arg 
    290                 295                 300 

Ser Pro Val Ser Phe Asp Ser Glu Ile Ile Met Met Asn His Val Tyr 
305                 310                 315                 320 

Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln Met Glu Glu Arg Leu Ala 
                325                 330                 335 

Glu Phe Ile Ser Ser Asn Thr Pro Asp Ser Val Leu Pro Leu Ala Asp 
            340                 345                 350 

Gly Ala Leu Ser Phe Ile His His Gln Val Ile Glu Met Ala Arg Asp 
        355                 360                 365 

Cys Leu Asp Lys Ser Arg Ser Gly Leu Ile Thr Ser Gln Tyr Phe Tyr 
    370                 375                 380 

Glu Leu Gln Glu Asn Leu Glu Lys Leu Leu Gln Asp Ala His Glu Arg 
385                 390                 395                 400 

Ser Glu Ser Ser Glu Val Ala Phe Val Met Gln Leu Val Lys Lys Leu 
                405                 410                 415 

Met Ile Ile Ile Ala Arg Pro Ala Arg Leu Leu Glu Cys Leu Glu Phe 
            420                 425                 430 

Asp Pro Glu Glu Phe Tyr His Leu Leu Glu Ala Ala Glu Gly His Ala 
        435                 440                 445 

Lys Glu Gly Gln Gly Ile Lys Cys Asp Ile Pro Arg Tyr Ile Val Ser 
    450                 455                 460 

Gln Leu Gly Leu Thr Arg Asp Pro Leu Glu Glu Met Ala Gln Leu Ser 
465                 470                 475                 480 

Ser Cys Asp Ser Pro Asp Thr Pro Glu Thr Asp Asp Ser Ile Glu Gly 
                485                 490                 495 

His Gly Ala Ser Leu Pro Ser Lys Lys Thr Pro Ser Glu Glu Asp Phe 
            500                 505                 510 

Glu Thr Ile Lys Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Phe Leu 
        515                 520                 525 

Val Arg His Lys Ser Thr Arg Gln Arg Phe Ala Met Lys Lys Ile Asn 
    530                 535                 540 

Lys Gln Asn Leu Ile Leu Arg Asn Gln Ile Gln Gln Ala Phe Val Glu 
545                 550                 555                 560 

Arg Asp Ile Leu Thr Phe Ala Glu Asn Pro Phe Val Val Ser Met Phe 
                565                 570                 575 

Cys Ser Phe Asp Thr Lys Arg His Leu Cys Met Val Met Glu Tyr Val 
            580                 585                 590 

Glu Gly Gly Asp Cys Ala Thr Leu Leu Lys Asn Ile Gly Ala Leu Pro 
        595                 600                 605 

Val Asp Met Val Arg Leu Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu 
    610                 615                 620 

Tyr Leu His Asn Tyr Gly Ile Val His Arg Asp Leu Lys Pro Asp Asn 
625                 630                 635                 640 

Leu Leu Ile Thr Ser Met Gly His Ile Lys Leu Thr Asp Phe Gly Leu 
                645                 650                 655 

Ser Lys Met Gly Leu Met Ser Leu Thr Thr Asn Leu Tyr Glu Gly His 
            660                 665                 670 

Ile Glu Lys Asp Ala Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr 
        675                 680                 685 

Pro Glu Tyr Ile Ala Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys 
    690                 695                 700 

Pro Val Asp Trp Trp Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val 
705                 710                 715                 720 

Gly Cys Val Pro Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln 
                725                 730                 735 

Val Ile Ser Asp Glu Ile Val Trp Pro Glu Gly Asp Glu Ala Leu Pro 
            740                 745                 750 

Pro Asp Ala Gln Asp Leu Thr Ser Lys Leu Leu His Gln Asn Pro Leu 
        755                 760                 765 

Glu Arg Leu Gly Thr Gly Ser Ala Tyr Glu Val Lys Gln His Pro Phe 
    770                 775                 780 

Phe Thr Gly Leu Asp Trp Thr Gly Leu Leu Arg Gln Lys Ala Glu Phe 
785                 790                 795                 800 

Ile Pro Gln Leu Glu Ser Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg 
                805                 810                 815 

Ser Glu Arg Tyr His His Met Asp Ser Glu Asp Glu Glu Glu Val Ser 
            820                 825                 830 

Glu Asp Gly Cys Leu Glu Ile Arg Gln Phe Ser Ser Cys Ser Pro Arg 
        835                 840                 845 

Phe Asn Lys Val Tyr Ser Ser Met Glu Arg Leu Ser Leu Leu Glu Glu 
    850                 855                 860 

Arg Arg Thr Pro Pro Pro Thr Lys Arg Ser Leu Ser Glu Glu Lys Glu 
865                 870                 875                 880 

Asp His Ser Asp Gly Leu Ala Gly Leu Lys Gly Arg Asp Arg Ser Trp 
                885                 890                 895 

Val Ile Gly Ser Pro Glu Ile Leu Arg Lys Arg Leu Ser Val Ser Glu 
            900                 905                 910 

Ser Ser His Thr Glu Ser Asp Ser Ser Pro Pro Met Thr Val Arg Arg 
        915                 920                 925 

Arg Cys Ser Gly Leu Leu Asp Ala Pro Arg Phe Pro Glu Gly Pro Glu 
    930                 935                 940 

Glu Ala Ser Ser Thr Leu Arg Arg Gln Pro Gln Glu Gly Ile Trp Val 
945                 950                 955                 960 

Leu Thr Pro Pro Ser Gly Glu Gly Val Ser Gly Pro Val Thr Glu His 
                965                 970                 975 

Ser Gly Glu Gln Arg Pro Lys Leu Asp Glu Glu Ala Val Gly Arg Ser 
            980                 985                 990 

Ser Gly Ser Ser Pro Ala Met Glu  Thr Arg Gly Arg Gly  Thr Ser Gln 
        995                 1000                 1005 

Leu Ala  Glu Gly Ala Thr Ala  Lys Ala Ile Ser Asp  Leu Ala Val 
    1010                 1015                 1020 

Arg Arg  Ala Arg His Arg Leu  Leu Ser Gly Asp Ser  Thr Glu Lys 
    1025                 1030                 1035 

Arg Thr  Ala Arg Pro Val Asn  Lys Val Ile Lys Ser  Ala Ser Ala 
    1040                 1045                 1050 

Thr Ala  Leu Ser Leu Leu Ile  Pro Ser Glu His His  Thr Cys Ser 
    1055                 1060                 1065 

Pro Leu  Ala Ser Pro Met Ser  Pro His Ser Gln Ser  Ser Asn Pro 
    1070                 1075                 1080 

Ser Ser  Arg Asp Ser Ser Pro  Ser Arg Asp Phe Leu  Pro Ala Leu 
    1085                 1090                 1095 

Gly Ser  Met Arg Pro Pro Ile  Ile Ile His Arg Ala  Gly Lys Lys 
    1100                 1105                 1110 

Tyr Gly  Phe Thr Leu Arg Ala  Ile Arg Val Tyr Met  Gly Asp Ser 
    1115                 1120                 1125 

Asp Val  Tyr Thr Val His His  Met Val Trp His Val  Glu Asp Gly 
    1130                 1135                 1140 

Gly Pro  Ala Ser Glu Ala Gly  Leu Arg Gln Gly Asp  Leu Ile Thr 
    1145                 1150                 1155 

His Val  Asn Gly Glu Pro Val  His Gly Leu Val His  Thr Glu Val 
    1160                 1165                 1170 

Val Glu  Leu Ile Leu Lys Ser  Gly Asn Lys Val Ala  Ile Ser Thr 
    1175                 1180                 1185 

Thr Pro  Leu Glu Asn Thr Ser  Ile Lys Val Gly Pro  Ala Arg Lys 
    1190                 1195                 1200 

Gly Ser  Tyr Lys Ala Lys Met  Ala Arg Arg Ser Lys  Arg Ser Arg 
    1205                 1210                 1215 

Gly Lys  Asp Gly Gln Glu Ser  Arg Lys Arg Ser Ser  Leu Phe Arg 
    1220                 1225                 1230 

Lys Ile  Thr Lys Gln Ala Ser  Leu Leu His Thr Ser  Arg Ser Leu 
    1235                 1240                 1245 

Ser Ser  Leu Asn Arg Ser Leu  Ser Ser Gly Glu Ser  Gly Pro Gly 
    1250                 1255                 1260 

Ser Pro  Thr His Ser His Ser  Leu Ser Pro Arg Ser  Pro Thr Gln 
    1265                 1270                 1275 

Gly Tyr  Arg Val Thr Pro Asp  Ala Val His Ser Val  Gly Gly Asn 
    1280                 1285                 1290 

Ser Ser  Gln Ser Ser Ser Pro  Ser Ser Ser Val Pro  Ser Ser Pro 
    1295                 1300                 1305 

Ala Gly  Ser Gly His Thr Arg  Pro Ser Ser Leu His  Gly Leu Ala 
    1310                 1315                 1320 

Pro Lys  Leu Gln Arg Gln Tyr  Arg Ser Pro Arg Arg  Lys Ser Ala 
    1325                 1330                 1335 

Gly Ser  Ile Pro Leu Ser Pro  Leu Ala His Thr Pro  Ser Pro Pro 
    1340                 1345                 1350 

Pro Pro  Thr Ala Ser Pro Gln  Arg Ser Pro Ser Pro  Leu Ser Gly 
    1355                 1360                 1365 

His Val  Ala Gln Ala Phe Pro  Thr Lys Leu His Leu  Ser Pro Pro 
    1370                 1375                 1380 

Leu Gly  Arg Gln Leu Ser Arg  Pro Lys Ser Ala Glu  Pro Pro Arg 
    1385                 1390                 1395 

Ser Pro  Leu Leu Lys Arg Val  Gln Ser Ala Glu Lys  Leu Ala Ala 
    1400                 1405                 1410 

Ala Leu  Ala Ala Ser Glu Lys  Lys Leu Ala Thr Ser  Arg Lys His 
    1415                 1420                 1425 

Ser Leu  Asp Leu Pro His Ser  Glu Leu Lys Lys Glu  Leu Pro Pro 
    1430                 1435                 1440 

Arg Glu  Val Ser Pro Leu Glu  Val Val Gly Ala Arg  Ser Val Leu 
    1445                 1450                 1455 

Ser Gly  Lys Gly Ala Leu Pro  Gly Lys Gly Val Leu  Gln Pro Ala 
    1460                 1465                 1470 

Pro Ser  Arg Ala Leu Gly Thr  Leu Arg Gln Asp Arg  Ala Glu Arg 
    1475                 1480                 1485 

Arg Glu  Ser Leu Gln Lys Gln  Glu Ala Ile Arg Glu  Val Asp Ser 
    1490                 1495                 1500 

Ser Glu  Asp Asp Thr Glu Glu  Gly Pro Glu Asn Ser  Gln Gly Ala 
    1505                 1510                 1515 

Gln Glu  Leu Ser Leu Ala Pro  His Pro Glu Val Ser  Gln Ser Val 
    1520                 1525                 1530 

Ala Pro  Lys Gly Ala Gly Glu  Ser Gly Glu Glu Asp  Pro Phe Pro 
    1535                 1540                 1545 

Ser Arg  Gly Pro Arg Ser Leu  Gly Pro Met Val Pro  Ser Leu Leu 
    1550                 1555                 1560 

Thr Gly  Ile Thr Leu Gly Pro  Pro Arg Met Glu Ser  Pro Ser Gly 
    1565                 1570                 1575 

Pro His  Arg Arg Leu Gly Ser  Pro Gln Ala Ile Glu  Glu Ala Ala 
    1580                 1585                 1590 

Ser Ser  Ser Ser Ala Gly Pro  Asn Leu Gly Gln Ser  Gly Ala Thr 
    1595                 1600                 1605 

Asp Pro  Ile Pro Pro Glu Gly  Cys Trp Lys Ala Gln  His Leu His 
    1610                 1615                 1620 

Thr Gln  Ala Leu Thr Ala Leu  Ser Pro Ser Thr Ser  Gly Leu Thr 
    1625                 1630                 1635 

Pro Thr  Ser Ser Cys Ser Pro  Pro Ser Ser Thr Ser  Gly Lys Leu 
    1640                 1645                 1650 

Ser Met  Trp Ser Trp Lys Ser  Leu Ile Glu Gly Pro  Asp Arg Ala 
    1655                 1660                 1665 

Ser Pro  Ser Arg Lys Ala Thr  Met Ala Gly Gly Leu  Ala Asn Leu 
    1670                 1675                 1680 

Gln Asp  Leu Glu Thr Gln Leu  Gln Pro Ser Leu Arg  Thr Cys Leu 
    1685                 1690                 1695 

Pro Gly  Ser Arg Gly Arg His  Ser His Leu Val Pro  Pro Asp Trp 
    1700                 1705                 1710 

Pro Ile  His Leu Met Arg Ile  Pro Ala Arg Ala Gly  Tyr Gly Ser 
    1715                 1720                 1725 

Leu Ser  Val His Lys Gln 
    1730 

 
           
             15  
             1063  
             PRT  
             Homo sapiens  
           
            15 

Met Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Met Gly Leu 
1               5                   10                  15 

Met Ser Leu Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala 
            20                  25                  30 

Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala 
        35                  40                  45 

Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp 
    50                  55                  60 

Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe 
65                  70                  75                  80 

Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Asp 
                85                  90                  95 

Ile Leu Trp Pro Glu Gly Asp Glu Ala Leu Pro Thr Glu Ala Gln Leu 
            100                 105                 110 

Leu Ile Ser Ser Leu Leu Gln Thr Asn Pro Leu Val Arg Leu Gly Ala 
        115                 120                 125 

Gly Gly Ala Phe Glu Val Lys Gln His Ser Phe Phe Arg Asp Leu Asp 
    130                 135                 140 

Trp Thr Gly Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro His Leu Glu 
145                 150                 155                 160 

Ser Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser Asp Arg Tyr His 
                165                 170                 175 

His Val Asn Ser Tyr Asp Glu Asp Asp Thr Thr Glu Glu Glu Pro Val 
            180                 185                 190 

Glu Ile Arg Gln Phe Ser Ser Cys Ser Pro Arg Phe Ser Lys Val Tyr 
        195                 200                 205 

Ser Ser Met Glu Gln Leu Ser Gln His Glu Pro Lys Thr Pro Val Ala 
    210                 215                 220 

Ala Ala Gly Ser Ser Lys Arg Glu Pro Ser Thr Lys Gly Pro Glu Glu 
225                 230                 235                 240 

Lys Val Ala Gly Lys Arg Glu Gly Leu Gly Gly Leu Thr Leu Arg Glu 
                245                 250                 255 

Lys Thr Trp Arg Gly Gly Ser Pro Glu Ile Lys Arg Phe Ser Ala Ser 
            260                 265                 270 

Glu Ala Ser Phe Leu Glu Gly Glu Ala Ser Pro Pro Leu Gly Ala Arg 
        275                 280                 285 

Arg Arg Phe Ser Ala Leu Leu Glu Pro Ser Arg Phe Ser Ala Pro Gln 
    290                 295                 300 

Glu Asp Glu Asp Glu Ala Arg Leu Arg Arg Pro Pro Arg Pro Ser Ser 
305                 310                 315                 320 

Asp Pro Ala Gly Ser Leu Asp Ala Arg Ala Pro Lys Glu Glu Thr Gln 
                325                 330                 335 

Gly Glu Gly Thr Ser Ser Ala Gly Asp Ser Glu Ala Thr Asp Arg Pro 
            340                 345                 350 

Arg Pro Gly Asp Leu Cys Pro Pro Ser Lys Asp Gly Asp Ala Ser Gly 
        355                 360                 365 

Pro Arg Ala Thr Asn Asp Leu Val Leu Arg Arg Ala Arg His Gln Gln 
    370                 375                 380 

Met Ser Gly Asp Val Ala Val Glu Lys Arg Pro Ser Arg Thr Gly Gly 
385                 390                 395                 400 

Lys Val Ile Lys Ser Ala Ser Ala Thr Ala Leu Ser Val Met Ile Pro 
                405                 410                 415 

Ala Val Asp Pro His Gly Ser Ser Pro Leu Ala Ser Pro Met Ser Pro 
            420                 425                 430 

Arg Ser Leu Ser Ser Asn Pro Ser Ser Arg Asp Ser Ser Pro Ser Arg 
        435                 440                 445 

Asp Tyr Ser Pro Ala Val Ser Gly Leu Arg Ser Pro Ile Thr Ile Gln 
    450                 455                 460 

Arg Ser Gly Lys Lys Tyr Gly Phe Thr Leu Arg Ala Ile Arg Val Tyr 
465                 470                 475                 480 

Met Gly Asp Thr Asp Val Tyr Ser Val His His Ile Val Trp His Val 
                485                 490                 495 

Glu Glu Gly Gly Pro Ala Gln Glu Ala Gly Leu Cys Ala Gly Asp Leu 
            500                 505                 510 

Ile Thr His Val Asn Gly Glu Pro Val His Gly Met Val His Pro Glu 
        515                 520                 525 

Val Val Glu Leu Ile Leu Lys Ser Gly Asn Lys Val Ala Val Thr Thr 
    530                 535                 540 

Thr Pro Phe Glu Asn Thr Ser Ile Arg Ile Gly Pro Ala Arg Arg Ser 
545                 550                 555                 560 

Ser Tyr Lys Ala Lys Met Ala Arg Arg Asn Lys Arg Pro Ser Ala Lys 
                565                 570                 575 

Glu Gly Gln Glu Ser Lys Lys Arg Ser Ser Leu Phe Arg Lys Ile Thr 
            580                 585                 590 

Lys Gln Ser Asn Leu Leu His Thr Ser Arg Ser Leu Ser Ser Leu Asn 
        595                 600                 605 

Arg Ser Leu Ser Ser Ser Asp Ser Leu Pro Gly Ser Pro Thr His Gly 
    610                 615                 620 

Leu Pro Ala Arg Ser Pro Thr His Ser Tyr Arg Ser Thr Pro Asp Ser 
625                 630                 635                 640 

Ala Tyr Leu Gly Ala Ser Ser Gln Ser Ser Ser Pro Ala Ser Ser Thr 
                645                 650                 655 

Pro Asn Ser Pro Ala Ser Ser Ala Ser His His Ile Arg Pro Ser Thr 
            660                 665                 670 

Leu His Gly Leu Ser Pro Lys Leu His Arg Gln Tyr Arg Ser Ala Arg 
        675                 680                 685 

Cys Lys Ser Ala Gly Asn Ile Pro Leu Ser Pro Leu Ala His Thr Pro 
    690                 695                 700 

Ser Pro Thr Gln Ala Ser Pro Pro Pro Leu Pro Gly His Thr Val Gly 
705                 710                 715                 720 

Ser Ser His Thr Thr Gln Ser Phe Pro Ala Lys Leu His Ser Ser Pro 
                725                 730                 735 

Pro Val Val Arg Pro Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro 
            740                 745                 750 

Leu Leu Lys Arg Val Gln Ser Ala Glu Lys Leu Gly Ala Ser Leu Ser 
        755                 760                 765 

Ala Asp Lys Lys Gly Ala Leu Arg Lys His Ser Leu Glu Val Gly His 
    770                 775                 780 

Pro Asp Phe Arg Lys Asp Phe His Gly Glu Leu Ala Leu His Ser Leu 
785                 790                 795                 800 

Ala Glu Ser Asp Gly Glu Thr Pro Pro Val Glu Gly Leu Gly Ala Pro 
                805                 810                 815 

Arg Gln Val Ala Val Arg Arg Leu Gly Arg Gln Glu Ser Pro Leu Ser 
            820                 825                 830 

Leu Gly Ala Asp Pro Leu Leu Pro Glu Gly Ala Ser Arg Pro Pro Val 
        835                 840                 845 

Ser Ser Lys Glu Lys Glu Ser Pro Gly Gly Ala Glu Ala Cys Thr Pro 
    850                 855                 860 

Pro Arg Ala Thr Thr Pro Gly Gly Arg Thr Leu Glu Arg Asp Val Gly 
865                 870                 875                 880 

Cys Thr Arg His Gln Ser Val Gln Thr Glu Asp Gly Thr Gly Gly Met 
                885                 890                 895 

Ala Arg Ala Val Ala Lys Ala Ala Leu Ser Pro Val Gln Glu His Glu 
            900                 905                 910 

Thr Gly Arg Arg Ser Ser Ser Gly Glu Ala Gly Thr Pro Leu Val Pro 
        915                 920                 925 

Ile Val Val Glu Pro Ala Arg Pro Gly Ala Lys Ala Val Val Pro Gln 
    930                 935                 940 

Pro Leu Gly Ala Asp Ser Lys Gly Leu Gln Glu Pro Ala Pro Leu Ala 
945                 950                 955                 960 

Pro Ser Val Pro Glu Ala Pro Arg Gly Arg Glu Arg Trp Val Leu Glu 
                965                 970                 975 

Val Val Glu Glu Arg Thr Thr Leu Ser Gly Pro Arg Ser Lys Pro Ala 
            980                 985                 990 

Ser Pro Lys Leu Ser Pro Glu Pro  Gln Thr Pro Ser Leu  Ala Pro Ala 
        995                 1000                 1005 

Lys Cys  Ser Ala Pro Ser Ser  Ala Val Thr Pro Val  Pro Pro Ala 
    1010                 1015                 1020 

Ser Leu  Leu Gly Ser Gly Thr  Lys Pro Gln Val Gly  Leu Thr Ser 
    1025                 1030                 1035 

Arg Cys  Pro Ala Glu Ala Val  Pro Pro Ala Gly Leu  Thr Lys Lys 
    1040                 1045                 1050 

Gly Val  Ser Ser Pro Ala Pro  Pro Gly Pro 
    1055                 1060 

 
           
             16  
             1139  
             PRT  
             Homo sapiens  
             
               misc_feature  
               (422)..(431)  
               Xaa can be any naturally occurring amino acid  
             
           
            16 

Met Met Asn His Val Tyr Arg Glu Arg Phe Pro Lys Ala Thr Ala Gln 
1               5                   10                  15 

Met Glu Gly Arg Leu Gln Glu Phe Leu Thr Ala Tyr Ala Pro Gly Ala 
            20                  25                  30 

Arg Leu Ala Leu Ala Asp Gly Val Leu Gly Phe Ile His His Gln Ile 
        35                  40                  45 

Val Glu Leu Ala Arg Asp Cys Leu Ala Lys Ser Gly Glu Asn Leu Val 
    50                  55                  60 

Thr Ser Arg Tyr Phe Leu Glu Met Gln Glu Lys Leu Glu Arg Leu Leu 
65                  70                  75                  80 

Gln Asp Ala His Glu Arg Ser Asp Ser Glu Glu Val Ser Phe Ile Val 
                85                  90                  95 

Gln Leu Val Arg Lys Leu Leu Ile Ile Ile Ser Arg Pro Ala Arg Leu 
            100                 105                 110 

Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr His Leu Leu Glu 
        115                 120                 125 

Ala Ala Glu Gly His Ala Arg Glu Gly Gln Gly Ile Lys Thr Asp Leu 
    130                 135                 140 

Pro Gln Tyr Ile Ile Gly Gln Leu Gly Leu Ala Lys Asp Pro Leu Glu 
145                 150                 155                 160 

Glu Met Val Pro Leu Ser His Leu Glu Glu Glu Gln Pro Pro Ala Pro 
                165                 170                 175 

Glu Ser Pro Glu Ser Arg Ala Leu Val Gly Gln Ser Arg Arg Lys Pro 
            180                 185                 190 

Cys Glu Ser Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn Gly Ala Tyr 
        195                 200                 205 

Gly Ala Val Tyr Leu Val Arg His Arg Asp Thr Arg Gln Arg Phe Ala 
    210                 215                 220 

Ile Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn Gln Ile Gln 
225                 230                 235                 240 

Gln Val Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu Asn Pro Phe 
                245                 250                 255 

Val Val Ser Met Phe Cys Ser Phe Glu Thr Arg Arg His Leu Cys Met 
            260                 265                 270 

Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu Leu Lys Asn 
        275                 280                 285 

Met Gly Pro Leu Pro Val Asp Met Ala Arg Leu Tyr Phe Ala Glu Thr 
    290                 295                 300 

Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val His Arg Asp 
305                 310                 315                 320 

Leu Lys Pro Asp Asn Leu Leu Ile Thr Ser Leu Gly His Ile Lys Leu 
                325                 330                 335 

Thr Asp Phe Gly Leu Ser Lys Ile Gly Leu Met Ser Met Ala Thr Asn 
            340                 345                 350 

Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe Ile Asp Lys 
        355                 360                 365 

Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro Glu Val Ile Phe Arg 
    370                 375                 380 

Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala Met Gly Val Val Leu 
385                 390                 395                 400 

Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp Thr Pro Glu 
                405                 410                 415 

Glu Leu Phe Gly Gln Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly 
            420                 425                 430 

Asp Glu Ala Leu Pro Ala Asp Ala Gln Asp Leu Ile Thr Arg Leu Leu 
        435                 440                 445 

Arg Gln Ser Pro Leu Asp Arg Leu Gly Thr Gly Gly Thr His Glu Val 
    450                 455                 460 

Lys Gln His Pro Phe Phe Leu Ala Leu Asp Trp Ala Gly Leu Leu Arg 
465                 470                 475                 480 

His Lys Ala Glu Phe Val Pro Gln Leu Glu Ala Glu Asp Asp Thr Ser 
                485                 490                 495 

Tyr Phe Asp Thr Arg Ser Glu Arg Tyr Arg His Leu Gly Ser Glu Asp 
            500                 505                 510 

Asp Glu Thr Asn Asp Glu Glu Ser Ser Thr Glu Ile Pro Gln Phe Ser 
        515                 520                 525 

Ser Cys Ser His Arg Phe Ser Lys Val Tyr Ser Ser Ser Glu Phe Leu 
    530                 535                 540 

Ala Val Gln Pro Thr Pro Thr Phe Ala Glu Arg Ser Phe Ser Glu Asp 
545                 550                 555                 560 

Arg Glu Glu Gly Trp Glu Arg Ser Glu Val Asp Tyr Gly Arg Arg Leu 
                565                 570                 575 

Ser Ala Asp Ile Arg Leu Arg Ser Trp Thr Ser Ser Gly Ser Ser Cys 
            580                 585                 590 

Gln Ser Ser Ser Ser Gln Pro Glu Arg Gly Pro Ser Pro Ser Leu Leu 
        595                 600                 605 

Asn Thr Ile Ser Leu Asp Thr Met Pro Lys Phe Ala Phe Ser Ser Glu 
    610                 615                 620 

Asp Glu Gly Val Gly Pro Gly Pro Ala Gly Pro Lys Arg Pro Val Phe 
625                 630                 635                 640 

Ile Leu Gly Glu Pro Asp Pro Pro Pro Ala Ala Thr Pro Val Met Pro 
                645                 650                 655 

Lys Pro Ser Ser Leu Ser Ala Asp Thr Ala Ala Leu Ser His Ala Arg 
            660                 665                 670 

Leu Arg Ser Asn Ser Ile Gly Ala Arg His Ser Thr Pro Arg Pro Leu 
        675                 680                 685 

Asp Ala Gly Arg Gly Arg Arg Leu Gly Gly Pro Arg Asp Pro Ala Pro 
    690                 695                 700 

Glu Lys Ser Arg Ala Ser Ser Ser Gly Gly Ser Gly Gly Gly Ser Gly 
705                 710                 715                 720 

Gly Arg Val Pro Lys Ser Ala Ser Val Ser Ala Leu Ser Leu Ile Ile 
                725                 730                 735 

Thr Ala Asp Asp Gly Ser Gly Gly Pro Leu Met Ser Pro Leu Ser Pro 
            740                 745                 750 

Arg Ser Leu Ser Ser Asn Pro Ser Ser Arg Asp Ser Ser Pro Ser Arg 
        755                 760                 765 

Asp Pro Ser Pro Val Cys Gly Ser Leu Arg Pro Pro Ile Val Ile His 
    770                 775                 780 

Ser Ser Gly Lys Lys Tyr Gly Phe Ser Leu Arg Ala Ile Arg Val Tyr 
785                 790                 795                 800 

Met Gly Asp Ser Asp Val Tyr Thr Val His His Val Val Trp Ser Val 
                805                 810                 815 

Glu Asp Gly Ser Pro Ala Gln Glu Ala Gly Leu Arg Ala Gly Asp Leu 
            820                 825                 830 

Ile Thr His Ile Asn Gly Glu Ser Val Leu Gly Leu Val His Met Asp 
        835                 840                 845 

Val Val Glu Leu Leu Leu Lys Ser Gly Asn Lys Ile Ser Leu Arg Thr 
    850                 855                 860 

Thr Ala Leu Glu Asn Thr Ser Ile Lys Val Gly Pro Ala Arg Lys Asn 
865                 870                 875                 880 

Val Ala Lys Gly Arg Met Ala Arg Arg Ser Lys Arg Ser Arg Arg Arg 
                885                 890                 895 

Glu Thr Gln Asp Arg Arg Lys Ser Leu Phe Lys Lys Ile Ser Lys Gln 
            900                 905                 910 

Thr Ser Val Leu His Thr Ser Arg Ser Phe Ser Ser Gly Leu His His 
        915                 920                 925 

Ser Leu Ser Ser Ser Glu Ser Leu Pro Gly Ser Pro Thr His Ser Leu 
    930                 935                 940 

Ser Pro Ser Pro Thr Thr Pro Cys Arg Ser Pro Ala Pro Asp Val Pro 
945                 950                 955                 960 

Ala Asp Thr Thr Ala Ser Pro Pro Ser Ala Ser Pro Ser Ser Ser Ser 
                965                 970                 975 

Pro Ala Ser Pro Ala Ala Ala Gly His Thr Arg Pro Ser Ser Leu His 
            980                 985                 990 

Gly Leu Ala Ala Lys Leu Gly Pro  Pro Arg Pro Lys Thr  Gly Arg Arg 
        995                 1000                 1005 

Lys Ser  Thr Ser Ser Ile Pro  Pro Ser Pro Leu Ala  Cys Pro Pro 
    1010                 1015                 1020 

Ile Ser  Ala Pro Pro Pro Arg  Ser Pro Ser Pro Leu  Pro Gly His 
    1025                 1030                 1035 

Pro Pro  Ala Pro Ala Arg Ser  Pro Arg Leu Arg Arg  Gly Gln Ser 
    1040                 1045                 1050 

Ala Asp  Lys Leu Gly Thr Gly  Glu Arg Leu Asp Gly  Glu Ala Gly 
    1055                 1060                 1065 

Arg Arg  Thr Arg Gly Pro Glu  Ala Glu Leu Val Val  Met Arg Arg 
    1070                 1075                 1080 

Leu His  Leu Ser Glu Arg Arg  Asp Ser Phe Lys Lys  Gln Glu Ala 
    1085                 1090                 1095 

Val Gln  Glu Val Ser Phe Asp  Glu Pro Gln Glu Glu  Ala Thr Gly 
    1100                 1105                 1110 

Leu Pro  Thr Ser Val Pro Gln  Ile Ala Val Glu Gly  Glu Glu Ala 
    1115                 1120                 1125 

Val Pro  Val Ala Leu Gly Pro  Thr Gly Arg Asp 
    1130                 1135 

 
           
             17  
             2429  
             PRT  
             Homo sapiens  
           
            17 

Met Asp Met Ser Asp Pro Asn Phe Trp Thr Val Leu Ser Asn Phe Thr 
1               5                   10                  15 

Leu Pro His Leu Arg Ser Gly Asn Arg Leu Arg Arg Thr Gln Ser Cys 
            20                  25                  30 

Arg Thr Ser Asn Arg Lys Ser Leu Ile Gly Asn Gly Gln Ser Pro Ala 
        35                  40                  45 

Leu Pro Arg Pro His Ser Pro Leu Ser Ala His Ala Gly Asn Ser Pro 
    50                  55                  60 

Gln Asp Ser Pro Arg Asn Phe Ser Pro Ser Ala Ser Ala His Phe Ser 
65                  70                  75                  80 

Phe Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser Leu Ala Ser Leu Pro 
                85                  90                  95 

Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr Val Ser Ser Ser 
            100                 105                 110 

Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro Tyr Gln Pro Thr Pro 
        115                 120                 125 

Asp Glu Leu His Phe Leu Ser Lys His Phe Cys Thr Thr Glu Ser Ile 
    130                 135                 140 

Ala Thr Glu Asn Arg Cys Arg Asn Thr Pro Met Arg Pro Arg Ser Arg 
145                 150                 155                 160 

Ser Leu Ser Pro Gly Arg Ser Pro Ala Cys Cys Asp His Glu Ile Ile 
                165                 170                 175 

Met Met Asn His Val Tyr Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln 
            180                 185                 190 

Met Glu Glu Arg Leu Lys Glu Ile Ile Thr Ser Tyr Ser Pro Asp Asn 
        195                 200                 205 

Val Leu Pro Leu Ala Asp Gly Val Leu Ser Phe Thr His His Gln Ile 
    210                 215                 220 

Ile Glu Leu Ala Arg Asp Cys Leu Asp Lys Ser His Gln Gly Leu Ile 
225                 230                 235                 240 

Thr Ser Arg Tyr Phe Leu Glu Leu Gln His Lys Leu Asp Lys Leu Leu 
                245                 250                 255 

Gln Glu Ala His Asp Arg Ser Glu Ser Gly Glu Leu Ala Phe Ile Lys 
            260                 265                 270 

Gln Leu Val Arg Lys Ile Leu Ile Val Ile Ala Arg Pro Ala Arg Leu 
        275                 280                 285 

Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr Tyr Leu Leu Glu 
    290                 295                 300 

Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly Ile Lys Thr Asp Ile 
305                 310                 315                 320 

Pro Arg Tyr Ile Ile Ser Gln Leu Gly Leu Asn Lys Asp Pro Leu Glu 
                325                 330                 335 

Glu Met Ala His Leu Gly Asn Tyr Asp Ser Gly Thr Ala Glu Thr Pro 
            340                 345                 350 

Glu Thr Asp Glu Ser Val Ser Ser Ser Asn Ala Ser Leu Lys Leu Arg 
        355                 360                 365 

Arg Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn 
    370                 375                 380 

Gly Ala Tyr Gly Ala Val Tyr Phe Val Arg His Lys Glu Ser Arg Gln 
385                 390                 395                 400 

Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn 
                405                 410                 415 

Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu 
            420                 425                 430 

Asn Pro Phe Val Val Ser Met Tyr Cys Ser Phe Glu Thr Arg Arg His 
        435                 440                 445 

Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu 
    450                 455                 460 

Met Lys Asn Met Gly Pro Leu Pro Val Asp Met Ala Arg Met Tyr Phe 
465                 470                 475                 480 

Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val 
                485                 490                 495 

His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr Ser Met Gly His 
            500                 505                 510 

Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly Leu Met Ser Met 
        515                 520                 525 

Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe 
    530                 535                 540 

Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro Glu Val 
545                 550                 555                 560 

Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala Met Gly 
                565                 570                 575 

Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp 
            580                 585                 590 

Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Ile Asn Trp 
        595                 600                 605 

Pro Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala Gln Asp Leu Ile Thr 
    610                 615                 620 

Leu Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu Gly Thr Gly Gly Ala 
625                 630                 635                 640 

Tyr Glu Val Lys Gln His Arg Phe Phe Arg Ser Leu Asp Trp Asn Ser 
                645                 650                 655 

Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp 
            660                 665                 670 

Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys Tyr His His Met Glu 
        675                 680                 685 

Thr Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp Phe Asn Val Glu Ile 
    690                 695                 700 

Arg Gln Phe Ser Ser Cys Ser His Arg Phe Ser Lys Val Phe Ser Ser 
705                 710                 715                 720 

Ile Asp Arg Ile Thr Gln Asn Ser Ala Glu Glu Lys Glu Asp Ser Val 
                725                 730                 735 

Asp Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr Glu Thr Leu Ser Trp 
            740                 745                 750 

Ser Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser Thr Ser Asn Ser Ser 
        755                 760                 765 

Asp Thr Glu Ser Asn Arg His Lys Leu Ser Ser Gly Leu Leu Pro Lys 
    770                 775                 780 

Leu Ala Ile Ser Thr Glu Gly Glu Gln Asp Glu Ala Ala Ser Cys Pro 
785                 790                 795                 800 

Gly Asp Pro His Glu Glu Pro Gly Lys Pro Ala Leu Pro Pro Glu Glu 
                805                 810                 815 

Cys Ala Gln Glu Glu Pro Glu Val Thr Thr Pro Ala Ser Thr Ile Ser 
            820                 825                 830 

Ser Ser Thr Leu Ser Val Gly Ser Phe Ser Glu His Leu Asp Gln Ile 
        835                 840                 845 

Asn Gly Arg Ser Glu Cys Val Asp Ser Thr Asp Asn Ser Ser Lys Pro 
    850                 855                 860 

Ser Ser Glu Pro Ala Ser His Met Ala Arg Gln Arg Leu Glu Ser Thr 
865                 870                 875                 880 

Glu Lys Lys Lys Ile Ser Gly Lys Val Thr Lys Ser Leu Ser Ala Ser 
                885                 890                 895 

Ala Leu Ser Leu Met Ile Pro Gly Asp Met Phe Ala Val Ser Pro Leu 
            900                 905                 910 

Gly Ser Pro Met Ser Pro His Ser Leu Ser Ser Asp Pro Ser Ser Ser 
        915                 920                 925 

Arg Asp Ser Ser Pro Ser Arg Asp Ser Ser Ala Ala Ser Ala Ser Pro 
    930                 935                 940 

His Gln Pro Ile Val Ile His Ser Ser Gly Lys Asn Tyr Gly Phe Thr 
945                 950                 955                 960 

Ile Arg Ala Ile Arg Val Tyr Val Gly Asp Ser Asp Ile Tyr Thr Val 
                965                 970                 975 

His His Ile Val Trp Asn Val Glu Glu Gly Ser Pro Ala Cys Gln Ala 
            980                 985                 990 

Gly Leu Lys Ala Gly Asp Leu Ile  Thr His Ile Asn Gly  Glu Pro Val 
        995                 1000                 1005 

His Gly  Leu Val His Thr Glu  Val Ile Glu Leu Leu  Leu Lys Ser 
    1010                 1015                 1020 

Gly Asn  Lys Val Ser Ile Thr  Thr Thr Pro Phe Glu  Asn Thr Ser 
    1025                 1030                 1035 

Ile Lys  Thr Gly Pro Ala Arg  Arg Asn Ser Tyr Lys  Ser Arg Met 
    1040                 1045                 1050 

Val Arg  Arg Ser Lys Lys Ser  Lys Lys Lys Glu Ser  Leu Glu Arg 
    1055                 1060                 1065 

Arg Arg  Ser Leu Phe Lys Lys  Leu Ala Lys Gln Pro  Ser Pro Leu 
    1070                 1075                 1080 

Leu His  Thr Ser Arg Ser Phe  Ser Cys Leu Asn Arg  Ser Leu Ser 
    1085                 1090                 1095 

Ser Gly  Glu Ser Leu Pro Gly  Ser Pro Thr His Ser  Leu Ser Pro 
    1100                 1105                 1110 

Arg Ser  Pro Thr Pro Ser Tyr  Arg Ser Thr Pro Asp  Phe Pro Ser 
    1115                 1120                 1125 

Gly Thr  Asn Ser Ser Gln Ser  Ser Ser Pro Ser Ser  Ser Ala Pro 
    1130                 1135                 1140 

Asn Ser  Pro Ala Gly Ser Gly  His Ile Arg Pro Ser  Thr Leu His 
    1145                 1150                 1155 

Gly Leu  Ala Pro Lys Leu Gly  Gly Gln Arg Tyr Arg  Ser Gly Arg 
    1160                 1165                 1170 

Arg Lys  Ser Ala Gly Asn Ile  Pro Leu Ser Pro Leu  Ala Arg Thr 
    1175                 1180                 1185 

Pro Ser  Pro Thr Pro Gln Pro  Thr Ser Pro Gln Arg  Ser Pro Ser 
    1190                 1195                 1200 

Pro Leu  Leu Gly His Ser Leu  Gly Asn Ser Lys Ile  Ala Gln Ala 
    1205                 1210                 1215 

Phe Pro  Ser Lys Met His Ser  Pro Pro Thr Ile Val  Arg His Ile 
    1220                 1225                 1230 

Val Arg  Pro Lys Ser Ala Glu  Pro Pro Arg Ser Pro  Leu Leu Lys 
    1235                 1240                 1245 

Arg Val  Gln Ser Glu Glu Lys  Leu Ser Pro Ser Tyr  Gly Ser Asp 
    1250                 1255                 1260 

Lys Lys  His Leu Cys Ser Arg  Lys His Ser Leu Glu  Val Thr Gln 
    1265                 1270                 1275 

Glu Glu  Val Gln Arg Glu Gln  Ser Gln Arg Glu Ala  Pro Leu Gln 
    1280                 1285                 1290 

Ser Leu  Asp Glu Asn Val Cys  Asp Val Pro Pro Leu  Ser Arg Ala 
    1295                 1300                 1305 

Arg Pro  Val Glu Gln Gly Cys  Leu Lys Arg Pro Val  Ser Arg Lys 
    1310                 1315                 1320 

Val Gly  Arg Gln Glu Ser Val  Asp Asp Leu Asp Arg  Asp Lys Leu 
    1325                 1330                 1335 

Lys Ala  Lys Val Val Val Lys  Lys Ala Asp Gly Phe  Pro Glu Lys 
    1340                 1345                 1350 

Gln Glu  Ser His Gln Lys Ser  His Gly Pro Gly Ser  Asp Leu Glu 
    1355                 1360                 1365 

Asn Phe  Ala Leu Phe Lys Leu  Glu Glu Arg Glu Lys  Lys Val Tyr 
    1370                 1375                 1380 

Pro Lys  Ala Val Glu Arg Ser  Ser Thr Phe Glu Asn  Lys Ala Ser 
    1385                 1390                 1395 

Met Gln  Glu Ala Pro Pro Leu  Gly Ser Leu Leu Lys  Asp Ala Leu 
    1400                 1405                 1410 

His Lys  Gln Ala Ser Val Arg  Ala Ser Glu Gly Ala  Met Ser Asp 
    1415                 1420                 1425 

Gly Pro  Val Pro Ala Glu His  Arg Gln Gly Gly Gly  Asp Phe Arg 
    1430                 1435                 1440 

Arg Ala  Pro Ala Pro Gly Thr  Leu Gln Asp Gly Leu  Cys His Ser 
    1445                 1450                 1455 

Leu Asp  Arg Gly Ile Ser Gly  Lys Gly Glu Gly Thr  Glu Lys Ser 
    1460                 1465                 1470 

Ser Gln  Ala Lys Glu Leu Leu  Arg Cys Glu Lys Leu  Asp Ser Lys 
    1475                 1480                 1485 

Leu Ala  Asn Ile Asp Tyr Leu  Arg Lys Lys Met Ser  Leu Glu Asp 
    1490                 1495                 1500 

Lys Glu  Asp Asn Leu Cys Pro  Val Leu Lys Pro Lys  Met Thr Ala 
    1505                 1510                 1515 

Gly Ser  His Glu Cys Leu Pro  Gly Asn Pro Val Arg  Pro Thr Gly 
    1520                 1525                 1530 

Gly Gln  Gln Glu Pro Pro Pro  Ala Ser Glu Ser Arg  Ala Phe Val 
    1535                 1540                 1545 

Ser Ser  Thr His Ala Ala Gln  Met Ser Ala Val Ser  Phe Val Pro 
    1550                 1555                 1560 

Leu Lys  Ala Leu Thr Gly Arg  Val Asp Ser Gly Thr  Glu Lys Pro 
    1565                 1570                 1575 

Gly Leu  Val Ala Pro Glu Ser  Pro Val Arg Lys Ser  Pro Ser Glu 
    1580                 1585                 1590 

Tyr Lys  Leu Glu Gly Arg Ser  Val Ser Cys Leu Lys  Pro Ile Glu 
    1595                 1600                 1605 

Gly Thr  Leu Asp Ile Ala Leu  Leu Ser Gly Pro Gln  Ala Ser Lys 
    1610                 1615                 1620 

Thr Glu  Leu Pro Ser Pro Glu  Ser Ala Gln Ser Pro  Ser Pro Ser 
    1625                 1630                 1635 

Gly Asp  Val Arg Ala Ser Val  Pro Pro Val Leu Pro  Ser Ser Ser 
    1640                 1645                 1650 

Gly Lys  Lys Asn Asp Thr Thr  Ser Ala Arg Glu Leu  Ser Pro Ser 
    1655                 1660                 1665 

Ser Leu  Lys Met Asn Lys Ser  Tyr Leu Leu Glu Pro  Trp Phe Leu 
    1670                 1675                 1680 

Pro Pro  Ser Arg Gly Leu Gln  Asn Ser Pro Ala Val  Ser Leu Pro 
    1685                 1690                 1695 

Asp Pro  Glu Phe Lys Arg Asp  Arg Lys Gly Pro His  Pro Thr Ala 
    1700                 1705                 1710 

Arg Ser  Pro Gly Thr Val Met  Glu Ser Asn Pro Gln  Gln Arg Glu 
    1715                 1720                 1725 

Gly Ser  Ser Pro Lys His Gln  Asp His Thr Thr Asp  Pro Lys Leu 
    1730                 1735                 1740 

Leu Thr  Cys Leu Gly Gln Asn  Leu His Ser Pro Asp  Leu Ala Arg 
    1745                 1750                 1755 

Pro Arg  Cys Pro Leu Pro Pro  Glu Ala Ser Pro Ser  Arg Glu Lys 
    1760                 1765                 1770 

Pro Gly  Leu Arg Glu Ser Ser  Glu Arg Gly Pro Pro  Thr Ala Arg 
    1775                 1780                 1785 

Ser Glu  Arg Ser Ala Ala Arg  Ala Asp Thr Cys Arg  Glu Pro Ser 
    1790                 1795                 1800 

Met Glu  Leu Cys Phe Pro Glu  Thr Ala Lys Thr Ser  Asp Asn Ser 
    1805                 1810                 1815 

Lys Asn  Leu Leu Ser Val Gly  Arg Thr His Pro Asp  Phe Tyr Thr 
    1820                 1825                 1830 

Gln Thr  Gln Ala Met Glu Lys  Ala Trp Ala Pro Gly  Gly Lys Thr 
    1835                 1840                 1845 

Asn His  Lys Asp Gly Pro Gly  Glu Ala Arg Pro Pro  Pro Arg Asp 
    1850                 1855                 1860 

Asn Ser  Ser Leu His Ser Ala  Gly Ile Pro Cys Glu  Lys Glu Leu 
    1865                 1870                 1875 

Gly Lys  Val Arg Arg Gly Val  Glu Pro Lys Pro Glu  Ala Leu Leu 
    1880                 1885                 1890 

Ala Arg  Arg Ser Leu Gln Pro  Pro Gly Ile Glu Ser  Glu Lys Ser 
    1895                 1900                 1905 

Glu Lys  Leu Ser Ser Phe Pro  Ser Leu Gln Lys Asp  Gly Ala Lys 
    1910                 1915                 1920 

Glu Pro  Glu Arg Lys Glu Gln  Pro Leu Gln Arg His  Pro Ser Ser 
    1925                 1930                 1935 

Ile Pro  Pro Pro Pro Leu Thr  Ala Lys Asp Leu Ser  Ser Pro Ala 
    1940                 1945                 1950 

Ala Arg  Gln His Cys Ser Ser  Pro Ser His Ala Ser  Gly Arg Glu 
    1955                 1960                 1965 

Pro Gly  Ala Lys Pro Ser Thr  Ala Glu Pro Ser Ser  Ser Pro Gln 
    1970                 1975                 1980 

Asp Pro  Pro Lys Pro Val Ala  Ala His Ser Glu Ser  Ser Ser His 
    1985                 1990                 1995 

Lys Pro  Arg Pro Gly Pro Asp  Pro Gly Pro Pro Lys  Thr Lys His 
    2000                 2005                 2010 

Pro Asp  Arg Ser Leu Ser Ser  Gln Lys Pro Ser Val  Gly Ala Thr 
    2015                 2020                 2025 

Lys Gly  Lys Glu Pro Ala Thr  Gln Ser Leu Gly Gly  Ser Ser Arg 
    2030                 2035                 2040 

Glu Gly  Lys Gly His Ser Lys  Ser Gly Pro Asp Val  Phe Pro Ala 
    2045                 2050                 2055 

Thr Pro  Gly Ser Gln Asn Lys  Ala Ser Asp Gly Ile  Gly Gln Gly 
    2060                 2065                 2070 

Glu Gly  Gly Pro Ser Val Pro  Leu His Thr Asp Arg  Ala Pro Leu 
    2075                 2080                 2085 

Asp Ala  Lys Pro Gln Pro Thr  Ser Gly Gly Arg Pro  Leu Glu Val 
    2090                 2095                 2100 

Leu Glu  Lys Pro Val His Leu  Pro Arg Pro Gly His  Pro Gly Pro 
    2105                 2110                 2115 

Ser Glu  Pro Ala Asp Gln Lys  Leu Ser Ala Val Gly  Glu Lys Gln 
    2120                 2125                 2130 

Thr Leu  Ser Pro Lys His Pro  Lys Pro Ser Thr Val  Lys Asp Cys 
    2135                 2140                 2145 

Pro Thr  Leu Cys Lys Gln Thr  Asp Asn Arg Gln Thr  Asp Lys Ser 
    2150                 2155                 2160 

Pro Ser  Gln Pro Ala Ala Asn  Thr Asp Arg Arg Ala  Glu Gly Lys 
    2165                 2170                 2175 

Lys Cys  Thr Glu Ala Leu Tyr  Ala Pro Ala Glu Gly  Asp Lys Leu 
    2180                 2185                 2190 

Glu Ala  Gly Leu Ser Phe Val  His Ser Glu Asn Arg  Leu Lys Gly 
    2195                 2200                 2205 

Ala Glu  Arg Pro Ala Ala Gly  Val Gly Lys Gly Phe  Pro Glu Ala 
    2210                 2215                 2220 

Arg Gly  Lys Gly Pro Gly Pro  Gln Lys Pro Pro Thr  Glu Ala Asp 
    2225                 2230                 2235 

Lys Pro  Asn Gly Met Lys Arg  Ser Pro Ser Ala Thr  Gly Gln Ser 
    2240                 2245                 2250 

Ser Phe  Arg Ser Thr Ala Leu  Pro Glu Lys Ser Leu  Ser Cys Ser 
    2255                 2260                 2265 

Ser Ser  Phe Pro Glu Thr Arg  Ala Gly Val Arg Glu  Ala Ser Ala 
    2270                 2275                 2280 

Ala Ser  Ser Asp Thr Ser Ser  Ala Lys Ala Ala Gly  Gly Met Leu 
    2285                 2290                 2295 

Glu Leu  Pro Ala Pro Ser Asn  Arg Asp His Arg Lys  Ala Gln Pro 
    2300                 2305                 2310 

Ala Gly  Glu Gly Arg Thr His  Met Thr Lys Ser Asp  Ser Leu Pro 
    2315                 2320                 2325 

Ser Phe  Arg Val Ser Thr Leu  Pro Leu Glu Ser His  His Pro Asp 
    2330                 2335                 2340 

Pro Asn  Thr Met Gly Gly Ala  Ser His Arg Asp Arg  Ala Leu Ser 
    2345                 2350                 2355 

Val Thr  Ala Thr Val Gly Glu  Thr Lys Gly Lys Asp  Pro Ala Pro 
    2360                 2365                 2370 

Ala Gln  Pro Pro Pro Ala Arg  Lys Gln Asn Val Gly  Arg Asp Val 
    2375                 2380                 2385 

Thr Lys  Pro Ser Pro Ala Pro  Asn Thr Asp Arg Pro  Ile Ser Leu 
    2390                 2395                 2400 

Ser Asn  Glu Lys Asp Phe Val  Val Arg Gln Arg Arg  Gly Lys Glu 
    2405                 2410                 2415 

Ser Leu  Arg Ser Ser Pro His  Lys Lys Ala Leu 
    2420                 2425 

 
           
             18  
             2092  
             PRT  
             Homo sapiens  
           
            18 

Met Ala His Leu Gly Asn Tyr Asp Ser Gly Thr Ala Glu Thr Pro Glu 
1               5                   10                  15 

Thr Asp Glu Ser Val Ser Ser Ser Asn Ala Ser Leu Lys Leu Arg Arg 
            20                  25                  30 

Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn Gly 
        35                  40                  45 

Ala Tyr Gly Ala Val Tyr Phe Val Arg His Lys Glu Ser Arg Gln Arg 
    50                  55                  60 

Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn Gln 
65                  70                  75                  80 

Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu Asn 
                85                  90                  95 

Pro Phe Val Val Ser Met Tyr Cys Ser Phe Glu Thr Arg Arg His Leu 
            100                 105                 110 

Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu Met 
        115                 120                 125 

Lys Asn Met Gly Pro Leu Pro Val Asp Met Ala Arg Met Tyr Phe Ala 
    130                 135                 140 

Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val His 
145                 150                 155                 160 

Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr Ser Met Gly His Ile 
                165                 170                 175 

Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly Leu Met Ser Met Thr 
            180                 185                 190 

Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe Leu 
        195                 200                 205 

Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro Glu Val Ile 
    210                 215                 220 

Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala Met Gly Ile 
225                 230                 235                 240 

Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp Thr 
                245                 250                 255 

Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Ile Asn Trp Pro 
            260                 265                 270 

Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala Gln Asp Leu Ile Thr Leu 
        275                 280                 285 

Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu Gly Thr Gly Gly Ala Tyr 
    290                 295                 300 

Glu Val Lys Gln His Arg Phe Phe Arg Ser Leu Asp Trp Asn Ser Leu 
305                 310                 315                 320 

Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp Asp 
                325                 330                 335 

Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys Tyr His His Met Glu Thr 
            340                 345                 350 

Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp Phe Asn Val Glu Ile Arg 
        355                 360                 365 

Gln Phe Ser Ser Cys Ser His Arg Phe Ser Lys Val Phe Ser Ser Ile 
    370                 375                 380 

Asp Arg Ile Thr Gln Asn Ser Ala Glu Glu Lys Glu Asp Ser Val Asp 
385                 390                 395                 400 

Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr Glu Thr Leu Ser Trp Ser 
                405                 410                 415 

Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser Thr Ser Asn Ser Ser Asp 
            420                 425                 430 

Thr Glu Ser Asn Arg His Lys Leu Ser Ser Gly Leu Leu Pro Lys Leu 
        435                 440                 445 

Ala Ile Ser Thr Glu Gly Glu Gln Asp Glu Ala Ala Ser Cys Pro Gly 
    450                 455                 460 

Asp Pro His Glu Glu Pro Gly Lys Pro Ala Leu Pro Pro Glu Glu Cys 
465                 470                 475                 480 

Ala Gln Glu Glu Pro Glu Val Thr Thr Pro Ala Ser Thr Ile Ser Ser 
                485                 490                 495 

Ser Thr Leu Ser Val Gly Ser Phe Ser Glu His Leu Asp Gln Ile Asn 
            500                 505                 510 

Gly Arg Ser Glu Cys Val Asp Ser Thr Asp Asn Ser Ser Lys Pro Ser 
        515                 520                 525 

Ser Glu Pro Ala Ser His Met Ala Arg Gln Arg Leu Glu Ser Thr Glu 
    530                 535                 540 

Lys Lys Lys Ile Ser Gly Lys Val Thr Lys Ser Leu Ser Ala Ser Ala 
545                 550                 555                 560 

Leu Ser Leu Met Ile Pro Gly Asp Met Phe Ala Val Ser Pro Leu Gly 
                565                 570                 575 

Ser Pro Met Ser Pro His Ser Leu Ser Ser Asp Pro Ser Ser Ser Arg 
            580                 585                 590 

Asp Ser Ser Pro Ser Arg Asp Ser Ser Ala Ala Ser Ala Ser Pro His 
        595                 600                 605 

Gln Pro Ile Val Ile His Ser Ser Gly Lys Asn Tyr Gly Phe Thr Ile 
    610                 615                 620 

Arg Ala Ile Arg Val Tyr Val Gly Asp Ser Asp Ile Tyr Thr Val His 
625                 630                 635                 640 

His Ile Val Trp Asn Val Glu Glu Gly Ser Pro Ala Cys Gln Ala Gly 
                645                 650                 655 

Leu Lys Ala Gly Asp Leu Ile Thr His Ile Asn Gly Glu Pro Val His 
            660                 665                 670 

Gly Leu Val His Thr Glu Val Ile Glu Leu Leu Leu Lys Ser Gly Asn 
        675                 680                 685 

Lys Val Ser Ile Thr Thr Thr Pro Phe Glu Asn Thr Ser Ile Lys Thr 
    690                 695                 700 

Gly Pro Ala Arg Arg Asn Ser Tyr Lys Ser Arg Met Val Arg Arg Ser 
705                 710                 715                 720 

Lys Lys Ser Lys Lys Lys Glu Ser Leu Glu Arg Arg Arg Ser Leu Phe 
                725                 730                 735 

Lys Lys Leu Ala Lys Gln Pro Ser Pro Leu Leu His Thr Ser Arg Ser 
            740                 745                 750 

Phe Ser Cys Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser Leu Pro Gly 
        755                 760                 765 

Ser Pro Thr His Ser Leu Ser Pro Arg Ser Pro Thr Pro Ser Tyr Arg 
    770                 775                 780 

Ser Thr Pro Asp Phe Pro Ser Gly Thr Asn Ser Ser Gln Ser Ser Ser 
785                 790                 795                 800 

Pro Ser Ser Ser Ala Pro Asn Ser Pro Ala Gly Ser Gly His Ile Arg 
                805                 810                 815 

Pro Ser Thr Leu His Gly Leu Ala Pro Lys Leu Gly Gly Gln Arg Tyr 
            820                 825                 830 

Arg Ser Gly Arg Arg Lys Ser Ala Gly Asn Ile Pro Leu Ser Pro Leu 
        835                 840                 845 

Ala Arg Thr Pro Ser Pro Thr Pro Gln Pro Thr Ser Pro Gln Arg Ser 
    850                 855                 860 

Pro Ser Pro Leu Leu Gly His Ser Leu Gly Asn Ser Lys Ile Ala Gln 
865                 870                 875                 880 

Ala Phe Pro Ser Lys Met His Ser Pro Pro Thr Ile Val Arg His Ile 
                885                 890                 895 

Val Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu Leu Lys Arg 
            900                 905                 910 

Val Gln Ser Glu Glu Lys Leu Ser Pro Ser Tyr Gly Ser Asp Lys Lys 
        915                 920                 925 

His Leu Cys Ser Arg Lys His Ser Leu Glu Val Thr Gln Glu Glu Val 
    930                 935                 940 

Gln Arg Glu Gln Ser Gln Arg Glu Ala Pro Leu Gln Ser Leu Asp Glu 
945                 950                 955                 960 

Asn Val Cys Asp Val Pro Pro Leu Ser Arg Ala Arg Pro Val Glu Gln 
                965                 970                 975 

Gly Cys Leu Lys Arg Pro Val Ser Arg Lys Val Gly Arg Gln Glu Ser 
            980                 985                 990 

Val Asp Asp Leu Asp Arg Asp Lys  Leu Lys Ala Lys Val  Val Val Lys 
        995                 1000                 1005 

Lys Ala  Asp Gly Phe Pro Glu  Lys Gln Glu Ser His  Gln Lys Ser 
    1010                 1015                 1020 

His Gly  Pro Gly Ser Asp Leu  Glu Asn Phe Ala Leu  Phe Lys Leu 
    1025                 1030                 1035 

Glu Glu  Arg Glu Lys Lys Val  Tyr Pro Lys Ala Val  Glu Arg Ser 
    1040                 1045                 1050 

Ser Thr  Phe Glu Asn Lys Ala  Ser Met Gln Glu Ala  Pro Pro Leu 
    1055                 1060                 1065 

Gly Ser  Leu Leu Lys Asp Ala  Leu His Lys Gln Ala  Ser Val Arg 
    1070                 1075                 1080 

Ala Ser  Glu Gly Ala Met Ser  Asp Gly Pro Val Pro  Ala Glu His 
    1085                 1090                 1095 

Arg Gln  Gly Gly Gly Asp Phe  Arg Arg Ala Pro Ala  Pro Gly Thr 
    1100                 1105                 1110 

Leu Gln  Asp Gly Leu Cys His  Ser Leu Asp Arg Gly  Ile Ser Gly 
    1115                 1120                 1125 

Lys Gly  Glu Gly Thr Glu Lys  Ser Ser Gln Ala Lys  Glu Leu Leu 
    1130                 1135                 1140 

Arg Cys  Glu Lys Leu Asp Ser  Lys Leu Ala Asn Ile  Asp Tyr Leu 
    1145                 1150                 1155 

Arg Lys  Lys Met Ser Leu Glu  Asp Lys Glu Asp Asn  Leu Cys Pro 
    1160                 1165                 1170 

Val Leu  Lys Pro Lys Met Thr  Ala Gly Ser His Glu  Cys Leu Pro 
    1175                 1180                 1185 

Gly Asn  Pro Val Arg Pro Thr  Gly Gly Gln Gln Glu  Pro Pro Pro 
    1190                 1195                 1200 

Ala Ser  Glu Ser Arg Ala Phe  Val Ser Ser Thr His  Ala Ala Gln 
    1205                 1210                 1215 

Met Ser  Ala Val Ser Phe Val  Pro Leu Lys Ala Leu  Thr Gly Arg 
    1220                 1225                 1230 

Val Asp  Ser Gly Thr Glu Lys  Pro Gly Leu Val Ala  Pro Glu Ser 
    1235                 1240                 1245 

Pro Val  Arg Lys Ser Pro Ser  Glu Tyr Lys Leu Glu  Gly Arg Ser 
    1250                 1255                 1260 

Val Ser  Cys Leu Lys Pro Ile  Glu Gly Thr Leu Asp  Ile Ala Leu 
    1265                 1270                 1275 

Leu Ser  Gly Pro Gln Ala Ser  Lys Thr Glu Leu Pro  Ser Pro Glu 
    1280                 1285                 1290 

Ser Ala  Gln Ser Pro Ser Pro  Ser Gly Asp Val Arg  Ala Ser Val 
    1295                 1300                 1305 

Pro Pro  Val Leu Pro Ser Ser  Ser Gly Lys Lys Asn  Asp Thr Thr 
    1310                 1315                 1320 

Ser Ala  Arg Glu Leu Ser Pro  Ser Ser Leu Lys Met  Asn Lys Ser 
    1325                 1330                 1335 

Tyr Leu  Leu Glu Pro Trp Phe  Leu Pro Pro Ser Arg  Gly Leu Gln 
    1340                 1345                 1350 

Asn Ser  Pro Ala Val Ser Leu  Pro Asp Pro Glu Phe  Lys Arg Asp 
    1355                 1360                 1365 

Arg Lys  Gly Pro His Pro Thr  Ala Arg Ser Pro Gly  Thr Val Met 
    1370                 1375                 1380 

Glu Ser  Asn Pro Gln Gln Arg  Glu Gly Ser Ser Pro  Lys His Gln 
    1385                 1390                 1395 

Asp His  Thr Thr Asp Pro Lys  Leu Leu Thr Cys Leu  Gly Gln Asn 
    1400                 1405                 1410 

Leu His  Ser Pro Asp Leu Ala  Arg Pro Arg Cys Pro  Leu Pro Pro 
    1415                 1420                 1425 

Glu Ala  Ser Pro Ser Arg Glu  Lys Pro Gly Leu Arg  Glu Ser Ser 
    1430                 1435                 1440 

Glu Arg  Gly Pro Pro Thr Ala  Arg Ser Glu Arg Ser  Ala Ala Arg 
    1445                 1450                 1455 

Ala Asp  Thr Cys Arg Glu Pro  Ser Met Glu Leu Cys  Phe Pro Glu 
    1460                 1465                 1470 

Thr Ala  Lys Thr Ser Asp Asn  Ser Lys Asn Leu Leu  Ser Val Gly 
    1475                 1480                 1485 

Arg Thr  His Pro Asp Phe Tyr  Thr Gln Thr Gln Ala  Met Glu Lys 
    1490                 1495                 1500 

Ala Trp  Ala Pro Gly Gly Lys  Thr Asn His Lys Asp  Gly Pro Gly 
    1505                 1510                 1515 

Glu Ala  Arg Pro Pro Pro Arg  Asp Asn Ser Ser Leu  His Ser Ala 
    1520                 1525                 1530 

Gly Ile  Pro Cys Glu Lys Glu  Leu Gly Lys Val Arg  Arg Gly Val 
    1535                 1540                 1545 

Glu Pro  Lys Pro Glu Ala Leu  Leu Ala Arg Arg Ser  Leu Gln Pro 
    1550                 1555                 1560 

Pro Gly  Ile Glu Ser Glu Lys  Ser Glu Lys Leu Ser  Ser Phe Pro 
    1565                 1570                 1575 

Ser Leu  Gln Lys Asp Gly Ala  Lys Glu Pro Glu Arg  Lys Glu Gln 
    1580                 1585                 1590 

Pro Leu  Gln Arg His Pro Ser  Ser Ile Pro Pro Pro  Pro Leu Thr 
    1595                 1600                 1605 

Ala Lys  Asp Leu Ser Ser Pro  Ala Ala Arg Gln His  Cys Ser Ser 
    1610                 1615                 1620 

Pro Ser  His Ala Ser Gly Arg  Glu Pro Gly Ala Lys  Pro Ser Thr 
    1625                 1630                 1635 

Ala Glu  Pro Ser Ser Ser Pro  Gln Asp Pro Pro Lys  Pro Val Ala 
    1640                 1645                 1650 

Ala His  Ser Glu Ser Ser Ser  His Lys Pro Arg Pro  Gly Pro Asp 
    1655                 1660                 1665 

Pro Gly  Pro Pro Lys Thr Lys  His Pro Asp Arg Ser  Leu Ser Ser 
    1670                 1675                 1680 

Gln Lys  Pro Ser Val Gly Ala  Thr Lys Gly Lys Glu  Pro Ala Thr 
    1685                 1690                 1695 

Gln Ser  Leu Gly Gly Ser Ser  Arg Glu Gly Lys Gly  His Ser Lys 
    1700                 1705                 1710 

Ser Gly  Pro Asp Val Phe Pro  Ala Thr Pro Gly Ser  Gln Asn Lys 
    1715                 1720                 1725 

Ala Ser  Asp Gly Ile Gly Gln  Gly Glu Gly Gly Pro  Ser Val Pro 
    1730                 1735                 1740 

Leu His  Thr Asp Arg Ala Pro  Leu Asp Ala Lys Pro  Gln Pro Thr 
    1745                 1750                 1755 

Ser Gly  Gly Arg Pro Leu Glu  Val Leu Glu Lys Pro  Val His Leu 
    1760                 1765                 1770 

Pro Arg  Pro Gly His Pro Gly  Pro Ser Glu Pro Ala  Asp Gln Lys 
    1775                 1780                 1785 

Leu Ser  Ala Val Gly Glu Lys  Gln Thr Leu Ser Pro  Lys His Pro 
    1790                 1795                 1800 

Lys Pro  Ser Thr Val Lys Asp  Cys Pro Thr Leu Cys  Lys Gln Thr 
    1805                 1810                 1815 

Asp Asn  Arg Gln Thr Asp Lys  Ser Pro Ser Gln Pro  Ala Ala Asn 
    1820                 1825                 1830 

Thr Asp  Arg Arg Ala Glu Gly  Lys Lys Cys Thr Glu  Ala Leu Tyr 
    1835                 1840                 1845 

Ala Pro  Ala Glu Gly Asp Lys  Leu Glu Ala Gly Leu  Ser Phe Val 
    1850                 1855                 1860 

His Ser  Glu Asn Arg Leu Lys  Gly Ala Glu Arg Pro  Ala Ala Gly 
    1865                 1870                 1875 

Val Gly  Lys Gly Phe Pro Glu  Ala Arg Gly Lys Gly  Pro Gly Pro 
    1880                 1885                 1890 

Gln Lys  Pro Pro Thr Glu Ala  Asp Lys Pro Asn Gly  Met Lys Arg 
    1895                 1900                 1905 

Ser Pro  Ser Ala Thr Gly Gln  Ser Ser Phe Arg Ser  Thr Ala Leu 
    1910                 1915                 1920 

Pro Glu  Lys Ser Leu Ser Cys  Ser Ser Ser Phe Pro  Glu Thr Arg 
    1925                 1930                 1935 

Ala Gly  Val Arg Glu Ala Ser  Ala Ala Ser Ser Asp  Thr Ser Ser 
    1940                 1945                 1950 

Ala Lys  Ala Ala Gly Gly Met  Leu Glu Leu Pro Ala  Pro Ser Asn 
    1955                 1960                 1965 

Arg Asp  His Arg Lys Ala Gln  Pro Ala Gly Glu Gly  Arg Thr His 
    1970                 1975                 1980 

Met Thr  Lys Ser Asp Ser Leu  Pro Ser Phe Arg Val  Ser Thr Leu 
    1985                 1990                 1995 

Pro Leu  Glu Ser His His Pro  Asp Pro Asn Thr Met  Gly Gly Ala 
    2000                 2005                 2010 

Ser His  Arg Asp Arg Ala Leu  Ser Val Thr Ala Thr  Val Gly Glu 
    2015                 2020                 2025 

Thr Lys  Gly Lys Asp Pro Ala  Pro Ala Gln Pro Pro  Pro Ala Arg 
    2030                 2035                 2040 

Lys Gln  Asn Val Gly Arg Asp  Val Thr Lys Pro Ser  Pro Ala Pro 
    2045                 2050                 2055 

Asn Thr  Asp Arg Pro Ile Ser  Leu Ser Asn Glu Lys  Asp Phe Val 
    2060                 2065                 2070 

Val Arg  Gln Arg Arg Gly Lys  Glu Ser Leu Arg Ser  Ser Pro His 
    2075                 2080                 2085 

Lys Lys  Ala Leu 
    2090