US20030036076A1

US20030036076A1 - CADs as modifiers of the p53 pathway and methods of use

Info

Publication number: US20030036076A1
Application number: US10/160,758
Authority: US
Inventors: Lori Friedman; Gregory Plowman; Marcia Belvin; Helen Francis-Lang; Danxi Li; Roel Funke
Original assignee: Lori Friedman; Plowman Gregory D.; Marcia Belvin; Helen Francis-Lang; Danxi Li; Funke Roel P.
Current assignee: Exelixis Inc
Priority date: 2001-06-05
Filing date: 2002-06-03
Publication date: 2003-02-20
Also published as: AU2002345500A1; US20030165809A1; WO2002098898A2; WO2002099083A3; WO2002099041A3; JP2005505255A; WO2002099048A3; WO2002099054A3; CA2449206A1; WO2002099050A3; EP1402067A4; EP1404374A4; WO2002099046A2; US20020192695A1; WO2002099042A2; WO2002099122A1; WO2002099052A2; WO2002099138A3; AU2002320264B2; WO2002099057A2

Abstract

Human CAD genes are identified as modulators of the p53 pathway, and thus are therapeutic targets for disorders associated with defective p53 function. Methods for identifying modulators of p53, comprising screening for agents that modulate the activity of CAD are provided.

Description

REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional patent applications No. 60/296,076 filed Jun. 5, 2001, 60/328,605 filed Oct. 10, 2001, and 60/357,253 filed Feb. 15, 2002. The contents of the prior applications are hereby incorporated in their entirety.[0001]

BACKGROUND OF THE INVENTION

The p53 gene is mutated in over 50 different types of human cancers, including familial and spontaneous cancers, and is believed to be the most commonly mutated gene in human cancer (Zambetti and Levine, FASEB (1993) 7:855-865; Hollstein, et al., Nucleic Acids Res. (1994) 22:3551-3555). Greater than 90% of mutations in the p53 gene are missense mutations that alter a single amino acid that inactivates p53 function. Aberrant forms of human p53 are associated with poor prognosis, more aggressive tumors, metastasis, and short survival rates (Mitsudomi et al., Clin Cancer Res October 2000; 6(10):4055-63; Koshland, Science (1993) 262:1953).

The human p53 protein normally functions as a central integrator of signals including DNA damage, hypoxia, nucleotide deprivation, and oncogene activation (Prives, Cell (1998) 95:5-8). In response to these signals, p53 protein levels are greatly increased with the result that,the accumulated p53 activates cell cycle arrest or apoptosis depending on the nature and strength of these signals. Indeed, multiple lines of experimental evidence have pointed to a key role for p53 as a tumor suppressor (Levine, Cell (1997) 88:323-331). For example, homozygous p53 “knockout” mice are developmentally normal but exhibit nearly 100% incidence of neoplasia in the first year of life (Donehower et al., Nature (1992) 356:215-221).

The biochemical mechanisms and pathways through which p53 functions in normal and cancerous cells are not fully understood, but one clearly important aspect of p53 function is its activity as a gene-specific transcriptional activator. Among the genes with known p53-response elements are several with well-characterized roles in either regulation of the cell cycle or apoptosis, including GADD45, p21/Waf1/Cip1, cyclin G, Bax, IGF-BP3, and MDM2 (Levine, Cell (1997) 88:323-331).

Cell-cell interactions that involve adhesion molecules are important in many developmental processes. Many adhesion molecules have been found to be conserved between Drosophila and vertebrates, indicating that these adhesion molecules involved in tissue morphogenesis evolved long before the divergence of the arthropods and chordates (Dunne, J. et al (1995) Genomics 30: 207-223) (Hortsch, M. and Goodman, C. (1991) Ann. Rev. Cell. Biol. 7: 505-557). Adhesion molecules have been classified into four major families: the immunoglobulin superfamily, the integrin superfamily, the selectin family, and the cadherin superfamily. Cadherins mediate homophilic, calcium-dependent cell-cell adhesion in a wide variety of tissues and are important in regulating morphogenesis. Loss of function may be play a role in the invasion and metastasis of malignant tumors. The original or classical adherins have a highly conserved domain structure, which typically includes five extracellular conserved repeated amino acid sequences (cadherin repeats).

The Drosophila ‘fat’ gene does not belong to the classical cadherin gene family, however it does encode a transmembrane protein containing 34 cadherin repeats in association with a number of other motifs (Mahoney, P. et al. (1991) Cell 67: 853-868). The Drosophila ‘fat’ locus encodes a tumor suppressor gene, and recessive (loss-of-function) mutations which lead to hyperplastic overgrowth of the imaginal discs, indicating that contact-dependent cell interactions may play an important role in regulating growth (Bryant, P. et al. (1988) Dev. Biol. 129: 541-554). This excessive cell proliferation occurs while maintaining normal epithelial organization and differentiation potential.

Cadherin related 23 (CDH23 or CAD23) is a protein with a single transmembrane domain and 27 cadherin repeats, is involved in sensorineural hearing and vestibular function, and gene mutations often cause Usher syndrome type 1D (USH1D), which is characterized by hearing loss, vestibular dysfunction and visual impairment (Bolz, H. et al. (2001) Nat Genet (1): 108-12). Mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse (Di Palma, F. et al. (2001) Nat Genet. 2001 (1): 103-7).

FAT tumor suppressor precursor (CAD7) is a member of the cadherin superfamily, and possibly functions in developmental processes and cell communication (Dunne et al, supra). The full-length human FAT cDNA encodes a large protein that most resembles the Drosophila ‘fat ’ protein in its possession of 34 cadherin repeats and other characteristics (Dunne, J. et al. (1995) supra). Expression analysis of FAT in fetal and adult tissues revealed that FAT mRNA is present in many epithelial and some endothelial and smooth muscle cells. The large FAT protein is predicted to contain nearly 4600 residues.

FAT2 is a protein containing multiple cadherin domains, has four epidermal growth factor (EGF)-like domains and two extracellular laminin G domains (Wu, Q. and Maniatis, T. (2000) Proc. Nat. Acad. Sci. 97: 3124-3129). Epidermal growth factor (EGF) is characterized by domains of approximately 50 amino acids with three disulfide bonds. EGF-like domains are thought to be involved in a number of extracellular events, including cell adhesion and receptor-ligand interactions. Proteins with EGF-like domains often contain more than 1,000 amino acids, have multiple copies of the EGF-like domain, and contain additional domains known to be involved in specific protein-protein interactions. FAT2 is expressed in the brain and has and contains sequence similarity to the rat gene MEGF1 (Nakayama, M. et al. (1998) Genomics 51: 27-34).

The ability to manipulate the genomes of model organisms such as Drosophila 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, Mechler B M et al., 1985 EMBO J 4:1551-1557; Gateff E. 1982 Adv. Cancer Res. 37: 33-74; Watson K L., et al., 1994 J Cell Sci. 18: 19-33; Miklos GL, and Rubin G M. 1996 Cell 86:521-529; Wassarman D A, et al., 1995 Curr Opin Gen Dev 5: 44-50; and Booth D R. 1999 Cancer Metastasis Rev. 18: 261-284). 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 p53, modifier genes can be identified that may be attractive candidate targets for novel therapeutics.

All references cited herein, including sequence information in referenced Genbank identifier numbers and website references, are incorporated herein in their entireties.

SUMMARY OF THE INVENTION

We have discovered genes that modify the p53 pathway in Drosophila, and identified their human orthologs, hereinafter referred to as CAD. The invention provides methods for utilizing these p53 modifier genes and polypeptides to identify candidate therapeutic agents that can be used in the treatment of disorders associated with defective p53 function. Preferred CAD-modulating agents specifically bind to CAD polypeptides and restore p53 function. Other preferred CAD-modulating agents are nucleic acid modulators such as antisense oligomers and RNAi that repress CAD gene expression or product activity by, for example, binding to and inhibiting the respective nucleic acid (i.e. DNA or mRNA).

CAD-specific modulating agents may be evaluated by any convenient in vitro or in vivo assay for molecular interaction with a CAD polypeptide or nucleic acid. In one embodiment, candidate p53 modulating agents are tested with an assay system comprising a CAD polypeptide or nucleic acid. Candidate agents that produce a change in the activity of the assay system relative to controls are identified as candidate p53 modulating agents. The assay system may be cell-based or cell-free. CAD-modulating agents include CAD related proteins (e.g. dominant negative mutants, and biotherapeutics); CAD-specific antibodies; CAD-specific antisense oligomers and other nucleic acid modulators; and chemical agents that specifically bind CAD or compete with CAD binding target. In one specific embodiment, a small molecule modulator is identified using an adhesion 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.

In another embodiment, candidate p53 pathway modulating agents are further tested using a second assay system that detects changes in the p53 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 p53 pathway, such as an angiogenic, apoptotic, or cell proliferation disorder (e.g. cancer).

The invention further provides methods for modulating the p53 pathway in a mammalian cell by contacting the mammalian cell with an agent that specifically binds a CAD 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 p53 pathway.

DETAILED DESCRIPTION OF THE INVENTION

Genetic screens were designed to identify modifiers of the p53 pathway in Drosophila in which p53 was overexpressed in the wing (Ollmann M, et al., Cell 2000 101: 91-101). The dachsous gene was identified as a modifier of the p53 pathway. Accordingly, vertebrate orthologs of these modifiers, and preferably the human orthologs, cadherin related (CAD) genes (i.e., nucleic acids and polypeptides) are attractive drug targets for the treatment of pathologies associated with a defective p53 signaling pathway, such as cancer.

In vitro and in vivo methods of assessing CAD function are provided herein. Modulation of the CAD or their respective binding partners is useful for understanding the association of the p53 pathway and its members in normal and disease conditions and for developing diagnostics and therapeutic modalities for p53 related pathologies. CAD-modulating agents that act by inhibiting or enhancing CAD expression, directly or indirectly, for example, by affecting a CAD function such as binding activity, can be identified using methods provided herein. CAD modulating agents are useful in diagnosis, therapy and pharmaceutical development.

Nucleic Acids and Polypeptides of the Invention

Sequences related to CAD nucleic acids and polypeptides that can be used in the invention are disclosed in Genbank (referenced by Genbank identifier (GI) number) as GI#s 12060936 (SEQ ID NO:1), 16507961 (SEQ ID NO:2), 16507963 (SEQ ID NO:3), 18576725 (SEQ ID NO:4), 1107686 (SEQ ID NO:5), 7407143 (SEQ ID NO:6), 13787216 (SEQ ID NO:7), and 16933556 (SEQ ID NO:10) for nucleic acid, and GI#s 12060937 (SEQ ID NO:11), 17366834 (SEQ ID NO:12), 8928104 (SEQ ID NO:13), 4885229 (SEQ ID NO:14), 7407144 (SEQ ID NO:15), and 16933557 (SEQ ID NO:16) for polypeptides. Additionally, newly identified nucleic acid sequences of SEQ ID NOs: 8 and 9 can also be used in the invention.

CADs are cell adhesion proteins with cadherin domains. The term “CAD polypeptide” refers to a full-length CAD protein or a functionally active fragment or derivative thereof. A “functionally active” CAD fragment or derivative exhibits one or more functional activities associated with a full-length, wild-type CAD protein, such as antigenic or immunogenic activity, adhesion activity, ability to bind natural cellular substrates, etc. The functional activity of CAD 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 & Sons, Inc., Somerset, N.J. Jersey) and as further discussed below. For purposes herein, functionally active fragments also include those fragments that comprise one or more structural domains of a CAD, such as a cadherin 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; http://pfam.wustl.edu). For example, the cadherin domains of CAD from GI# 17366834 (SEQ ID NO:12) are located at approximately amino acid residues 38 to 121, 137 to 227, 241 to 337, 353 to 451, 465 to 552, 566 to 662, 676 to 769, 783 to 879, 895 to 986, 1000 to 1091, 1107 to 1199, 1214 to 1304, 1318 to 1409, 1424 to 1518, 1533 to 1625, 1639 to 1735, 1750 to 1842, 1856 to 1947, 1964 to 2060, 2074 to 2165, 2179 to 2284, 2301 to 2393, 2407 to 2500, 2514 to 2602, 2618 to 2711, 2733 to 2828, and 2851 to 2951 (PFAM 00028). Likewise, the cadherin domains of GI# 4885229 (SEQ ID NO:14) are located at approximately amino acid residues 39 to 140, 154 to 248, 372 to 454, 468 to 560, 574 to 664, 722 to 813, 827 to 918, 932 to 1023, 1039 to 1130, 1144 to 1236, 1250 to 1346, 1363 to 1447, 1461 to 1553, 1567 to 1661, 1675 to 1759, 1773 to 1871, 1887 to 1973, 1987 to 2073, 2089 to 2178, 2190 to 2277, 2291 to 2384, 2398 to 2486, 2500 to 2590, 2604 to 2696, 2710 to 2802, 2816 to 2911, 2925 to 3016, 3030 to 3118, 3132 to 3223, 3237 to 3328, 3342 to 3433, 3447 to 3538, and 3553 to 3634; the cadherin domains of GI# 7407144 (SEQ ID NO:15) are located at approximately amino acid residues 38 to 139, 153 to 247, 367 to 449, 463 to 553, 569 to 659, 720 to 811, 825 to 916, 930 to 1019, 1037 to 1128, 1142 to 1233, 1247 to 1337, 1354 to 1438, 1453 to 1546, 1560 to 1651, 1665 to 1749, 1763 to 1861, 1877 to 1959, 1973 to 2061, 2075 to 2164, 2176 to 2263, 2277 to 2370, 2384 to 2472, 2486 to 2576, 2590 to 2682, 2696 to 2786, 2802 to 2897, 2911 to 3002, 3016 to 3104, 3119 to 3209, 3223 to 3312, 3326 to 3417, 3431 to 3522, and 3536 to 3620; and the cadherin domains of GI# 16933557 (SEQ ID NO: 16) are located at approximately amino acid residues 47 to 134, 148 to 246, 260 to 353, 371 to 463, 478 to 569, 583 to 676, 690 to 781, 795 to 885, 899 to 989, 1005 to 1096, 1110 to 1202, 1222 to 1312, 1337 to 1427, 1441 to 1537, 1550 to 1640, 1654 to 1742, 1756 to 1846, 1860 to 1951, 1974 to 2059, 2073 to 2162, 2176 to 2268, 2281 to 2367, 2381 to 2473, 2487 to 2593, 2607 to 2697, 2711 to 2804, and 2818 to 2923. Methods for obtaining CAD 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:11, 12, 13, 14, 15, or 16(a CAD). In further preferred embodiments, the fragment comprises the entire adhesion (functionally active) domain.

The term “CAD nucleic acid” refers to a DNA or RNA molecule that encodes a CAD polypeptide. Preferably, the CAD 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 CAD. 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 Drosophila, 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; http://blast.wustl.edu/blast/README.html) 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.

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.

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 http://www.ebi.ac.uk/MPsrch/; 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. O. 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.”

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:1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 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 & 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, 2, 3, 4, 5, 6, 7, 8, 9, or 10 under stringent hybridization conditions that comprise: 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'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'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 0.2×SSC and 0.1% SDS (sodium dodecyl sulfate).

In other embodiments, moderately stringent hybridization conditions are used that comprise: pretreatment of filters containing nucleic acid for 6 h at 40° C. in a solution containing 35% formamide, 5×SSC, 50 mM Tris-HCl (pH7.5), 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 (pH7.5), 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.

Alternatively, low stringency conditions can be used that comprise: 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'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.

Isolation, Production, Expression, and Mis-expression of CAD Nucleic Acids and Polypeptides

CAD nucleic acids and polypeptides, useful for identifying and testing agents that modulate CAD function and for other applications related to the involvement of CAD in the p53 pathway. CAD 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 a CAD protein for assays used to assess CAD 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 ^ndedition, Elsevier Science, New York, 1995; Doonan S (ed.) Protein Purification Protocols, Humana Press, New Jersey, 1996; Coligan J E et al, Current Protocols in Protein Science (eds.), 1999, John Wiley & Sons, New York). In particular embodiments, recombinant CAD is expressed in a cell line known to have defective p53 function (e.g. SAOS-2 osteoblasts, H1299 lung cancer cells, C33A and HT3 cervical cancer cells, HT-29 and DLD-1 colon cancer cells, among others, available from American Type Culture Collection (ATCC), Manassas, Va.). The recombinant cells are used in cell-based screening assay systems of the invention, as described further below.

The nucleotide sequence encoding a CAD polypeptide can be inserted into any appropriate expression vector. The necessary transcriptional and translational signals, including promoter/enhancer element, can derive from the native CAD 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. A host cell strain that modulates the expression of, modifies, and/or specifically processes the gene product may be used.

To detect expression of the CAD gene product, the expression vector can comprise a promoter operably linked to a CAD 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 CAD gene product based on the physical or functional properties of the CAD protein in in vitro assay systems (e.g. immunoassays).

The CAD 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).

Once a recombinant cell that expresses the CAD 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, cite purification reference). Alternatively, native CAD 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.

The methods of this invention may also use cells that have been engineered for altered expression (mis-expression) of CAD or other genes associated with the p53 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).

Genetically Modified Animals

Animal models that have been genetically modified to alter CAD expression may be used in in vivo assays to test for activity of a candidate p53 modulating agent, or to further assess the role of CAD in a p53 pathway process such as apoptosis or cell proliferation. Preferably, the altered CAD expression results in a detectable phenotype, such as decreased or increased levels of cell proliferation, angiogenesis, or apoptosis compared to control animals having normal CAD expression. The genetically modified animal may additionally have altered p53 expression (e.g. p53 knockout). Preferred genetically modified animals are mammals such as primates, rodents (preferably mice), cows, horses, goats, sheep, pigs, dogs and cats. 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.

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).

In one embodiment, the transgenic animal is a “knock-out” animal having a heterozygous or homozygous alteration in the sequence of an endogenous CAD gene that results in a decrease of CAD function, preferably such that CAD 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 CAD gene is used to construct a homologous recombination vector suitable for altering an endogenous CAD 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).

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 CAD gene, e.g., by introduction of additional copies of CAD, or by operatively inserting a regulatory sequence that provides for altered expression of an endogenous copy of the CAD gene. Such regulatory sequences include inducible, tissue-specific, and constitutive promoters and enhancer elements. The knock-in can be homozygous or heterozygous.

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'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).

The genetically modified animals can be used in genetic studies to further elucidate the p53 pathway, as animal models of disease and disorders implicating defective p53 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 CAD function and phenotypic changes are compared with appropriate control animals such as genetically modified animals that receive placebo treatment, and/or animals with unaltered CAD expression that receive candidate therapeutic agent.

In addition to the above-described genetically modified animals having altered CAD function, animal models having defective p53 function (and otherwise normal CAD function), can be used in the methods of the present invention. For example, a p53 knockout mouse can be used to assess, in vivo, the activity of a candidate p53 modulating agent identified in one of the in vitro assays described below. p53 knockout mice are described in the literature (Jacks et al., Nature 2001;410:1111-1116, 1043-1044; Donehower et al., supra). Preferably, the candidate p53 modulating agent when administered to a model system with cells defective in p53 function, produces a detectable phenotypic change in the model system indicating that the p53 function is restored, i.e., the cells exhibit normal cell cycle progression.

Modulating Agents

The invention provides methods to identify agents that interact with and/or modulate the function of CAD and/or the p53 pathway. Such agents are useful in a variety of diagnostic and therapeutic applications associated with the p53 pathway, as well as in further analysis of the CAD protein and its contribution to the p53 pathway. Accordingly, the invention also provides methods for modulating the p53 pathway comprising the step of specifically modulating CAD activity by administering a CAD-interacting or -modulating agent.

In a preferred embodiment, CAD-modulating agents inhibit or enhance CAD activity or otherwise affect normal CAD function, including transcription, protein expression, protein localization, and cellular or extra-cellular activity. In a further preferred embodiment, the candidate p53 pathway-modulating agent specifically modulates the function of the CAD. The phrases “specific modulating agent”, “specifically modulates”, etc., are used herein to refer to modulating agents that directly bind to the CAD polypeptide or nucleic acid, and preferably inhibit, enhance, or otherwise alter, the function of the CAD. The term also encompasses modulating agents that alter the interaction of the CAD with a binding partner or substrate (e.g. by binding to a binding partner of a CAD, or to a protein/binding partner complex, and inhibiting function).

Preferred CAD-modulating agents include small molecule compounds; CAD-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's Pharmaceutical Sciences” Mack Publishing Co., Easton, Pa. 19 ^thedition.

Small Molecule Modulators

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 CAD 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 CAD-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).

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 p53 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.

Protein Modulators

Specific CAD-interacting proteins are useful in a variety of diagnostic and therapeutic applications related to the p53 pathway and related disorders, as well as in validation assays for other CAD-modulating agents. In a preferred embodiment, CAD-interacting proteins affect normal CAD function, including transcription, protein expression, protein localization, and cellular or extra-cellular activity. In another embodiment, CAD-interacting proteins are useful in detecting and providing information about the function of CAD proteins, as is relevant to p53 related disorders, such as cancer (e.g., for diagnostic means).

A CAD-interacting protein may be endogenous, i.e. one that naturally interacts genetically or biochemically with a CAD, such as a member of the CAD pathway that modulates CAD expression, localization, and/or activity. CAD-modulators include dominant negative forms of CAD-interacting proteins and of CAD proteins themselves. Yeast two-hybrid and variant screens offer preferred methods for identifying endogenous CAD-interacting proteins (Finley, R. L. et al. (1996) in DNA Cloning-Expression Systems: A Practical Approach, eds. Glover D. & Hames B. D (Oxford University Press, Oxford, England), pp. 169-203; Fashema S F 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 J R 3 ^rd, Trends Genet (2000) 16:5-8).

A CAD-interacting protein may be an exogenous protein, such as a CAD-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). CAD antibodies are further discussed below.

In preferred embodiments, a CAD-interacting protein specifically binds a CAD protein. In alternative preferred embodiments, a CAD-modulating agent binds a CAD substrate, binding partner, or cofactor.

Antibodies

In another embodiment, the protein modulator is a CAD specific antibody agonist or antagonist. The antibodies have therapeutic and diagnostic utilities, and can be used in screening assays to identify CAD modulators. The antibodies can also be used in dissecting the portions of the CAD pathway responsible for various cellular responses and in the general processing and maturation of the CAD.

Antibodies that specifically bind CAD polypeptides can be generated using known methods. Preferably the antibody is specific to a mammalian ortholog of CAD polypeptide, and more preferably, to human CAD. 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 CAD which are particularly antigenic can be selected, for example, by routine screening of CAD 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 shown in any of SEQ ID NOs:11, 12, 13, 14, 15, or 16. Monoclonal antibodies with affinities of 10 ⁸M⁻¹preferably 10⁹M⁻¹to 10¹⁰M⁻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 CAD or substantially purified fragments thereof. If CAD fragments are used, they preferably comprise at least 10, and more preferably, at least 20 contiguous amino acids of a CAD protein. In a particular embodiment, CAD-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'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.

The presence of CAD-specific antibodies is assayed by an appropriate assay such as a solid phase enzyme-linked immunosorbant assay (ELISA) using immobilized corresponding CAD polypeptides. Other assays, such as radioimmunoassays or fluorescent assays might also be used.

Chimeric antibodies specific to CAD 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).

CAD-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).

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).

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).

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'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' 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).

Specific Biotherapeutics

In a preferred embodiment, a CAD-interacting protein may have biotherapeutic applications. Biotherapeutic agents formulated in pharmaceutically acceptable carriers and dosages may be used to activate or inhibit signal transduction pathways. This modulation may be accomplished by binding a ligand, thus inhibiting the activity of the pathway; or by binding a receptor, either to inhibit activation of, or to activate, the receptor. Alternatively, the biotherapeutic may itself be a ligand capable of activating or inhibiting a receptor. Biotherapeutic agents and methods of producing them are described in detail in U.S. Pat. No. 6,146,628.

When the CAD is a ligand, it may be used as a biotherapeutic agent to activate or inhibit its natural receptor. Alternatively, antibodies against CAD, as described in the previous section, may be used as biotherapeutic agents.

When the CAD is a receptor, its ligand(s), antibodies to the ligand(s) or the CAD itself may be used as biotherapeutics to modulate the activity of CAD in the p53 pathway.

Nucleic Acid Modulators

Other preferred CAD-modulating agents comprise nucleic acid molecules, such as antisense oligomers or double stranded RNA (dsRNA), which generally inhibit CAD activity. Preferred nucleic acid modulators interfere with the function of the CAD nucleic acid such as DNA replication, transcription, translocation of the CAD RNA to the site of protein translation, translation of protein from the CAD RNA, splicing of the CAD RNA to yield one or more mRNA species, or catalytic activity which may be engaged in or facilitated by the CAD RNA.

In one embodiment, the antisense oligomer is an oligonucleotide that is sufficiently complementary to a CAD mRNA to bind to and prevent translation, preferably by binding to the 5′ untranslated region. CAD-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.

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).

Alternative preferred CAD 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); 4 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).

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, a CAD-specific nucleic acid modulator is used in an assay to further elucidate the role of the CAD in the p53 pathway, and/or its relationship to other members of the pathway. In another aspect of the invention, a CAD-specific antisense oligomer is used as a therapeutic agent for treatment of p53-related disease states.

Assay Systems

The invention provides assay systems and screening methods for identifying specific modulators of CAD 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's specific biochemical or molecular effect with respect to the CAD nucleic acid or protein. In general, secondary assays further assess the activity of a CAD modulating agent identified by a primary assay and may confirm that the modulating agent affects CAD in a manner relevant to the p53 pathway. In some cases, CAD modulators will be directly tested in a secondary assay.

In a preferred embodiment, the screening method comprises contacting a suitable assay system comprising a CAD polypeptide with a candidate agent under conditions whereby, but for the presence of the agent, the system provides a reference activity (e.g. adhesion 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 CAD activity, and hence the p53 pathway.

Primary Assays

The type of modulator tested generally determines the type of primary assay.

Primary Assays for Small Molecule Modulators

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.

Cell-based screening assays usually require systems for recombinant expression of CAD 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 CAD-interacting proteins are used in screens to identify small molecule modulators, the binding specificity of the interacting protein to the CAD protein may be assayed by various known methods such as substrate processing (e.g. ability of the candidate CAD-specific binding agents to function as negative effectors in CAD-expressing cells), binding equilibrium constants (usually at least about 10 ⁷M⁻¹, preferably at least about 10⁸M⁻¹, more preferably at least about 10⁹M⁻¹), and immunogenicity (e.g. ability to elicit CAD 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.

The screening assay may measure a candidate agent's ability to specifically bind to or modulate activity of a CAD polypeptide, a fusion protein thereof, or to cells or membranes bearing the polypeptide or fusion protein. The CAD polypeptide can be full length or a fragment thereof that retains functional CAD activity. The CAD polypeptide may be fused to another polypeptide, such as a peptide tag for detection or anchoring, or to another tag. The CAD polypeptide is preferably human CAD, or is an ortholog or derivative thereof as described above. In a preferred embodiment, the screening assay detects candidate agent-based modulation of CAD interaction with a binding target, such as an endogenous or exogenous protein or other substrate that has CAD-specific binding activity, and can be used to assess normal CAD gene function.

Suitable assay formats that may be adapted to screen for CAD 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).

A variety of suitable assay systems may be used to identify candidate CAD and p53 pathway modulators (e.g. U.S. Pat. Nos. 5,550,019 and 6,133,437 (apoptosis assays); U.S. Pat. No. 6,020,135 (p53 modulation), among others). Specific preferred assays are described in more detail below.

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 a CAD, and that optionally has defective p53 function (e.g. p53 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 p53 modulating agents. In some embodiments of the invention, an apoptosis assay may be used as a secondary assay to test a candidate p53 modulating agents that is initially identified using a cell-free assay system. An apoptosis assay may also be used to test whether CAD function plays a direct role in apoptosis. For example, an apoptosis assay may be performed on cells that over- or under-express CAD relative to wild type cells. Differences in apoptotic response compared to wild type cells suggests that the CAD plays a direct role in the apoptotic response. Apoptosis assays are described further in U.S. Pat. No. 6,133,437.

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.

Cell Proliferation may also be examined using [ ³H]-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 [³H]-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 L S 3800 Liquid Scintillation Counter).

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 CAD are seeded in soft agar plates, and colonies are measured and counted after two weeks incubation.

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 a CAD may be stained with propidium iodide and evaluated in a flow cytometer (available from Becton Dickinson).

Accordingly, a cell proliferation or cell cycle assay system may comprise a cell that expresses a CAD, and that optionally has defective p53 function (e.g. p53 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 p53 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 p53 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 CAD 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 CAD relative to wild type cells. Differences in proliferation or cell cycle compared to wild type cells suggests that the CAD plays a direct role in cell proliferation or cell cycle.

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 HFS 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 a CAD, and that optionally has defective p53 function (e.g. p53 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 p53 modulating agents. In some embodiments of the invention, the angiogenesis assay may be used as a secondary assay to test a candidate p53 modulating agents that is initially identified using another assay system. An angiogenesis assay may also be used to test whether CAD function plays a direct role in cell proliferation. For example, an angiogenesis assay may be performed on cells that over- or under-express CAD relative to wild type cells. Differences in angiogenesis compared to wild type cells suggests that the CAD plays a direct role in angiogenesis.

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 CAD 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 a CAD, and that optionally has a mutated p53 (e.g. p53 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 p53 modulating agents. In some embodiments of the invention, the hypoxic induction assay may be used as a secondary assay to test a candidate p53 modulating agents that is initially identified using another assay system. A hypoxic induction assay may also be used to test whether CAD 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 CAD relative to wild type cells. Differences in hypoxic response compared to wild type cells suggests that the CAD plays a direct role in hypoxic induction.

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.

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.

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. May-June 2001;12(3):346-53).

Primary Assays for Antibody Modulators

For antibody modulators, appropriate primary assays test is a binding assay that tests the antibody's affinity to and specificity for the CAD 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 CAD-specific antibodies; others include FACS assays, radioimmunoassays, and fluorescent assays.

Primary Assays for Nucleic Acid Modulators

For nucleic acid modulators, primary assays may test the ability of the nucleic acid modulator to inhibit or enhance CAD gene expression, preferably mRNA expression. In general, expression analysis comprises comparing CAD expression in like populations of cells (e.g., two pools of cells that endogenously or recombinantly express CAD) 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 CAD mRNA expression is reduced in cells treated with the nucleic acid modulator (e.g., Current Protocols in Molecular Biology (1994) Ausubel F M et al., eds., John Wiley & 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 CAD 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).

Secondary Assays

Secondary assays may be used to further assess the activity of CAD-modulating agent identified by any of the above methods to confirm that the modulating agent affects CAD in a manner relevant to the p53 pathway. As used herein, CAD-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's interaction with CAD.

Secondary assays generally compare like populations of cells or animals (e.g., two pools of cells or animals that endogenously or recombinantly express CAD) in the presence and absence of the candidate modulator. In general, such assays test whether treatment of cells or animals with a candidate CAD-modulating agent results in changes in the p53 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 p53 or interacting pathways.

Cell-based Assays

Cell based assays may use a variety of mammalian cell lines known to have defective p53 function (e.g. SAOS-2 osteoblasts, H1299 lung cancer cells, C33A and HT3 cervical cancer cells, HT-29 and DLD-1 colon cancer cells, among others, available from American Type Culture Collection (ATCC), Manassas, Va.). Cell based assays may detect endogenous p53 pathway activity or may rely on recombinant expression of p53 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.

Animal Assays

A variety of non-human animal models of normal or defective p53 pathway may be used to test candidate CAD modulators. Models for defective p53 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 p53 pathway. Assays generally require systemic delivery of the candidate modulators, such as by oral administration, injection, etc.

In a preferred embodiment, p53 pathway activity is assessed by monitoring neovascularization and angiogenesis. Animal models with defective and normal p53 are used to test the candidate modulator's affect on CAD 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 CAD. 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.

In another preferred embodiment, the effect of the candidate modulator on CAD is assessed via tumorigenicity assays. In one example, xenograft human tumors are 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 CAD endogenously are injected in the flank, 1×10 ⁵to 1×10⁷cells 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.

Diagnostic and Therapeutic Uses

Specific CAD-modulating agents are useful in a variety of diagnostic and therapeutic applications where disease or disease prognosis is related to defects in the p53 pathway, such as angiogenic, apoptotic, or cell proliferation disorders. Accordingly, the invention also provides methods for modulating the p53 pathway in a cell, preferably a cell pre-determined to have defective p53 function, comprising the step of administering an agent to the cell that specifically modulates CAD activity. Preferably, the modulating agent produces a detectable phenotypic change in the cell indicating that the p53 function is restored, i.e., for example, the cell undergoes normal proliferation or progression through the cell cycle.

The discovery that CAD is implicated in p53 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 p53 pathway and for the identification of subjects having a predisposition to such diseases and disorders.

Various expression analysis methods can be used to diagnose whether CAD 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 & 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 p53 signaling that express a CAD, are identified as amenable to treatment with a CAD modulating agent. In a preferred application, the p53 defective tissue overexpresses a CAD 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 CAD cDNA sequences as probes, can determine whether particular tumors express or overexpress CAD. Alternatively, the TaqMan® is used for quantitative RT-PCR analysis of CAD expression in cell lines, normal tissues and tumor samples (PE Applied Biosystems).

Various other diagnostic methods may be performed, for example, utilizing reagents such as the CAD oligonucleotides, and antibodies directed against a CAD, as described above for: (1) the detection of the presence of CAD gene mutations, or the detection of either over- or under-expression of CAD mRNA relative to the non-disorder state; (2) the detection of either an over- or an under-abundance of CAD gene product relative to the non-disorder state; and (3) the detection of perturbations or abnormalities in the signal transduction pathway mediated by CAD.

Thus, in a specific embodiment, the invention is drawn to a method for diagnosing a disease in a patient, the method comprising: a) obtaining a biological sample from the patient; b) contacting the sample with a probe for CAD expression; c) comparing results from step (b) with a control; and d) determining whether step (c) indicates a likelihood of disease. 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

The following experimental section and examples are offered by way of illustration and not by way of limitation. [0114]
I. Drosophila p53 Screen [0115]
The Drosophila p53 gene was overexpressed specifically in the wing using the vestigial margin quadrant enhancer. Increasing quantities of Drosophila p53 (titrated using different strength transgenic inserts in 1 or 2 copies) caused deterioration of normal wing morphology from mild to strong, with phenotypes including disruption of pattern and polarity of wing hairs, shortening and thickening of wing veins, progressive crumpling of the wing and appearance of dark “death” inclusions in wing blade. In a screen designed to identify enhancers and suppressors of Drosophila p53, homozygous females carrying two copies of p53 were crossed to 5663 males carrying random insertions of a piggyBac transposon (Fraser M et al., Virology (1985) 145:356-361). Progeny containing insertions were compared to non-insertion-bearing sibling progeny for enhancement or suppression of the p53 phenotypes. Sequence information surrounding the piggyBac insertion site was used to identify the modifier genes. Modifiers of the wing phenotype were identified as members of the p53 pathway. Dachsous was a moderate enhancer of the wing phenotype. Human orthologs of the modifiers, are referred to herein as CAD. [0116]
BLAST analysis (Altschul et al., supra) was employed to identify Targets from Drosophila modifiers. For example, representative sequences from CAD, GI# 17366834 (SEQ ID NO:12), GI# 4885229 (SEQ ID NO:14), GI# 7407144 (SEQ ID NO:15), and GI#16933557 (SEQ ID NO:16) share 29%, 27%, 27%, and 34% amino acid identity, respectively, with the Drosophila dachsous. [0117]
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; http://pfam.wustl.edu), 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. November 2000;10(11):1679-89) programs. For example, the cadherin domains of CAD from GI# 17366834 (SEQ ID NO:12) are located at approximately amino acid residues 38 to 121, 137 to 227, 241 to 337, 353 to 451, 465 to 552, 566 to 662, 676 to 769, 783 to 879, 895 to 986, 1000 to 1091, 1107 to 1199, 1214 to 1304, 1318 to 1409, 1424 to 1518, 1533 to 1625, 1639 to 1735, 1750 to 1842, 1856 to 1947, 1964 to 2060, 2074 to 2165, 2179 to 2284, 2301 to 2393, 2407 to 2500, 2514 to 2602, 2618 to 2711, 2733 to 2828, and 2851 to 2951 (PFAM 00028). Likewise, the cadherin domains of GI# 4885229 (SEQ ID NO:14) are located at approximately amino acid residues 39 to 140, 154 to 248, 372 to 454, 468 to 560, 574 to 664, 722 to 813, 827 to 918, 932 to 1023, 1039 to 1130, 1144 to 1236, 1250 to 1346, 1363 to 1447, 1461 to 1553, 1567 to 1661, 1675 to 1759, 1773 to 1871, 1887 to 1973, 1987 to 2073, 2089 to 2178, 2190 to 2277, 2291 to 2384, 2398 to 2486, 2500 to 2590, 2604 to 2696, 2710 to 2802, 2816 to 2911, 2925 to 3016, 3030 to 3118, 3132 to 3223, 3237 to 3328, 3342 to 3433, 3447 to 3538, and 3553 to 3634; the cadherin domains of GI# 7407144 (SEQ ID NO:15) are located at approximately amino acid residues 38 to 139, 153 to 247, 367 to 449, 463 to 553, 569 to 659, 720 to 811, 825 to 916, 930 to 1019, 1037 to 1128, 1142 to 1233, 1247 to 1337, 1354 to 1438, 1453 to 1546, 1560 to 1651, 1665 to 1749, 1763 to 1861, 1877 to 1959, 1973 to 2061, 2075 to 2164, 2176 to 2263, 2277 to 2370, 2384 to 2472, 2486 to 2576, 2590 to 2682, 2696 to 2786, 2802 to 2897, 2911 to 3002, 3016 to 3104, 3119 to 3209, 3223 to 3312, 3326 to 3417, 3431 to 3522, and 3536 to 3620; and the cadherin domains of GI# 16933557 (SEQ ID NO:16) are located at approximately amino acid residues 47 to 134, 148 to 246, 260 to 353, 371 to 463, 478 to 569, 583 to 676, 690 to 781, 795 to 885, 899 to 989, 1005 to 1096, 1110 to 1202, 1222 to 1312, 1337 to 1427, 1441 to 1537, 1550 to 1640, 1654 to 1742, 1756 to 1846, 1860 to 1951, 1974 to 2059, 2073 to 2162, 2176 to 2268, 2281 to 2367, 2381 to 2473, 2487 to 2593, 2607 to 2697, 2711 to 2804, and 2818 to 2923. [0118]
Further, GI#s 17366834 (SEQ ID NO:12), 4885229 (SEQ ID NO:14), and 7407144 (SEQ ID NO:15) each have one transmembrane domain with start and end amino acids of 3068 to 3090,4181 to 4203, and 4049 to 4071, respectively. CAD protein of GI#16933557 (SQE ID NO:???) has two transmembrane domains with start and end amino acids of 20 to 42 and 2939 to 2961. [0119]
II. High-Throughput in vitro Fluorescence Polarization Assay [0120]
Fluorescently-labeled CAD 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 CAD activity. [0121]
III. High-Throughput in vitro Binding Assay. [0122]
[0123] ³³P-labeled CAD peptide is added in an assay buffer (100 mM KCl, 20 mM HEPES pH 7.6, 1 mM MgCl₂, 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 p53 modulating agents.
IV. Immunoprecipitations and Immunoblotting [0124]
For coprecipitation of transfected proteins, 3×10[0125] ⁶appropriate recombinant cells containing the CAD 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.
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). [0126]
V. Expression Analysis [0127]
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, and Ambion. [0128]
TaqMan analysis was used to assess expression levels of the disclosed genes in various samples. [0129]
RNA was extracted from each tissue sample using Qiagen (Valencia, Calif.) RNeasy kits, following manufacturer'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., http://www.appliedbiosystems.com/). [0130]
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. [0131]
Taqman reactions were carried out following manufacturer'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). [0132]
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)>2×STDEV(all normal samples)). [0133]

Results are shown in Table 1. Data presented in bold indicate that greater than 50% of tested tumor samples of the tissue type indicated in row 1 exhibited over expression of the gene listed in column 1, relative to normal samples. Underlined data indicates that between 25% to 49% of tested tumor samples exhibited over expression. 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


	breast	.	.	colon	.	.	kidney	.	.	lung	.	.	ovary

GI#12060936 (SEQ ID NO:1)	0	3	.	1	26	.	10	19	.	2	14	.	1	4
GI#1107686 (SEQ ID NO:5)	1	3	.	8	26	.	6	19	.	8	14	.	1	4
GI#7407143 (SEQ ID NO:6)	1	3	.	10	26	.	2	19	.	7	14	.	2	4

[0135]
1 16 1 10065 DNA Homo sapiens 1 atggggcgcc atgttgccac cagctgccac gtggcctggc ttttggtgct gatctctgga 60 tgctggggcc aggtgaaccg gctgcccttc ttcaccaacc acttctttga tacatacctg 120 ctgatcagcg aggacacgcc tgtgggttct tctgtgaccc agttgctggc ccaagacatg 180 gacaatgacc ccctggtgtt tggcgtgtct ggggaggagg cctctcgctt ctttgcagtg 240 gagcctgaca ctggcgtggt gtggctccgg cagccactgg acagagagac caagtcagag 300 ttcaccgtgg agttctctgt cagcgaccac cagggggtga tcacacggaa ggtgaacatc 360 caggttgggg atgtgaatga caacgcgccc acatttcaca atcagcccta cagcgtccgc 420 atccctgaga atacaccagt ggggacgccc atcttcatcg tgaatgccac agaccccgac 480 ttgggggcag ggggcagcgt cctctactcc ttccagcccc cctcccaatt cttcgccatt 540 gacagcgccc gcggtatcgt cacagtgatc cgggagctgg actacgagac cacacaggcc 600 taccagctca cggtcaacgc cacagatcaa gacaagacca ggcctctgtc caccctggcc 660 aacttggcca tcatcatcac agatgtccag gacatggacc ccatcttcat caacctgcct 720 tacagcacca acatctacga gcattctcct ccgggcacga cggtgcgcat catcaccgcc 780 atagaccagg ataaaggacg tccccggggc attggctaca ccatcgtttc agggaatacc 840 aacagcatct ttgccctgga ctacatcagc ggagtgctga ccttgaatgg cctgctggac 900 cgggagaacc ccctgtacag ccatggcttc atcctgactg tgaagggcac ggagctgaac 960 gatgaccgca ccccatctga cgctacagtc accacgacct tcaatatcct ggttattgac 1020 atcaatgaca atgccccgga gttcaacagc tccgagtaca gcgtggccat cactgagctg 1080 gcacaggtcg gctttgccct tccactcttc atccaggtgg tggacaagga tgagaatttg 1140 ggcctgaaca gcatgtttga ggtgtacttg gtggggaaca actcccacca cttcatcatc 1200 tccccgacct ccgtccaggg gaaggcggac attcgtattc gggtggccat cccactggac 1260 tacgagaccg tggaccgcta cgactttgat ctctttgcca atgagagtgt gcctgaccat 1320 gtgggctatg ccaaggtgaa gatcactctc atcaatgaaa atgacaaccg gcccatcttc 1380 agccagccac tgtacaacat cagcctgtac gagaacgtca ccgtggggac ctctgtgctg 1440 acagtcctgg caactgacaa tgatgcaggc acctttgggg aagtcagcta cttcttcagt 1500 gatgaccctg acaggttctc gctggacaag gacacgggac tcatcatgct gattgccagg 1560 ctggactatg agctcatcca gcgcttcacc ctgacgatca ttgcccggga cgggggcggc 1620 gaggagacca caggccgggt caggatcaat gtgttggatg tcaacgacaa cgtgcccacc 1680 ttccagaagg atgcctacgt gggtgctctg cgggagaacg agccttctgt cacacagctg 1740 gtgcggctcc gggcaacaga tgaagactcc cctcccaaca accagatcac ctacagcatt 1800 gtcagtgcat ctgcctttgg cagctacttc gacatcagcc tgtacgaggg ctatggagtg 1860 atcagcgtca gtcgccccct ggattatgaa cagatatcca atgggctgat ttatctgacg 1920 gtcatggcca tggatgctgg caacccccct ctcaacagca ccgtccctgt caccatcgag 1980 gtgtttgatg agaatgacaa ccctcccacc ttcagcaagc ccgcctactt cgtctccgtg 2040 gtggagaaca tcatggcagg agccacggtg ctgttcctga atgccacaga cctggaccgc 2100 tcccgggagt acggccagga gtccatcatc tactccttgg aaggctccac ccagtttcgg 2160 atcaatgccc gctcagggga aatcaccacc acgtctctgc ttgaccgaga gaccaagtct 2220 gaatacatcc tcatcgttcg cgcagtggac gggggtgtgg gccacaacca gaaaactggc 2280 atcgccaccg taaacatcac cctcctggac atcaacgaca accaccccac gtggaaggac 2340 gcaccctact acatcaacct ggtggagatg acccctccag actctgatgt gaccacggtg 2400 gtggctgttg acccagacct gggggagaat ggcaccctgg tgtacagcat ccagccaccc 2460 aacaagttct acagcctcaa cagcaccacg ggcaagatcc gcaccaccca cgccatgctg 2520 gaccgggaga accccgaccc ccatgaggcc gagctgatgc gcaaaatcgt cgtctctgtt 2580 actgactgtg gcaggccccc tctgaaagcc accagcagtg ccacagtgtt tgtgaacctc 2640 ttggatctca atgacaatga ccccaccttt cagaacctgc cttttgtggc cgaggtgctt 2700 gaaggcatcc cggcgggggt ctccatctac caagtggtgg ccatcgacct cgatgagggc 2760 ctgaacggcc tggtgtccta ccgcatgccg gtgggcatgc cccgcatgga cttcctcatc 2820 aacagcagca gcggcgtggt ggtcaccacc accgagctgg accgcgagcg catcgcggag 2880 taccagctgc gggtggtggc cagtgatgca ggcacgccca ccaagagctc caccagcacg 2940 ctcaccatcc atgtgctgga tgtgaacgac gagacgccca ccttcttccc ggccgtgtac 3000 aatgtgtctg tgtccgagga cgtgccacgc gagttccggg tggtctggct gaactgcacg 3060 gacaacgacg tgggcctcaa tgcagagctc agctacttca tcacaggtgg caacgtggat 3120 gggaagttca gcgtgggtta ccgcgatgcc gttgtgagaa ccgtggtggg cctggaccgg 3180 gagaccacag ccgcctacat gctcatcctg gaggccatcg acaacggccc tgtagggaag 3240 cgacacacgg gcacagccac cgtgttcgtc actgtcctgg atgtgaatga caaccggccc 3300 atctttctgc agagcagcta tgaggccagc gtccctgagg acatccctga aggccacagc 3360 atcttgcagc tgaaagccac ggacgcagat gagggcgagt ttgggcgtgt gtggtaccgc 3420 atcctccatg gtaaccatgg caacaacttc cggatccatg tcagcaatgg gctcctgatg 3480 cgagggcccc ggcccctgga ccgggagcgg aactcatccc acgtgctgat agtggaggcc 3540 tacaaccacg acctgggccc catgcggagc tccgtcaggg tgattgtgta cgtggaggac 3600 atcaacgatg aggcccccgt gttcacacag cagcagtaca gccgtctggg gcttcgagag 3660 accgcaggca ttggaacgtc agtcatcgtg gtccaagcca cagaccgaga ctctggggat 3720 ggtggcctgg tgaactaccg catcctgtcg ggcgcagagg ggaagtttga gattgacgag 3780 agcacagggc ttatcatcac cgtgaattac ctggactacg agaccaagac cagctacatg 3840 atgaatgtgt cggccactga ccaggccccg cccttcaacc agggcttctg cagcgtctac 3900 atcactctgc tcaacgagct ggacgaggcc gtgcagttct ccaatgcctc atacgaggct 3960 gccatcctgg agaatctggc actgggtact gagattgtgc gggtccaggc ctactccatc 4020 gacaacctca accaaatcac gtaccgcttc gacgcctaca ccagcaccca ggccaaagcc 4080 ctcttcaaga tagacgccat cacgggtgtg atcacagtcc agggcctggt ggaccgtgag 4140 aagggcgact tctatacctt gacagtggtg gcagatgacg gcggccccaa ggtggactcc 4200 accgtgaagg tctacatcac tgtgctggac gagaatgaca acagcccccg gtttgacttc 4260 acctccgact cggcggtcag catacccgag gactgccctg tgggccagcg agtggctact 4320 gtcaaggcct gggaccctga tgctggcagc aatgggcagg tggtcttctc cctggcctct 4380 ggcaacatcg cgggggcctt tgagatcgtc accaccaatg actccattgg cgaagtgttt 4440 gtggccaggc ccctggacag agaagagctg gatcactaca tcctccaggt tgtggcttct 4500 gaccgaggca cccctccacg gaagaaggac cacatcctgc aggtgaccat cctggacatc 4560 aatgacaacc ctccagtcat cgagagcccc tttggataca atgtcagtgt gaatgagaac 4620 gtgggtggag gtactgctgt ggtccaggtg agagccactg accgtgacat cgggatcaac 4680 agtgttctgt cctactacat caccgagggc aacaaggaca tgaccttccg catggaccgc 4740 atcagcggtg agatcgccac acggcctgcc ccgcctgacc gcgagcgcca gagcttctac 4800 cacctggtgg ccactgtgga ggacgagggc accccaaccc tgtcggccac cacgcacgtg 4860 tacgtgacca ttgtggatga gaatgataac gcgcccatgt tccagcagcc ccactatgag 4920 gtgctgctgg atgagggccc agacacgctc aacaccagcc tcatcaccat ccaggcactg 4980 gacctggatg agggtcccaa cggcacagtc acctatgcca tcgtcgcagg caacatcgtc 5040 aacaccttcc gcatcgacag acacatgggt gtcatcactg ctgccaaaga gctggactac 5100 gagatcagcc acggccgcta caccctgatc gtcactgcca cagaccagtg ccccatctta 5160 tcccaccgcc tcacctctac caccacggtg cttgtgaatg tgaatgacat caacgacaat 5220 gtgcctacct tcccccggga ctatgaggga ccatttgaag tcactgaggg ccagccgggg 5280 cccagagtgt ggaccttcct ggcccatgac cgagactcag gacccaacgg gcaggtggag 5340 tacagcatca tggatggaga ccctctgggg gagtttgtga tctctcctgt ggagggggtg 5400 ctaagggtcc ggaaggacgt ggagctggac cgggagacca tcgccttcta caacctgacc 5460 atctgtgccc gtgaccgggg gatgccccca ctcagctcca caatgctggt ggggatccgg 5520 gtgctggaca tcaacgacaa cgaccctgtg ctgctgaacc tgcccatgaa catcaccatc 5580 agcgagaaca gccctgtctc cagctttgtc gcccatgtcc tggccagtga cgctgacagt 5640 ggctgcaatg cacgcctcac cttcaacatc actgcgggca accgcgagcg ggccttcttc 5700 atcaatgcca cgacagggat cgtcactgtg aaccggcccc tggaccgcga gcggatccca 5760 gagtacaagc tgaccatttc tgtgaaggac aacccggaga atccacgcat agccaggagg 5820 gattatgact tgcttctgat cttcctttct gatgagaatg acaaccaccc cctcttcact 5880 aaaagcacct accaggcaga ggtgatggaa aactctcccg ctggcacccc tctcacggtg 5940 ctcaatgggc ccatcctggc cctggatgca gaccaagaca tctacgccgt ggtgacctac 6000 cagctgctgg gtgcccagag tggcctcttt gacatcaaca gcagcaccgg tgtggtgacc 6060 gtgaggtcag gtgtcatcat tgaccgggag gcattctcgc cacccatcct ggagctgctg 6120 ctgctggctg aggacatcgg gctgctcaac agcacggccc acctgctcat caccatcctg 6180 gatgacaatg acaaccggcc cacctttagc cctgccaccc tcactgtcca tctgctagag 6240 aactgcccgc ctggattctc agtccttcaa gtcacagcca cagatgagga cagtggcctc 6300 aatggggagc tggtctaccg aatagaagct ggggctcagg accgcttcct cattcatctg 6360 gtcaccgggg tcatccgtgt tggtaatgcc accatcgaca gagaggagca ggagtcctac 6420 aggctaacgg tggtggccac cgaccggggc accgttcctc tctcgggcac agccattgtc 6480 accattctga tcgatgacat caatgactcc cgccccgagt tcctcaaccc catccagaca 6540 gtgagcgtgc tggagtcggc tgagccaggc actgtcattg ccaatatcac ggccattgac 6600 cacgacctca acccaaagct agagtaccac attgtcggca ttgtggccaa ggacgacact 6660 gatcgcctgg tgcccaacca ggaggacgcc tttgctgtga atatcaacac aggatctgta 6720 atggtgaagt cccccatgaa tcgggagctg gttgccacct atgaggtcac tctctcagtg 6780 attgacaatg ccagcgacct accagagcgc tctgtcagtg tgccaaatgc caagctgact 6840 gtcaacgtcc tggacgtcaa tgacaatacg ccccagttca agccctttgg gatcacctac 6900 tacatggagc ggatcctgga gggggccacc cctgggacca cactcattgc tgtggcagcc 6960 gtggaccctg acaagggcct taatgggctg gtcacctaca ccctgctgga cctggtgccc 7020 ccagggtatg tccagctgga ggactcctcg gcagggaagg tcattgccaa ccggacagtg 7080 gactacgagg aggtgcactg gctcaacttt accgtgaggg cctcagacaa cgggtccccg 7140 ccccgggcag ctgagatccc tgtctacctg gaaatcgtgg acatcaatga caacaacccc 7200 atctttgacc agccctccta ccaggaggct gtctttgagg atgtgcctgt gggcacaatc 7260 atcctgacag tcactgccac tgatgctgac tcaggcaact ttgcactcat tgagtacagc 7320 cttggagatg gagagagcaa gtttgccatc aaccccacca cgggtgacat ctatgtgctg 7380 tcttctctgg accgggagaa gaaggaccac tatatcctga ctgccttggc caaagacaac 7440 cctggggatg tagccagcaa ccgtcgcgaa aattcagtgc aggtggtgat ccaagtgctg 7500 gatgtcaatg actgccggcc acagttctcc aagccccagt tcagcacaag cgtgtatgag 7560 aatgagccgg cgggcacctc ggtcatcacc atgatggcca ctgaccagga tgaaggtccc 7620 aatggagagt tgacctactc acttgagggc cctggcgtgg aggccttcca tgtggacatg 7680 gactcgggct tggtgaccac acagcggcca ctgcagtcct acgagaagtt cagtctgacc 7740 gtggtggcca cagatggtgg agagccccca ctctggggca ccaccatgct cctggtggag 7800 gtcatcgacg tcaatgacaa ccgccctgtc tttgtgcgcc cacccaacgg caccatcctc 7860 cacatcagag aggagatccc gctgcgctcc aacgtgtacg aggtctacgc cacggacaag 7920 gatgagggcc tcaacggggc ggtgcgctac agcttcctga agactgcggg caaccgggac 7980 tgggagttct tcatcatcga cccaatcagc ggcctcatcc agactgctca gcgcctggac 8040 cgcgagtcgc aggcggtgta cagcctcatc ttggtggcca gcgacctggg ccagccagtg 8100 ccatacgaga ctatgcagcc gctgcaggtg gccctggagg acatcgatga caacgaaccc 8160 cttttcgtga ggcctccaaa aggcagcccc cagtaccagc tgctgacagt gcctgagcac 8220 tcaccacgcg gcaccctcgt gggcaacgtg acaggcgcag tggatgcaga tgagggcccc 8280 aacgcgatcg tgtactactt catcgcagcc ggcaacgaag agaagaactt ccatctgcag 8340 cccgatgggt gtctgctggt gctgcgggac ctggaccggg agcgagaagc catcttctcc 8400 ttcatcgtca aggcctccag caatcgcagc tggacacctc cccgtggacc ctccccaacc 8460 ctcgacctgg ttgctgacct cacactgcag gaggtgcgcg ttgtgctaga ggacatcaac 8520 gaccagccac cacgcttcac caaggctgag tacactgcag gggtggccac cgacgccaag 8580 gtgggctcag agttgatcca ggtgctggcc ctggatgcag acattggcaa caacagcctt 8640 gtcttctaca gcattctggc catccactac ttccgggccc ttgccaacga ctctgaagat 8700 gtgggccagg tcttcaccat ggggagcatg gacggcattc tgcgcacctt cgacctcttc 8760 atggcctaca gccccggcta cttcgtggtg gacattgtgg cccgagacct ggcaggccac 8820 aacgacacgg ccatcatcgg catctacatc ctgagggacg accagcgcgt caagatcgtc 8880 attaacgaga tccccgaccg tgtgcgcggc ttcgaggagg agttcatcca cctgctctcc 8940 aacatcactg gggccattgt caatactgac aatgtgcagt tccatgtgga caagaagggc 9000 cgggtgaact ttgcgcagac agaactgctt atccacgtgg tgaaccgcga taccaaccgc 9060 atcctggacg tggaccgggt gatccagatg atcgatgaga acaaggagca gctacggaat 9120 cttttccgga actacaacgt cctggacgtg cagcctgcca tctctgtccg gctgccggat 9180 gacatgtctg ccctgcagat ggcgatcatc gtcctggcta tcctcctgtt cctggccgcc 9240 atgctctttg tcctcatgaa ctggtactac aggactgtac acaagaggaa gctcaaggcc 9300 attgtggctg gctcagctgg gaatcgtggc ttcatcgaca tcatggacat gcctaacacc 9360 aacaagtact cctttgatgg agccaaccct gtgtggctgg atcccttctg tcggaacctg 9420 gagctggccg cccaggcgga gcatgaggat gacctaccgg agaacctgag tgagatcgcc 9480 gacctgtgga acagccccac gcgcacccat ggaacttttg ggcgtgagcc agcagctgtc 9540 aagcctgatg atgaccgata cctgcgggct gccatccagg agtatgacaa cattgccaag 9600 ctgggccaga tcattcgtga ggggccaatc aagggctcgc tgctgaaggt ggtcctggag 9660 gattacctgc ggctcaaaaa gctctttgca cagcggatgg tgcaaaaagc ctcctcctgc 9720 cactcctcca tctctgagct gatacagact gagctggacg aggagccagg agaccacagc 9780 ccagggcagg gtagcctgcg cttccgccac aagccaccag tggagctcaa ggggcccgat 9840 gggatccatg tggtgcacgg cagcacgggc acgctgctgg ccaccgacct caacagcctg 9900 cccgaggaag accagaaggg cctgggccgc tcgctggaga cgctgaccgc tgccgaggcc 9960 actgccttcg agcgcaacgc ccgcacagaa tccgccaaat ccacacccct gcacaaactt 10020 cgcgacgtga tcatggagac ccccctggag atcacagagc tgtga 10065 2 11073 DNA Homo sapiens 2 gcggcggcgg cggctcggga gagagggacg cgggctgcag gcgcgatgct tggctagagg 60 acgcgtccga cggcggccgg acgctgaggt ggtcggggct agtcagcccg gcctgggcat 120 ggagcgcggg gtggcagagc ctctggacgt ttggggcgcg cccagtccga gcccccggcg 180 cgcctgaagt tgcgagcggc gagcggcgag cggcgagcgg cccgcggaga cccaggagct 240 gccggcacgc cgcggatgag ccttcgcgcc ggcgggaaga cgcggcggtg gccagggcca 300 gagcaggcgg cccgcggggg ccgatccggc ggagagcaga gcccgaggcg aggcgaggcg 360 cggcgccgct gcacacacgc acacggagcc atggggcgcc atgttgccac cagctgccac 420 gtggcctggc ttttggtgct gatctctgga tgctggggcc aggtgaaccg gctgcccttc 480 ttcaccaacc acttctttga tacatacctg ctgatcagcg aggacacgcc tgtgggttct 540 tctgtgaccc agttgctggc ccaagacatg gacaatgacc ccctggtgtt tggcgtgtct 600 ggggaggagg cctctcgctt ctttgcagtg gagcctgaca ctggcgtggt gtggctccgg 660 cagccactgg acagagagac caagtcagag ttcaccgtgg agttctctgt cagcgaccac 720 cagggggtga tcacacggaa ggtgaacatc caggttgggg atgtgaatga caacgcgccc 780 acatttcaca atcagcccta cagcgtccgc atccctgaga atacaccagt ggggacgccc 840 atcttcatcg tgaatgccac agaccccgac ttgggggcag ggggcagcgt cctctactcc 900 ttccagcccc cctcccaatt cttcgccatt gacagcgccc gcggtatcgt cacagtgatc 960 cgggagctgg actacgagac cacacaggcc taccagctca cggtcaacgc cacagatcaa 1020 gacaagacca ggcctctgtc caccctggcc aacttggcca tcatcatcac agatgtccag 1080 gacatggacc ccatcttcat caacctgcct tacagcacca acatctacga gcattctcct 1140 ccgggcacga cggtgcgcat catcaccgcc atagaccagg ataaaggacg tccccggggc 1200 attggctaca ccatcgtttc agggaatacc aacagcatct ttgccctgga ctacatcagc 1260 ggagtgctga ccttgaatgg cctgctggac cgggagaacc ccctgtacag ccatggcttc 1320 atcctgactg tgaagggcac ggagctgaac gatgaccgca ccccatctga cgctacagtc 1380 accacgacct tcaatatcct ggttattgac atcaatgaca atgccccgga gttcaacagc 1440 tccgagtaca gcgtggccat cactgagctg gcacaggtcg gctttgccct tccactcttc 1500 atccaggtgg tggacaagga tgagaatttg ggcctgaaca gcatgtttga ggtgtacttg 1560 gtggggaaca actcccacca cttcatcatc tccccgacct ccgtccaggg gaaggcggac 1620 attcgtattc gggtggccat cccactggac tacgagaccg tggaccgcta cgactttgat 1680 ctctttgcca atgagagtgt gcctgaccat gtgggctatg ccaaggtgaa gatcactctc 1740 atcaatgaaa atgacaaccg gcccatcttc agccagccac tgtacaacat cagcctgtac 1800 gagaacgtca ccgtggggac ctctgtgctg acagtcctgg caactgacaa tgatgcaggc 1860 acctttgggg aagtcagcta cttcttcagt gatgaccctg acaggttctc gctggacaag 1920 gacacgggac tcatcatgct gattgccagg ctggactatg agctcatcca gcgcttcacc 1980 ctgacgatca ttgcccggga cgggggcggc gaggagacca caggccgggt caggatcaat 2040 gtgttggatg tcaacgacaa cgtgcccacc ttccagaagg atgcctacgt gggtgctctg 2100 cgggagaacg agccttctgt cacacagctg gtgcggctcc gggcaacaga tgaagactcc 2160 cctcccaaca accagatcac ctacagcatt gtcagtgcat ctgcctttgg cagctacttc 2220 gacatcagcc tgtacgaggg ctatggagtg atcagcgtca gtcgccccct ggattatgaa 2280 cagatatcca atgggctgat ttatctgacg gtcatggcca tggatgctgg caacccccct 2340 ctcaacagca ccgtccctgt caccatcgag gtgtttgatg agaatgacaa ccctcccacc 2400 ttcagcaagc ccgcctactt cgtctccgtg gtggagaaca tcatggcagg agccacggtg 2460 ctgttcctga atgccacaga cctggaccgc tcccgggagt acggccagga gtccatcatc 2520 tactccttgg aaggctccac ccagtttcgg atcaatgccc gctcagggga aatcaccacc 2580 acgtctctgc ttgaccgaga gaccaagtct gaatacatcc tcatcgttcg cgcagtggac 2640 gggggtgtgg gccacaacca gaaaactggc atcgccaccg taaacatcac cctcctggac 2700 atcaatgaca accaccccac gtggaaggac gcaccctact acatcaacct ggtggagatg 2760 acccctccag actctgatgt gaccacggtg gtggctgttg acccagacct gggggagaat 2820 ggcaccctgg tgtacagcat ccagccaccc aacaagttct acagcctcaa cagcaccacg 2880 ggcaagatcc gcaccaccca cgccatgctg gaccgggaga accccgaccc ccatgaggcc 2940 gagctgatgc gcaaaatcgt cgtctctgtt actgactgtg gcaggccccc tctgaaagcc 3000 accagcagtg ccacagtgtt tgtgaacctc ttggatctca atgacaatga ccccaccttt 3060 cagaacctgc cttttgtggc cgaggtgctt gaaggcatcc cggcgggggt ctccatctac 3120 caagtggtgg ccatcgacct cgatgagggc ctgaacggcc tggtgtccta ccgcatgccg 3180 gtgggcatgc cccgcatgga cttcctcatc aacagcagca gcggcgtggt ggtcaccacc 3240 accgagctgg accgcgagcg catcgcggag taccagctgc gggtggtggc cagtgatgca 3300 ggcacgccca ccaagagctc caccagcacg ctcaccatcc atgtgctgga tgtgaacgac 3360 gagacgccca ccttcttccc ggccgtgtac aatgtgtctg tgtccgagga cgtgccacgc 3420 gagttccggg tggtctggct gaactgcacg gacaacgacg tgggcctcaa tgcagagctc 3480 agctacttca tcacaggtgg caacgtggat gggaagttca gcgtgggtta ccgcgatgcc 3540 gttgtgagaa ccgtggtggg cctggaccgg gagaccacag ccgcctacat gctcatcctg 3600 gaggccatcg acaacggccc tgtagggaag cgacacacgg gcacagccac cgtgttcgtc 3660 actgtcctgg atgtgaatga caaccggccc atctttctgc agagcagcta tgaggccagc 3720 gtccctgagg acatccctga aggccacagc atcttgcagc tgaaagccac ggacgcagat 3780 gagggcgagt ttgggcgtgt gtggtaccgc atcctccatg gtaaccatgg caacaacttc 3840 cggatccatg tcagcaatgg gctcctgatg cgagggcccc ggcccctgga ccgggagcgg 3900 aactcatccc acgtgctgat agtggaggcc tacaaccacg acctgggccc catgcggagc 3960 tccgtcaggg tgattgtgta cgtggaggac atcaacgatg aggcccccgt gttcacacag 4020 cagcagtaca gccgtctggg gcttcgagag accgcaggca ttggaacgtc agtcatcgtg 4080 gtccaagcca cagaccgaga ctctggggat ggtggcctgg tgaactaccg catcctgtcg 4140 ggcgcagagg ggaagtttga gattgacgag agcacagggc ttatcatcac cgtgaattac 4200 ctggactacg agaccaagac cagctacatg atgaatgtgt cggccactga ccaggccccg 4260 cccttcaacc agggcttctg cagcgtctac atcactctgc tcaacgagct ggacgaggcc 4320 gtgcagttct ccaatgcctc atacgaggct gccatcctgg agaatctggc actgggtact 4380 gagattgtgc gggtccaggc ctactccatc gacaacctca accaaatcac gtaccgcttc 4440 aacgcctaca ccagcaccca ggccaaagcc ctcttcaaga tagacgccat cacgggtgtg 4500 atcacagtcc agggcctggt ggaccgtgag aagggcgact tctatacctt gacagtggtg 4560 gcagatgacg gcggccccaa ggtggactcc accgtgaagg tctacatcac tgtgctggac 4620 gagaatgaca acagcccccg gtttgacttc acctccgact cggcggtcag catacccgag 4680 gactgccctg tgggccagcg agtggctact gtcaaggcct gggaccctga tgctggcagc 4740 aatgggcagg tggtcttctc cctggcctct ggcaacatcg cgggggcctt tgagatcgtc 4800 accaccaatg actccattgg cgaagtgttt gtggccaggc ccctggacag agaagagctg 4860 gatcactaca tcctccaggt tgtggcttct gaccgaggca cccctccacg gaagaaggac 4920 cacatcctgc aggtgaccat cctggacatc aatgacaacc ctccagtcat cgagagcccc 4980 tttggataca atgtcagtgt gaatgagaac gtgggtggag gtactgctgt ggtccaggtg 5040 agagccactg accgtgacat cgggatcaac agtgttctgt cctactacat caccgagggc 5100 aacaaggaca tggccttccg catggaccgc atcagcggtg agatcgccac acggcctgcc 5160 ccgcctgacc gcgagcgcca gagcttctac cacctggtgg ccactgtgga ggacgagggc 5220 accccaaccc tgtcggccac cacgcacgtg tacgtgacca ttgtggatga gaatgataac 5280 gcgcccatgt tccagcagcc ccactatgag gtgctgctgg atgagggccc agacacgctc 5340 aacaccagcc tcatcaccat ccaggcactg gacctggatg agggtcccaa cggcacagtc 5400 acctatgcca tcgtcgcagg caacatcgtc aacaccttcc gcatcgacag acacatgggt 5460 gtcatcactg ctgccaaaga gctggactac gagatcagcc acggccgcta caccctgatc 5520 gtcactgcca cagaccagtg ccccatctta tcccaccgcc tcacctctac caccacggtg 5580 cttgtgaatg tgaatgacat caacgacaat gtgcctacct tcccccggga ctatgaggga 5640 ccatttgaag tcactgaggg ccagccgggg cccagagtgt ggaccttcct ggcccatgac 5700 cgagactcag gacccaacgg gcaggtggag tacagcatca tggatggaga ccctctgggt 5760 gagtttgtga tctctcctgt ggagggggtg ctaagggtcc ggaaggacgt ggagctggac 5820 cgggagacca tcgccttcta caacctgacc atctgtgccc gtgaccgggg gatgccccca 5880 ctcagctcca caatgctggt ggggatccgg gtgctggaca tcaacgacaa cgaccctgtg 5940 ctgctgaacc tgcccatgaa catcaccatc agcgagaaca gccctgtctc cagctttgtc 6000 gcccatgtcc tggccagtga cgctgacagt ggctgcaatg cacgcctcac cttcaacatc 6060 actgcgggca accgcgagcg ggccttcttc atcaatgcca cgacagggat cgtcactgtg 6120 aaccggcccc tggaccgcga gcggatccca gagtacaagc tgaccatttc tgtgaaggac 6180 aacccggaga atccacgcat agccaggagg gattatgact tgcttctgat cttcctttct 6240 gatgagaatg acaaccaccc cctcttcact aaaagcacct accaggcaga ggtgatggaa 6300 aactctcccg ctggcacccc tctcacggtg ctcaatgggc ccatcctggc cctggatgca 6360 gaccaagaca tctacgccgt ggtgacctac cagctgctgg gtgcccagag tggcctcttt 6420 gacatcaaca gcagcaccgg tgtggtgacc gtgaggtcag gtgtcatcat tgaccgggag 6480 gcattctcgc cacccatcct ggagctgctg ctgctggctg aggacatcgg gctgctcaac 6540 agcacggccc acctgctcat caccatcctg gatgacaatg acaaccggcc cacctttagc 6600 cctgccaccc tcactgtcca tctgctagag aactgcccgc ctggattctc agtccttcaa 6660 gtcacagcca cagatgagga cagtggcctc aatggggagc tggtctaccg aatagaagct 6720 ggggctcagg accgcttcct cattcatctg gtcaccgggg tcatccgtgt tggtaatgcc 6780 accatcgaca gagaggagca ggagtcctac aggctaacgg tggtggccac cgaccggggc 6840 accgttcctc tctcgggcac agccattgtc accattctga tcgatgacat caatgactcc 6900 cgccccgagt tcctcaaccc catccagaca gtgagcgtgc tggagtcggc tgagccaggc 6960 actgtcattg ccaatatcac ggccattgac cacgacctca acccaaagct agagtaccac 7020 attgtcggca ttgtggccaa ggacgacact gatcgcctgg tgcccaacca ggaggacgcc 7080 tttgctgtga atatcaacac aggatctgta atggtgaagt cccccatgaa tcgggagctg 7140 gttgccacct atgaggtcac tctctcagtg attgacaatg ccagcgacct accagagcgc 7200 tctgtcagtg tgccaaatgc caagctgact gtcaacgtcc tggacgtcaa tgacaatacg 7260 ccccagttca agccctttgg gatcacctac tacatggagc ggatcctgga gggggccacc 7320 cctgggacca cactcattgc tgtggcagcc gtggaccctg acaagggcct taatgggctg 7380 gtcacctaca ccctgctgga cctggtgccc ccagggtatg tccagctgga ggactcctcg 7440 gcagggaagg tcattgccaa ccggacagtg gactacgagg aggtgcactg gctcaacttt 7500 accgtgaggg cctcagacaa cgggtccccg ccccgggcag ctgagatccc tgtctacctg 7560 gaaatcgtgg acatcaatga caacaacccc atctttgacc agccctccta ccaggaggct 7620 gtctttgagg atgtgcctgt gggcacaatc atcctgacag tcactgccac tgatgctgac 7680 tcaggcaact ttgcactcat tgagtacagc cttggagatg gagagagcaa gtttgccatc 7740 aaccccacca cgggtgacat ctatgtgctg tcttctctgg accgggagaa gaaggaccac 7800 tatatcctga ctgccttggc caaagacaac cctggggatg tagccagcaa ccgtcgcgaa 7860 aattcagtgc aggtggtgat ccaagtgctg gatgtcaatg actgccggcc acagttctcc 7920 aagccccagt tcagcacaag cgtgtatgag aatgagccgg cgggcacctc ggtcatcacc 7980 atgatggcca ctgaccagga tgaaggtccc aatggagagt tgacctactc acttgagggc 8040 cctggcgtgg aggccttcca tgtggacatg gactcgggct tggtgaccac acagcggcca 8100 ctgcagtcct acgagaagtt cagtctgacc gtggtggcca cagatggtgg agagccccca 8160 ctctggggca ccaccatgct cctggtggag gtcatcgacg tcaatgacaa ccgccctgtc 8220 tttgtgcgcc cacccaacgg caccatcctc cacatcagag aggagatccc gctgcgctcc 8280 aacgtgtacg aggtctacgc cacggacaag gatgagggcc tcaacggggc ggtgcgctac 8340 agcttcctga agactgcggg caaccgggac tgggagttct tcatcatcga cccaatcagc 8400 ggcctcatcc agactgctca gcgcctggac cgcgagtcgc aggcggtgta cagcctcatc 8460 ttggtggcca gcgacctggg ccagccagtg ccatacgaga ctatgcagcc gctgcaggtg 8520 gccctggagg acatcgatga caacgaaccc cttttcgtga ggcctccaaa aggcagcccc 8580 cagtaccagc tgctgacagt gcctgagcac tcaccacgcg gcaccctcgt gggcaacgtg 8640 acaggcgcag tggatgcaga tgagggcccc aacgcgatcg tgtactactt catcgcagcc 8700 ggcaacgaag agaagaactt ccatctgcag cccgatgggt gtctgctggt gctgcgggac 8760 ctggaccggg agcgagaagc catcttctcc ttcatcgtca aggcctccag caatcgcagc 8820 tggacacctc cccgtggacc ctccccaacc ctcgacctgg ttgctgacct cacactgcag 8880 gaggtgcgcg ttgtgctaga ggacatcaac gaccagccac cacgcttcac caaggctgag 8940 tacactgcag gggtggccac cgacgccaag gtgggctcag agttgatcca ggtgctggcc 9000 ctggatgcag acattggcaa caacagcctt gtcttctaca gcattctggc catccactac 9060 ttccgggccc ttgccaacga ctctgaagat gtgggccagg tcttcaccat ggggagcatg 9120 gacggcattc tgcgcacctt cgacctcttc atggcctaca gccccggcta cttcgtggtg 9180 gacattgtgg cccgagacct ggcaggccac aacgacacgg ccatcatcgg catctacatc 9240 ctgagggacg accagcgcgt caagatcgtc attaacgaga tccccgaccg tgtgcgcggc 9300 ttcgaggagg agttcatcca cctgctctcc aacatcactg gggccattgt caatactgac 9360 aatgtgcagt tccatgtgga caagaagggc cgggtgaact ttgcgcagac agaactgctt 9420 atccacgtgg tgaaccgcga taccaaccgc atcctggacg tggaccgggt gatccagatg 9480 atcgatgaga acaaggagca gctacggaat cttttccgga actacaacgt cctggacgtg 9540 cagcctgcca tctctgtccg gctgccggat gacatgtctg ccctgcagat ggcgatcatc 9600 gtcctggcta tcctcctgtt cctggccgcc atgctctttg tcctcatgaa ctggtactac 9660 aggactgtac acaagaggaa gctcaaggcc attgtggctg gctcagctgg gaatcgtggc 9720 ttcatcgaca tcatggacat gcctaacacc aacaagtact cctttgatgg agccaaccct 9780 gtgtggctgg atcccttctg tcggaacctg gagctggccg cccaggcgga gcatgaggat 9840 gacctaccgg agaacctgag tgagatcgcc gacctgtgga acagccccac gcgcacccag 9900 ggaacttttg ggcgtgagcc agcagctgtc aagcctgatg atgaccgata cctgcgggct 9960 gccatccagg agtatgacaa cattgccaag ctgggccaga tcattcgtga ggggccaatc 10020 aagggctcgc tgctgaaggt ggtcctggag gattacctgc ggctcaaaaa gctctttgca 10080 cagcggatgg tgcaaaaagc ctcctcctgc cactcctcca tctctgagct gatacagact 10140 gagctggacg aggagccagg agaccacagc ccagggcagg gtagcctgcg cttccgccac 10200 aagccaccag tggagctcaa ggggcccgat gggatccatg tggtgcacgg cagcacgggc 10260 acgctgctgg ccaccgacct caacagcctg cccgaggaag accagaaggg cctgggccgc 10320 tcgctggaga cgctgaccgc tgccgaggcc actgccttcg agcgcaacgc ccgcacagaa 10380 tccgccaaat ccacacccct gcacaaactt cgcgacgtga tcatggagac ccccctggag 10440 atcacagagc tgtgactaga cagggaagcc ttgtgggtgt gagcagcacc catccaccgt 10500 cccctcccag ggagcaaggg cagggacagg gccggtcggg ggggaccctc caaggccagg 10560 ccttggggac aaccttggct tggccctggc agcccgcatc agctgctcag atcccacttt 10620 tgccagacgc tcattcagca tctgacctct accttcataa gatctgttat ttttataaga 10680 aaaccaaaca aaaatgttaa gcatctaagg acaaggtaag gagggtcact ggggcccaag 10740 agtctgggga ccagcttggc tcaggctgag ctgaaagagg ccaaacaggc cctcctccct 10800 cccagctcca ccccgcaagc accatcccct ccggctaagc aggcgcaagg gaggcccagc 10860 gcggacatcc cctgctggcc ggacacccga ctccagtcca agtctcgcta catttccgcc 10920 acatccctct ctgctggacg tccaggtgga ggtggcatcc ccacgtggac aagaaagtca 10980 atgtcaatga acaagcattc tctccatttc actggcttcc caaatgtgtg cccagcttat 11040 aaacagaagt gactgatgtt ccctccggtt ttg 11073 3 2022 DNA Homo sapiens 3 gcggcggcgg cggctcggga gagagggacg cgggctgcag gcgcgatgct tggctagagg 60 acgcgtccga cggcggccgg acgctgaggt ggtcggggct agtcagcccg gcctgggcat 120 ggagcgcggg gtggcagagc ctctggacgt ttggggcgcg cccagtccga gcccccggcg 180 cgcctgaagt tgcgagcggc gagcggcgag cggcgagcgg cccgcggaga cccaggagct 240 gccggcacgc cgcggatgag ccttcgcgcc ggcgggaaga cgcggcggtg gccagggcca 300 gagcaggcgg cccgcggggg ccgatccggc ggagagcaga gcccgaggcg aggcgaggcg 360 cggcgccgct gcacacacgc acacggagcc atggggcgcc atgttgccac cagctgccac 420 gtggcctggc ttttggtgct gatctctgga tgctggggcc aggtgaaccg gctgcccttc 480 ttcaccaacc acttctttga tacatacctg ctgatcagcg aggacacgcc tgtgggttct 540 tctgtgaccc agttgctggc ccaagacatg gacaatgacc ccctggtgtt tggcgtgtct 600 ggggaggagg cctctcgctt ctttgcagtg gagcctgaca ctggcgtggt gtggctccgg 660 cagccactgg acagagagac caagtcagag ttcaccgtgg agttctctgt cagcgaccac 720 cagggggtga tcacacggaa ggtgaacatc caggttgggg atgtgaatga caacgcgccc 780 acatttcaca atcagcccta cagcgtccgc atccctgaga atacaccagt ggggacgccc 840 atcttcatcg tgaatgccac agaccccgac ttgggggcag ggggcagcgt cctctactcc 900 ttccagcccc cctcccaatt cttcgccatt gacagcgccc gcggtatcgt cacagtgatc 960 cgggagctgg actacgagac cacacaggcc taccagctca cggtcaacgc cacagatcaa 1020 gacaagacca ggcctctgtc caccctggcc aacttggcca tcatcatcac agatgtccag 1080 gacatggacc ccatcttcat caacctgcct tacagcacca acatctacga gcattctcct 1140 ccgggcacga cggtgcgcat catcaccgcc atagaccagg ataaaggacg tccccggggc 1200 attggctaca ccatcgtttc agggaatacc aacagcatct ttgccctgga ctacatcagc 1260 ggagtgctga ccttgaatgg cctgctggac cgggagaacc ccctgtacag ccatggcttc 1320 atcctgactg tgaagggcac ggagctgaac gatgaccgca ccccatctga cgctacagtc 1380 accacgacct tcaatatcct ggttattgac atcaatgaca atgccccgga gttcaacagc 1440 tccgagtaca gcgtggccat cactgagctg gcacaggtcg gctttgccct tccactcttc 1500 atccaggtgg tggacaagga tgagaatttg ggcctgaaca gcatgtttga ggtgtacttg 1560 gtggggaaca actcccacca cttcatcatc tccccgacct ccgtccaggg gaaggcggac 1620 attcgtattc gggtggccat cccactggac tacgagaccg tggaccgcta cgactttgat 1680 ctctttgcca atgagagtgt gcctgaccat gtgggctatg ccaaggtgaa gatcactctc 1740 atcaatgaaa atgacaaccg gcccatcttc agccagccac tgtacaacat cagcctgtac 1800 gagaacgtca ccgtggggac ctctgtgctg acagtcctgg tgagtccccg cttcactgca 1860 gggccactga gctctccagg gccgactgtg gtgaggcacc cagagggatt ttgtccaagg 1920 gacctcagca atcagggaag gaggcacccc caaatccctg agctgtgttt gttggtgtat 1980 taaataaagt ttttggactc ttaaaaaaaa aaaaaaaaaa aa 2022 4 10455 DNA Homo sapiens 4 gcggcggcgg cggctcggga gagagggacg cgggctgcag gcgcgatgct tggctagagg 60 acgcgtccga cggcggccgg acgctgaggt ggtcggggct agtcagcccg gcctgggcat 120 ggagcgcggg gtggcagagc ctctggacgt ttggggcgcg cccagtccga gcccccggcg 180 cgcctgaagt tgcgagcggc gagcggcgag cggcgagcgg cccgcggaga cccaggagct 240 gccggcacgc cgcggatgag ccttcgcgcc ggcgggaaga cgcggcggtg gccagggcca 300 gagcaggcgg cccgcggggg ccgatccggc ggagagcaga gcccgaggcg aggcgaggcg 360 cggcgccgct gcacacacgc acacggagcc atggggcgcc atgttgccac cagctgccac 420 gtggcctggc ttttggtgct gatctctgga tgctggggcc aggtgaaccg gctgcccttc 480 ttcaccaacc acttctttga tacatacctg ctgatcagcg aggacacgcc tgtgggttct 540 tctgtgaccc agttgctggc ccaagacatg gacaatgacc ccctggtgtt tggcgtgtct 600 ggggaggagg cctctcgctt ctttgcagtg gagcctgaca ctggcgtggt gtggctccgg 660 cagccactgg acagagagac caagtcagag ttcaccgtgg agttctctgt cagcgaccac 720 cagggggtga tcacacggaa ggtgaacatc caggttgggg atgtgaatga caacgcgccc 780 acatttcaca atcagcccta cagcgtccgc atccctgaga atacaccagt ggggacgccc 840 atcttcatcg tgaatgccac agaccccgac ttgggggcag ggggcagcgt cctctactcc 900 ttccagcccc cctcccaatt cttcgccatt gacagcgccc gcggtatcgt cacagtgatc 960 cgggagctgg actacgagac cacacaggcc taccagctca cggtcaacgc cacagatcaa 1020 gacaagacca ggcctctgtc caccctggcc aacttggcca tcatcatcac agatgtccag 1080 gacatggacc ccatcttcat caacctgcct tacagcacca acatctacga gcattctcct 1140 ccgggcacga cggtgcgcat catcaccgcc atagaccagg ataaaggacg tccccggggc 1200 attggctaca ccatcgtttc agggaatacc aacagcatct ttgccctgga ctacatcagc 1260 ggagtgctga ccttgaatgg cctgctggac cgggagaacc ccctgtacag ccatggcttc 1320 atcctgactg tgaagggcac ggagctgaac gatgaccgca ccccatctga cgctacagtc 1380 accacgacct tcaatatcct ggttattgac atcaatgaca atgccccgga gttcaacagc 1440 tccgagtaca gcgtggccat cactgagctg gcacaggtcg gctttgccct tccactcttc 1500 atccaggtgg tggacaagga tgagacccag ggcctgaaca gcatgtttga ggtgtacttg 1560 gtggggaaca actcccacca cttcatcatc tccccgacct ccgtccaggg gaaggcggac 1620 attcgtattc gggtggccat cccactggac tacgagaccg tggaccgcta cgactttgat 1680 ctctttgcca atgagagtgt gcctgaccat gtgggctatg ccaaggtgaa gatcactctc 1740 atcaatgaaa atgacaaccg gcccatcttc agccagccac tgtacaacat cagcctgtac 1800 gagaacgtca ccgtggggac ctctgtgctg acagtcctgg caactgacaa tgatgcagcc 1860 acctttgggg aagtcagcta cttcttcagt gatgaccctg acaggttctc gctggacaag 1920 gacacgggac tcatcatgct gattgccagg ctggactatg agctcatcca gcgcttcacc 1980 ctgacgatca ttgcccggga cgggggcggc gaggagacca caggccgggt caggatcaat 2040 gtgttggatg tcaacgacaa cgtgcccacc ttccagaagg atgcctacgt gggtgctctg 2100 cgggagaacg agccttctgt cacacagctg gtgcggctcc gggcaacaga tgaagactcc 2160 cctcccaaca accagatcac ctacagcatt gtcagtgcat ctgcctttgg cagctacttc 2220 gacatcagcc tgtacgaggg ctatggagtg atcagcgtca gtcgccccct ggattatgaa 2280 cagatatcca atgggctgat ttatctgacg gtcatggcca tggatgctgg caacccccct 2340 ctcaacagca ccgtccctgt caccatcgag gtgtttgatg agaatgacaa ccctcccacc 2400 ttcagcaagc ccgcctactt cgtctccgtg gtggagaaca tcatggcagg agccacggtg 2460 ctgttcctga atgccacaga cctggaccgc tcccgggagt acggccagga gtccatcatc 2520 tactccttgg aaggctccac ccagtttcgg atcaatgccc gctcagggga aatcaccacc 2580 acgtctctgc ttgaccgaga gaccaagtct gaatacatcc tcatcgttcg cgcagtggac 2640 gggggtgtgg gccacaacca gaaaactggc atcgccaccg taaacatcac cctcctggac 2700 atcaatgaca accaccccac gtggaaggac gcaccctact acatcaacct ggtggagatg 2760 acccctccag actctgatgt gaccacggtg gtggctgttg acccagacct gggggagaat 2820 ggcaccctgg tgtacagcat ccagccaccc aacaagttct acagcctcaa cagcaccacg 2880 ggcaagatcc gcaccaccca cgccatgctg gaccgggaga accccgaccc ccatgaggcc 2940 gagctgatgc gcaaaatcgt cgtctctgtt actgactgtg gcaggccccc tctgaaagcc 3000 accagcagtg ccacagtgtt tgtgaacctc ttggatctca atgacaatga ccccaccttt 3060 cagaacctgc cttttgtggc cgaggtgctt gaaggcatcc cggcgggggt ctccatctac 3120 caagtggtgg ccatcgacct cgatgagggc ctgaacggcc tggtgtccta ccgcatgccg 3180 gtgggcatgc cccgcatgga cttcctcatc aacagcagca gcggcgtggt ggtcaccacc 3240 accgagctgg accgcgagcg catcgcggag taccagctgc gggtggtggc cagtgatgca 3300 ggcacgccca ccaagagctc caccagcacg ctcaccatcc atgtgctgga tgtgaacgac 3360 gagacgccca ccttcttccc ggccgtgtac aatgtgtctg tgtccgagga cgtgccacgc 3420 gagttccggg tggtctggct gaactgcacg gacaacgacg tgggcctcaa tgcagagctc 3480 agctacttca tcacaggtgg caacgtggat gggaagttca gcgtgggtta ccgcgatgcc 3540 gttgtgagaa ccgtggtggg cctggaccgg gagaccacag ccgcctacat gctcatcctg 3600 gaggccatcg acaacggccc tgtagggaag cgacacacgg gcacagccac cgtgttcgtc 3660 actgtcctgg atgtgaatga caaccggccc atctttctgc agagcagcta tgaggccagc 3720 gtccctgagg acatccctga aggccacagc atcttgcagc tgaaagccac ggacgcagat 3780 gagggcgagt ttgggcgtgt gtggtaccgc atcctccatg gtaaccatgg caacaacttc 3840 cggatccatg tcagcaatgg gctcctgatg cgagggcccc ggcccctgga ccgggagcgg 3900 aactcatccc acgtgctgat agtggaggcc tacaaccacg acctgggccc catgcggagc 3960 tccgtcaggg tgattgtgta cgtggaggac atcaacgatg aggcccccgt gttcacacag 4020 cagcagtaca gccgtctggg gcttcgagag accgcaggca ttggaacgtc agtcatcgtg 4080 gtccaagcca cagaccgaga ctctggggat ggtggcctgg tgaactaccg catcctgtcg 4140 ggcgcagagg ggaagtttga gattgacgag agcacagggc ttatcatcac cgtgaattac 4200 ctggactacg agaccaagac cagctacatg atgaatgtgt cggccactga ccaggccccg 4260 cccttcaacc agggcttctg cagcgtctac atcactctgc tcaacgagct ggacgaggcc 4320 gtgcagttct ccaatgcctc atacgaggct gccatcctgg agaatctggc actgggtact 4380 gagattgtgc gggtccaggc ctactccatc gacaacctca accaaatcac gtaccgcttc 4440 aacgcctaca ccagcaccca ggccaaagcc ctcttcaaga tagacgccat cacgggtgtg 4500 atcacagtcc agggcctggt ggaccgtgag aagggcgact tctatacctt gacagtggtg 4560 gcagatgacg gcggccccaa ggtggactcc accgtgcagg tctacatcac tgtgctggac 4620 gagaatgaca acagcccccg gtttgacttc acctccgact cggcggtcag catacccgag 4680 gactgccctg tgggccagcg agtggctact gtcaaggcct gggaccctga tgctggcagc 4740 aatgggcagg tggtcttctc cctggcctct ggcaacatcg cgggggcctt tgagatcgtc 4800 accaccaatg actccattgg cgaagtgttt gtggccaggc ccctggacag agaagagctg 4860 gatcactaca tcctccaggt tgtggcttct gaccgaggca cccctccacg gaagaaggac 4920 cacatcctgc aggtgaccat cctggacatc aatgacaacc ctccagtcat cgagagcccc 4980 tttggataca atgtcagtgt gaatgagaac gtgggtggag gtactgctgt ggtccaggtg 5040 agagccactg accgtgacat cgggatcaac agtgttctgt cctactacat caccgagggc 5100 aacaaggaca tggccttccg catggaccgc atcagcggtg agatcgccac acggcctgcc 5160 ccgcctgacc gcgagcgcca gagcttctac cacctggtgg ccactgtgga ggacgagggc 5220 accccaaccc tgtcggccac cacgcacgtg tacgtgacca ttgtggatga gaatgataac 5280 gcgcccatgt tccagcagcc ccactatgag gtgctgctgg atgagggccc agacacgctc 5340 aacaccagcc tcatcaccat ccaggcactg gacctggatg agggtcccaa cggcacagtc 5400 acctatgcca tcgtcgcagg caacatcgtc aacaccttcc gcatcgacag acacatgggt 5460 gtcatcactg ctgccaaaga gctggactac gagatcagcc acggccgcta caccctgatc 5520 gtcactgcca cagaccagtg ccccatctta tcccaccgcc tcacctctac caccacggtg 5580 cttgtgaatg tgaatgacat caacgacaat gtgcctacct tcccccggga ctatgaggga 5640 ccatttgaag tcactgaggg ccagccgggg cccagagtgt ggaccttcct ggcccatgac 5700 cgagactcag gacccaacgg gcaggtggag tacagcatca tggatggaga ccctctgggt 5760 gagtttgtga tctctcctgt ggagggggtg ctaagggtcc ggaaggacgt ggagctggac 5820 cgggagacca tcgccttcta caacctgacc atctgtgccc gtgaccgggg gatgccccca 5880 ctcagctcca caatgctggt ggggatccgg gtgctggaca tcaacgacaa cgaccctgtg 5940 ctgctgaacc tgcccatgaa catcaccatc agcgagaaca gccctgtctc cagctttgtc 6000 gcccatgtcc tggccagtga cgctgacagt ggctgcaatg cacgcctcac cttcaacatc 6060 actgcgggca accgcgagcg ggccttcttc atcaatgcca cgacagggat cgtcactgtg 6120 aaccggcccc tggaccgcga gcggatccca gagtacaagc tgaccatttc tgtgaaggac 6180 aacccggaga atccacgcat agccaggagg gattatgact tgcttctgat cttcctttct 6240 gatgagaatg acaaccaccc cctcttcact aaaagcacct accaggcaga ggtgatggaa 6300 aactctcccg ctggcacccc tctcacggtg ctcaatgggc ccatcctggc cctggatgca 6360 gaccaagaca tctacgccgt ggtgacctac cagctgctgg gtgcccagag tggcctcttt 6420 gacatcaaca gcagcaccgg tgtggtgacc gtgaggtcag gtgtcatcat tgaccgggag 6480 gcattctcgc cacccatcct ggagctgctg ctgctggctg aggacatcgg gctgctcaac 6540 agcacggccc acctgctcat caccatcctg gatgacaatg acaaccggcc cacctttagc 6600 cctgccaccc tcactgtcca tctgctagag aactgcccgc ctggattctc agtccttcaa 6660 gtcacagcca cagatgagga cagtggcctc aatggggagc tggtctaccg aatagaagct 6720 ggggctcagg accgcttcct cattcatctg gtcaccgggg tcatccgtgt tggtaatgcc 6780 accatcgaca gagaggagca ggagtcctac aggctaacgg tggtggccac cgaccggggc 6840 accgttcctc tctcgggcac agccattgtc accattctga tcgatgacat caatgactcc 6900 cgccccgagt tcctcaaccc catccagaca gtgagcgtgc tggagtcggc tgagccaggc 6960 actgtcattg ccaatatcac ggccattgac cacgacctca acccaaagct agagtaccac 7020 attgtcggca ttgtggccaa ggacgacact gatcgcctgg tgcccaacca ggaggacgcc 7080 tttgctgtga atatcaacac aggatctgta atggtgaagt cccccatgaa tcgggagctg 7140 gttgccacct atgaggtcac tctctcagtg attgacaatg ccagcgacct accagagcgc 7200 tctgtcagtg tgccaaatgc caagctgact gtcaacgtcc tggacgtcaa tgacaatacg 7260 ccccagttca agccctttgg gatcacctac tacatggagc ggatcctgga gggggccacc 7320 cctgggacca cactcattgc tgtggcagcc gtggaccctg acaagggcct taatgggctg 7380 gtcacctaca ccctgctgga cctggtgccc ccagggtatg tccagctgga ggactcctcg 7440 gcagggaagg tcattgccaa ccggacagtg gactacgagg aggtgcactg gctcaacttt 7500 accgtgaggg cctcagacaa cgggtccccg ccccgggcag ctgagatccc tgtctacctg 7560 gaaatcgtgg acatcaatga caacaacccc atctttgacc agccctccta ccaggaggct 7620 gtctttgagg atgtgcctgt gggcacaatc atcctgacag tcactgccac tgatgctgac 7680 tcaggcaact ttgcactcat tgagtacagc cttggagatg gagagagcaa gtttgccatc 7740 aaccccacca cgggtgacat ctatgtgctg tcttctctgg accgggagaa gaaggaccac 7800 tatatcctga ctgccttggc caaagacaac cctggggatg tagccagcaa ccgtcgcgaa 7860 aattcagtgc aggtggtgat ccaagtgctg gatgtcaatg actgccggcc acagttctcc 7920 aagccccagt tcagcacaag cgtgtatgag aatgagccgg cgggcacctc ggtcatcacc 7980 atgatggcca ctgaccagga tgaaggtccc aatggagagt tgacctactc acttgagggc 8040 cctggcgtgg aggccttcca tgtggacatg gactcgggct tggtgaccac acagcggcca 8100 ctgcagtcct acgagaagtt cagtctgacc gtggtggcca cagatggtgg agagccccca 8160 ctctggggca ccaccatgct cctggtggag gtcatcgacg tcaatgacaa ccgccctgtc 8220 tttgtgcgcc cacccaacgg caccatcctc cacatcagag aggagatccc gctgcgctcc 8280 aacgtgtacg aggtctacgc cacggacaag gatgagggcc tcaacggggc ggtgcgctac 8340 agcttcctga agactgcggg caaccgggac tgggagttct tcatcatcga cccaatcagc 8400 ggcctcatcc agactgctca gcgcctggac cgcgagtcgc aggcggtgta cagcctcatc 8460 ttggtggcca gcgacctggg ccagccagtg ccatacgaga ctatgcagcc gctgcaggtg 8520 gccctggagg acatcgatga caacgaaccc cttttcgtga ggcctccaaa aggcagcccc 8580 cagtaccagc tgctgacagt gcctgagcac tcaccacgcg gcaccctcgt gggcaacgtg 8640 acaggcgcag tggatgcaga tgagggcccc aacgcgatcg tgtactactt catcgcagcc 8700 ggcaacgaag agaagaactt ccatctgcag cccgatgggt gtctgctggt gctgcgggac 8760 ctggaccggg agcgagaagc catcttctcc ttcatcgtca aggcctccag caatcgcagc 8820 tggacacctc cccgtggacc ctccccaacc ctcgacctgg ttgctgacct cacactgcag 8880 gaggtgcgcg ttgtgctaga ggacatcaac gaccagccac cacgcttcac caaggctgag 8940 tacactgcag gggtggccac cgacgccaag gtgggctcag agttgatcca ggtgctggcc 9000 ctggatgcag acattggcaa caacagcctt gtcttctaca gcattctggc catccactac 9060 ttccgggccc ttgccaacga ctctgaagat gtgggccagg tcttcaccat ggggagcatg 9120 gacggcattc tgcgcacctt cgacctcttc atggcctaca gccccggcta cttcgtggtg 9180 gacattgtgg cccgagacct ggcaggccac aacgacacgg ccatcatcgg catctacatc 9240 ctgagggacg accagcgcgt caagatcgtc attaacgaga tccccgaccg tgtgcgcggc 9300 ttcgaggagg agttcatcca cctgctctcc aacatcactg gggccattgt caatactgac 9360 aatgtgcagt tccatgtgga caagaagggc cgggtgaact ttgcgcagac agaactgctt 9420 atccacgtgg tgaaccgcga taccaaccgc atcctggacg tggaccgggt gatccagatg 9480 atcgatgaga acaaggagca gctacggaat cttttccgga actacaacgt cctggacgtg 9540 cagcctgcca tctctgtccg gctgccggat gacatgtctg ccctgcagat ggcgatcatc 9600 gtcctggcta tcctcctgtt cctggccgcc atgctctttg tcctcatgaa ctggtactac 9660 aggactgtac acaagaggaa gctcaaggcc attgtggctg gctcagctgg gaatcgtggc 9720 ttcatcgaca tcatggacat gcctaacacc aacaagtact cctttgatgg agccaaccct 9780 gtgtggctgg atcccttctg tcggaacctg gagctggccg cccaggcgga gcatgaggat 9840 gacctaccgg agaacctgag tgagatcgcc gacctgtgga acagccccac gcgcacccat 9900 ggaacttttg ggcgtgagcc agcagctgtc aagcctgatg atgaccgata cctgcgggct 9960 gccatccagg agtatgacaa cattgccaag ctgggccaga tcattcgtga ggggccaatc 10020 aagggctcgc tgctgaaggt ggtcctggag gattacctgc ggctcaaaaa gctctttgca 10080 cagcggatgg tgcaaaaagc ctcctcctgc cactcctcca tctctgagct gatacagact 10140 gagctggacg aggagccagg agaccacagc ccagggcagg gtagcctgcg cttccgccac 10200 aagccaccag tggagctcaa ggggcccgat gggatccatg tggtgcacgg cagcacgggc 10260 acgctgctgg ccaccgacct caacagcctg cccgaggaag accagaaggg cctgggccgc 10320 tcgctggaga cgctgaccgc tgccgaggcc actgccttcg agcgcaacgc ccgcacagaa 10380 tccgccaaat ccacacccct gcacaaactt cgcgacgtga tcatggagac ccccctggag 10440 atcacagagc tgtga 10455 5 14756 DNA Homo sapiens 5 ctgggcggcc gggcgcgggg agagggcgcg ggagcggctc gtgcggcagg taccatgcgg 60 acgcgcgagc ccggcgaggc cccggcaggc ccgtccctgc tcgggggcgc gctgagacgg 120 cgggtgagct ccacgagagc gccgtcgcca cttcgggcca actttgcgat tcccgacagt 180 taagcaatgg ggagacattt ggctttgctc ctgcttctgc tccttctctt ccaacatttt 240 ggagacagtg atggcagcca acgacttgaa cagactcctc tgcagtttac acacctcgag 300 tacaacgtca ccgtgcagga gaactctgca gctaagactt atgtggggca tcctgtcaag 360 atgggtgttt acattacaca tccagcgtgg gaagtaaggt acaaaattgt ttccggagac 420 agtgaaaacc tgttcaaagc tgaagagtac attctcggag acttttgctt tctaagaata 480 aggaccaaag gaggaaatac agctattctt aatagagaag tgaaggatca ctacacattg 540 atagtgaaag cacttgaaaa aaatactaat gtggaggcgc gaacaaaggt cagggtgcag 600 gtgctggata caaatgactt gagaccgtta ttctcaccca cctcatacag cgtttcttta 660 cctgaaaaca cagctataag gaccagtatc gcaagagtca gcgccacgga tgcagacata 720 ggaaccaacg gggaatttta ctacagtttt aaagatcgaa cagatatgtt tgctattcac 780 ccaaccagtg gtgtgatagt gttaactggt agacttgatt acctagagac caagctctat 840 gagatggaaa tcctcgctgc ggaccgtggc atgaagttgt atgggagcag tggcatcagc 900 agcatggcca agctaacggt gcacatcgaa caggccaatg aatgtgctcc ggtgataaca 960 gcagtgacat tgtcaccatc agaactggac agggacccag catatgcaat tgtgacagtg 1020 gatgactgcg atcagggtgc caatggtgac atagcatctt taagcatcgt ggcaggtgac 1080 cttctccagc agtttagaac agtgaggtcc tttccaggga gtaaggagta taaagtcaaa 1140 gccatcggtg acattgattg ggacagtcat cctttcggct acaatctcac actacaggct 1200 aaagataaag gaactccgcc ccagttctct tctgttaaag tcattcacgt gacttctcca 1260 cagttcaaag ccgggccagt caagtttgaa aaggatgttt acagagcaga aataagtgaa 1320 tttgctcctc ccaacacacc tgtggtcatg gtaaaggcca ttcctgctta ttcccatttg 1380 aggtatgttt ttaaaaggac acctggaaaa gctaaattca gtttaaatta caacactggt 1440 ctcatttcta ttttagaacc agttaaaaga cagcaggcag cccattttga acttgaagta 1500 acaacaagtg acagaaaagc gtccaccaag gtcttggtga aagtcttagg tgcaaatagc 1560 aatccccctg aatttaccca gacagcgtac aaagctgctt ttgatgagaa cgtgcccatt 1620 ggtactacta tcatgagcct gagtgccgta gaccctgatg agggtgagaa tgggtacgtg 1680 acatacagta tcgcaaattt aaatcatgtg ccgtttgcga ttgaccattt cactggtgcc 1740 gtgagtacgt cagaaaacct ggactacgaa ctgatgcctc gggtttatac tctgaggatt 1800 cgtgcatcag actggggctt gccgtaccgc cgggaagtcg aagtccttgc tacaattact 1860 ctcaataact tgaatgacaa cacacctttg tttgagaaaa taaattgtga agggacaatt 1920 cccagagatc taggcgtggg agagcaaata accactgttt ctgctattga tgcagatgaa 1980 cttcagttgg tacagtatca gattgaagct ggaaatgaac tggatttgtt tagtttaaac 2040 cccaactcgg gggtattgtc attaaagcga tcgctaatgg atggcttagg tgcaaaggtg 2100 tctttccaca gtctgagaat cacagctaca gatggagaaa attttgccac accattatat 2160 atcaacataa cagtggctgc cagtcacaag ctggtaaact tgcagtgtga agagactggt 2220 gttgccaaaa tgctggcaga gaagctcctg caggcaaata aattacacaa ccagggagag 2280 gtggaggata ttttcttcga ttctcactct gtcaatgctc acataccgca gtttagaagc 2340 actcttccga ctggtattca ggtaaaggaa aaccagcctg tgggttccag tgtaattttc 2400 atgaactcca ctgaccttga cactggcttc aatggaaaac tggtctatgc tgtttctgga 2460 ggaaatgagg atagttgctt catgattgat atggaaacag gaatgctgaa aattttatct 2520 cctcttgacc gtgaaacaac agacaaatac accctgaata ttaccgtcta tgaccttggg 2580 ataccccaga aggctgcgtg gcgtcttcta catgtcgtgg ttgtcgatgc caatgataat 2640 ccacccgagt ttttacagga gagctatttt gtggaagtga gtgaagacaa ggaggtacat 2700 agtgaaatca tccaggttga agccacagat aaagacctgg ggcccaacgg acacgtgacg 2760 tactcaattc ttacagacac agacacattt tcaattgaca gcgtgacggg tgttgttaac 2820 atcgcacgcc ctctggatcg agagctgcag catgagcact ccttaaagat tgaggccagg 2880 gaccaagcca gagaagagcc tcagctgttc tccactgtcg ttgtgaaagt atcactagaa 2940 gatgttaatg acaacccacc tacatttatt ccacctaatt atcgtgtgaa agtccgagag 3000 gatcttccag aaggaaccgt catcatgtgg ttagaagccc acgatcctga tttaggtcag 3060 tctggtcagg tgagatacag ccttctggac cacggagaag gaaacttcga tgtggataaa 3120 ctcagtggag cagttaggat cgtccagcag ttggactttg agaagaagca agtgtataat 3180 ctcactgtga gggccaaaga caagggaaag ccagtttctc tgtcttctac ttgctatgtt 3240 gaagttgagg tggttgatgt gaatgagaac ctgcacccac ccgtgttttc cagctttgtg 3300 gaaaagggga cagtgaaaga agatgcacct gttggttcat tggtaatgac ggtgtcggct 3360 catgatgagg acgccggaag agatggggag atccgatact ccattagaga tggctctggc 3420 gttggtgttt tcaaaatagg tgaagagaca ggtgtcatag agacgtcaga tcgactggac 3480 cgtgaatcga cctcccatta ttggctaaca gtctttgcaa ccgatcaggg tgtcgtgcct 3540 ctttcatcgt tcatagagat ctacatagag gttgaggatg tcaatgacaa tgcaccacag 3600 acatcagagc ctgtttatta cccagaaatc atggaaaatt ctcctaaaga tgtatctgtg 3660 gtccagatcg aggcatttga tccagattcg agctctaatg acaagctcat gtacaaaatt 3720 acaagtggaa atccacaagg attcttttca atacatccta aaacaggtct catcacaact 3780 acgtcaagga agctagaccg agaacagcaa gatgaacaca tattagaggt tactgtgaca 3840 gacaatggta gtccccccaa atcaaccatt gcaagagtca ttgtgaaaat ccttgatgaa 3900 aatgacaaca aacctcagtt tctgcaaaag ttctacaaaa tcagactccc tgagcgggaa 3960 aagccagacc gagaaagaaa tgccagacgg gagccgctct atcgcgtcat agccaccgac 4020 aaggatgagg gccccaatgc agaaatctcc tacagcatcg aagacgggaa tgagcatggc 4080 aaatttttca tcgaaccgaa aactggagtg gtttcgtcca agaggttttc agcagctgga 4140 gaatatgata ttctttcaat taaggcagtt gacaatggtc gccctcaaaa gtcatcaacc 4200 accagactcc atattgaatg gatctccaag cccaaacagt ccctggagcc catttcattt 4260 gaagaatcat tttttacctt tactgtgatg gaaagtgacc ccgttgctca catgattgga 4320 gtaatatctg tggagcctcc tggcataccc ctttggtttg acatcactgg tggcaactac 4380 gacagtcact tcgatgtgga caagggaact ggaaccatca ttgttgccaa acctcttgat 4440 gcagaacaga agtcaaacta caacctcaca gtcgaggcta cagatggaac caccactatc 4500 ctcactcagg tattcatcaa agtaatagac acaaatgacc atcgtcctca gttttctaca 4560 tcaaagtatg aagttgttat tcctgaagat acagcgccag aaacagaaat tttgcaaatc 4620 agtgctgtgg atcaggatga gaaaaacaaa ctaatctaca ctctgcagag cagtagagat 4680 ccactgagtc tcaagaaatt tcgtcttgat cctgcaaccg gctctctcta tacttctgag 4740 aaactggatc atgaagctgt ttcaccagca cacctcacgg tcatggtacg agatcaagat 4800 gtgcctgtaa aacgcaactt tgcaaggatt gtggtcaatg tcagcgacac gaatgaccac 4860 gccccgtggt tcaccgcttc ctcctacaaa gggcgggttt atgaatcggc agccgttggc 4920 tcagttgtgt tgcaggtgac ggctctggac aaggacaaag ggaaaaatgc tgaagtgctg 4980 tactcgatcg agtcaggaaa tattggaaat attggaaatt cttttatgat tgatcctgtc 5040 ttgggctcta ttaaaactgc caaagaatta gatcgaagta accaagcgga gtatgattta 5100 atggtaaaag ctacagataa gggcagtcca ccaatgagtg aaataacttc tgtgcgtatc 5160 tttgtcacaa ttgctgacaa cgcctctccg aagtttacat caaaagaata ttctgttgaa 5220 cttagtgaaa ctgtcagcat tgggagtttc gttgggatgg ttacagccca tagtcaatca 5280 tcagtggtgt atgaaataaa agatggaaat acaggtgatg cttttgatat taatccacat 5340 tctggaacta tcatcactca gaaagccctg gactttgaaa ctttgcccat ttacacattg 5400 ataatacaag gaactaacat ggctggtttg tccactaata caacggttct agttcacttg 5460 caggatgaga atgacaacgc gccagttttt atgcaggcag aatatacagg actcattagt 5520 gaatcagcct caattaacag cgtggtccta acagacagga atgtcccact ggtgattcga 5580 gcagctgatg ctgataaaga ctcaaatgct ttgcttgtat atcacattgt tgaaccatct 5640 gtacacacat attttgctat tgattctagc actggtgcta ttcatacagt actaagtctg 5700 gactatgaag aaacaagtat ttttcacttt accgtccaag tgcatgacat gggaacccca 5760 cgtttatttg ctgagtatgc agcgaatgta acagtacatg taattgacat taatgactgc 5820 ccccctgtgt ttgccaagcc attatatgaa gcatctcttt tgttaccaac atacaaagga 5880 gtaaaagtca tcacagtaaa tgctacagat gctgattcaa gtgcattctc acagttgatt 5940 tactccatca ccgaaggcaa catcggggag aagttttcta tggactacaa gactggtgct 6000 ctcactgtcc aaaacacaac tcagttaaga agccgctacg agctaaccgt tagagcttcc 6060 gatggcagat ttgccggcct tacctctgtc aaaattaatg tgaaagaaag caaagaaagt 6120 cacctaaagt ttacccagga tgtctactct gcggtagtga aagagaattc caccgaggcc 6180 gaaacattag ctgtcattac tgctattggg agtccaatca atgagccttt gttttatcac 6240 atcctcaacc cagatcgcag atttaaaata agccgcactt caggggttct gtcaaccact 6300 ggcacgccct tcgatcgtga gcagcaggag gcgtttgatg tggttgtaga agtgatagag 6360 gaacataagc cttctgcagt ggcccacgtt gtcgtgaagg tcattgtaga agaccaaaat 6420 gataatgcgc cggtgtttgt caaccttccc tactacgccg ttgttaaagt ggacactgag 6480 gtgggccatg tcattcgcta tgtcactgct gtagacagag acagtggcag aaacggggaa 6540 gtgcattact acctcaagga acatcatgaa cactttcaaa ttggaccctt gggtgaaatt 6600 tcactgaaaa agcaatttga gcttgacacc ttaaataaag aatatcttgt tacagtggtt 6660 gcaaaagatg gagggaaccc ggccttttca gcggaagtta tcgttccgat cactgtcatg 6720 aataaagcca tgcctgtgtt tgaaaaacct ttctacagtg cagagattgc agagagcatc 6780 caggtgcaca gccctgtggt ccacgtgcag gctaacagcc cggaaggcct gaaagtgttc 6840 tacagcatca cagacggaga ccctttcagc cagttcacta ttaacttcaa tactggagtt 6900 atcaatgtca tagctcctct ggactttgag gcccacccgg catataagct gagcatacgc 6960 gcaactgact ccttgacggg cgctcatgct gaagtatttg tggacatcat agtagacgac 7020 atcaatgata accctcctgt gtttgctcag cagtcttatg cggtgaccct gtctgaggca 7080 tctgtaattg gaacgtctgt tgttcaagtt agagccaccg attctgattc agaaccaaat 7140 agaggaatct cataccagat gtttgggaat cacagcaaga gtcatgatca ttttcatgta 7200 gacagcagca ctggcctcat ctcactactc agaaccctgg attacgagca gtcccggcag 7260 cacacgattt ttgtgagggc agttgatggt ggtatgccca cgctgagcag tgatgtgatt 7320 gtcacggtgg acgttaccga cctcaatggt aatccaccac tctttgaaca acagatttat 7380 gaagccagaa ttagcgagca cgcccctcat gggcatttcg tgacctgtgt aaaagcctat 7440 gatgcagaca gttcagacat agacaagttg cagtattcca ttctgtctgg caatgatcat 7500 aaacattttg tcattgacag tgcaacaggg attatcaccc tctcaaacct gcaccggcac 7560 gccctgaagc cattttacag tcttaacctg tcagtgtctg atggagtttt tagaagttcc 7620 acccaggttc atgtaactgt aattggaggc aatttgcaca gtcctgcttt ccttcagaac 7680 gaatatgaag tggaactagc tgaaaacgct cccctacata ccctggtgat ggaggtgaaa 7740 actacggatg gggattctgg tatttatggt cacgttactt accatattgt aaatgacttt 7800 gccaaagaca gattttacat aaatgagaga ggacagatat ttactttgga aaaacttgat 7860 cgagaaaccc cggcggagaa agtgatctca gtccgtttaa tggctaagga tgctggagga 7920 aaagttgctt tctgcaccgt gaatgtcatc cttacagatg acaatgacaa tgcaccacaa 7980 tttcgagcaa ccaaatacga agtgaatatc gggtccagtg ctgctaaagg gacttcagtc 8040 gtaaagtctg caagtgatgc cgatgagggc tccaatgccg acatcaccta tgccattgaa 8100 gcagactctg aaagtgtaaa agagaatttg gaaattaaca aactgtccgg cgtaatcact 8160 acaaaggaga gcctcattgg cttggaaaat gaattcttca ctttctttgt tagagctgtg 8220 gataatgggt ctccatcaaa agaatctgtt gttcttgtct atgttaaaat ccttccaccg 8280 gaaatgcagc ttccaaaatt ttcagaacct ttctatacct ttacagtgtc agaggacgtg 8340 cctgttggaa cagagataga tctcatccga gcagaacata gtgggactgt tctttacagc 8400 ctggtcaaag ggaatactcc agaaagcaat agggatgagt cctttgtgat tgacagacag 8460 agcgggagac tgaagttgga gaagagtctt gatcatgaga caactaagtg gtatcagttt 8520 tccatactgg ccaggtgcac tcaagatgac catgagatgg tggcttctgt agatgttagt 8580 atccaagtga aagatgcaaa tgacaacagc ccggtctttg aatctagtcc atatgaggca 8640 ttcattgttg aaaacctgcc agggggaagt agagtaattc agatcagggc atctgatgct 8700 gactcaggaa ccaacggcca agttatgtat agcctggatc agtcacaaag tgtggaagtc 8760 attgaatcct ttgccattaa catggaaaca ggctggatta caactttaaa ggaacttgac 8820 catgaaaaga gagacaatta ccagattaaa gtggttgcat cagatcatgg tgaaaagatc 8880 cagctatcct ccacagccat tgtggatgtt accgtcaccg atgtcaacga tagtccacca 8940 cgattcacgg ccgagatcta taaagggact gtgagtgagg atgaccccca aggtggggtg 9000 attgccatct taagtaccac ggatgctgat tctgaagaga tcaacagaca agttacatat 9060 ttcataacag gaggggatcc tttaggacag tttgccgttg aaactataca gaatgaatgg 9120 aaggtatatg tgaagaaacc tctagacagg gaaaaaaggg acaattacct tcttactatc 9180 acggcaactg atggcacctt ctcatcaaaa gcgatagttg aagtgaaagt tctggatgca 9240 aatgacaaca gtccagtttg tgaaaagact ttatattcag acactattcc tgaagacgtc 9300 cttcctggaa aattgatcat gcagatctct gctacagacg cagacatccg ctctaacgct 9360 gaaattactt acacgttatt gggttcaggt gcagaaaaat tcaaactaaa tccagacaca 9420 ggtgaactga aaacgtcaac cccccttgat cgtgaggagc aagctgttta tcatcttctc 9480 gtcagggcca cagatggagg aggaagattc tgccaagcca gtattgtcgt cacgctagaa 9540 gatgtgaacg ataacgcccc cgaattctct gccgatcctt atgccatcac cgtgtttgaa 9600 aacacagagc cgggaacgct gctgacaaga gtgcaggcca cagatgccga cgcaggatta 9660 aatcggaaga ttttatactc actgattgac tctgctgatg ggcagttctc cattaacgaa 9720 ttatctggaa ttattcagtt agaaaaacct ttggacagag aactccaggc agtatacacc 9780 ctctctttga aagctgtgga tcaaggcttg ccaaggaggc tgactgccac tggcactgtg 9840 attgtatcag ttcttgacat aaatgacaac ccccctgtgt ttgagtaccg tgaatatggt 9900 gccaccgtgt ctgaggacat tcttgttgga actgaagttc ttcaagtgta tgcagcaagt 9960 cgggatattg aagcaaatgc agaaatcacc tactcaataa taagtggaaa tgaacatggg 10020 aaattcagca tagattctaa aacaggggcc gtatttatca ttgagaatct ggattatgag 10080 agctctcatg agtattacct aacagtagag gccactgatg gaggcacgcc ttcactgagc 10140 gacgttgcca ctgtgaacgt taatgtaaca gatatcaacg ataatacccc tgtgttcagc 10200 caagacacct acacgacagt catcagtgaa gatgccgttc ttgagcagtc tgtcatcacg 10260 gttatggccg atgatgccga tggaccttcc aacagccaca tccactactc aattatagat 10320 ggcaaccaag gaagctcgtt cacaattgac cccgtcaggg gagaagtcaa agtgaccaaa 10380 cttctcgacc gagaaacgat ttcaggttac acgctcacgg ttcaagcttc tgataatggc 10440 agtccaccca gagtcaacac gacgaccgtg aacatcgatg tgtccgatgt caatgacaac 10500 gcgcccgtct tctccagggg aaactacagt gtcattatcc aggaaaataa gccagtgggc 10560 ttcagcgtgc tgcagctggt agtaacagat gaggattctt cccataacgg tccacccttc 10620 ttctttacta ttgtaactgg aaatgatgag aaggcttttg aagttaaccc gcaaggagtc 10680 ctcctgacat catctgccat caagaggaag gagaaagatc attacttact gcaggtgaag 10740 gtggcagata atggaaagcc tcagttgtca tctttgacat acattgacat tagggtaatt 10800 gaggagagca tctatccgcc tgcgattttg cccctggaga ttttcatcac ctcttctgga 10860 gaagaatact caggtggcgt cattgggaag atccatgcca cagaccagga cgtgtatgat 10920 actctaacct acagtctcga ccctcagatg gacaacctgt tctctgtttc cagcacaggg 10980 ggcaagctga tagcacacaa aaagctagac atagggcaat accttctcaa tgtcagcgta 11040 acagatggga agttcacgac ggtggccgac atcacagtgc atatcagaca agtcacacag 11100 gagatgttga accacaccat cgcgatccgc tttgccaacc tcactccgga agaattcgtt 11160 ggtgactact ggcgcaactt ccagcgagct ttacggaaca tcctgggtgt gaggaggaac 11220 gacatacaga ttgttagttt gcagtcctct gaacctcacc cacatctgga cgtcttactt 11280 tttgtagaga aaccaggtag tgctcagatc tcaacaaaac aacttctgca caagattaac 11340 tcttccgtga ctgacattga ggaaatcatt ggagttagga tactgaatgt attccagaaa 11400 ctctgcgcgg gactggactg cccctggaag ttctgcgatg aaaaggtgtc tgtggatgaa 11460 agtgtgatgt caacacacag cacagccaga ctgagttttg tgactccccg ccaccacagg 11520 gcagcggtgt gtctctgcaa agagggaagg tgcccacctg tccaccatgg ctgtgaagat 11580 gatccgtgcc ctgagggatc cgaatgtgtg tctgatccct gggaggagaa acacacctgt 11640 gtctgtccca gcggcaggtt tggtcagtgc ccagggagtt catctatgac actgactgga 11700 aacagctacg tgaaataccg tctgacggaa aatgaaaaca aattagagat gaaactgacc 11760 atgaggctca gaacatattc cacgcatgcg gttgtcatgt atgctcgagg aactgactat 11820 agcatcttgg agattcatca tggaaggctg cagtacaagt ttgactgtgg aagtggccct 11880 ggaattgtct ctgttcagag cattcaggtc aatgatgggc agtggcacgc agtggccctg 11940 gaagtgaatg gaaactatgc tcgcttggtt ctagaccaag ttcatactgc atcgggcaca 12000 gccccaggga ctctgaaaac cctgaacctg gataactatg tgttttttgg tggccacatc 12060 cgtcagcagg gaacaaggca tggaagaagt cctcaagttg gtaatggttt caggggttgt 12120 atggactcca tttatttgaa tgggcaggag ctccctttaa acagcaaacc cagaagctat 12180 gcacacatcg aagagtcggt ggatgtatct ccaggctgct tcctgacggc cacggaagac 12240 tgcgccagca acccttgcca gaatggaggc gtttgcaatc cgtcacctgc tggaggttat 12300 tactgcaaat gcagtgcctt gtacataggg acccactgtg agataagcgt caatccgtgt 12360 tcctccaacc catgcctcta tgggggcacg tgtgttgtcg acaacggagg ctttgtttgc 12420 cagtgtagag gattatatac tggtcagagg tgtcagctta gtccatactg caaagatgaa 12480 ccctgtaaga atggcggaac atgctttgac agtttggatg gcgccgtttg tcagtgtgat 12540 tcgggtttta ggggagaaag gtgtcagagt gatatcgacg agtgctctgg aaacccttgc 12600 ctgcacgggg ccctctgtga gaacacgcac ggctcctatc actgcaactg cagccacgag 12660 tacaggggac gtcactgcga ggatgctgcg cccaaccagt atgtgtccac gccgtggaac 12720 attgggttgg cggaaggaat tggaatcgtt gtgtttgttg cagggatatt tttactggtg 12780 gtggtgtttg ttctctgccg taagatgatt agtcggaaaa agaagcatca ggctgaacct 12840 aaagacaagc acctgggacc cgctacggct ttcttgcaaa gaccgtattt tgattccaag 12900 ctaaataaga acatttactc agacatacca ccccaggtgc ctgtccggcc tatttcctac 12960 accccgagta ttccaagtga ctcaagaaac aatctggacc gaaattcctt cgaaggatct 13020 gctatcccag agcatcccga attcagcact tttaaccccg agtctgtgca cgggcaccga 13080 aaagcagtgg cggtctgcag cgtggcgcca aacctgcctc ccccaccccc ttcaaactcc 13140 ccttctgaca gcgactccat ccagaagcct agctgggact ttgactatga cacaaaagtg 13200 gtggatcttg atccctgtct ttccaagaag cctctagagg aaaagccttc ccagccatac 13260 agtgcccggg aaagcctgtc tgaagtgcag tccctgagct ccttccagtc cgaatcgtgc 13320 gatgacaatg ggtatcactg ggatacatca gattggatgc caagcgttcc tctgccggac 13380 atacaagagt tccccaacta tgaggtgatt gatgagcaga cacccctgta ctcagcagat 13440 ccaaacgcca tcgatacgga ctattaccct ggaggctacg acatcgaaag tgattttcct 13500 ccacccccag aagacttccc cgcagctgat gagctaccac cgttaccgcc cgaattcagc 13560 aatcagtttg aatccatcca ccctcctaga gacatgcctg ccgcgggtag cttgggttct 13620 tcatcaagaa accggcagag gttcaacttg aatcagtatt tgcccaattt ttatcccctc 13680 gatatgtctg aacctcaaac aaaaggcact ggtgagaata gtacttgtag agaaccccat 13740 gccccttacc cgccagggta tcaaagacac ttcgaggcgc ccgctgtcga gagcatgccc 13800 atgtctgtgt acgcctccac cgcctcctgc tctgacgtgt cagcctgctg cgaagtggag 13860 tccgaggtca tgatgagtga ctatgagagc ggggacgacg gccacttcga agaggtgacg 13920 atcccgcccc tggattccca gcagcacacg gaagtctgac tctcaactcc ccccaaagtg 13980 cctgacttta gtgaacctag aggtgatgtg agtaatccgc gctgttcttt gcagcagtgc 14040 ttccaagctt tttttggtga gccgaatggg catggctgcg ctggatcctg cgcctctgga 14100 cgtgctagcc atttccagtg tcccaactac tgtcatcgtg aggttttcat cggctgtgcc 14160 atttcccaac gtcttttggg atttacatct gtctgtgtta aaataatcaa acgaaaaatc 14220 agtcctgtgt tgtcagcatg attcatgtat ttatatagat ttgattattt taattttcct 14280 gtctcttttt tttgtaaatt ttatgtacag atttgatttt tcatagtttt aactagattt 14340 ccaagatatt ttgtgcattt gtttcaactg aattttggtg gtgtcagtgc cattatctag 14400 caccctgatt tttttttttt tactataacc agggtttcat tctgtctttt tccactgaag 14460 tgtgacattt tgttagtaca tttcagtgta gtcattcatt tctagctgta cataggatga 14520 aggagagatc agatacatga acatgtctta catgggttgc tgtatttaga attataaaca 14580 tttttcatta ttggaaagtg taacggggac cttctgcata cctgtttaga accaaaacca 14640 ccatgacaca gtttttatag tgtctgtata tttgtgatgc aatggtcttg taaaggtttt 14700 taatgaaaac taccattagc cagtctttct tactgacaat aaattattaa taaaat 14756 6 14536 DNA Homo sapiens 6 ggagttttcc accatgacta ttgccctgct gggttttgcc atattcttgc tccattgtgc 60 gacctgtgag aagcctctag aagggattct ctcctcctct gcttggcact tcacacactc 120 ccattacaat gccaccatct atgaaaattc ttctcccaag acctatgtgg agagcttcga 180 gaaaatgggc atctacctcg cggagccaca gtgggcagtg aggtaccgga tcatctctgg 240 ggatgtggcc aatgtattta aaactgagga gtatgtggtg ggcaacttct gcttcctaag 300 aataaggaca aagagcagca acacagctct tctgaacaga gaggtgcgag acagctacac 360 cctcatcatc caagccacag agaagacctt ggagttggaa gctttgaccc gtgtggtggt 420 ccacatcctg gaccagaatg acctgaagcc tctcttctct ccaccttcgt acagagtcac 480 catctctgag gacatgcccc tgaagagccc catctgcaag gtgactgcca cagatgctga 540 tctaggccag aatgctgagt tctattatgc ctttaacaca aggtcagaga tgtttgccat 600 ccatcccacc agcggtgtgg tcactgtggc tgggaagctt aacgtcacct ggcgaggaaa 660 gcatgagctc caggtgctag ctgtggaccg catgcggaaa atctctgagg gcaatgggtt 720 tggcagcctg gctgcacttg tggttcatgt ggagcctgcc ctcaggaagc ccccagccat 780 tgcttcggtg gtggtgactc caccagacag caatgatggt accacctatg ccactgtact 840 ggtcgatgca aatagctcag gagctgaagt ggagtcagtg gaagttgttg gtggtgaccc 900 tggaaagcac ttcaaagcca tcaagtctta tgcccggagc aatgagttca gtttggtgtc 960 tgtcaaagac atcaactgga tggagtacct tcatgggttc aacctcagcc tccaggccag 1020 gagtgggagc ggcccttatt tttattccca gatcaggggc tttcacctac caccttccaa 1080 actgtcttcc ctcaaattcg agaaggctgt ttacagagtg cagcttagtg agttttcccc 1140 tcctggcagc cgcgtggtga tggtgagagt caccccagcc ttccccaacc tgcagtatgt 1200 tctaaagcca tcttcagaga atgtaggatt taaacttaat gctcgaactg ggttgatcac 1260 caccacaaag ctcatggact tccacgacag agcccactat cagctacaca tcagaacctc 1320 accgggccag gcctccaccg tggtggtcat tgacattgtg gactgcaaca accatgcccc 1380 cctcttcaac aggtcttcct atgatggtac cttggatgag aacatccctc caggcaccag 1440 tgttttggct gtgactgcca ctgaccggga tcatggggaa aatggatatg tcacctattc 1500 cattgctgga ccaaaagctt tgccattttc tattgacccc tacctgggga tcatctccac 1560 ctccaaaccc atggactatg aactcatgaa aagaatttat accttccggg taagagcatc 1620 agactgggga tccccttttc gccgggagaa ggaagtgtcc atttttcttc agctcaggaa 1680 cttgaatgac aaccagccta tgtttgaaga agtcaactgt acagggtcta tccgccaaga 1740 ctggccagta gggaaatcga taatgactat gtcagccata gatgtggatg agcttcagaa 1800 cctaaaatac gagattgtat caggcaatga actagagtat tttgatctaa atcatttctc 1860 cggagtgata tccctcaaac gcccttttat caatcttact gctggtcaac ccaccagtta 1920 ttccctgaag attacagcct cagatggcaa aaactatgcc tcacccacaa ctttgaatat 1980 tactgtggtg aaggaccctc attttgaagt tcctgtaaca tgtgataaaa caggggtatt 2040 gacacaattc acaaagacta tcctccactt tattgggctt cagaaccagg agtccagtga 2100 tgaggaattc acttctttaa gcacatatca gattaatcat tacaccccac agtttgagga 2160 ccacttcccc caatccattg atgtccttga gagtgtccct atcaacaccc ccttggcccg 2220 cctagcagcc actgaccctg atgctggttt taatggcaaa ctggtctatg tgattgcaga 2280 tggcaatgag gagggctgct ttgacataga gctggagaca gggctgctca ctgtagctgc 2340 tcccttggac tatgaagcca ccaatttcta catcctcaat gtaacagtat atgacctggg 2400 cacaccccag aagtcctcct ggaagctgct gacagtgaat gtgaaagact ggaatgacaa 2460 cgcacccaga tttcctcccg gtgggtacca gttaaccatc tcggaggaca cagaagttgg 2520 aaccacaatt gcagagctga caaccaaaga tgctgactcg gaagacaatg gcagggttcg 2580 ctacaccctg ctaagtccca cagagaagtt ctccctccac cctctcactg gggaactggt 2640 tgttacagga cacctggacc gcgaatcaga gcctcggtac atactcaagg tggaggccag 2700 ggatcagccc agcaaaggcc accagctctt ctctgtcact gacctgataa tcacattgga 2760 ggatgtcaac gacaactctc cccagtgcat cacagaacac aacaggctga aggttccaga 2820 ggacctgccc cccgggactg tcttgacatt tctggatgcc tctgatcctg acctgggccc 2880 cgcaggtgaa gtgcgatatg ttctgatgga tggcgcccat gggaccttcc gggtggacct 2940 gatgacaggg gcgctcattc tggagagaga gctggacttt gagaggcgag ctgggtacaa 3000 tctgagcctg tgggccagtg atggtgggag gcccctagcc cgcaggactc tctgccatgt 3060 ggaggtgatc gtcctggatg tgaatgagaa tctccaccct ccccactttg cctccttcgt 3120 gcaccagggc caggtgcagg agaacagccc ctcgggaact caggtgattg tagtggctgc 3180 ccaggacgat gacagtggct tggatgggga gctccagtac ttcctgcgtg ctggcactgg 3240 actcgcagcc ttcagcatca accaagatac aggaatgatt cagactctgg cacccctgga 3300 ccgagaattt gcatcttact actggttgac ggtattagca gtggacaggg gttctgtgcc 3360 cctctcttct gtaactgaag tctacatcga ggttacggat gccaatgaca acccacccca 3420 gatgtcccaa gctgtgttct acccctccat ccaggaggat gctcccgtgg gcacctctgt 3480 gcttcaactg gatgcctggg acccagactc cagctccaaa gggaagctga ccttcaacat 3540 caccagtggg aactacatgg gattctttat gattcaccct gttacaggtc tcctatctac 3600 agcccagcag ctggacagag agaacaagga tgaacacatc ctggaggtga ctgtgctgga 3660 caatggggaa ccctcactga agtccacctc cagggtggtg gtaggcatct tggacgtcaa 3720 tgacaatcca cctatattct cccacaagct cttcaatgtc cgccttccag agaggctgag 3780 ccctgtgtcc cctgggcctg tgtacaggct ggtggcttca gacctggatg agggtcttaa 3840 tggcagagtc acctacagta tcgaggacag ctatgaggag gccttcagta tcgacctggt 3900 cacaggtgtg gtttcatcca acagcacttt tacagctgga gagtacaaca tcctaacgat 3960 caaggcaaca gacagtgggc agccaccact ctcagccagt gtccggctac acattgagtg 4020 gatcccttgg ccccggccgt cctccatccc tctggccttt gatgagacct actacagctt 4080 tacggtcatg gagacggacc ctgtgaacca catggtgggg gtcatcagcg tagagggcag 4140 acccggactc ttctggttca acatctcagg tggggataag gacatggact ttgacattga 4200 gaagaccaca ggcagcatcg tcattgccag gcctcttgat accaggagaa ggtcgaacta 4260 taacttgact gttgaggtga cagatgggtc ccgcaccatt gccacacagg tccacatctt 4320 catgattgcc aacattaacc accatcggcc ccagtttctg gaaactcgtt atgaagtcag 4380 agttccccag gacaccgtgc caggggtaga gctcctgcga gtccaggcca tagatcaaga 4440 caagggcaaa agcctcatct ataccataca tggcagccaa gacccaggaa gtgccagcct 4500 cttccagctg gacccaagca gtggtgtcct ggtaacggtg ggaaaattgg acctcggctc 4560 ggggccctcc cagcacacac tgacagtcat ggtccgagac caggaaatac ctatcaagag 4620 gaacttcgtg tgggtgacca ttcatgtgga ggatggaaac ctccacccac cccgcttcac 4680 tcagctccat tatgaggcaa gtgttcctga caccatagcc cccggcacag agctgctgca 4740 ggtccgagcc atggatgctg accggggagt caatgctgag gtccactact ccctcctgaa 4800 agggaacagc gaaggtttct tcaacatcaa tgccctgcta ggcatcatta ctctagctca 4860 aaagcttgat caggcaaatc atgccccaca tactctgaca gtgaaggcag aagatcaagg 4920 ctccccacaa tggcatgacc tggctacagt gatcattcat gtctatccct cagataggag 4980 tgcccccatc ttttcaaaat ctgagtactt tgtagagatc cctgaatcaa tccctgttgg 5040 ttccccaatc ctccttgtct ctgctatgag cccctctgaa gttacctatg agttaagaga 5100 gggaaataag gatggagtct tctctatgaa ctcatattct ggccttattt ccacccagaa 5160 gaaattggac catgagaaaa tctcgtctta ccagctgaaa atccgaggca gcaatatggc 5220 aggtgcattt actgatgtca tggtggtggt tgacataatt gatgaaaatg acaatgctcc 5280 tatgttctta aagtcaactt ttgtgggcca aattagtgaa gcagctccac tgtatagcat 5340 gatcatggat aaaaacaaca acccctttgt gattcatgcc tctgacagtg acaaagaagc 5400 taattccttg ttggtctata aaattttgga gccggaggcc ttgaagtttt tcaaaattga 5460 tcccagcatg ggaaccctaa ccattgtatc agagatggat tatgagagca tgccctcttt 5520 ccaattctgt gtctatgtcc atgaccaagg aagccctgta ttatttgcac ccagacctgc 5580 ccaagtcatc attcatgtca gagatgtgaa tgattcccct cccagattct cagaacagat 5640 atatgaggta gcaatagtcg ggcctatcca tccaggcatg gagcttctca tggtgcgggc 5700 cagcgatgaa gactcagaag tcaattatag catcaaaact ggcaatgctg atgaagctgt 5760 taccatccat cctgtcactg gtagcatatc tgtgctgaat cctgctttcc tgggactctc 5820 tcggaagctc accatcaggg cttctgatgg cttgtatcaa gacactgcgc tggtaaaaat 5880 ttctttgacc caagtgcttg acaaaagctt gcagtttgat caggatgtct actgggcagc 5940 tgtgaaggag aacttgcagg acagaaaggc actggtgatt cttggtgccc agggcaatca 6000 tttgaatgac accctttcct actttctctt gaatggcaca gatatgtttc atatggtcca 6060 gtcagcaggt gtgttgcaga caagaggtgt ggcgtttgac cgggagcagc aggacactca 6120 tgagttggca gtggaagtga gggacaatcg gacacctcag cgggtggctc agggtttggt 6180 cagagtctct attgaggatg tcaatgacaa tccccccaaa tttaagcatc tgccctatta 6240 cacaatcatc caagatggca cagagccagg ggatgtcctc tttcaggtat ctgccactga 6300 tgaggacttg gggacaaatg gggctgttac atatgaattt gcagaagatt acacatattt 6360 ccgaattgac ccctatcttg gggacatatc actcaagaaa ccctttgatt atcaagcttt 6420 aaataaatat cacctcaaag tcattgctcg ggatggagga acgccatccc tccagagtga 6480 ggaagaggta cttgtcactg tgagaaataa atccaaccca ctgtttcaga gtccttatta 6540 caaagtcaga gtacctgaaa atatcaccct ctatacccca attctccaca cccaggcccg 6600 gagtccagag ggactccggc tcatctacaa cattgtggag gaagaaccct tgatgctgtt 6660 caccactgac ttcaagactg gtgtcctaac agtaacaggg cctttggact atgagtccaa 6720 gaccaaacat gtgttcacag tcagagccac ggatacagct ctggggtcat tttctgaagc 6780 cacagtggaa gtcctagtgg aggatgtcaa tgataaccct cccacttttt cccaattggt 6840 ctataccact tccatctcag aaggcttgcc tgctcagacc cctgtgatcc aactgttggc 6900 ttctgaccag gactcagggc ggaaccgtga cgtctcttat cagattgtgg aggatggctc 6960 agatgtttcc aagttcttcc agatcaatgg gagcacaggg gagatgtcca cagttcaaga 7020 actggattat gaagcccaac aacactttca tgtgaaagtc agggccatgg ataaaggaga 7080 tcccccactc actggtgaaa cccttgtggt tgtcaatgtg tctgatatca atgacaaccc 7140 cccagagttc agacaacctc aatatgaagc caatgtcagt gaactggcaa cctgtggaca 7200 cctggttctt aaagtccagg ctattgaccc tgacagcaga gacacctccc gcctggagta 7260 cctgattctt tctggcaatc aggacaggca cttcttcatt aacagctcat cgggaataat 7320 ttctatgttc aacctttgca aaaagcacct ggactcttct tacaatttga gggtaggtgc 7380 ttctgatgga gtcttccgag caactgtgcc tgtgtacatc aacactacaa atgccaacaa 7440 gtacagccca gagttccagc agcaccttta tgaggcagaa ttagcagaga atgcaatggt 7500 tggaaccaag gtgattgatt tgctagccat agacaaagat agtggtccct atggcactat 7560 agattatact atcatcaata aactagcaag tgagaagttc tccataaacc ccaatggcca 7620 gattgccact ctgcagaaac tggatcggga aaattcaaca gagagagtca ttgctattaa 7680 ggtcatggct cgggatggag gaggaagagt agccttctgc acggtgaaga tcatcctcac 7740 agatgaaaat gacaaccccc cacagttcaa agcatctgag tacacagtat ccattcaatc 7800 caatgtcagt aaagactctc cggttatcca ggtgttggcc tatgatgcag atgaaggtca 7860 gaacgcagat gtcacctact cagtgaaccc agaggaccta gttaaagatg tcattgaaat 7920 taacccagtc actggtgtgg tcaaggtgaa agacagcctg gtgggattgg aaaatcagac 7980 ccttgacttc ttcatcaaag cccaagatgg aggccctcct cactggaact ctctggtgcc 8040 agtacgactt caggtggttc ctaaaaaagt atccttaccg aaattttctg aacctttgta 8100 tactttctct gcacctgaag accttccaga ggggtctgaa attgggattg ttaaagcagt 8160 ggcagctcaa gatccagtca tctacagtct agtgcggggc actacacctg agagcaacaa 8220 ggatggtgtc ttctccctag acccagacac aggggtcata aaggtgagga agcccatgga 8280 ccacgaatcc accaaattgt accagattga tgtgatggca cattgccttc agaacactga 8340 tgtggtgtcc ttggtctctg tcaacatcca agtgggagac gtcaatgaca ataggcctgt 8400 atttgaggct gatccatata aggctgtcct cactgagaat atgccagtgg ggacctcagt 8460 cattcaagtg actgccattg acaaggacac tgggagagat ggccaggtga gctacaggct 8520 gtctgcagac cctggtagca atgtccatga gctctttgcc attgacagtg agagtggttg 8580 gatcaccaca ctccaggaac ttgactgtga gacctgccag acttatcatt ttcatgtggt 8640 ggcctatgac cacggacaga ccatccagct atcctctcag gccctggttc aggtctccat 8700 tacagatgag aatgacaatg ctccccgatt tgcttctgaa gagtacagag gatctgtggt 8760 tgagaacagt gagcctggcg aactggtggc gactctaaag accctggatg ctgacatttc 8820 tgagcagaac aggcaggtca cctgctacat cacagaggga gaccccctgg gccagtttgg 8880 catcagccaa gttggagatg agtggaggat ttcctcaagg aagaccctgg accgcgagca 8940 tacagccaag tacttgctca gagtcacagc atctgatggc aagttccagg cttcggtcac 9000 tgtggagatc tttgtcctgg acgtcaatga taacagccca cagtgttcac agcttctcta 9060 tactggcaag gttcatgaag atgtatttcc aggacacttc attttgaagg tttctgccac 9120 agacttggac actgatacca atgctcagat cacatattct ctgcatggcc ctggggcgca 9180 tgaattcaag ctggatcctc atacagggga gctgaccaca ctcactgccc tagaccgaga 9240 aaggaaggat gtgttcaacc ttgttgccaa ggcgacggat ggaggtggcc gatcgtgcca 9300 ggcagacatc accctccatg tggaggatgt gaatgacaat gccccgcggt tcttccccag 9360 ccactgtgct gtggctgtct tcgacaacac cacagtgaag acccctgtgg ctgtagtatt 9420 tgcccgggat cccgaccaag gcgccaatgc ccaggtggtt tactctctgc cggattcagc 9480 cgaaggccac ttttccatcg acgccaccac gggggtgatc cgcctggaaa agccgctgca 9540 ggtcaggccc caggcaccac tggagctcac ggtccgtgcc tctgacctgg gcaccccaat 9600 accgctgtcc acgctgggca ccgtcacagt ctcggtggtg ggcctagaag actacctgcc 9660 cgtgttcctg aacaccgagc acagcgtgca ggtgcccgag gacgccccac ctggcacgga 9720 ggtgctgcag ctggccaccc tcactcgccc gggcgcagag aagaccggct accgcgtggt 9780 cagcgggaac gagcaaggca ggttccgcct ggatgctcgc acagggatcc tgtatgtcaa 9840 cgcaagcctg gactttgaga caagccccaa gtacttcctg tccattgagt gcagccggaa 9900 gagctcctct tccctcagtg acgtgaccac agtcatggtc aacatcactg atgtcaatga 9960 acaccggccc caattccccc aagatccata tagcacaagg gtcttagaga atgcccttgt 10020 gggtgacgtc atcctcacgg tatcagcgac tgatgaagat ggacccctaa atagtgacat 10080 tacctatagc ctcataggag ggaaccagct tgggcacttc accattcacc ccaaaaaggg 10140 ggagctacag gtggccaagg ccctggaccg ggaacaggcc tctagttatt ccctgaagct 10200 ccgagccaca gacagtgggc agcctccact gcatgaggac acagacatcg ctatccaagt 10260 ggctgatgtc aatgataacc caccgagatt cttccagctc aactacagca ccactgtcca 10320 ggagaactcc cccattggca gcaaagtcct gcagctgatc ctgagtgacc cagattctcc 10380 agagaatggc cccccctact cgtttcgaat caccaagggg aacaacggct ctgccttccg 10440 agtgaccccg gatggatggc tggtgactgc tgagggccta agcaggaggg ctcaggaatg 10500 gtatcagctt cagatccagg cgtcagacag tggcatccct cccctctcgt ctttgacgtc 10560 tgtccgtgtc catgtcacag agcagagcca ctatgcacct tctgctctcc cactggagat 10620 cttcatcact gttggagagg atgagttcca gggtggcatg gtgggtaaga tccatgccac 10680 agaccgagac ccccaggaca cgctgaccta tagcctggca gaagaggaga ccctgggcag 10740 gcacttctca gtgggtgcgc ctgatggcaa gattatcgcc gcccagggcc tgcctcgtgg 10800 ccactactcg ttcaacgtca cggtcagcga tgggaccttc accacgactg ctggggtcca 10860 tgtgtacgtg tggcatgtgg ggcaggaggc tctgcagcag gccatgtgga tgggcttcta 10920 ccagctcacc cccgaggagc tggtgagtga ccactggcgg aacctgcaga ggttcctcag 10980 ccataagctg gacatcaaac gggctaacat tcacttggcc agcctccagc ctgcagaggc 11040 cgtggctggt gtggatgtgc tcctggtctt tgaggggcat tctggaacct tctacgagtt 11100 tcaggagcta gcatccatca tcactcactc agccaaggag atggagcatt cagtgggggt 11160 tcagatgcgg tcagctatgc ccatggtgcc ctgccagggg ccaacctgcc agggtcaaat 11220 ctgccataac acagtgcatc tggaccccaa ggttgggccc acgtacagca ccgccaggct 11280 cagcatccta accccgcggc accacctgca gaggagctgc tcctgcaatg gtactgctac 11340 aaggttcagt ggtcagagct atgtgcggta cagggcccca gcggctcgga actggcacat 11400 ccatttctat ctgaaaacac tccagccaca ggccattctt ctattcacca atgaaacagc 11460 gtccgtctcc ctgaagctgg ccagtggagt gccccagctg gaataccact gtctgggtgg 11520 tttctatgga aacctttcct cccagcgcca tgtgaatgac cacgagtggc actccatcct 11580 ggtggaggag atggacgctt ccattcgcct gatggttgac agcatgggca acacctccct 11640 tgtggtccca gagaactgcc gtggtctgag gcccgaaagg cacctcttgc tgggcggcct 11700 cattctgttg cattcttcct cgaatgtctc ccagggcttt gaaggctgcc tggatgctgt 11760 cgtggtcaac gaagaggctc tagatctgct ggcccctggc aagacggtgg caggcttgct 11820 ggagacacaa gccctcaccc agtgctgcct ccacagtgac tactgcagcc agaacacatg 11880 cctcaatggt gggaagtgct catggaccca tggggcaggc tatgtctgca aatgtccccc 11940 acagttctct gggaagcact gtgaacaagg aagggagaac tgtacttttg caccctgcct 12000 ggaaggtgga acttgcatcc tctcccccaa aggagcttcc tgtaactgcc ctcatcctta 12060 cacaggagac aggtgtgaaa tggaggcgag gggttgttca gaaggacact gcctagtcac 12120 tcccgagatc caaagggggg actgggggca gcaggagtta ctgatcatca cagtggccgt 12180 ggcgttcatt atcataagca ctgtcgggct tctcttctac tgccgccgtt gcaagtctca 12240 caagcctgtg gccatggagg acccagacct cctggccagg agtgttggtg ttgacaccca 12300 agccatgcct gccatcgagc tcaacccatt gagtgccagc tcctgcaaca acctcaacca 12360 accggaaccc agcaaggcct ctgttccaaa tgaactcgtc acatttggac ccaattctaa 12420 gcaacggcca gtggtctgca gtgtgccccc cagactcccg ccagctgcgg tcccttccca 12480 ctctgacaat gagcctgtca ttaagagaac ctggtccagc gaggagatgg tgtaccctgg 12540 cggagccatg gtctggcccc ctacttactc caggaacgaa cgctgggaat acccccactc 12600 cgaagtgact cagggccctc tgccgccctc ggctcaccgc cactcaaccc cagtcgtgat 12660 gccagagcct aatggcctct atgggggctt ccccttcccc ctggagatgg aaaacaagcg 12720 ggcacctctc ccaccccgtt acagcaacca gaacctggaa gatctgatgc cctctcggcc 12780 ccctagtccc cgggagcgcc tggttgcccc ctgtctcaat gagtacacgg ccatcagcta 12840 ctaccactcg cagttccggc agggaggggg agggccctgc ctggcagacg ggggctacaa 12900 gggggtgggt atgcgcctca gccgagctgg gccctcttat gctgtctgtg aggtggaggg 12960 ggcacctctt gcaggccagg gccagccccg ggtgcccccc aactatgagg gctctgacat 13020 ggtggagagt gattatggca gctgtgagga ggtcatgttc tagcttccca ttcccagagc 13080 aaggcaggcg ggaggccaag gactggactt ggcttatttc ttcctgtctc gtagggggtg 13140 agttgagtgt ggctgggaga gtgggaggga agccctcagc ccaggctgtt gtcccttgaa 13200 atgtgctctt ccaatccccc acctagtccc tgagggtgga gggaagctga ggatagagct 13260 ccagaaacag cactagggtc ccaggagagg ggcatttcta gagcagtgac cctggaaaac 13320 caggaacaat tgactcctgg ggtgggcgac agacaggagg gctccctgat ctgccggctc 13380 tcagtccccg gggcaaagcc tgattgactg tgctggctca acttcaccaa gatgcattct 13440 catacctgcc cacagctcca ttttggaggc aggcaggttg gtgcctgaca gacaaccact 13500 acgcgggccg tacagaggag ctctagaggg ctgcgtggca tcctcctagg ggctgagagg 13560 tgagcagcag gggagcgggc acagtcccct ctgcccctgc ctcagtcgag cactcactgt 13620 gtctttgtca agtgtctgct ccacgtcagg cactgtgctt tgcaccgggg agaaaatggt 13680 gatggagggc aacaaggact ccgaggagca ccaccaggcc tcgggcccca gaggtcccgc 13740 tcctcagcct acacgcagag gaacgggccc acctcagagt cacaccactg gctgccagtc 13800 agggcctgcc aggagtctac acagctctga accttctttg ttaaagaatt cagacctcat 13860 ggaactctgg gttcttcatc ccaagtttcc caggcacttt tggccaaagg aaggaaggaa 13920 ctaattcttc attttaaaaa ttcttaggca ctttttgacc ttgctgtctg gatgagtttc 13980 ctcaatggga tttttcttcc ctagacacaa ggaagtctga actcctattt agggccggtt 14040 ggaagcaggg agctggaccg cagtgtccag gctggacacc tgccattgcc tcctctccac 14100 tgcagacgcc tgcccatcaa gtattacctg cagcgactca accctatgca tggagggtca 14160 atgtgggcac atgtctacac atgtgggtgc ccatggatag tacgtgtgta cacatgtgta 14220 gagtgtatgt agccaggagt ggtggggacc agaagcctct gtggcctttg gtgacctcac 14280 cactccctcc cacccagtcc ctccctctgg tccactgcct tttcatatgt gttgtttctg 14340 gagacagaag tcaaaaggaa gagcagtgga gccttgccca cagggctgct gcttcatgcg 14400 agagggagat gtgtgggcga gagccaattt gtgtgagtgg tttgtggctg tgtgtgtgac 14460 tgtgagtgtg agtgacagat acatagtttc attggtcatt ttttttttta acaataaagt 14520 atcttttttt actgtt 14536 7 14536 DNA Homo sapiens 7 ggagttttcc accatgacta ttgccctgct gggttttgcc atattcttgc tccattgtgc 60 gacctgtgag aagcctctag aagggattct ctcctcctct gcttggcact tcacacactc 120 ccattacaat gccaccatct atgaaaattc ttctcccaag acctatgtgg agagcttcga 180 gaaaatgggc atctacctcg cggagccaca gtgggcagtg aggtaccgga tcatctctgg 240 ggatgtggcc aatgtattta aaactgagga gtatgtggtg ggcaacttct gcttcctaag 300 aataaggaca aagagcagca acacagctct tctgaacaga gaggtgcgag acagctacac 360 cctcatcatc caagccacag agaagacctt ggagttggaa gctttgaccc gtgtggtggt 420 ccacatcctg gaccagaatg acctgaagcc tctcttctct ccaccttcgt acagagtcac 480 catctctgag gacatgcccc tgaagagccc catctgcaag gtgactgcca cagatgctga 540 tctaggccag aatgctgagt tctattatgc ctttaacaca aggtcagaga tgtttgccat 600 ccatcccacc agcggtgtgg tcactgtggc tgggaagctt aacgtcacct ggcgaggaaa 660 gcatgagctc caggtgctag ctgtggaccg catgcggaaa atctctgagg gcaatgggtt 720 tggcagcctg gctgcacttg tggttcatgt ggagcctgcc ctcaggaagc ccccagccat 780 tgcttcggtg gtggtgactc caccagacag caatgatggt accacctatg ccactgtact 840 ggtcgatgca aatagctcag gagctgaagt ggagtcagtg gaagttgttg gtggtgaccc 900 tggaaagcac ttcaaagcca tcaagtctta tgcccggagc aatgagttca gtttggtgtc 960 tgtcaaagac atcaactgga tggagtacct tcatgggttc aacctcagcc tccaggccag 1020 gagtgggagc ggcccttatt tttattccca gatcaggggc tttcacctac caccttccaa 1080 actgtcttcc ctcaaattcg agaaggctgt ttacagagtg cagcttagtg agttttcccc 1140 tcctggcagc cgcgtggtga tggtgagagt caccccagcc ttccccaacc tgcagtatgt 1200 tctaaagcca tcttcagaga atgtaggatt taaacttaat gctcgaactg ggttgatcac 1260 caccacaaag ctcatggact tccacgacag agcccactat cagctacaca tcagaacctc 1320 accgggccag gcctccaccg tggtggtcat tgacattgtg gactgcaaca accatgcccc 1380 cctcttcaac aggtcttcct atgatggtac cttggatgag aacatccctc caggcaccag 1440 tgttttggct gtgactgcca ctgaccggga tcatggggaa aatggatatg tcacctattc 1500 cattgctgga ccaaaagctt tgccattttc tattgacccc tacctgggga tcatctccac 1560 ctccaaaccc atggactatg aactcatgaa aagaatttat accttccggg taagagcatc 1620 agactgggga tccccttttc gccgggagaa ggaagtgtcc atttttcttc agctcaggaa 1680 cttgaatgac aaccagccta tgtttgaaga agtcaactgt acagggtcta tccgccaaga 1740 ctggccagta gggaaatcga taatgactat gtcagccata gatgtggatg agcttcagaa 1800 cctaaaatac gagattgtat caggcaatga actagagtat tttgatctaa atcatttctc 1860 cggagtgata tccctcaaac gcccttttat caatcttact gctggtcaac ccaccagtta 1920 ttccctgaag attacagcct cagatggcaa aaactatgcc tcacccacaa ctttgaatat 1980 tactgtggtg aaggaccctc attttgaagt tcctgtaaca tgtgataaaa caggggtatt 2040 gacacaattc acaaagacta tcctccactt tattgggctt cagaaccagg agtccagtga 2100 tgaggaattc acttctttaa gcacatatca gattaatcat tacaccccac agtttgagga 2160 ccacttcccc caatccattg atgtccttga gagtgtccct atcaacaccc ccttggcccg 2220 cctagcagcc actgaccctg atgctggttt taatggcaaa ctggtctatg tgattgcaga 2280 tggcaatgag gagggctgct ttgacataga gctggagaca gggctgctca ctgtagctgc 2340 tcccttggac tatgaagcca ccaatttcta catcctcaat gtaacagtat atgacctggg 2400 cacaccccag aagtcctcct ggaagctgct gacagtgaat gtgaaagact ggaatgacaa 2460 cgcacccaga tttcctcccg gtgggtacca gttaaccatc tcggaggaca cagaagttgg 2520 aaccacaatt gcagagctga caaccaaaga tgctgactcg gaagacaatg gcagggttcg 2580 ctacaccctg ctaagtccca cagagaagtt ctccctccac cctctcactg gggaactggt 2640 tgttacagga cacctggacc gcgaatcaga gcctcggtac atactcaagg tggaggccag 2700 ggatcagccc agcaaaggcc accagctctt ctctgtcact gacctgataa tcacattgga 2760 ggatgtcaac gacaactctc cccagtgcat cacagaacac aacaggctga aggttccaga 2820 ggacctgccc cccgggactg tcttgacatt tctggatgcc tctgatcctg acctgggccc 2880 cgcaggtgaa gtgcgatatg ttctgatgga tggcgcccat gggaccttcc gggtggacct 2940 gatgacaggg gcgctcattc tggagagaga gctggacttt gagaggcgag ctgggtacaa 3000 tctgagcctg tgggccagtg atggtgggag gcccctagcc cgcaggactc tctgccatgt 3060 ggaggtgatc gtcctggatg tgaatgagaa tctccaccct ccccactttg cctccttcgt 3120 gcaccagggc caggtgcagg agaacagccc ctcgggaact caggtgattg tagtggctgc 3180 ccaggacgat gacagtggct tggatgggga gctccagtac ttcctgcgtg ctggcactgg 3240 actcgcagcc ttcagcatca accaagatac aggaatgatt cagactctgg cacccctgga 3300 ccgagaattt gcatcttact actggttgac ggtattagca gtggacaggg gttctgtgcc 3360 cctctcttct gtaactgaag tctacatcga ggttacggat gccaatgaca acccacccca 3420 gatgtcccaa gctgtgttct acccctccat ccaggaggat gctcccgtgg gcacctctgt 3480 gcttcaactg gatgcctggg acccagactc cagctccaaa gggaagctga ccttcaacat 3540 caccagtggg aactacatgg gattctttat gattcaccct gttacaggtc tcctatctac 3600 agcccagcag ctggacagag agaacaagga tgaacacatc ctggaggtga ctgtgctgga 3660 caatggggaa ccctcactga agtccacctc cagggtggtg gtaggcatct tggacgtcaa 3720 tgacaatcca cctatattct cccacaagct cttcaatgtc cgccttccag agaggctgag 3780 ccctgtgtcc cctgggcctg tgtacaggct ggtggcttca gacctggatg agggtcttaa 3840 tggcagagtc acctacagta tcgaggacag cgatgaggag gccttcagta tcgacctggt 3900 cacaggtgtg gtttcatcca gcagcacttt tacagctgga gagtacaaca tcctaacgat 3960 caaggcaaca gacagtgggc agccaccact ctcagccagt gtccggctac acattgagtg 4020 gatcccttgg ccccggccgt cctccatccc tctggccttt gatgagacct actacagctt 4080 tacggtcatg gagacggacc ctgtgaacca catggtgggg gtcatcagcg tagagggcag 4140 acccggactc ttctggttca acatctcagg tggggataag gacatggact ttgacattga 4200 gaagaccaca ggcagcatcg tcattgccag gcctcttgat accaggagaa ggtcgaacta 4260 taacttgact gttgaggtga cagatgggtc ccgcaccatt gccacacagg tccacatctt 4320 catgattgcc aacattaacc accatcggcc ccagtttctg gaaactcgtt atgaagtcag 4380 agttccccag gacaccgtgc caggggtaga gctcctgcga gtccaggcca tagatcaaga 4440 caagggcaaa agcctcatct ataccataca tggcagccaa gacccaggaa gtgccagcct 4500 cttccagctg gacccaagca gtggtgtcct ggtaacggtg ggaaaattgg acctcggctc 4560 ggggccctcc cagcacacac tgacagtcat ggtccgagac caggaaatac ctatcaagag 4620 gaacttcgtg tgggtgacca ttcatgtgga ggatggaaac ctccacccac cccgcttcac 4680 tcagctccat tatgaggcaa gtgttcctga caccatagcc cccggcacag agctgctgca 4740 ggtccgagcc atggatgctg accggggagt caatgctgag gtccactact ccctcctgaa 4800 agggaacagc gaaggtttct tcaacatcaa tgccctgcta ggcatcatta ctctagctca 4860 aaagcttgat caggcaaatc atgccccaca tactctgaca gtgaaggcag aagatcaagg 4920 ctccccacaa tggcatgacc tggctacagt gatcattcat gtctatccct cagataggag 4980 tgcccccatc ttttcaaaat ctgagtactt tgtagagatc cctgaatcaa tccctgttgg 5040 ttccccaatc ctccttgtct ctgctatgag cccctctgaa gttacctatg agttaagaga 5100 gggaaataag gatggagtct tctctatgaa ctcatattct ggccttattt ccacccagaa 5160 gaaattggac catgagaaaa tctcgtctta ccagctgaaa atccgaggca gcaatatggc 5220 aggtgcattt actgatgtca tggtggtggt tgacataatt gatgaaaatg acaatgctcc 5280 tatgttctta aagtcaactt ttgtgggcca aattagtgaa gcagctccac tgtatagcat 5340 gatcatggat aaaaacaaca acccctttgt gattcatgcc tctgacagtg acaaagaagc 5400 taattccttg ttggtctata aaattttgga gccggaggcc ttgaagtttt tcaaaattga 5460 tcccagcatg ggaaccctaa ccattgtatc agagatggat tatgagagca tgccctcttt 5520 ccaattctgt gtctatgtcc atgaccaagg aagccctgta ttatttgcac ccagacctgc 5580 ccaagtcatc attcatgtca gagatgtgaa tgattcccct cccagattct cagaacagat 5640 atatgaggta gcaatagtcg ggcctatcca tccaggcatg gagcttctca tggtgcgggc 5700 cagcgatgaa gactcagaag tcaattatag catcaaaact ggcaatgctg atgaagctgt 5760 taccatccat cctgtcactg gtagcatatc tgtgctgaat cctgctttcc tgggactctc 5820 tcggaagctc accatcaggg cttctgatgg cttgtatcaa gacactgcgc tggtaaaaat 5880 ttctttgacc caagtgcttg acaaaagctt gcagtttgat caggatgtct actgggcagc 5940 tgtgaaggag aacttgcagg acagaaaggc actggtgatt cttggtgccc agggcaatca 6000 tttgaatgac accctttcct actttctctt gaatggcaca gatatgtttc atatggtcca 6060 gtcagcaggt gtgttgcaga caagaggtgt ggcgtttgac cgggagcagc aggacactca 6120 tgagttggca gtggaagtga gggacaatcg gacacctcag cgggtggctc agggtttggt 6180 cagagtctct attgaggatg tcaatgacaa tccccccaaa tttaagcatc tgccctatta 6240 cacaatcatc caagatggca cagagccagg ggatgtcctc tttcaggtat ctgccactga 6300 tgaggacttg gggacaaatg gggctgttac atatgaattt gcagaagatt acacatattt 6360 ccgaattgac ccctatcttg gggacatatc actcaagaaa ccctttgatt atcaagcttt 6420 aaataaatat cacctcaaag tcattgctcg ggatggagga acgccatccc tccagagtga 6480 ggaagaggta cttgtcactg tgagaaataa atccaaccca ctgtttcaga gtccttatta 6540 caaagtcaga gtacctgaaa atatcaccct ctatacccca attctccaca cccaggcccg 6600 gagtccagag ggactccggc tcatctacaa cattgtggag gaagaaccct tgatgctgtt 6660 caccactgac ttcaagactg gtgtcctaac agtaacaggg cctttggact atgagtccaa 6720 gaccaaacat gtgttcacag tcagagccac ggatacagct ctggggtcat tttctgaagc 6780 cacagtggaa gtcctagtgg aggatgtcaa tgataaccct cccacttttt cccaattggt 6840 ctataccact tccatctcag aaggcttgcc tgctcagacc cctgtgatcc aactgttggc 6900 ttctgaccag gactcagggc ggaaccgtga cgtctcttat cagattgtgg aggatggctc 6960 agatgtttcc aagttcttcc agatcaatgg gagcacaggg gagatgtcca cagttcaaga 7020 actggattat gaagcccaac aacactttca tgtgaaagtc agggccatgg ataaaggaga 7080 tcccccactc actggtgaaa cccttgtggt tgtcaatgtg tctgatatca atgacaaccc 7140 cccagagttc agacaacctc aatatgaagc caatgtcagt gaactggcaa cctgtggaca 7200 cctggttctt aaagtccagg ctattgaccc tgacagcaga gacacctccc gcctggagta 7260 cctgattctt tctggcaatc aggacaggca cttcttcatt aacagctcat cgggaataat 7320 ttctatgttc aacctttgca aaaagcacct ggactcttct tacaatttga gggtaggtgc 7380 ttctgatgga gtcttccgag caactgtgcc tgtgtacatc aacactacaa atgccaacaa 7440 gtacagccca gagttccagc agcaccttta tgaggcagaa ttagcagaga atgcaatggt 7500 tggaaccaag gtgattgatt tgctagccat agacaaagat agtggtccct atggcactat 7560 agattatact atcatcaata aactagcaag tgagaagttc tccataaacc ccaatggcca 7620 gattgccact ctgcagaaac tggatcggga aaattcaaca gagagagtca ttgctattaa 7680 ggtcatggct cgggatggag gaggaagagt agccttctgc acggtgaaga tcatcctcac 7740 agatgaaaat gacaaccccc cacagttcaa agcatctgag tacacagtat ccattcaatc 7800 caatgtcagt aaagactctc cggttatcca ggtgttggcc tatgatgcag atgaaggtca 7860 gaacgcagat gtcacctact cagtgaaccc agaggaccta gttaaagatg tcattgaaat 7920 taacccagtc actggtgtgg tcaaggtgaa agacagcctg gtgggattgg aaaatcagac 7980 ccttgacttc ttcatcaaag cccaagatgg aggccctcct cactggaact ctctggtgcc 8040 agtacgactt caggtggttc ctaaaaaagt atccttaccg aaattttctg aacctttgta 8100 tactttctct gcacctgaag accttccaga ggggtctgaa attgggattg ttaaagcagt 8160 ggcagctcaa gatccagtca tctacagtct agtgcggggc actacacctg agagcaacaa 8220 ggatggtgtc ttctccctag acccagacac aggggtcata aaggtgagga agcccatgga 8280 ccacgaatcc accaaattgt accagattga tgtgatggca cattgccttc agaacactga 8340 tgtggtgtcc ttggtctctg tcaacatcca agtgggagac gtcaatgaca ataggcctgt 8400 atttgaggct gatccatata aggctgtcct cactgagaat atgccagtgg ggacctcagt 8460 cattcaagtg actgccattg acaaggacac tgggagagat ggccaggtga gctacaggct 8520 gtctgcagac cctggtagca atgtccatga gctctttgcc attgacagtg agagtggttg 8580 gatcaccaca ctccaggaac ttgactgtga gacctgccag acttatcatt ttcatgtggt 8640 ggcctatgac cacggacaga ccatccagct atcctctcag gccctggttc aggtctccat 8700 tacagatgag aatgacaatg ctccccgatt tgcttctgaa gagtacagag gatctgtggt 8760 tgagaacagt gagcctggcg aactggtggc gactctaaag accctggatg ctgacatttc 8820 tgagcagaac aggcaggtca cctgctacat cacagaggga gaccccctgg gccagtttgg 8880 catcagccaa gttggagatg agtggaggat ttcctcaagg aagaccctgg accgcgagca 8940 tacagccaag tacttgctca gagtcacagc atctgatggc aagttccagg cttcggtcac 9000 tgtggagatc tttgtcctgg acgtcaatga taacagccca cagtgttcac agcttctcta 9060 tactggcaag gttcatgaag atgtatttcc aggacacttc attttgaagg tttctgccac 9120 agacttggac actgatacca atgctcagat cacatattct ctgcatggcc ctggggcgca 9180 tgaattcaag ctggatcctc atacagggga gctgaccaca ctcactgccc tagaccgaga 9240 aaggaaggat gtgttcaacc ttgttgccaa ggcgacggat ggaggtggcc gatcgtgcca 9300 ggcagacatc accctccatg tggaggatgt gaatgacaat gccccgcggt tcttccccag 9360 ccactgtgct gtggctgtct tcgacaacac cacagtgaag acccctgtgg ctgtagtatt 9420 tgcccgggat cccgaccaag gcgccaatgc ccaggtggtt tactctctgc cggattcagc 9480 cgaaggccac ttttccatcg acgccaccac gggggtgatc cgcctggaaa agccgctgca 9540 ggtcaggccc caggcaccac tggagctcac ggtccgtgcc tctgacctgg gcaccccaat 9600 accgctgtcc acgctgggca ccgtcacagt ctcggtggtg ggcctagaag actacctgcc 9660 cgtgttcctg aacaccgagc acagcgtgca ggtgcccgag gacgccccac ctggcacgga 9720 ggtgctgcag ctggccaccc tcactcgccc gggcgcagag aagaccggct accgcgtggt 9780 cagcgggaac gagcaaggca ggttccgcct ggatgctcgc acagggatcc tgtatgtcaa 9840 cgcaagcctg gactttgaga caagccccaa gtacttcctg tccattgagt gcagccggaa 9900 gagctcctct tccctcagtg acgtgaccac agtcatggtc aacatcactg atgtcaatga 9960 acaccggccc caattccccc aagatccata tagcacaagg gtcttagaga atgcccttgt 10020 gggtgacgtc atcctcacgg tatcagcgac tgatgaagat ggacccctaa atagtgacat 10080 tacctatagc ctcataggag ggaaccagct tgggcacttc accattcacc ccaaaaaggg 10140 ggagctacag gtggccaagg ccctggaccg ggaacaggcc tctagttatt ccctgaagct 10200 ccgagccaca gacagtgggc agcctccact gcatgaggac acagacatcg ctatccaagt 10260 ggctgatgtc aatgataacc caccgagatt cttccagctc aactacagca ccactgtcca 10320 ggagaactcc cccattggca gcaaagtcct gcagctgatc ctgagtgacc cagattctcc 10380 agagaatggc cccccctact cgtttcgaat caccaagggg aacaacggct ctgccttccg 10440 agtgaccccg gatggatggc tggtgactgc tgagggccta agcaggaggg ctcaggaatg 10500 gtatcagctt cagatccagg cgtcagacag tggcatccct cccctctcgt ctttgacgtc 10560 tgtccgtgtc catgtcacag agcagagcca ctatgcacct tctgctctcc cactggagat 10620 cttcatcact gttggagagg atgagttcca gggtggcatg gtgggtaaga tccatgccac 10680 agaccgagac ccccaggaca cgctgaccta tagcctggca gaagaggaga ccctgggcag 10740 gcacttctca gtgggtgcgc ctgatggcaa gattatcgcc gcccagggcc tgcctcgtgg 10800 ccactactcg ttcaacgtca cggtcagcga tgggaccttc accacgactg ctggggtcca 10860 tgtgtacgtg tggcatgtgg ggcaggaggc tctgcagcag gccatgtgga tgggcttcta 10920 ccagctcacc cccgaggagc tggtgagtga ccactggcgg aacctgcaga ggttcctcag 10980 ccataagctg gacatcaaac gggctaacat tcacttggcc agcctccagc ctgcagaggc 11040 cgtggctggt gtggatgtgc tcctggtctt tgaggggcat tctggaacct tctacgagtt 11100 tcaggagcta gcatccatca tcactcactc agccaaggag atggagcatt cagtgggggt 11160 tcagatgcgg tcagctatgc ccatggtgcc ctgccagggg ccaacctgcc agggtcaaat 11220 ctgccataac acagtgcatc tggaccccaa ggttgggccc acgtacagca ccgccaggct 11280 cagcatccta accccgcggc accacctgca gaggagctgc tcctgcaatg gtactgctac 11340 aaggttcagt ggtcagagct atgtgcggta cagggcccca gcggctcgga actggcacat 11400 ccatttctat ctgaaaacac tccagccaca ggccattctt ctattcacca atgaaacagc 11460 gtccgtctcc ctgaagctgg ccagtggagt gccccagctg gaataccact gtctgggtgg 11520 tttctatgga aacctttcct cccagcgcca tgtgaatgac cacgagtggc actccatcct 11580 ggtggaggag atggacgctt ccattcgcct gatggttgac agcatgggca acacctccct 11640 tgtggtccca gagaactgcc gtggtctgag gcccgaaagg cacctcttgc tgggcggcct 11700 cattctgttg cattcttcct cgaatgtctc ccagggcttt gaaggctgcc tggatgctgt 11760 cgtggtcaac gaagaggctc tagatctgct ggcccctggc aagacggtgg caggcttgct 11820 ggagacacaa gccctcaccc agtgctgcct ccacagtgac tactgcagcc agaacacatg 11880 cctcaatggt gggaagtgct catggaccca tggggcaggc tatgtctgca aatgtccccc 11940 acagttctct gggaagcact gtgaacaagg aagggagaac tgtacttttg caccctgcct 12000 ggaaggtgga acttgcatcc tctcccccaa aggagcttcc tgtaactgcc ctcatcctta 12060 cacaggagac aggtgtgaaa tggaggcgag gggttgttca gaaggacact gcctagtcac 12120 tcccgagatc caaagggggg actgggggca gcaggagtta ctgatcatca cagtggccgt 12180 ggcgttcatt atcataagca ctgtcgggct tctcttctac tgccgccgtt gcaagtctca 12240 caagcctgtg gccatggagg acccagacct cctggccagg agtgttggtg ttgacaccca 12300 agccatgcct gccatcgagc tcaacccatt gagtgccagc tcctgcaaca acctcaacca 12360 accggaaccc agcaaggcct ctgttccaaa tgaactcgtc acatttggac ccaattctaa 12420 gcaacggcca gtggtctgca gtgtgccccc cagactcccg ccagctgcgg tcccttccca 12480 ctctgacaat gagcctgtca ttaagagaac ctggtccagc gaggagatgg tgtaccctgg 12540 cggagccatg gtctggcccc ctacttactc caggaacgaa cgctgggaat acccccactc 12600 cgaagtgact cagggccctc tgccgccctc ggctcaccgc cactcaaccc cagtcgtgat 12660 gccagagcct aatggcctct atgggggctt ccccttcccc ctggagatgg aaaacaagcg 12720 ggcacctctc ccaccccgtt acagcaacca gaacctggaa gatctgatgc cctctcggcc 12780 ccctagtccc cgggagcgcc tggttgcccc ctgtctcaat gagtacacgg ccatcagcta 12840 ctaccactcg cagttccggc agggaggggg agggccctgc ctggcagacg ggggctacaa 12900 gggggtgggt atgcgcctca gccgagctgg gccctcttat gctgtctgtg aggtggaggg 12960 ggcacctctt gcaggccagg gccagccccg ggtgcccccc aactatgagg gctctgacat 13020 ggtggagagt gattatggca gctgtgagga ggtcatgttc tagcttccca ttcccagagc 13080 aaggcaggcg ggaggccaag gactggactt ggcttatttc ttcctgtctc gtagggggtg 13140 agttgagtgt ggctgggaga gtgggaggga agccctcagc ccaggctgtt gtcccttgaa 13200 atgtgctctt ccaatccccc acctagtccc tgagggtgga gggaagctga ggatagagct 13260 ccagaaacag cactagggtc ccaggagagg ggcatttcta gagcagtgac cctggaaaac 13320 caggaacaat tgactcctgg ggtgggcgac agacaggagg gctccctgat ctgccggctc 13380 tcagtccccg gggcaaagcc tgattgactg tgctggctca acttcaccaa gatgcattct 13440 catacctgcc cacagctcca ttttggaggc aggcaggttg gtgcctgaca gacaaccact 13500 acgcgggccg tacagaggag ctctagaggg ctgcgtggca tcctcctagg ggctgagagg 13560 tgagcagcag gggagcgggc acagtcccct ctgcccctgc ctcagtcgag cactcactgt 13620 gtctttgtca agtgtctgct ccacgtcagg cactgtgctt tgcaccgggg agaaaatggt 13680 gatggagggc aacaaggact ccgaggagca ccaccaggcc tcgggcccca gaggtcccgc 13740 tcctcagcct acacgcagag gaacgggccc acctcagagt cacaccactg gctgccagtc 13800 agggcctgcc aggagtctac acagctctga accttctttg ttaaagaatt cagacctcat 13860 ggaactctgg gttcttcatc ccaagtttcc caggcacttt tggccaaagg aaggaaggaa 13920 ctaattcttc attttaaaaa ttcttaggca ctttttgacc ttgctgtctg gatgagtttc 13980 ctcaatggga tttttcttcc ctagacacaa ggaagtctga actcctattt agggccggtt 14040 ggaagcaggg agctggaccg cagtgtccag gctggacacc tgccattgcc tcctctccac 14100 tgcagacgcc tgcccatcaa gtattacctg cagcgactca accctatgca tggagggtca 14160 atgtgggcac atgtctacac atgtgggtgc ccatggatag tacgtgtgta cacatgtgta 14220 gagtgtatgt agccaggagt ggtggggacc agaagcctct gtggcctttg gtgacctcac 14280 cactccctcc cacccagtcc ctccctctgg tccactgcct tttcatatgt gttgtttctg 14340 gagacagaag tcaaaaggaa gagcagtgga gccttgccca cagggctgct gcttcatgcg 14400 agagggagat gtgtgggcga gagccaattt gtgtgagtgg tttgtggctg tgtgtgtgac 14460 tgtgagtgtg agtgacagat acatagtttc attggtcatt ttttttttta acaataaagt 14520 atcttttttt actgtt 14536 8 3174 DNA Homo sapiens 8 ccaccatgac tattgccctg ctgggttttg ccatattctt gctccattgt gcgacctgtg 60 agaagcctct agaagggatt ctctcctcct ctgcttggca cttcacacac tcccattaca 120 atgccaccat ctatgaaaat tcttctccca agacctatgt ggagagcttc gagaaaatgg 180 gcatctacct cgcggagcca cagtgggcag tgaggtaccg gatcatctct ggggatgtgg 240 ccaatgtatt taaaactgag gagtatgtgg tgggcaactt ctgcttccta agaataagga 300 caaagagcag caacacagct cttctgaaca gagaggtgcg agacagctac accctcatca 360 tccaagccac agagaagacc ttggagttgg aagctttgac ccgtgtggtg gtccacatcc 420 tggaccagaa tgacctgaag cctctcttct ctccaccttc gtacagagtc accatctctg 480 aggacatgcc cctgaagagc cccatctgca aggtgactgc cacagatgct gatctaggcc 540 agaatgctga gttctattat gcctttaaca caaggtcaga gatgtttgcc atccatccca 600 ccagcggtgt ggtcactgtg gctgggaagc ttaacgtcac ctggcgagga aagcatgagc 660 tccaggtgct agctgtggac cgcatgcgga aaatctctga gggcaatggg tttggcagcc 720 tggctgcact tgtggttcat gtggagcctg ccctcaggaa gcccccagcc attgcttcgg 780 tggtggtgac tccaccagac agcaatgatg gtaccaccta tgccactgta ctggtcgatg 840 caaatagctc aggagctgaa gtggagtcag tggaagttgt tggtggtgac cctggaaagc 900 acttcaaagc catcaagtct tatgcccgga gcaatgagtt cagtttggtg tctgtcaaag 960 acatcaactg gatggagtac cttcatgggt tcaacctcag cctccaggcc aggagtggga 1020 gcggccctta tttttattcc cagatcaggg gctttcacct accaccttcc aaactgtctt 1080 ccctcaaatt cgagaaggct gtttacagag tgcagcttag tgagttttcc cctcctggca 1140 gccgcgtggt gatggtgaga gtcaccccag ccttccccaa cctgcagtat gttctaaagc 1200 catcttcaga gaatgtagga tttaaactta atgctcgaac tgggttgatc accaccacaa 1260 agctcatgga cttccacgac agagcccact atcagctaca catcagaacc tcaccgggcc 1320 aggcctccac cgtggtggtc attgacattg tggactgcaa caaccatgcc cccctcttca 1380 acaggtcttc ctatgatggt accttggatg agaacatccc tccaggcacc agtgttttgg 1440 ctgtgactgc cactgaccgg gatcatgggg aaaatggata tgtcacctat tccattgctg 1500 gaccaaaagc tttgccattt tctattgacc cttacctggg gatcatctcc acctccaaac 1560 ccatggacta tgaactcatg aaaagaattt ataccttccg ggtaagagca tcagactggg 1620 gatccccttt tcgccgggag aaggaagtgt ccatttttct tcagctcagg aacttgaatg 1680 acaaccagcc tatgtttgaa gaagtcaact gtacagggtc tatccgccaa gactggccag 1740 tagggaaatc gataatgact atgtcagcca tagatgtgga tgagcttcag aacctaaaat 1800 acgagattgt atcaggcaat gaactagagt attttgatct aaatcatttc tccggagtga 1860 tatccctcaa acgccctttt atcaatctta ctgctggtca acccaccagt tattccctga 1920 agattacagc ctcagatggc aaaaactatg cctcacccac aactttgaat attactgtgg 1980 tgaaggaccc tcattttgaa gttcctgtaa catgtgataa aacaggggta ttgacacaat 2040 tcacaaagac tatcctccac tttattgggc ttcagaacca ggagtccagt gatgaggaat 2100 tcacttcttt aagcacatat cagattaatc attacacccc acagtttgag gaccacttcc 2160 cccaatccat tgatgtcctt gagagtgtcc ctatcaacac ccccttggcc cgcctagcag 2220 ccactgaccc tgatgctggt tttaatggca aactggtcta tgtgattgca gatggcaatg 2280 aggagggctg ctttgacata gagctggaga cagggctgct cactgtagct gctcccttgg 2340 actatgaagc caccaatttc tacatcctca atgtaacagt atatgacctg ggcacacccc 2400 agaagtcctc ctggaagctg ctgacagtga atgtgaaaga ctggaatgac aacgcaccca 2460 gatttcctcc cggtgggtac cagttaacca tctcggagga cacagaagtt ggaaccacaa 2520 ttgcagagct gacaaccaaa gatgctgact cggaagacaa tggcagggtt cgctacaccc 2580 tgctaagtcc cacagagaag ttctccctcc accctctcac tggggaactg gttgttacag 2640 gacacctgga ccgcgaatca gagcctcggt acatactcaa ggtggaggcc agggatcagc 2700 ccagcaaagg ccaccagctc ttctctgtca ctgacctgat aatcacattg gaggatgtca 2760 acgacaactc tccccagtgc atcacagaac acaacaggct gaaggttcca gaggacctgc 2820 cccccgggac tgtcttgaca tttctggatg cctctgatcc tgacctgggc cccgcaggtg 2880 aagtgcgata tgttctgatg gatggcgccc atgggacctt ccgggtggac ctgatgacag 2940 gggcgctcat tctggagaga gagctggact ttgagaggcg agctgggtac aatctgagcc 3000 tgtgggccag tgatggtggg aggcccctag cccgcaggac tctctgccat gtggaggtga 3060 tcgtcctgga tgtgaatgag aatctccacc ctccccactt tgcctccttc gtgcaccagg 3120 gccaggtgca ggagaacagc ccctcgggaa ctcaggtgat tgtagtggct gccc 3174 9 1285 DNA Homo sapiens 9 cagcaggcca tgtggatggg cttctaccag ctcacccccg aggagctggt gagtgaccac 60 tggcggaacc tgcagaggtt cctcagccat aagctggaca tcaaacgggc taacattcac 120 ttggccagcc tccagcctgc agaggccgtg gctggtgtgg acgtgctcct ggtctttgag 180 gggcattctg gaaccttcta cgagtttcag gagctagcat ccatcatcac tcactcagcc 240 aaggagatgg agcattcagt gggggttcag atgcggtcag ctatgcccat ggtgccctgc 300 caggggccaa cctgccaggg tcaaatctgc cataacacag tgcatctgga ccccaaggtt 360 gggcccacgt acagcaccgc caggctcagc atcctaaccc cgcggcacca cctgcagagg 420 agctgctcct gcaatggtac tgctacaagg ttcagtggtc agagctatgt gcggtacagg 480 gccccagcgg ctcggaactg gcacatccat ttctatctga aaacactcca gccacaggcc 540 attcttctat tcaccaatga aacagcgtcc gtctccctga agctggccag tggagtgccc 600 cagctggaat accactgtct gggtggtttc tatggaaacc tttcctccca gcgccatgtg 660 aatgaccacg agtggcactc catcctggtg gaggagatgg acgcttccat tcgcctgatg 720 gttgacagca tgggcaacac ctcccttgtg gtcccagaga actgccgtgg tctgaggccc 780 gaaaggcacc tcttgctggg cggcctcatt ctgttgcatt cttcctcgaa tgtctcccag 840 ggctttgaag gctgcctgga tgctgtcgtg gtcaacgaag aggctctaga tctgctggcc 900 cctggcaaga cggtggcagg cttgctggag acacaagccc tcacccagtg ctgcctccac 960 agtgactact gcagccagaa cacatgcctc aatggtggga agtgctcatg gacccacggg 1020 gcaggctatg tctgcaaatg tcccccacag ttctctggga agcactgtga acaaggaagg 1080 gagaactgta cttttgcacc ctgcctggaa ggtggaactt gcatcctctc ccccaaagga 1140 gcttcctgta actgccctca tccttacaca ggagacaggt gtgaaatgga ggcgaggggt 1200 tgttcagaag gacactgcct agtcactccc gagatccaaa ggggggactg ggggcagcag 1260 gagttactga tcatcacagt ggccg 1285 10 10531 DNA Homo sapiens 10 gggggctgac cgcggccgga cggcgcccca gcaccgggcg agggagcccg cgtcgcgcgg 60 aggtcaggga gcctgagctg gagccagggc cccagtggga cctgacccaa agtctgaggt 120 caagctgggc ccagagcctg gcctggagct ggagcccaag gcacagctgg actacccttg 180 tcatgcagaa ggagctgggc attgtgcctt cctgccctgg catgaagagc cccaggcccc 240 acctcctgct accattgctg ctgctgctgc tgctgctgct gggggctggg gtgccaggtg 300 cctggggtca ggctgggagc ctggacttgc agattgatga ggagcagcca gcgggtacac 360 tgattggcga catcagtgcg gggcttccgg caggcacggc agctcctctc atgtacttca 420 tctctgccca agagggcagc ggcgtgggca cagacctggc cattgacgaa cacagtgggg 480 tcgtccgtac agcccgtgtc ttggaccgtg agcagcggga ccgctaccgc ttcactgcag 540 tcactcctga tggtgccacc gtagaagtta cagtgcgagt ggctgacatc aacgaccatg 600 ctccagcctt cccacaggct cgggctgccc tgcaggtacc tgagcataca gcttttggca 660 cccgctaccc actggagcct gctcgtgatg cagatgctgg gcgtctggga acccagggct 720 atgcgctatc tggtgatggg gctggagaga ccttccggct ggagacacgc cccggtccag 780 atgggactcc agtacctgag ctggtagtta ctggggaact ggaccgagag aaccgctcac 840 actatatgct acagctggag gcctatgatg gtggttcacc cccccggagg gcccaggccc 900 tgctggacgt gacactgctg gacatcaatg accatgcccc ggctttcaat cagagccgct 960 accatgctgt ggtgtctgag agcctggccc ctggcagtcc tgtcttgcag gtgttcgcat 1020 ctgatgccga tgctggtgtc aatggggctg tgacttacga gatcaaccgg aggcagagcg 1080 agggtgatgg acccttctcc atcgacgcac acacggggct gctgcagtta gagcggccac 1140 tggactttga gcagcggcgg gtccatgaac tggtggtgca agcacgagat ggtggggctc 1200 accctgagct gggctcggcc tttgtgactg tgcatgtgcg agatgccaat gacaatcagc 1260 cctccatgac tgtcatcttt ctcagtgcag atggctcccc ccaagtgtct gaggccgccc 1320 cacctggaca gctcgttgct cgcatctctg tgtcagaccc agatgatggt gactttgccc 1380 atgtcaatgt gtccctggaa ggtggagagg gccactttgc cctaagcacc caagacagcg 1440 tcatctatct ggtgtgtgtg gctcggcggc tggatcgaga ggagagggat gcctataact 1500 tgagggttac agccacagac tcaggctcac ctccactgcg ggctgaggct gcctttgtgc 1560 tgcacgtcac tgatgtcaac gacaatgcac ctgcctttga ccgccagctc taccgacctg 1620 agcccctgcc tgaggttgcg ctgcctggca gctttgtagt gcgggtgact gctcgggatc 1680 ctgaccaagg caccaatggt caggtcactt atagcctagc ccctggcgcc cacacccact 1740 ggttctccat tgaccccacc tcaggcatta tcactacggc tgcctcactg gactatgagt 1800 tggaacctca gccacagctg attgtggtgg ccacagatgg tggcctgccc cctctagcct 1860 cctctgccac agttagcgtg gccctgcaag atgtgaatga taatgagccc caattccaga 1920 ggactttcta caatgcctca ctgcctgagg gcacccagcc tggaacttgc ttcctgcagg 1980 tgacagccac agacgcggat agtggcccat ttggcctcct ctcctattcc ttgggtgctg 2040 gacttgggtc ctccggatct cccccattcc gcattgatgc ccatagcggt gatgtgtgca 2100 caacccggac cctggaccgt gaccaggggc cctcaagctt tgacttcaca gtgacagctg 2160 tggatggggg aggcctcaag tccatggtat atgtgaaggt gtttctgtca gacgagaatg 2220 acaaccctcc tcagttttat ccacgggagt atgctgccag tataagtgcc cagagtccac 2280 caggcacagc tgtgctgagg ttgcgtgccc atgaccctga ccagggatcc catgggcgac 2340 tctcctacca tatcctggct ggcaacagcc ccccactttt taccttggat gagcaatcag 2400 ggctgttgac agtagcctgg cccttggcca gacgggccaa ttctgtggtg cagctggaga 2460 tcggggctga ggacggaggt ggcctacagg cagaacccag tgcccgagtg gacatcagca 2520 ttgtgcctgg aacccccaca ccacccatat ttgagcaact acagtatgtt ttttctgtgc 2580 cagaggatgt ggcaccaggc accagtgtgg gcatagtcca ggcacacaac ccaccaggtc 2640 gcttggcacc tgtgaccctt tccctatcag gtggggatcc ccgaggactc ttctccctag 2700 atgcggtatc aggactgttg caaacacttc gccctctgga ccgggagcta ctgggaccag 2760 tgttggagct ggaggtgcga gcaggcagtg gagtgccccc agctttcgct gtagctcggg 2820 tgcgtgtgct gctggatgat gtgaatgaca actcccctgc ctttcctgca cctgaagaca 2880 cggtattgct accaccaaac actgccccag ggactcccat ctatacactg cgggctcttg 2940 accccgactc aggtgttaac agtcgagtca cctttaccct gcttgctggg ggtggtggag 3000 ccttcaccgt ggaccccacc acaggccatg tacggcttat gaggcctctg gggccctcag 3060 gagggccagc ccatgagctg gagctggagg cccgggatgg gggctcccca ccacgcacca 3120 gccactttcg actacgggtg gtggtacagg atgtgggaac ccgtgggctg gctccccgat 3180 tcaacagccc tacctaccgt gtggacctgc cctcaggcac cactgctgga actcaggtcc 3240 tgcaagtgca ggcccaagca ccagatgggg gccctatcac ctatcacctt gcagcagagg 3300 gagcaagtag cccctttggc ctggagccac agagtgggtg gctatgggtg cgggcagcac 3360 tagaccgtga ggcccaggaa ttgtacatac tgaaggtaat ggcagtgtct gggtccaaag 3420 ctgagttggg gcagcagaca ggcacagcca ccgtgagggt cagcatcctc aaccagaatg 3480 aacacagtcc ccgcttgtct gaggatccca ccttcctggc tgtggctgag aaccagcccc 3540 cagggaccag cgtgggccga gtctttgcca ctgaccgaga ctcaggaccc aatggacgtc 3600 tgacctacag cctgcaacag ctgtctgaag acagcaaggc cttccgcatc cacccccaga 3660 ctggagaagt gaccacactc caaaccctgg accgtgagca gcagagcagc tatcagctcc 3720 tggtgcaggt gcaggatgga gggagcccac cccgcagcac cacaggcact gtgcatgttg 3780 cagtgcttga cctcaacgac aacagcccca cgttcctgca ggcttcagga gctgctggtg 3840 ggggcctccc tatacaggta ccagaccgcg tgcctccagg aacactggtg acgactctgc 3900 aggcgaagga tccagatgag ggggagaatg ggaccatctt gtacacgcta actggtcctg 3960 gctcagagct tttctctctg caccctcact caggggagct gctcactgca gctcccctga 4020 tccgagcaga gcggccccac tatgtgctga cactgagtgc tcatgaccaa ggcagccctc 4080 ctcgaagtgc cagcctccag ctgctggtgc aggtgcttcc ctcagctcgc ttggccgagc 4140 cgcccccaga tctcgcagag cgggacccag cggcaccagt gcctgtcgtg ctgacggtga 4200 cagcagctga gggactgcgg cccggctctc tgttgggctc ggtggcagcg ccagagcccg 4260 cgggtgtggg tgcactcacc tacacactgg tgggcggtgc cgatcccgag ggcaccttcg 4320 cgctggatgc ggcctcaggg cgcttgtacc tggcgcggcc cctggacttc gaagctggcc 4380 cgccgtggcg cgcgctcacg gtacgcgctg aggggccggg aggcgcgggc gcgcggctgc 4440 tgcgagtgca ggtgcaagtg caggacgaga atgagcatgc gcccgccttt gcgcgcgacc 4500 cgctggcgct ggcgctgcca gagaacccgg agcccggcgc agcgctgtac actttccgcg 4560 cgtcggacgc cgacggcccc ggccccaata gcgacgtgcg ctaccgcctg ctgcgccagg 4620 agccgcccgt gccggcgctt cgcctggacg cgcgcaccgg ggcgctcagc gctccgcgcg 4680 gcctggaccg agagaccact cccgcgctgc tgctgctggt ggaagccacc gaccggcccg 4740 ccaacgccag ccgccgtcgt gcagcgcgcg tttcagcgcg cgtcttcgtc acggatgaga 4800 atgacaacgc gcctgtcttc gcctcgccgt cacgcgtgcg cctcccagag gaccagccgc 4860 ctgggcccgc ggccctgcac gtggtagccc gggacccgga tctgggcgag gctgcacgcg 4920 tgtcctatcg gctggcatct ggcggggacg gccacttccg gctgcactca agcactggag 4980 cgctgtccgt ggtgcggccg ttggaccgcg aacaacgagc tgagcacgta ctgacagtgg 5040 tggcctcaga ccacggctcc ccgccgcgct cggccacgca ggtcctgacc gtcagtgtcg 5100 ctgacgtcaa cgacgaggcg cctactttcc agcagcagga gtacagcgtc ctcttgcgtg 5160 agaacaaccc tcctggcaca tctctgctca ccctgcgagc aaccgacccc gacgtggggg 5220 ccaacgggca agtgacttat ggaggcgtct ctagcgaaag cttttctctg gatcctgaca 5280 ctggtgttct cacgactctt cgggccctgg atcgagagga acaggaggag atcaacctga 5340 cagtgtatgc ccaggacagg ggctcacctc ctcagttaac gcatgtcact gttcgagtgg 5400 ctgtggagga tgagaatgac catgcaccaa cctttgggag tgcccatctc tctctggagg 5460 tgcctgaggg ccaggacccc cagaccctta ccatgcttcg ggcctctgat ccagatgtgg 5520 gagccaatgg gcagttgcag taccgcatcc tagatgggga cccatcagga gcctttgtcc 5580 tagaccttgc ttctggagag tttggcacca tgcggccact agacagagaa gtggagccag 5640 ctttccagct gaggatagag gcccgggatg gaggccagcc agctctcagt gccacgctgc 5700 ttttgacagt gacagtgctg gatgccaatg accatgctcc agcctttcct gtgcctgcct 5760 actcggtgga ggtgccggag gatgtgcctg cagggaccct gctgctgcag ctacaggctc 5820 atgaccctga tgctggagct aatggccatg tgacctacta cctgggcgcc ggtacagcag 5880 gagccttcct gctggagccc agctctggag aactgcgcac agctgcagcc ttggacagag 5940 aacagtgtcc cagctacacc ttttctgtga gtgcagtgga tggtgcagct gctgggcccc 6000 taagcaccac agtgtctgtc accatcacgg tgcgcgatgt caatgaccat gcacccacct 6060 tccccaccag tcctctgcgc ctacgtctgc cccgcccagg ccccagcttc agtaccccaa 6120 ccctggctct ggccacactg agagctgaag atcgtgatgc tggtgccaat gcttccattc 6180 tgtaccggct ggcaggcaca ccacctcctg gcactactgt ggactcttac actggtgaaa 6240 tccgcgtggc ccgctctcct gtagctctag gcccccgaga tcgtgtcctc ttcattgtgg 6300 ccactgatct tggccgtcca gctcgctctg ccactggtgt gatcattgtt ggactgcagg 6360 gggaagctga gcgtggaccc cgctttcccc gggctagcag tgaggctacg attcgtgaga 6420 atgcgccccc agggactcct attgtctccc ccagggccgt ccatgcagga ggcacaaatg 6480 gacccatcac ctacagcatt ctcagtggga atgagaaagg gacattctcc atccagccta 6540 gtacaggtgc catcacagtt cgctcagcag aggggctaga cttcgaggtg agtccacggc 6600 tgcgactggt gctgcaggca gagagtggag gagcctttgc cttcactgtg ctgaccctga 6660 ccctgcaaga tgccaacgac aatgctcccc gtttcctgcg gccccattat gtggccttcc 6720 ttcctgagtc ccggcccttg gaggggcccc tgctgcaggt ggaggcggat gacctggatc 6780 aaggctctgg aggacagatt tcctacagtc tggctgcatc ccagccggca cgtggattgt 6840 tccacgtaga cccaaccaca ggcactatca ctaccacagc catcctggac cgtgagatct 6900 gggctgaaac acggttggtg ctgatggcca cagacagagg gagcccagcc ctggtgggct 6960 cagctacctt gacggtgatg gtcatcgaca ccaatgacaa tcgccccacc atcccccaac 7020 cctgggagct ccgagtgtca gaagatgcgt tattgggctc agagattgca caggtaacag 7080 ggaatgatgt ggactcagga cccgtgctgt ggtatgtgct aagcccatct gggccccagg 7140 atcccttcag tgttggccgc tatggaggcc gtgtctccct cacggggccc ctggactttg 7200 agcagtgtga ccgctaccag ctgcagctgc tggcacatga tgggcctcat gagggccgtg 7260 ccaacctcac agtgcttgtg gaggatgtca atgacaatgc acctgccttc tcacagagcc 7320 tctaccaggt aatgctgctt gagcacacac ccccaggcag tgccattctc tccgtctctg 7380 ccactgatcg ggactcaggt gccaacggtc acatttccta ccacctggct tcccctgccg 7440 atggcttcag tgttgacccc aacaatggga ccctgttcac aatagtggga acagtggcct 7500 tgggccatga cgggtcagga gcagtggatg tggtgctgga agcacgagac cacggggctc 7560 caggccgggc agcacgagcc acagtgcacg tgcagctgca ggaccagaac gaccacgccc 7620 cgagcttcac attgtcacac taccgtgtgg ctgtgactga agacctgccc cctggctcca 7680 ctctgctcac cctggaggct acagatgctg atggaagccg cagccatgcc gctgtggact 7740 acagcatcat cagtggcaac tggggccgag tcttccagct ggaacccagg ctggctgagg 7800 ctggggagag tgctggacca ggcccccggg cactgggctg cctggtgttg cttgaacctc 7860 tagactttga aagcctgaca cagtacaatc taacagtggc tgcagctgac cgtgggcagc 7920 caccccaaag ctcagtcgtg ccagtcactg tcactgtact agatgtcaat gacaacccac 7980 ctgtctttac ccgagcatcc taccgtgtga cagtacctga ggacacacct gttggagctg 8040 agctgctgca tgtagaggcc tctgacgctg accctggccc tcatggcctc gtgcgtttca 8100 ctgtcagctc aggcgaccca tcagggctct ttgagctgga tgagagctca ggcaccttgc 8160 gactggccca tgccctggac tgtgagaccc aggctcgaca tcagcttgta gtacaggctg 8220 ctgaccctgc tggtgcacac tttgctttgg caccagtgac aattgaggtc caggatgtga 8280 atgatcatgg cccagccttc ccactgaact tactcagcac cagcgtggcc gagaatcagc 8340 ctccaggcac tctcgtgacc actctgcatg caatcgacgg ggatgctggg gcttttggga 8400 ggctccgtta cagcctgttg gaggctgggc caggacctga gggccgtgag gcatttgcac 8460 tgaacagctc aacaggggag ttgcgtgcgc gagtgccctt tgactatgag cacacagaaa 8520 gcttccggct gctggtgggt gctgctgatg ctgggaatct ctcagcctct gtcactgtgt 8580 cggtgctagt gactggagag gatgagtatg accctgtatt tctggcacca gctttccact 8640 tccaagtgcc cgaaggtgcc cggcgtggcc acagcttggg tcacgtgcag gccacagatg 8700 aggatggggg tgccgatggc ctggttctgt attcccttgc cacctcttcc ccctattttg 8760 gtattaacca gactacagga gccctgtacc tgcgggtgga cagtcgggca ccaggcagcg 8820 gaacagccac ctctgggggt gggggccgga cccggcggga agcaccacgg gagctgaggc 8880 tggaggtgat agcacggggg cctctgcctg gttcccggag tgccacagtg cctgtgaccg 8940 tggatatcac ccacaccgca ctgggcctgg cacctgacct caacctgcta ttagtagggg 9000 ccgtggcagc ctccttggga gttgtggtgg tgcttgcact ggcagccctg gtcctaggac 9060 ttgttcgggc ccgtagccgc aaggctgagg cagcccctgg cccaatgtca caggcagcac 9120 ccctagccag tgactcactg cagaaactgg gccgggagcc acctagtcca ccaccctctg 9180 agcacctcta tcaccagact cttcccagct atggtgggcc aggagctgga ggaccctacc 9240 cccgtggtgg ctccttggac ccttcacatt caagtggccg aggatcagca gaggctgcag 9300 aggatgatga gatccgcatg atcaatgagt tcccccgtgt ggccagtgtg gcctcctctc 9360 tggctgcccg tggccctgac tcaggcatcc agcaggatgc agatggtctg agtgacacat 9420 cctgcgaacc acctgcccct gacacctggt ataagggccg aaaggcaggg ctgctgctgc 9480 caggtgcagg agccactctc tacagagagg aggggccccc agccactgcc acagccttcc 9540 tggggggctg tggcctgagc cctgcaccca ctggggacta tggcttccca gcagatggca 9600 agccatgtgt ggcaggtgcg ctgacagcca ttgtggccgg cgaggaggag ctccgtggca 9660 gctataactg ggactacctg ctgagctggt gccctcagtt ccaaccactg gccagtgtct 9720 tcacagagat cgctcggctc aaggatgaag ctcggccatg tcccccagct ccccgtatcg 9780 acccaccacc cctcatcact gccgtggccc acccaggagc caagtctgtg ccccccaagc 9840 cagcaaacac agctgcagcc cgggccatct tcccaccagc ttctcaccgc tcccccatca 9900 gccatgaagg ctccctgtcc tcagctgcca tgtcccccag cttctcaccc tctctgtctc 9960 ctctggctgc tcgctcaccc gttgtctcac catttggggt ggcccagggt ccctcagcct 10020 cagcactcag cgcagagtct ggcctggagc cacctgatga cacggagctg cacatctagc 10080 tgtggcccag gctgggcccc gacctgggat gcgcacagtg tccccaacgc aggccccact 10140 ctgagcctgc cctgggcagc ctcggactat gactggctac ggggaggcca ccaccaggcc 10200 ccagctctcc accctgaact ccccagcccc ctcagagtac taggaccaca gaagccctgt 10260 tgctcactga cctgtgacca ggtccaatgt ggggagaaat atgaaggagg tagcagccct 10320 gggttctcct cagtgaggga tccctgccct gcaccagcac cctgagatgg agctgagact 10380 ttatttattg ggggtagggg gatggaggag gtccctccaa catgtttgga cccagctcct 10440 ttgggttcca ctgacacccc tgcccctgcc cctgcccaga accaagtgcc atttctcact 10500 ctggagcctt aataaactgc aatttgtatc c 10531 11 3354 PRT Homo sapiens 11 Met Gly Arg His Val Ala Thr Ser Cys His Val Ala Trp Leu Leu Val 1 5 10 15 Leu Ile Ser Gly Cys Trp Gly Gln Val Asn Arg Leu Pro Phe Phe Thr 20 25 30 Asn His Phe Phe Asp Thr Tyr Leu Leu Ile Ser Glu Asp Thr Pro Val 35 40 45 Gly Ser Ser Val Thr Gln Leu Leu Ala Gln Asp Met Asp Asn Asp Pro 50 55 60 Leu Val Phe Gly Val Ser Gly Glu Glu Ala Ser Arg Phe Phe Ala Val 65 70 75 80 Glu Pro Asp Thr Gly Val Val Trp Leu Arg Gln Pro Leu Asp Arg Glu 85 90 95 Thr Lys Ser Glu Phe Thr Val Glu Phe Ser Val Ser Asp His Gln Gly 100 105 110 Val Ile Thr Arg Lys Val Asn Ile Gln Val Gly Asp Val Asn Asp Asn 115 120 125 Ala Pro Thr Phe His Asn Gln Pro Tyr Ser Val Arg Ile Pro Glu Asn 130 135 140 Thr Pro Val Gly Thr Pro Ile Phe Ile Val Asn Ala Thr Asp Pro Asp 145 150 155 160 Leu Gly Ala Gly Gly Ser Val Leu Tyr Ser Phe Gln Pro Pro Ser Gln 165 170 175 Phe Phe Ala Ile Asp Ser Ala Arg Gly Ile Val Thr Val Ile Arg Glu 180 185 190 Leu Asp Tyr Glu Thr Thr Gln Ala Tyr Gln Leu Thr Val Asn Ala Thr 195 200 205 Asp Gln Asp Lys Thr Arg Pro Leu Ser Thr Leu Ala Asn Leu Ala Ile 210 215 220 Ile Ile Thr Asp Val Gln Asp Met Asp Pro Ile Phe Ile Asn Leu Pro 225 230 235 240 Tyr Ser Thr Asn Ile Tyr Glu His Ser Pro Pro Gly Thr Thr Val Arg 245 250 255 Ile Ile Thr Ala Ile Asp Gln Asp Lys Gly Arg Pro Arg Gly Ile Gly 260 265 270 Tyr Thr Ile Val Ser Gly Asn Thr Asn Ser Ile Phe Ala Leu Asp Tyr 275 280 285 Ile Ser Gly Val Leu Thr Leu Asn Gly Leu Leu Asp Arg Glu Asn Pro 290 295 300 Leu Tyr Ser His Gly Phe Ile Leu Thr Val Lys Gly Thr Glu Leu Asn 305 310 315 320 Asp Asp Arg Thr Pro Ser Asp Ala Thr Val Thr Thr Thr Phe Asn Ile 325 330 335 Leu Val Ile Asp Ile Asn Asp Asn Ala Pro Glu Phe Asn Ser Ser Glu 340 345 350 Tyr Ser Val Ala Ile Thr Glu Leu Ala Gln Val Gly Phe Ala Leu Pro 355 360 365 Leu Phe Ile Gln Val Val Asp Lys Asp Glu Asn Leu Gly Leu Asn Ser 370 375 380 Met Phe Glu Val Tyr Leu Val Gly Asn Asn Ser His His Phe Ile Ile 385 390 395 400 Ser Pro Thr Ser Val Gln Gly Lys Ala Asp Ile Arg Ile Arg Val Ala 405 410 415 Ile Pro Leu Asp Tyr Glu Thr Val Asp Arg Tyr Asp Phe Asp Leu Phe 420 425 430 Ala Asn Glu Ser Val Pro Asp His Val Gly Tyr Ala Lys Val Lys Ile 435 440 445 Thr Leu Ile Asn Glu Asn Asp Asn Arg Pro Ile Phe Ser Gln Pro Leu 450 455 460 Tyr Asn Ile Ser Leu Tyr Glu Asn Val Thr Val Gly Thr Ser Val Leu 465 470 475 480 Thr Val Leu Ala Thr Asp Asn Asp Ala Gly Thr Phe Gly Glu Val Ser 485 490 495 Tyr Phe Phe Ser Asp Asp Pro Asp Arg Phe Ser Leu Asp Lys Asp Thr 500 505 510 Gly Leu Ile Met Leu Ile Ala Arg Leu Asp Tyr Glu Leu Ile Gln Arg 515 520 525 Phe Thr Leu Thr Ile Ile Ala Arg Asp Gly Gly Gly Glu Glu Thr Thr 530 535 540 Gly Arg Val Arg Ile Asn Val Leu Asp Val Asn Asp Asn Val Pro Thr 545 550 555 560 Phe Gln Lys Asp Ala Tyr Val Gly Ala Leu Arg Glu Asn Glu Pro Ser 565 570 575 Val Thr Gln Leu Val Arg Leu Arg Ala Thr Asp Glu Asp Ser Pro Pro 580 585 590 Asn Asn Gln Ile Thr Tyr Ser Ile Val Ser Ala Ser Ala Phe Gly Ser 595 600 605 Tyr Phe Asp Ile Ser Leu Tyr Glu Gly Tyr Gly Val Ile Ser Val Ser 610 615 620 Arg Pro Leu Asp Tyr Glu Gln Ile Ser Asn Gly Leu Ile Tyr Leu Thr 625 630 635 640 Val Met Ala Met Asp Ala Gly Asn Pro Pro Leu Asn Ser Thr Val Pro 645 650 655 Val Thr Ile Glu Val Phe Asp Glu Asn Asp Asn Pro Pro Thr Phe Ser 660 665 670 Lys Pro Ala Tyr Phe Val Ser Val Val Glu Asn Ile Met Ala Gly Ala 675 680 685 Thr Val Leu Phe Leu Asn Ala Thr Asp Leu Asp Arg Ser Arg Glu Tyr 690 695 700 Gly Gln Glu Ser Ile Ile Tyr Ser Leu Glu Gly Ser Thr Gln Phe Arg 705 710 715 720 Ile Asn Ala Arg Ser Gly Glu Ile Thr Thr Thr Ser Leu Leu Asp Arg 725 730 735 Glu Thr Lys Ser Glu Tyr Ile Leu Ile Val Arg Ala Val Asp Gly Gly 740 745 750 Val Gly His Asn Gln Lys Thr Gly Ile Ala Thr Val Asn Ile Thr Leu 755 760 765 Leu Asp Ile Asn Asp Asn His Pro Thr Trp Lys Asp Ala Pro Tyr Tyr 770 775 780 Ile Asn Leu Val Glu Met Thr Pro Pro Asp Ser Asp Val Thr Thr Val 785 790 795 800 Val Ala Val Asp Pro Asp Leu Gly Glu Asn Gly Thr Leu Val Tyr Ser 805 810 815 Ile Gln Pro Pro Asn Lys Phe Tyr Ser Leu Asn Ser Thr Thr Gly Lys 820 825 830 Ile Arg Thr Thr His Ala Met Leu Asp Arg Glu Asn Pro Asp Pro His 835 840 845 Glu Ala Glu Leu Met Arg Lys Ile Val Val Ser Val Thr Asp Cys Gly 850 855 860 Arg Pro Pro Leu Lys Ala Thr Ser Ser Ala Thr Val Phe Val Asn Leu 865 870 875 880 Leu Asp Leu Asn Asp Asn Asp Pro Thr Phe Gln Asn Leu Pro Phe Val 885 890 895 Ala Glu Val Leu Glu Gly Ile Pro Ala Gly Val Ser Ile Tyr Gln Val 900 905 910 Val Ala Ile Asp Leu Asp Glu Gly Leu Asn Gly Leu Val Ser Tyr Arg 915 920 925 Met Pro Val Gly Met Pro Arg Met Asp Phe Leu Ile Asn Ser Ser Ser 930 935 940 Gly Val Val Val Thr Thr Thr Glu Leu Asp Arg Glu Arg Ile Ala Glu 945 950 955 960 Tyr Gln Leu Arg Val Val Ala Ser Asp Ala Gly Thr Pro Thr Lys Ser 965 970 975 Ser Thr Ser Thr Leu Thr Ile His Val Leu Asp Val Asn Asp Glu Thr 980 985 990 Pro Thr Phe Phe Pro Ala Val Tyr Asn Val Ser Val Ser Glu Asp Val 995 1000 1005 Pro Arg Glu Phe Arg Val Val Trp Leu Asn Cys Thr Asp Asn Asp 1010 1015 1020 Val Gly Leu Asn Ala Glu Leu Ser Tyr Phe Ile Thr Gly Gly Asn 1025 1030 1035 Val Asp Gly Lys Phe Ser Val Gly Tyr Arg Asp Ala Val Val Arg 1040 1045 1050 Thr Val Val Gly Leu Asp Arg Glu Thr Thr Ala Ala Tyr Met Leu 1055 1060 1065 Ile Leu Glu Ala Ile Asp Asn Gly Pro Val Gly Lys Arg His Thr 1070 1075 1080 Gly Thr Ala Thr Val Phe Val Thr Val Leu Asp Val Asn Asp Asn 1085 1090 1095 Arg Pro Ile Phe Leu Gln Ser Ser Tyr Glu Ala Ser Val Pro Glu 1100 1105 1110 Asp Ile Pro Glu Gly His Ser Ile Leu Gln Leu Lys Ala Thr Asp 1115 1120 1125 Ala Asp Glu Gly Glu Phe Gly Arg Val Trp Tyr Arg Ile Leu His 1130 1135 1140 Gly Asn His Gly Asn Asn Phe Arg Ile His Val Ser Asn Gly Leu 1145 1150 1155 Leu Met Arg Gly Pro Arg Pro Leu Asp Arg Glu Arg Asn Ser Ser 1160 1165 1170 His Val Leu Ile Val Glu Ala Tyr Asn His Asp Leu Gly Pro Met 1175 1180 1185 Arg Ser Ser Val Arg Val Ile Val Tyr Val Glu Asp Ile Asn Asp 1190 1195 1200 Glu Ala Pro Val Phe Thr Gln Gln Gln Tyr Ser Arg Leu Gly Leu 1205 1210 1215 Arg Glu Thr Ala Gly Ile Gly Thr Ser Val Ile Val Val Gln Ala 1220 1225 1230 Thr Asp Arg Asp Ser Gly Asp Gly Gly Leu Val Asn Tyr Arg Ile 1235 1240 1245 Leu Ser Gly Ala Glu Gly Lys Phe Glu Ile Asp Glu Ser Thr Gly 1250 1255 1260 Leu Ile Ile Thr Val Asn Tyr Leu Asp Tyr Glu Thr Lys Thr Ser 1265 1270 1275 Tyr Met Met Asn Val Ser Ala Thr Asp Gln Ala Pro Pro Phe Asn 1280 1285 1290 Gln Gly Phe Cys Ser Val Tyr Ile Thr Leu Leu Asn Glu Leu Asp 1295 1300 1305 Glu Ala Val Gln Phe Ser Asn Ala Ser Tyr Glu Ala Ala Ile Leu 1310 1315 1320 Glu Asn Leu Ala Leu Gly Thr Glu Ile Val Arg Val Gln Ala Tyr 1325 1330 1335 Ser Ile Asp Asn Leu Asn Gln Ile Thr Tyr Arg Phe Asp Ala Tyr 1340 1345 1350 Thr Ser Thr Gln Ala Lys Ala Leu Phe Lys Ile Asp Ala Ile Thr 1355 1360 1365 Gly Val Ile Thr Val Gln Gly Leu Val Asp Arg Glu Lys Gly Asp 1370 1375 1380 Phe Tyr Thr Leu Thr Val Val Ala Asp Asp Gly Gly Pro Lys Val 1385 1390 1395 Asp Ser Thr Val Lys Val Tyr Ile Thr Val Leu Asp Glu Asn Asp 1400 1405 1410 Asn Ser Pro Arg Phe Asp Phe Thr Ser Asp Ser Ala Val Ser Ile 1415 1420 1425 Pro Glu Asp Cys Pro Val Gly Gln Arg Val Ala Thr Val Lys Ala 1430 1435 1440 Trp Asp Pro Asp Ala Gly Ser Asn Gly Gln Val Val Phe Ser Leu 1445 1450 1455 Ala Ser Gly Asn Ile Ala Gly Ala Phe Glu Ile Val Thr Thr Asn 1460 1465 1470 Asp Ser Ile Gly Glu Val Phe Val Ala Arg Pro Leu Asp Arg Glu 1475 1480 1485 Glu Leu Asp His Tyr Ile Leu Gln Val Val Ala Ser Asp Arg Gly 1490 1495 1500 Thr Pro Pro Arg Lys Lys Asp His Ile Leu Gln Val Thr Ile Leu 1505 1510 1515 Asp Ile Asn Asp Asn Pro Pro Val Ile Glu Ser Pro Phe Gly Tyr 1520 1525 1530 Asn Val Ser Val Asn Glu Asn Val Gly Gly Gly Thr Ala Val Val 1535 1540 1545 Gln Val Arg Ala Thr Asp Arg Asp Ile Gly Ile Asn Ser Val Leu 1550 1555 1560 Ser Tyr Tyr Ile Thr Glu Gly Asn Lys Asp Met Thr Phe Arg Met 1565 1570 1575 Asp Arg Ile Ser Gly Glu Ile Ala Thr Arg Pro Ala Pro Pro Asp 1580 1585 1590 Arg Glu Arg Gln Ser Phe Tyr His Leu Val Ala Thr Val Glu Asp 1595 1600 1605 Glu Gly Thr Pro Thr Leu Ser Ala Thr Thr His Val Tyr Val Thr 1610 1615 1620 Ile Val Asp Glu Asn Asp Asn Ala Pro Met Phe Gln Gln Pro His 1625 1630 1635 Tyr Glu Val Leu Leu Asp Glu Gly Pro Asp Thr Leu Asn Thr Ser 1640 1645 1650 Leu Ile Thr Ile Gln Ala Leu Asp Leu Asp Glu Gly Pro Asn Gly 1655 1660 1665 Thr Val Thr Tyr Ala Ile Val Ala Gly Asn Ile Val Asn Thr Phe 1670 1675 1680 Arg Ile Asp Arg His Met Gly Val Ile Thr Ala Ala Lys Glu Leu 1685 1690 1695 Asp Tyr Glu Ile Ser His Gly Arg Tyr Thr Leu Ile Val Thr Ala 1700 1705 1710 Thr Asp Gln Cys Pro Ile Leu Ser His Arg Leu Thr Ser Thr Thr 1715 1720 1725 Thr Val Leu Val Asn Val Asn Asp Ile Asn Asp Asn Val Pro Thr 1730 1735 1740 Phe Pro Arg Asp Tyr Glu Gly Pro Phe Glu Val Thr Glu Gly Gln 1745 1750 1755 Pro Gly Pro Arg Val Trp Thr Phe Leu Ala His Asp Arg Asp Ser 1760 1765 1770 Gly Pro Asn Gly Gln Val Glu Tyr Ser Ile Met Asp Gly Asp Pro 1775 1780 1785 Leu Gly Glu Phe Val Ile Ser Pro Val Glu Gly Val Leu Arg Val 1790 1795 1800 Arg Lys Asp Val Glu Leu Asp Arg Glu Thr Ile Ala Phe Tyr Asn 1805 1810 1815 Leu Thr Ile Cys Ala Arg Asp Arg Gly Met Pro Pro Leu Ser Ser 1820 1825 1830 Thr Met Leu Val Gly Ile Arg Val Leu Asp Ile Asn Asp Asn Asp 1835 1840 1845 Pro Val Leu Leu Asn Leu Pro Met Asn Ile Thr Ile Ser Glu Asn 1850 1855 1860 Ser Pro Val Ser Ser Phe Val Ala His Val Leu Ala Ser Asp Ala 1865 1870 1875 Asp Ser Gly Cys Asn Ala Arg Leu Thr Phe Asn Ile Thr Ala Gly 1880 1885 1890 Asn Arg Glu Arg Ala Phe Phe Ile Asn Ala Thr Thr Gly Ile Val 1895 1900 1905 Thr Val Asn Arg Pro Leu Asp Arg Glu Arg Ile Pro Glu Tyr Lys 1910 1915 1920 Leu Thr Ile Ser Val Lys Asp Asn Pro Glu Asn Pro Arg Ile Ala 1925 1930 1935 Arg Arg Asp Tyr Asp Leu Leu Leu Ile Phe Leu Ser Asp Glu Asn 1940 1945 1950 Asp Asn His Pro Leu Phe Thr Lys Ser Thr Tyr Gln Ala Glu Val 1955 1960 1965 Met Glu Asn Ser Pro Ala Gly Thr Pro Leu Thr Val Leu Asn Gly 1970 1975 1980 Pro Ile Leu Ala Leu Asp Ala Asp Gln Asp Ile Tyr Ala Val Val 1985 1990 1995 Thr Tyr Gln Leu Leu Gly Ala Gln Ser Gly Leu Phe Asp Ile Asn 2000 2005 2010 Ser Ser Thr Gly Val Val Thr Val Arg Ser Gly Val Ile Ile Asp 2015 2020 2025 Arg Glu Ala Phe Ser Pro Pro Ile Leu Glu Leu Leu Leu Leu Ala 2030 2035 2040 Glu Asp Ile Gly Leu Leu Asn Ser Thr Ala His Leu Leu Ile Thr 2045 2050 2055 Ile Leu Asp Asp Asn Asp Asn Arg Pro Thr Phe Ser Pro Ala Thr 2060 2065 2070 Leu Thr Val His Leu Leu Glu Asn Cys Pro Pro Gly Phe Ser Val 2075 2080 2085 Leu Gln Val Thr Ala Thr Asp Glu Asp Ser Gly Leu Asn Gly Glu 2090 2095 2100 Leu Val Tyr Arg Ile Glu Ala Gly Ala Gln Asp Arg Phe Leu Ile 2105 2110 2115 His Leu Val Thr Gly Val Ile Arg Val Gly Asn Ala Thr Ile Asp 2120 2125 2130 Arg Glu Glu Gln Glu Ser Tyr Arg Leu Thr Val Val Ala Thr Asp 2135 2140 2145 Arg Gly Thr Val Pro Leu Ser Gly Thr Ala Ile Val Thr Ile Leu 2150 2155 2160 Ile Asp Asp Ile Asn Asp Ser Arg Pro Glu Phe Leu Asn Pro Ile 2165 2170 2175 Gln Thr Val Ser Val Leu Glu Ser Ala Glu Pro Gly Thr Val Ile 2180 2185 2190 Ala Asn Ile Thr Ala Ile Asp His Asp Leu Asn Pro Lys Leu Glu 2195 2200 2205 Tyr His Ile Val Gly Ile Val Ala Lys Asp Asp Thr Asp Arg Leu 2210 2215 2220 Val Pro Asn Gln Glu Asp Ala Phe Ala Val Asn Ile Asn Thr Gly 2225 2230 2235 Ser Val Met Val Lys Ser Pro Met Asn Arg Glu Leu Val Ala Thr 2240 2245 2250 Tyr Glu Val Thr Leu Ser Val Ile Asp Asn Ala Ser Asp Leu Pro 2255 2260 2265 Glu Arg Ser Val Ser Val Pro Asn Ala Lys Leu Thr Val Asn Val 2270 2275 2280 Leu Asp Val Asn Asp Asn Thr Pro Gln Phe Lys Pro Phe Gly Ile 2285 2290 2295 Thr Tyr Tyr Met Glu Arg Ile Leu Glu Gly Ala Thr Pro Gly Thr 2300 2305 2310 Thr Leu Ile Ala Val Ala Ala Val Asp Pro Asp Lys Gly Leu Asn 2315 2320 2325 Gly Leu Val Thr Tyr Thr Leu Leu Asp Leu Val Pro Pro Gly Tyr 2330 2335 2340 Val Gln Leu Glu Asp Ser Ser Ala Gly Lys Val Ile Ala Asn Arg 2345 2350 2355 Thr Val Asp Tyr Glu Glu Val His Trp Leu Asn Phe Thr Val Arg 2360 2365 2370 Ala Ser Asp Asn Gly Ser Pro Pro Arg Ala Ala Glu Ile Pro Val 2375 2380 2385 Tyr Leu Glu Ile Val Asp Ile Asn Asp Asn Asn Pro Ile Phe Asp 2390 2395 2400 Gln Pro Ser Tyr Gln Glu Ala Val Phe Glu Asp Val Pro Val Gly 2405 2410 2415 Thr Ile Ile Leu Thr Val Thr Ala Thr Asp Ala Asp Ser Gly Asn 2420 2425 2430 Phe Ala Leu Ile Glu Tyr Ser Leu Gly Asp Gly Glu Ser Lys Phe 2435 2440 2445 Ala Ile Asn Pro Thr Thr Gly Asp Ile Tyr Val Leu Ser Ser Leu 2450 2455 2460 Asp Arg Glu Lys Lys Asp His Tyr Ile Leu Thr Ala Leu Ala Lys 2465 2470 2475 Asp Asn Pro Gly Asp Val Ala Ser Asn Arg Arg Glu Asn Ser Val 2480 2485 2490 Gln Val Val Ile Gln Val Leu Asp Val Asn Asp Cys Arg Pro Gln 2495 2500 2505 Phe Ser Lys Pro Gln Phe Ser Thr Ser Val Tyr Glu Asn Glu Pro 2510 2515 2520 Ala Gly Thr Ser Val Ile Thr Met Met Ala Thr Asp Gln Asp Glu 2525 2530 2535 Gly Pro Asn Gly Glu Leu Thr Tyr Ser Leu Glu Gly Pro Gly Val 2540 2545 2550 Glu Ala Phe His Val Asp Met Asp Ser Gly Leu Val Thr Thr Gln 2555 2560 2565 Arg Pro Leu Gln Ser Tyr Glu Lys Phe Ser Leu Thr Val Val Ala 2570 2575 2580 Thr Asp Gly Gly Glu Pro Pro Leu Trp Gly Thr Thr Met Leu Leu 2585 2590 2595 Val Glu Val Ile Asp Val Asn Asp Asn Arg Pro Val Phe Val Arg 2600 2605 2610 Pro Pro Asn Gly Thr Ile Leu His Ile Arg Glu Glu Ile Pro Leu 2615 2620 2625 Arg Ser Asn Val Tyr Glu Val Tyr Ala Thr Asp Lys Asp Glu Gly 2630 2635 2640 Leu Asn Gly Ala Val Arg Tyr Ser Phe Leu Lys Thr Ala Gly Asn 2645 2650 2655 Arg Asp Trp Glu Phe Phe Ile Ile Asp Pro Ile Ser Gly Leu Ile 2660 2665 2670 Gln Thr Ala Gln Arg Leu Asp Arg Glu Ser Gln Ala Val Tyr Ser 2675 2680 2685 Leu Ile Leu Val Ala Ser Asp Leu Gly Gln Pro Val Pro Tyr Glu 2690 2695 2700 Thr Met Gln Pro Leu Gln Val Ala Leu Glu Asp Ile Asp Asp Asn 2705 2710 2715 Glu Pro Leu Phe Val Arg Pro Pro Lys Gly Ser Pro Gln Tyr Gln 2720 2725 2730 Leu Leu Thr Val Pro Glu His Ser Pro Arg Gly Thr Leu Val Gly 2735 2740 2745 Asn Val Thr Gly Ala Val Asp Ala Asp Glu Gly Pro Asn Ala Ile 2750 2755 2760 Val Tyr Tyr Phe Ile Ala Ala Gly Asn Glu Glu Lys Asn Phe His 2765 2770 2775 Leu Gln Pro Asp Gly Cys Leu Leu Val Leu Arg Asp Leu Asp Arg 2780 2785 2790 Glu Arg Glu Ala Ile Phe Ser Phe Ile Val Lys Ala Ser Ser Asn 2795 2800 2805 Arg Ser Trp Thr Pro Pro Arg Gly Pro Ser Pro Thr Leu Asp Leu 2810 2815 2820 Val Ala Asp Leu Thr Leu Gln Glu Val Arg Val Val Leu Glu Asp 2825 2830 2835 Ile Asn Asp Gln Pro Pro Arg Phe Thr Lys Ala Glu Tyr Thr Ala 2840 2845 2850 Gly Val Ala Thr Asp Ala Lys Val Gly Ser Glu Leu Ile Gln Val 2855 2860 2865 Leu Ala Leu Asp Ala Asp Ile Gly Asn Asn Ser Leu Val Phe Tyr 2870 2875 2880 Ser Ile Leu Ala Ile His Tyr Phe Arg Ala Leu Ala Asn Asp Ser 2885 2890 2895 Glu Asp Val Gly Gln Val Phe Thr Met Gly Ser Met Asp Gly Ile 2900 2905 2910 Leu Arg Thr Phe Asp Leu Phe Met Ala Tyr Ser Pro Gly Tyr Phe 2915 2920 2925 Val Val Asp Ile Val Ala Arg Asp Leu Ala Gly His Asn Asp Thr 2930 2935 2940 Ala Ile Ile Gly Ile Tyr Ile Leu Arg Asp Asp Gln Arg Val Lys 2945 2950 2955 Ile Val Ile Asn Glu Ile Pro Asp Arg Val Arg Gly Phe Glu Glu 2960 2965 2970 Glu Phe Ile His Leu Leu Ser Asn Ile Thr Gly Ala Ile Val Asn 2975 2980 2985 Thr Asp Asn Val Gln Phe His Val Asp Lys Lys Gly Arg Val Asn 2990 2995 3000 Phe Ala Gln Thr Glu Leu Leu Ile His Val Val Asn Arg Asp Thr 3005 3010 3015 Asn Arg Ile Leu Asp Val Asp Arg Val Ile Gln Met Ile Asp Glu 3020 3025 3030 Asn Lys Glu Gln Leu Arg Asn Leu Phe Arg Asn Tyr Asn Val Leu 3035 3040 3045 Asp Val Gln Pro Ala Ile Ser Val Arg Leu Pro Asp Asp Met Ser 3050 3055 3060 Ala Leu Gln Met Ala Ile Ile Val Leu Ala Ile Leu Leu Phe Leu 3065 3070 3075 Ala Ala Met Leu Phe Val Leu Met Asn Trp Tyr Tyr Arg Thr Val 3080 3085 3090 His Lys Arg Lys Leu Lys Ala Ile Val Ala Gly Ser Ala Gly Asn 3095 3100 3105 Arg Gly Phe Ile Asp Ile Met Asp Met Pro Asn Thr Asn Lys Tyr 3110 3115 3120 Ser Phe Asp Gly Ala Asn Pro Val Trp Leu Asp Pro Phe Cys Arg 3125 3130 3135 Asn Leu Glu Leu Ala Ala Gln Ala Glu His Glu Asp Asp Leu Pro 3140 3145 3150 Glu Asn Leu Ser Glu Ile Ala Asp Leu Trp Asn Ser Pro Thr Arg 3155 3160 3165 Thr His Gly Thr Phe Gly Arg Glu Pro Ala Ala Val Lys Pro Asp 3170 3175 3180 Asp Asp Arg Tyr Leu Arg Ala Ala Ile Gln Glu Tyr Asp Asn Ile 3185 3190 3195 Ala Lys Leu Gly Gln Ile Ile Arg Glu Gly Pro Ile Lys Gly Ser 3200 3205 3210 Leu Leu Lys Val Val Leu Glu Asp Tyr Leu Arg Leu Lys Lys Leu 3215 3220 3225 Phe Ala Gln Arg Met Val Gln Lys Ala Ser Ser Cys His Ser Ser 3230 3235 3240 Ile Ser Glu Leu Ile Gln Thr Glu Leu Asp Glu Glu Pro Gly Asp 3245 3250 3255 His Ser Pro Gly Gln Gly Ser Leu Arg Phe Arg His Lys Pro Pro 3260 3265 3270 Val Glu Leu Lys Gly Pro Asp Gly Ile His Val Val His Gly Ser 3275 3280 3285 Thr Gly Thr Leu Leu Ala Thr Asp Leu Asn Ser Leu Pro Glu Glu 3290 3295 3300 Asp Gln Lys Gly Leu Gly Arg Ser Leu Glu Thr Leu Thr Ala Ala 3305 3310 3315 Glu Ala Thr Ala Phe Glu Arg Asn Ala Arg Thr Glu Ser Ala Lys 3320 3325 3330 Ser Thr Pro Leu His Lys Leu Arg Asp Val Ile Met Glu Thr Pro 3335 3340 3345 Leu Glu Ile Thr Glu Leu 3350 12 3354 PRT Homo sapiens 12 Met Gly Arg His Val Ala Thr Ser Cys His Val Ala Trp Leu Leu Val 1 5 10 15 Leu Ile Ser Gly Cys Trp Gly Gln Val Asn Arg Leu Pro Phe Phe Thr 20 25 30 Asn His Phe Phe Asp Thr Tyr Leu Leu Ile Ser Glu Asp Thr Pro Val 35 40 45 Gly Ser Ser Val Thr Gln Leu Leu Ala Gln Asp Met Asp Asn Asp Pro 50 55 60 Leu Val Phe Gly Val Ser Gly Glu Glu Ala Ser Arg Phe Phe Ala Val 65 70 75 80 Glu Pro Asp Thr Gly Val Val Trp Leu Arg Gln Pro Leu Asp Arg Glu 85 90 95 Thr Lys Ser Glu Phe Thr Val Glu Phe Ser Val Ser Asp His Gln Gly 100 105 110 Val Ile Thr Arg Lys Val Asn Ile Gln Val Gly Asp Val Asn Asp Asn 115 120 125 Ala Pro Thr Phe His Asn Gln Pro Tyr Ser Val Arg Ile Pro Glu Asn 130 135 140 Thr Pro Val Gly Thr Pro Ile Phe Ile Val Asn Ala Thr Asp Pro Asp 145 150 155 160 Leu Gly Ala Gly Gly Ser Val Leu Tyr Ser Phe Gln Pro Pro Ser Gln 165 170 175 Phe Phe Ala Ile Asp Ser Ala Arg Gly Ile Val Thr Val Ile Arg Glu 180 185 190 Leu Asp Tyr Glu Thr Thr Gln Ala Tyr Gln Leu Thr Val Asn Ala Thr 195 200 205 Asp Gln Asp Lys Thr Arg Pro Leu Ser Thr Leu Ala Asn Leu Ala Ile 210 215 220 Ile Ile Thr Asp Val Gln Asp Met Asp Pro Ile Phe Ile Asn Leu Pro 225 230 235 240 Tyr Ser Thr Asn Ile Tyr Glu His Ser Pro Pro Gly Thr Thr Val Arg 245 250 255 Ile Ile Thr Ala Ile Asp Gln Asp Lys Gly Arg Pro Arg Gly Ile Gly 260 265 270 Tyr Thr Ile Val Ser Gly Asn Thr Asn Ser Ile Phe Ala Leu Asp Tyr 275 280 285 Ile Ser Gly Val Leu Thr Leu Asn Gly Leu Leu Asp Arg Glu Asn Pro 290 295 300 Leu Tyr Ser His Gly Phe Ile Leu Thr Val Lys Gly Thr Glu Leu Asn 305 310 315 320 Asp Asp Arg Thr Pro Ser Asp Ala Thr Val Thr Thr Thr Phe Asn Ile 325 330 335 Leu Val Ile Asp Ile Asn Asp Asn Ala Pro Glu Phe Asn Ser Ser Glu 340 345 350 Tyr Ser Val Ala Ile Thr Glu Leu Ala Gln Val Gly Phe Ala Leu Pro 355 360 365 Leu Phe Ile Gln Val Val Asp Lys Asp Glu Asn Leu Gly Leu Asn Ser 370 375 380 Met Phe Glu Val Tyr Leu Val Gly Asn Asn Ser His His Phe Ile Ile 385 390 395 400 Ser Pro Thr Ser Val Gln Gly Lys Ala Asp Ile Arg Ile Arg Val Ala 405 410 415 Ile Pro Leu Asp Tyr Glu Thr Val Asp Arg Tyr Asp Phe Asp Leu Phe 420 425 430 Ala Asn Glu Ser Val Pro Asp His Val Gly Tyr Ala Lys Val Lys Ile 435 440 445 Thr Leu Ile Asn Glu Asn Asp Asn Arg Pro Ile Phe Ser Gln Pro Leu 450 455 460 Tyr Asn Ile Ser Leu Tyr Glu Asn Val Thr Val Gly Thr Ser Val Leu 465 470 475 480 Thr Val Leu Ala Thr Asp Asn Asp Ala Gly Thr Phe Gly Glu Val Ser 485 490 495 Tyr Phe Phe Ser Asp Asp Pro Asp Arg Phe Ser Leu Asp Lys Asp Thr 500 505 510 Gly Leu Ile Met Leu Ile Ala Arg Leu Asp Tyr Glu Leu Ile Gln Arg 515 520 525 Phe Thr Leu Thr Ile Ile Ala Arg Asp Gly Gly Gly Glu Glu Thr Thr 530 535 540 Gly Arg Val Arg Ile Asn Val Leu Asp Val Asn Asp Asn Val Pro Thr 545 550 555 560 Phe Gln Lys Asp Ala Tyr Val Gly Ala Leu Arg Glu Asn Glu Pro Ser 565 570 575 Val Thr Gln Leu Val Arg Leu Arg Ala Thr Asp Glu Asp Ser Pro Pro 580 585 590 Asn Asn Gln Ile Thr Tyr Ser Ile Val Ser Ala Ser Ala Phe Gly Ser 595 600 605 Tyr Phe Asp Ile Ser Leu Tyr Glu Gly Tyr Gly Val Ile Ser Val Ser 610 615 620 Arg Pro Leu Asp Tyr Glu Gln Ile Ser Asn Gly Leu Ile Tyr Leu Thr 625 630 635 640 Val Met Ala Met Asp Ala Gly Asn Pro Pro Leu Asn Ser Thr Val Pro 645 650 655 Val Thr Ile Glu Val Phe Asp Glu Asn Asp Asn Pro Pro Thr Phe Ser 660 665 670 Lys Pro Ala Tyr Phe Val Ser Val Val Glu Asn Ile Met Ala Gly Ala 675 680 685 Thr Val Leu Phe Leu Asn Ala Thr Asp Leu Asp Arg Ser Arg Glu Tyr 690 695 700 Gly Gln Glu Ser Ile Ile Tyr Ser Leu Glu Gly Ser Thr Gln Phe Arg 705 710 715 720 Ile Asn Ala Arg Ser Gly Glu Ile Thr Thr Thr Ser Leu Leu Asp Arg 725 730 735 Glu Thr Lys Ser Glu Tyr Ile Leu Ile Val Arg Ala Val Asp Gly Gly 740 745 750 Val Gly His Asn Gln Lys Thr Gly Ile Ala Thr Val Asn Ile Thr Leu 755 760 765 Leu Asp Ile Asn Asp Asn His Pro Thr Trp Lys Asp Ala Pro Tyr Tyr 770 775 780 Ile Asn Leu Val Glu Met Thr Pro Pro Asp Ser Asp Val Thr Thr Val 785 790 795 800 Val Ala Val Asp Pro Asp Leu Gly Glu Asn Gly Thr Leu Val Tyr Ser 805 810 815 Ile Gln Pro Pro Asn Lys Phe Tyr Ser Leu Asn Ser Thr Thr Gly Lys 820 825 830 Ile Arg Thr Thr His Ala Met Leu Asp Arg Glu Asn Pro Asp Pro His 835 840 845 Glu Ala Glu Leu Met Arg Lys Ile Val Val Ser Val Thr Asp Cys Gly 850 855 860 Arg Pro Pro Leu Lys Ala Thr Ser Ser Ala Thr Val Phe Val Asn Leu 865 870 875 880 Leu Asp Leu Asn Asp Asn Asp Pro Thr Phe Gln Asn Leu Pro Phe Val 885 890 895 Ala Glu Val Leu Glu Gly Ile Pro Ala Gly Val Ser Ile Tyr Gln Val 900 905 910 Val Ala Ile Asp Leu Asp Glu Gly Leu Asn Gly Leu Val Ser Tyr Arg 915 920 925 Met Pro Val Gly Met Pro Arg Met Asp Phe Leu Ile Asn Ser Ser Ser 930 935 940 Gly Val Val Val Thr Thr Thr Glu Leu Asp Arg Glu Arg Ile Ala Glu 945 950 955 960 Tyr Gln Leu Arg Val Val Ala Ser Asp Ala Gly Thr Pro Thr Lys Ser 965 970 975 Ser Thr Ser Thr Leu Thr Ile His Val Leu Asp Val Asn Asp Glu Thr 980 985 990 Pro Thr Phe Phe Pro Ala Val Tyr Asn Val Ser Val Ser Glu Asp Val 995 1000 1005 Pro Arg Glu Phe Arg Val Val Trp Leu Asn Cys Thr Asp Asn Asp 1010 1015 1020 Val Gly Leu Asn Ala Glu Leu Ser Tyr Phe Ile Thr Gly Gly Asn 1025 1030 1035 Val Asp Gly Lys Phe Ser Val Gly Tyr Arg Asp Ala Val Val Arg 1040 1045 1050 Thr Val Val Gly Leu Asp Arg Glu Thr Thr Ala Ala Tyr Met Leu 1055 1060 1065 Ile Leu Glu Ala Ile Asp Asn Gly Pro Val Gly Lys Arg His Thr 1070 1075 1080 Gly Thr Ala Thr Val Phe Val Thr Val Leu Asp Val Asn Asp Asn 1085 1090 1095 Arg Pro Ile Phe Leu Gln Ser Ser Tyr Glu Ala Ser Val Pro Glu 1100 1105 1110 Asp Ile Pro Glu Gly His Ser Ile Leu Gln Leu Lys Ala Thr Asp 1115 1120 1125 Ala Asp Glu Gly Glu Phe Gly Arg Val Trp Tyr Arg Ile Leu His 1130 1135 1140 Gly Asn His Gly Asn Asn Phe Arg Ile His Val Ser Asn Gly Leu 1145 1150 1155 Leu Met Arg Gly Pro Arg Pro Leu Asp Arg Glu Arg Asn Ser Ser 1160 1165 1170 His Val Leu Ile Val Glu Ala Tyr Asn His Asp Leu Gly Pro Met 1175 1180 1185 Arg Ser Ser Val Arg Val Ile Val Tyr Val Glu Asp Ile Asn Asp 1190 1195 1200 Glu Ala Pro Val Phe Thr Gln Gln Gln Tyr Ser Arg Leu Gly Leu 1205 1210 1215 Arg Glu Thr Ala Gly Ile Gly Thr Ser Val Ile Val Val Gln Ala 1220 1225 1230 Thr Asp Arg Asp Ser Gly Asp Gly Gly Leu Val Asn Tyr Arg Ile 1235 1240 1245 Leu Ser Gly Ala Glu Gly Lys Phe Glu Ile Asp Glu Ser Thr Gly 1250 1255 1260 Leu Ile Ile Thr Val Asn Tyr Leu Asp Tyr Glu Thr Lys Thr Ser 1265 1270 1275 Tyr Met Met Asn Val Ser Ala Thr Asp Gln Ala Pro Pro Phe Asn 1280 1285 1290 Gln Gly Phe Cys Ser Val Tyr Ile Thr Leu Leu Asn Glu Leu Asp 1295 1300 1305 Glu Ala Val Gln Phe Ser Asn Ala Ser Tyr Glu Ala Ala Ile Leu 1310 1315 1320 Glu Asn Leu Ala Leu Gly Thr Glu Ile Val Arg Val Gln Ala Tyr 1325 1330 1335 Ser Ile Asp Asn Leu Asn Gln Ile Thr Tyr Arg Phe Asp Ala Tyr 1340 1345 1350 Thr Ser Thr Gln Ala Lys Ala Leu Phe Lys Ile Asp Ala Ile Thr 1355 1360 1365 Gly Val Ile Thr Val Gln Gly Leu Val Asp Arg Glu Lys Gly Asp 1370 1375 1380 Phe Tyr Thr Leu Thr Val Val Ala Asp Asp Gly Gly Pro Lys Val 1385 1390 1395 Asp Ser Thr Val Lys Val Tyr Ile Thr Val Leu Asp Glu Asn Asp 1400 1405 1410 Asn Ser Pro Arg Phe Asp Phe Thr Ser Asp Ser Ala Val Ser Ile 1415 1420 1425 Pro Glu Asp Cys Pro Val Gly Gln Arg Val Ala Thr Val Lys Ala 1430 1435 1440 Trp Asp Pro Asp Ala Gly Ser Asn Gly Gln Val Val Phe Ser Leu 1445 1450 1455 Ala Ser Gly Asn Ile Ala Gly Ala Phe Glu Ile Val Thr Thr Asn 1460 1465 1470 Asp Ser Ile Gly Glu Val Phe Val Ala Arg Pro Leu Asp Arg Glu 1475 1480 1485 Glu Leu Asp His Tyr Ile Leu Gln Val Val Ala Ser Asp Arg Gly 1490 1495 1500 Thr Pro Pro Arg Lys Lys Asp His Ile Leu Gln Val Thr Ile Leu 1505 1510 1515 Asp Ile Asn Asp Asn Pro Pro Val Ile Glu Ser Pro Phe Gly Tyr 1520 1525 1530 Asn Val Ser Val Asn Glu Asn Val Gly Gly Gly Thr Ala Val Val 1535 1540 1545 Gln Val Arg Ala Thr Asp Arg Asp Ile Gly Ile Asn Ser Val Leu 1550 1555 1560 Ser Tyr Tyr Ile Thr Glu Gly Asn Lys Asp Met Thr Phe Arg Met 1565 1570 1575 Asp Arg Ile Ser Gly Glu Ile Ala Thr Arg Pro Ala Pro Pro Asp 1580 1585 1590 Arg Glu Arg Gln Ser Phe Tyr His Leu Val Ala Thr Val Glu Asp 1595 1600 1605 Glu Gly Thr Pro Thr Leu Ser Ala Thr Thr His Val Tyr Val Thr 1610 1615 1620 Ile Val Asp Glu Asn Asp Asn Ala Pro Met Phe Gln Gln Pro His 1625 1630 1635 Tyr Glu Val Leu Leu Asp Glu Gly Pro Asp Thr Leu Asn Thr Ser 1640 1645 1650 Leu Ile Thr Ile Gln Ala Leu Asp Leu Asp Glu Gly Pro Asn Gly 1655 1660 1665 Thr Val Thr Tyr Ala Ile Val Ala Gly Asn Ile Val Asn Thr Phe 1670 1675 1680 Arg Ile Asp Arg His Met Gly Val Ile Thr Ala Ala Lys Glu Leu 1685 1690 1695 Asp Tyr Glu Ile Ser His Gly Arg Tyr Thr Leu Ile Val Thr Ala 1700 1705 1710 Thr Asp Gln Cys Pro Ile Leu Ser His Arg Leu Thr Ser Thr Thr 1715 1720 1725 Thr Val Leu Val Asn Val Asn Asp Ile Asn Asp Asn Val Pro Thr 1730 1735 1740 Phe Pro Arg Asp Tyr Glu Gly Pro Phe Glu Val Thr Glu Gly Gln 1745 1750 1755 Pro Gly Pro Arg Val Trp Thr Phe Leu Ala His Asp Arg Asp Ser 1760 1765 1770 Gly Pro Asn Gly Gln Val Glu Tyr Ser Ile Met Asp Gly Asp Pro 1775 1780 1785 Leu Gly Glu Phe Val Ile Ser Pro Val Glu Gly Val Leu Arg Val 1790 1795 1800 Arg Lys Asp Val Glu Leu Asp Arg Glu Thr Ile Ala Phe Tyr Asn 1805 1810 1815 Leu Thr Ile Cys Ala Arg Asp Arg Gly Met Pro Pro Leu Ser Ser 1820 1825 1830 Thr Met Leu Val Gly Ile Arg Val Leu Asp Ile Asn Asp Asn Asp 1835 1840 1845 Pro Val Leu Leu Asn Leu Pro Met Asn Ile Thr Ile Ser Glu Asn 1850 1855 1860 Ser Pro Val Ser Ser Phe Val Ala His Val Leu Ala Ser Asp Ala 1865 1870 1875 Asp Ser Gly Cys Asn Ala Arg Leu Thr Phe Asn Ile Thr Ala Gly 1880 1885 1890 Asn Arg Glu Arg Ala Phe Phe Ile Asn Ala Thr Thr Gly Ile Val 1895 1900 1905 Thr Val Asn Arg Pro Leu Asp Arg Glu Arg Ile Pro Glu Tyr Lys 1910 1915 1920 Leu Thr Ile Ser Val Lys Asp Asn Pro Glu Asn Pro Arg Ile Ala 1925 1930 1935 Arg Arg Asp Tyr Asp Leu Leu Leu Ile Phe Leu Ser Asp Glu Asn 1940 1945 1950 Asp Asn His Pro Leu Phe Thr Lys Ser Thr Tyr Gln Ala Glu Val 1955 1960 1965 Met Glu Asn Ser Pro Ala Gly Thr Pro Leu Thr Val Leu Asn Gly 1970 1975 1980 Pro Ile Leu Ala Leu Asp Ala Asp Gln Asp Ile Tyr Ala Val Val 1985 1990 1995 Thr Tyr Gln Leu Leu Gly Ala Gln Ser Gly Leu Phe Asp Ile Asn 2000 2005 2010 Ser Ser Thr Gly Val Val Thr Val Arg Ser Gly Val Ile Ile Asp 2015 2020 2025 Arg Glu Ala Phe Ser Pro Pro Ile Leu Glu Leu Leu Leu Leu Ala 2030 2035 2040 Glu Asp Ile Gly Leu Leu Asn Ser Thr Ala His Leu Leu Ile Thr 2045 2050 2055 Ile Leu Asp Asp Asn Asp Asn Arg Pro Thr Phe Ser Pro Ala Thr 2060 2065 2070 Leu Thr Val His Leu Leu Glu Asn Cys Pro Pro Gly Phe Ser Val 2075 2080 2085 Leu Gln Val Thr Ala Thr Asp Glu Asp Ser Gly Leu Asn Gly Glu 2090 2095 2100 Leu Val Tyr Arg Ile Glu Ala Gly Ala Gln Asp Arg Phe Leu Ile 2105 2110 2115 His Leu Val Thr Gly Val Ile Arg Val Gly Asn Ala Thr Ile Asp 2120 2125 2130 Arg Glu Glu Gln Glu Ser Tyr Arg Leu Thr Val Val Ala Thr Asp 2135 2140 2145 Arg Gly Thr Val Pro Leu Ser Gly Thr Ala Ile Val Thr Ile Leu 2150 2155 2160 Ile Asp Asp Ile Asn Asp Ser Arg Pro Glu Phe Leu Asn Pro Ile 2165 2170 2175 Gln Thr Val Ser Val Leu Glu Ser Ala Glu Pro Gly Thr Val Ile 2180 2185 2190 Ala Asn Ile Thr Ala Ile Asp His Asp Leu Asn Pro Lys Leu Glu 2195 2200 2205 Tyr His Ile Val Gly Ile Val Ala Lys Asp Asp Thr Asp Arg Leu 2210 2215 2220 Val Pro Asn Gln Glu Asp Ala Phe Ala Val Asn Ile Asn Thr Gly 2225 2230 2235 Ser Val Met Val Lys Ser Pro Met Asn Arg Glu Leu Val Ala Thr 2240 2245 2250 Tyr Glu Val Thr Leu Ser Val Ile Asp Asn Ala Ser Asp Leu Pro 2255 2260 2265 Glu Arg Ser Val Ser Val Pro Asn Ala Lys Leu Thr Val Asn Val 2270 2275 2280 Leu Asp Val Asn Asp Asn Thr Pro Gln Phe Lys Pro Phe Gly Ile 2285 2290 2295 Thr Tyr Tyr Met Glu Arg Ile Leu Glu Gly Ala Thr Pro Gly Thr 2300 2305 2310 Thr Leu Ile Ala Val Ala Ala Val Asp Pro Asp Lys Gly Leu Asn 2315 2320 2325 Gly Leu Val Thr Tyr Thr Leu Leu Asp Leu Val Pro Pro Gly Tyr 2330 2335 2340 Val Gln Leu Glu Asp Ser Ser Ala Gly Lys Val Ile Ala Asn Arg 2345 2350 2355 Thr Val Asp Tyr Glu Glu Val His Trp Leu Asn Phe Thr Val Arg 2360 2365 2370 Ala Ser Asp Asn Gly Ser Pro Pro Arg Ala Ala Glu Ile Pro Val 2375 2380 2385 Tyr Leu Glu Ile Val Asp Ile Asn Asp Asn Asn Pro Ile Phe Asp 2390 2395 2400 Gln Pro Ser Tyr Gln Glu Ala Val Phe Glu Asp Val Pro Val Gly 2405 2410 2415 Thr Ile Ile Leu Thr Val Thr Ala Thr Asp Ala Asp Ser Gly Asn 2420 2425 2430 Phe Ala Leu Ile Glu Tyr Ser Leu Gly Asp Gly Glu Ser Lys Phe 2435 2440 2445 Ala Ile Asn Pro Thr Thr Gly Asp Ile Tyr Val Leu Ser Ser Leu 2450 2455 2460 Asp Arg Glu Lys Lys Asp His Tyr Ile Leu Thr Ala Leu Ala Lys 2465 2470 2475 Asp Asn Pro Gly Asp Val Ala Ser Asn Arg Arg Glu Asn Ser Val 2480 2485 2490 Gln Val Val Ile Gln Val Leu Asp Val Asn Asp Cys Arg Pro Gln 2495 2500 2505 Phe Ser Lys Pro Gln Phe Ser Thr Ser Val Tyr Glu Asn Glu Pro 2510 2515 2520 Ala Gly Thr Ser Val Ile Thr Met Met Ala Thr Asp Gln Asp Glu 2525 2530 2535 Gly Pro Asn Gly Glu Leu Thr Tyr Ser Leu Glu Gly Pro Gly Val 2540 2545 2550 Glu Ala Phe His Val Asp Met Asp Ser Gly Leu Val Thr Thr Gln 2555 2560 2565 Arg Pro Leu Gln Ser Tyr Glu Lys Phe Ser Leu Thr Val Val Ala 2570 2575 2580 Thr Asp Gly Gly Glu Pro Pro Leu Trp Gly Thr Thr Met Leu Leu 2585 2590 2595 Val Glu Val Ile Asp Val Asn Asp Asn Arg Pro Val Phe Val Arg 2600 2605 2610 Pro Pro Asn Gly Thr Ile Leu His Ile Arg Glu Glu Ile Pro Leu 2615 2620 2625 Arg Ser Asn Val Tyr Glu Val Tyr Ala Thr Asp Lys Asp Glu Gly 2630 2635 2640 Leu Asn Gly Ala Val Arg Tyr Ser Phe Leu Lys Thr Ala Gly Asn 2645 2650 2655 Arg Asp Trp Glu Phe Phe Ile Ile Asp Pro Ile Ser Gly Leu Ile 2660 2665 2670 Gln Thr Ala Gln Arg Leu Asp Arg Glu Ser Gln Ala Val Tyr Ser 2675 2680 2685 Leu Ile Leu Val Ala Ser Asp Leu Gly Gln Pro Val Pro Tyr Glu 2690 2695 2700 Thr Met Gln Pro Leu Gln Val Ala Leu Glu Asp Ile Asp Asp Asn 2705 2710 2715 Glu Pro Leu Phe Val Arg Pro Pro Lys Gly Ser Pro Gln Tyr Gln 2720 2725 2730 Leu Leu Thr Val Pro Glu His Ser Pro Arg Gly Thr Leu Val Gly 2735 2740 2745 Asn Val Thr Gly Ala Val Asp Ala Asp Glu Gly Pro Asn Ala Ile 2750 2755 2760 Val Tyr Tyr Phe Ile Ala Ala Gly Asn Glu Glu Lys Asn Phe His 2765 2770 2775 Leu Gln Pro Asp Gly Cys Leu Leu Val Leu Arg Asp Leu Asp Arg 2780 2785 2790 Glu Arg Glu Ala Ile Phe Ser Phe Ile Val Lys Ala Ser Ser Asn 2795 2800 2805 Arg Ser Trp Thr Pro Pro Arg Gly Pro Ser Pro Thr Leu Asp Leu 2810 2815 2820 Val Ala Asp Leu Thr Leu Gln Glu Val Arg Val Val Leu Glu Asp 2825 2830 2835 Ile Asn Asp Gln Pro Pro Arg Phe Thr Lys Ala Glu Tyr Thr Ala 2840 2845 2850 Gly Val Ala Thr Asp Ala Lys Val Gly Ser Glu Leu Ile Gln Val 2855 2860 2865 Leu Ala Leu Asp Ala Asp Ile Gly Asn Asn Ser Leu Val Phe Tyr 2870 2875 2880 Ser Ile Leu Ala Ile His Tyr Phe Arg Ala Leu Ala Asn Asp Ser 2885 2890 2895 Glu Asp Val Gly Gln Val Phe Thr Met Gly Ser Met Asp Gly Ile 2900 2905 2910 Leu Arg Thr Phe Asp Leu Phe Met Ala Tyr Ser Pro Gly Tyr Phe 2915 2920 2925 Val Val Asp Ile Val Ala Arg Asp Leu Ala Gly His Asn Asp Thr 2930 2935 2940 Ala Ile Ile Gly Ile Tyr Ile Leu Arg Asp Asp Gln Arg Val Lys 2945 2950 2955 Ile Val Ile Asn Glu Ile Pro Asp Arg Val Arg Gly Phe Glu Glu 2960 2965 2970 Glu Phe Ile His Leu Leu Ser Asn Ile Thr Gly Ala Ile Val Asn 2975 2980 2985 Thr Asp Asn Val Gln Phe His Val Asp Lys Lys Gly Arg Val Asn 2990 2995 3000 Phe Ala Gln Thr Glu Leu Leu Ile His Val Val Asn Arg Asp Thr 3005 3010 3015 Asn Arg Ile Leu Asp Val Asp Arg Val Ile Gln Met Ile Asp Glu 3020 3025 3030 Asn Lys Glu Gln Leu Arg Asn Leu Phe Arg Asn Tyr Asn Val Leu 3035 3040 3045 Asp Val Gln Pro Ala Ile Ser Val Arg Leu Pro Asp Asp Met Ser 3050 3055 3060 Ala Leu Gln Met Ala Ile Ile Val Leu Ala Ile Leu Leu Phe Leu 3065 3070 3075 Ala Ala Met Leu Phe Val Leu Met Asn Trp Tyr Tyr Arg Thr Val 3080 3085 3090 His Lys Arg Lys Leu Lys Ala Ile Val Ala Gly Ser Ala Gly Asn 3095 3100 3105 Arg Gly Phe Ile Asp Ile Met Asp Met Pro Asn Thr Asn Lys Tyr 3110 3115 3120 Ser Phe Asp Gly Ala Asn Pro Val Trp Leu Asp Pro Phe Cys Arg 3125 3130 3135 Asn Leu Glu Leu Ala Ala Gln Ala Glu His Glu Asp Asp Leu Pro 3140 3145 3150 Glu Asn Leu Ser Glu Ile Ala Asp Leu Trp Asn Ser Pro Thr Arg 3155 3160 3165 Thr His Gly Thr Phe Gly Arg Glu Pro Ala Ala Val Lys Pro Asp 3170 3175 3180 Asp Asp Arg Tyr Leu Arg Ala Ala Ile Gln Glu Tyr Asp Asn Ile 3185 3190 3195 Ala Lys Leu Gly Gln Ile Ile Arg Glu Gly Pro Ile Lys Gly Ser 3200 3205 3210 Leu Leu Lys Val Val Leu Glu Asp Tyr Leu Arg Leu Lys Lys Leu 3215 3220 3225 Phe Ala Gln Arg Met Val Gln Lys Ala Ser Ser Cys His Ser Ser 3230 3235 3240 Ile Ser Glu Leu Ile Gln Thr Glu Leu Asp Glu Glu Pro Gly Asp 3245 3250 3255 His Ser Pro Gly Gln Gly Ser Leu Arg Phe Arg His Lys Pro Pro 3260 3265 3270 Val Glu Leu Lys Gly Pro Asp Gly Ile His Val Val His Gly Ser 3275 3280 3285 Thr Gly Thr Leu Leu Ala Thr Asp Leu Asn Ser Leu Pro Glu Glu 3290 3295 3300 Asp Gln Lys Gly Leu Gly Arg Ser Leu Glu Thr Leu Thr Ala Ala 3305 3310 3315 Glu Ala Thr Ala Phe Glu Arg Asn Ala Arg Thr Glu Ser Ala Lys 3320 3325 3330 Ser Thr Pro Leu His Lys Leu Arg Asp Val Ile Met Glu Thr Pro 3335 3340 3345 Leu Glu Ile Thr Glu Leu 3350 13 4590 PRT Homo sapiens 13 Met Gly Arg His Leu Ala Leu Leu Leu Leu Leu Leu Leu Leu Phe Gln 1 5 10 15 His Phe Gly Asp Ser Asp Gly Ser Gln Arg Leu Glu Gln Thr Pro Leu 20 25 30 Gln Phe Thr His Leu Glu Tyr Asn Val Thr Val Gln Glu Asn Ser Ala 35 40 45 Ala Lys Thr Tyr Val Gly His Pro Val Lys Met Gly Val Tyr Ile Thr 50 55 60 His Pro Ala Trp Glu Val Arg Tyr Lys Ile Val Ser Gly Asp Ser Glu 65 70 75 80 Asn Leu Phe Lys Ala Glu Glu Tyr Ile Leu Gly Asp Phe Cys Phe Leu 85 90 95 Arg Ile Arg Thr Lys Gly Gly Asn Thr Ala Ile Leu Asn Arg Glu Val 100 105 110 Lys Asp His Tyr Thr Leu Ile Val Lys Ala Leu Glu Lys Asn Thr Asn 115 120 125 Val Glu Ala Arg Thr Lys Val Arg Val Gln Val Leu Asp Thr Asn Asp 130 135 140 Leu Arg Pro Leu Phe Ser Pro Thr Ser Tyr Ser Val Ser Leu Pro Glu 145 150 155 160 Asn Thr Ala Ile Arg Thr Ser Ile Ala Arg Val Ser Ala Thr Asp Ala 165 170 175 Asp Ile Gly Thr Asn Gly Glu Phe Tyr Tyr Ser Phe Lys Asp Arg Thr 180 185 190 Asp Met Phe Ala Ile His Pro Thr Ser Gly Val Ile Val Leu Thr Gly 195 200 205 Arg Leu Asp Tyr Leu Glu Thr Lys Leu Tyr Glu Met Glu Ile Leu Ala 210 215 220 Ala Asp Arg Gly Met Lys Leu Tyr Gly Ser Ser Gly Ile Ser Ser Met 225 230 235 240 Ala Lys Leu Thr Val His Ile Glu Gln Ala Asn Glu Cys Ala Pro Val 245 250 255 Ile Thr Ala Val Thr Leu Ser Pro Ser Glu Leu Asp Arg Asp Pro Ala 260 265 270 Tyr Ala Ile Val Thr Val Asp Asp Cys Asp Gln Gly Ala Asn Gly Asp 275 280 285 Ile Ala Ser Leu Ser Ile Val Ala Gly Asp Leu Leu Gln Gln Phe Arg 290 295 300 Thr Val Arg Ser Phe Pro Gly Ser Lys Glu Tyr Lys Val Lys Ala Ile 305 310 315 320 Gly Asp Ile Asp Trp Asp Ser His Pro Phe Gly Tyr Asn Leu Thr Leu 325 330 335 Gln Ala Lys Asp Lys Gly Thr Pro Pro Gln Phe Ser Ser Val Lys Val 340 345 350 Ile His Val Thr Ser Pro Gln Phe Lys Ala Gly Pro Val Lys Phe Glu 355 360 365 Lys Asp Val Tyr Arg Ala Glu Ile Ser Glu Phe Ala Pro Pro Asn Thr 370 375 380 Pro Val Val Met Val Lys Ala Ile Pro Ala Tyr Ser His Leu Arg Tyr 385 390 395 400 Val Phe Lys Arg Thr Pro Gly Lys Ala Lys Phe Ser Leu Asn Tyr Asn 405 410 415 Thr Gly Leu Ile Ser Ile Leu Glu Pro Val Lys Arg Gln Gln Ala Ala 420 425 430 His Phe Glu Leu Glu Val Thr Thr Ser Asp Arg Lys Ala Ser Thr Lys 435 440 445 Val Leu Val Lys Val Leu Gly Ala Asn Ser Asn Pro Pro Glu Phe Thr 450 455 460 Gln Thr Ala Tyr Lys Ala Ala Phe Asp Glu Asn Val Pro Ile Gly Thr 465 470 475 480 Thr Ile Met Ser Leu Ser Ala Val Asp Pro Asp Glu Gly Glu Asn Gly 485 490 495 Tyr Val Thr Tyr Ser Ile Ala Asn Leu Asn His Val Pro Phe Ala Ile 500 505 510 Asp His Phe Thr Gly Ala Val Ser Thr Ser Glu Asn Leu Asp Tyr Glu 515 520 525 Leu Met Pro Arg Val Tyr Thr Leu Arg Ile Arg Ala Ser Asp Trp Gly 530 535 540 Leu Pro Tyr Arg Arg Glu Val Glu Val Leu Ala Thr Ile Thr Leu Asn 545 550 555 560 Asn Leu Asn Asp Asn Thr Pro Leu Phe Glu Lys Ile Asn Cys Glu Gly 565 570 575 Thr Ile Pro Arg Asp Leu Gly Val Gly Glu Gln Ile Thr Thr Val Ser 580 585 590 Ala Ile Asp Ala Asp Glu Leu Gln Leu Val Gln Tyr Gln Ile Glu Ala 595 600 605 Gly Asn Glu Leu Asp Leu Phe Ser Leu Asn Pro Asn Ser Gly Val Leu 610 615 620 Ser Leu Lys Arg Ser Leu Met Asp Gly Leu Gly Ala Lys Val Ser Phe 625 630 635 640 His Ser Leu Arg Ile Thr Ala Thr Asp Gly Glu Asn Phe Ala Thr Pro 645 650 655 Leu Tyr Ile Asn Ile Thr Val Ala Ala Ser His Lys Leu Val Asn Leu 660 665 670 Gln Cys Glu Glu Thr Gly Val Ala Lys Met Leu Ala Glu Lys Leu Leu 675 680 685 Gln Ala Asn Lys Leu His Asn Gln Gly Glu Val Glu Asp Ile Phe Phe 690 695 700 Asp Ser His Ser Val Asn Ala His Ile Pro Gln Phe Arg Ser Thr Leu 705 710 715 720 Pro Thr Gly Ile Gln Val Lys Glu Asn Gln Pro Val Gly Ser Ser Val 725 730 735 Ile Phe Met Asn Ser Thr Asp Leu Asp Thr Gly Phe Asn Gly Lys Leu 740 745 750 Val Tyr Ala Val Ser Gly Gly Asn Glu Asp Ser Cys Phe Met Ile Asp 755 760 765 Met Glu Thr Gly Met Leu Lys Ile Leu Ser Pro Leu Asp Arg Glu Thr 770 775 780 Thr Asp Lys Tyr Thr Leu Asn Ile Thr Val Tyr Asp Leu Gly Ile Pro 785 790 795 800 Gln Lys Ala Ala Trp Arg Leu Leu His Val Val Val Val Asp Ala Asn 805 810 815 Asp Asn Pro Pro Glu Phe Leu Gln Glu Ser Tyr Phe Val Glu Val Ser 820 825 830 Glu Asp Lys Glu Val His Ser Glu Ile Ile Gln Val Glu Ala Thr Asp 835 840 845 Lys Asp Leu Gly Pro Asn Gly His Val Thr Tyr Ser Ile Leu Thr Asp 850 855 860 Thr Asp Thr Phe Ser Ile Asp Ser Val Thr Gly Val Val Asn Ile Ala 865 870 875 880 Arg Pro Leu Asp Arg Glu Leu Gln His Glu His Ser Leu Lys Ile Glu 885 890 895 Ala Arg Asp Gln Ala Arg Glu Glu Pro Gln Leu Phe Ser Thr Val Val 900 905 910 Val Lys Val Ser Leu Glu Asp Val Asn Asp Asn Pro Pro Thr Phe Ile 915 920 925 Pro Pro Asn Tyr Arg Val Lys Val Arg Glu Asp Leu Pro Glu Gly Thr 930 935 940 Val Ile Met Trp Leu Glu Ala His Asp Pro Asp Leu Gly Gln Ser Gly 945 950 955 960 Gln Val Arg Tyr Ser Leu Leu Asp His Gly Glu Gly Asn Phe Asp Val 965 970 975 Asp Lys Leu Ser Gly Ala Val Arg Ile Val Gln Gln Leu Asp Phe Glu 980 985 990 Lys Lys Gln Val Tyr Asn Leu Thr Val Arg Ala Lys Asp Lys Gly Lys 995 1000 1005 Pro Val Ser Leu Ser Ser Thr Cys Tyr Val Glu Val Glu Val Val 1010 1015 1020 Asp Val Asn Glu Asn Leu His Pro Pro Val Phe Ser Ser Phe Val 1025 1030 1035 Glu Lys Gly Thr Val Lys Glu Asp Ala Pro Val Gly Ser Leu Val 1040 1045 1050 Met Thr Val Ser Ala His Asp Glu Asp Ala Gly Arg Asp Gly Glu 1055 1060 1065 Ile Arg Tyr Ser Ile Arg Asp Gly Ser Gly Val Gly Val Phe Lys 1070 1075 1080 Ile Gly Glu Glu Thr Gly Val Ile Glu Thr Ser Asp Arg Leu Asp 1085 1090 1095 Arg Glu Ser Thr Ser His Tyr Trp Leu Thr Val Phe Ala Thr Asp 1100 1105 1110 Gln Gly Val Val Pro Leu Ser Ser Phe Ile Glu Ile Tyr Ile Glu 1115 1120 1125 Val Glu Asp Val Asn Asp Asn Ala Pro Gln Thr Ser Glu Pro Val 1130 1135 1140 Tyr Tyr Pro Glu Ile Met Glu Asn Ser Pro Lys Asp Val Ser Val 1145 1150 1155 Val Gln Ile Glu Ala Phe Asp Pro Asp Ser Ser Ser Asn Asp Lys 1160 1165 1170 Leu Met Tyr Lys Ile Thr Ser Gly Asn Pro Gln Gly Phe Phe Ser 1175 1180 1185 Ile His Pro Lys Thr Gly Leu Ile Thr Thr Thr Ser Arg Lys Leu 1190 1195 1200 Asp Arg Glu Gln Gln Asp Glu His Ile Leu Glu Val Thr Val Thr 1205 1210 1215 Asp Asn Gly Ser Pro Pro Lys Ser Thr Ile Ala Arg Val Ile Val 1220 1225 1230 Lys Ile Leu Asp Glu Asn Asp Asn Lys Pro Gln Phe Leu Gln Lys 1235 1240 1245 Phe Tyr Lys Ile Arg Leu Pro Glu Arg Glu Lys Pro Asp Arg Glu 1250 1255 1260 Arg Asn Ala Arg Arg Glu Pro Leu Tyr Arg Val Ile Ala Thr Asp 1265 1270 1275 Lys Asp Glu Gly Pro Asn Ala Glu Ile Ser Tyr Ser Ile Glu Asp 1280 1285 1290 Gly Asn Glu His Gly Lys Phe Phe Ile Glu Pro Lys Thr Gly Val 1295 1300 1305 Val Ser Ser Lys Arg Phe Ser Ala Ala Gly Glu Tyr Asp Ile Leu 1310 1315 1320 Ser Ile Lys Ala Val Asp Asn Gly Arg Pro Gln Lys Ser Ser Thr 1325 1330 1335 Thr Arg Leu His Ile Glu Trp Ile Ser Lys Pro Lys Gln Ser Leu 1340 1345 1350 Glu Pro Ile Ser Phe Glu Glu Ser Phe Phe Thr Phe Thr Val Met 1355 1360 1365 Glu Ser Asp Pro Val Ala His Met Ile Gly Val Ile Ser Val Glu 1370 1375 1380 Pro Pro Gly Ile Pro Leu Trp Phe Asp Ile Thr Gly Gly Asn Tyr 1385 1390 1395 Asp Ser His Phe Asp Val Asp Lys Gly Thr Gly Thr Ile Ile Val 1400 1405 1410 Ala Lys Pro Leu Asp Ala Glu Gln Lys Ser Asn Tyr Asn Leu Thr 1415 1420 1425 Val Glu Ala Thr Asp Gly Thr Thr Thr Ile Leu Thr Gln Val Phe 1430 1435 1440 Ile Lys Val Ile Asp Thr Asn Asp His Arg Pro Gln Phe Ser Thr 1445 1450 1455 Ser Lys Tyr Glu Val Val Ile Pro Glu Asp Thr Ala Pro Glu Thr 1460 1465 1470 Glu Ile Leu Gln Ile Ser Ala Val Asp Gln Asp Glu Lys Asn Lys 1475 1480 1485 Leu Ile Tyr Thr Leu Gln Ser Ser Arg Asp Pro Leu Ser Leu Lys 1490 1495 1500 Lys Phe Arg Leu Asp Pro Ala Thr Gly Ser Leu Tyr Thr Ser Glu 1505 1510 1515 Lys Leu Asp His Glu Ala Val Ser Pro Ala His Leu Thr Val Met 1520 1525 1530 Val Arg Asp Gln Asp Val Pro Val Lys Arg Asn Phe Ala Arg Ile 1535 1540 1545 Val Val Asn Val Ser Asp Thr Asn Asp His Ala Pro Trp Phe Thr 1550 1555 1560 Ala Ser Ser Tyr Lys Gly Arg Val Tyr Glu Ser Ala Ala Val Gly 1565 1570 1575 Ser Val Val Leu Gln Val Thr Ala Leu Asp Lys Asp Lys Gly Lys 1580 1585 1590 Asn Ala Glu Val Leu Tyr Ser Ile Glu Ser Gly Asn Ile Gly Asn 1595 1600 1605 Ile Gly Asn Ser Phe Met Ile Asp Pro Val Leu Gly Ser Ile Lys 1610 1615 1620 Thr Ala Lys Glu Leu Asp Arg Ser Asn Gln Ala Glu Tyr Asp Leu 1625 1630 1635 Met Val Lys Ala Thr Asp Lys Gly Ser Pro Pro Met Ser Glu Ile 1640 1645 1650 Thr Ser Val Arg Ile Phe Val Thr Ile Ala Asp Asn Ala Ser Pro 1655 1660 1665 Lys Phe Thr Ser Lys Glu Tyr Ser Val Glu Leu Ser Glu Thr Val 1670 1675 1680 Ser Ile Gly Ser Phe Val Gly Met Val Thr Ala His Ser Gln Ser 1685 1690 1695 Ser Val Val Tyr Glu Ile Lys Asp Gly Asn Thr Gly Asp Ala Phe 1700 1705 1710 Asp Ile Asn Pro His Ser Gly Thr Ile Ile Thr Gln Lys Ala Leu 1715 1720 1725 Asp Phe Glu Thr Leu Pro Ile Tyr Thr Leu Ile Ile Gln Gly Thr 1730 1735 1740 Asn Met Ala Gly Leu Ser Thr Asn Thr Thr Val Leu Val His Leu 1745 1750 1755 Gln Asp Glu Asn Asp Asn Ala Pro Val Phe Met Gln Ala Glu Tyr 1760 1765 1770 Thr Gly Leu Ile Ser Glu Ser Ala Ser Ile Asn Ser Val Val Leu 1775 1780 1785 Thr Asp Arg Asn Val Pro Leu Val Ile Arg Ala Ala Asp Ala Asp 1790 1795 1800 Lys Asp Ser Asn Ala Leu Leu Val Tyr His Ile Val Glu Pro Ser 1805 1810 1815 Val His Thr Tyr Phe Ala Ile Asp Ser Ser Thr Gly Ala Ile His 1820 1825 1830 Thr Val Leu Ser Leu Asp Tyr Glu Glu Thr Ser Ile Phe His Phe 1835 1840 1845 Thr Val Gln Val His Asp Met Gly Thr Pro Arg Leu Phe Ala Glu 1850 1855 1860 Tyr Ala Ala Asn Val Thr Val His Val Ile Asp Ile Asn Asp Cys 1865 1870 1875 Pro Pro Val Phe Ala Lys Pro Leu Tyr Glu Ala Ser Leu Leu Leu 1880 1885 1890 Pro Thr Tyr Lys Gly Val Lys Val Ile Thr Val Asn Ala Thr Asp 1895 1900 1905 Ala Asp Ser Ser Ala Phe Ser Gln Leu Ile Tyr Ser Ile Thr Glu 1910 1915 1920 Gly Asn Ile Gly Glu Lys Phe Ser Met Asp Tyr Lys Thr Gly Ala 1925 1930 1935 Leu Thr Val Gln Asn Thr Thr Gln Leu Arg Ser Arg Tyr Glu Leu 1940 1945 1950 Thr Val Arg Ala Ser Asp Gly Arg Phe Ala Gly Leu Thr Ser Val 1955 1960 1965 Lys Ile Asn Val Lys Glu Ser Lys Glu Ser His Leu Lys Phe Thr 1970 1975 1980 Gln Asp Val Tyr Ser Ala Val Val Lys Glu Asn Ser Thr Glu Ala 1985 1990 1995 Glu Thr Leu Ala Val Ile Thr Ala Ile Gly Ser Pro Ile Asn Glu 2000 2005 2010 Pro Leu Phe Tyr His Ile Leu Asn Pro Asp Arg Arg Phe Lys Ile 2015 2020 2025 Ser Arg Thr Ser Gly Val Leu Ser Thr Thr Gly Thr Pro Phe Asp 2030 2035 2040 Arg Glu Gln Gln Glu Ala Phe Asp Val Val Val Glu Val Ile Glu 2045 2050 2055 Glu His Lys Pro Ser Ala Val Ala His Val Val Val Lys Val Ile 2060 2065 2070 Val Glu Asp Gln Asn Asp Asn Ala Pro Val Phe Val Asn Leu Pro 2075 2080 2085 Tyr Tyr Ala Val Val Lys Val Asp Thr Glu Val Gly His Val Ile 2090 2095 2100 Arg Tyr Val Thr Ala Val Asp Arg Asp Ser Gly Arg Asn Gly Glu 2105 2110 2115 Val His Tyr Tyr Leu Lys Glu His His Glu His Phe Gln Ile Gly 2120 2125 2130 Pro Leu Gly Glu Ile Ser Leu Lys Lys Gln Phe Glu Leu Asp Thr 2135 2140 2145 Leu Asn Lys Glu Tyr Leu Val Thr Val Val Ala Lys Asp Gly Gly 2150 2155 2160 Asn Pro Ala Phe Ser Ala Glu Val Ile Val Pro Ile Thr Val Met 2165 2170 2175 Asn Lys Ala Met Pro Val Phe Glu Lys Pro Phe Tyr Ser Ala Glu 2180 2185 2190 Ile Ala Glu Ser Ile Gln Val His Ser Pro Val Val His Val Gln 2195 2200 2205 Ala Asn Ser Pro Glu Gly Leu Lys Val Phe Tyr Ser Ile Thr Asp 2210 2215 2220 Gly Asp Pro Phe Ser Gln Phe Thr Ile Asn Phe Asn Thr Gly Val 2225 2230 2235 Ile Asn Val Ile Ala Pro Leu Asp Phe Glu Ala His Pro Ala Tyr 2240 2245 2250 Lys Leu Ser Ile Arg Ala Thr Asp Ser Leu Thr Gly Ala His Ala 2255 2260 2265 Glu Val Phe Val Asp Ile Ile Val Asp Asp Ile Asn Asp Asn Pro 2270 2275 2280 Pro Val Phe Ala Gln Gln Ser Tyr Ala Val Thr Leu Ser Glu Ala 2285 2290 2295 Ser Val Ile Gly Thr Ser Val Val Gln Val Arg Ala Thr Asp Ser 2300 2305 2310 Asp Ser Glu Pro Asn Arg Gly Ile Ser Tyr Gln Met Phe Gly Asn 2315 2320 2325 His Ser Lys Ser His Asp His Phe His Val Asp Ser Ser Thr Gly 2330 2335 2340 Leu Ile Ser Leu Leu Arg Thr Leu Asp Tyr Glu Gln Ser Arg Gln 2345 2350 2355 His Thr Ile Phe Val Arg Ala Val Asp Gly Gly Met Pro Thr Leu 2360 2365 2370 Ser Ser Asp Val Ile Val Thr Val Asp Val Thr Asp Leu Asn Gly 2375 2380 2385 Asn Pro Pro Leu Phe Glu Gln Gln Ile Tyr Glu Ala Arg Ile Ser 2390 2395 2400 Glu His Ala Pro His Gly His Phe Val Thr Cys Val Lys Ala Tyr 2405 2410 2415 Asp Ala Asp Ser Ser Asp Ile Asp Lys Leu Gln Tyr Ser Ile Leu 2420 2425 2430 Ser Gly Asn Asp His Lys His Phe Val Ile Asp Ser Ala Thr Gly 2435 2440 2445 Ile Ile Thr Leu Ser Asn Leu His Arg His Ala Leu Lys Pro Phe 2450 2455 2460 Tyr Ser Leu Asn Leu Ser Val Ser Asp Gly Val Phe Arg Ser Ser 2465 2470 2475 Thr Gln Val His Val Thr Val Ile Gly Gly Asn Leu His Ser Pro 2480 2485 2490 Ala Phe Leu Gln Asn Glu Tyr Glu Val Glu Leu Ala Glu Asn Ala 2495 2500 2505 Pro Leu His Thr Leu Val Met Glu Val Lys Thr Thr Asp Gly Asp 2510 2515 2520 Ser Gly Ile Tyr Gly His Val Thr Tyr His Ile Val Asn Asp Phe 2525 2530 2535 Ala Lys Asp Arg Phe Tyr Ile Asn Glu Arg Gly Gln Ile Phe Thr 2540 2545 2550 Leu Glu Lys Leu Asp Arg Glu Thr Pro Ala Glu Lys Val Ile Ser 2555 2560 2565 Val Arg Leu Met Ala Lys Asp Ala Gly Gly Lys Val Ala Phe Cys 2570 2575 2580 Thr Val Asn Val Ile Leu Thr Asp Asp Asn Asp Asn Ala Pro Gln 2585 2590 2595 Phe Arg Ala Thr Lys Tyr Glu Val Asn Ile Gly Ser Ser Ala Ala 2600 2605 2610 Lys Gly Thr Ser Val Val Lys Ser Ala Ser Asp Ala Asp Glu Gly 2615 2620 2625 Ser Asn Ala Asp Ile Thr Tyr Ala Ile Glu Ala Asp Ser Glu Ser 2630 2635 2640 Val Lys Glu Asn Leu Glu Ile Asn Lys Leu Ser Gly Val Ile Thr 2645 2650 2655 Thr Lys Glu Ser Leu Ile Gly Leu Glu Asn Glu Phe Phe Thr Phe 2660 2665 2670 Phe Val Arg Ala Val Asp Asn Gly Ser Pro Ser Lys Glu Ser Val 2675 2680 2685 Val Leu Val Tyr Val Lys Ile Leu Pro Pro Glu Met Gln Leu Pro 2690 2695 2700 Lys Phe Ser Glu Pro Phe Tyr Thr Phe Thr Val Ser Glu Asp Val 2705 2710 2715 Pro Val Gly Thr Glu Ile Asp Leu Ile Arg Ala Glu His Ser Gly 2720 2725 2730 Thr Val Leu Tyr Ser Leu Val Lys Gly Asn Thr Pro Glu Ser Asn 2735 2740 2745 Arg Asp Glu Ser Phe Val Ile Asp Arg Gln Ser Gly Arg Leu Lys 2750 2755 2760 Leu Glu Lys Ser Leu Asp His Glu Thr Thr Lys Trp Tyr Gln Phe 2765 2770 2775 Ser Ile Leu Ala Arg Cys Thr Gln Asp Asp His Glu Met Val Ala 2780 2785 2790 Ser Val Asp Val Ser Ile Gln Val Lys Asp Ala Asn Asp Asn Ser 2795 2800 2805 Pro Val Phe Glu Ser Ser Pro Tyr Glu Ala Phe Ile Val Glu Asn 2810 2815 2820 Leu Pro Gly Gly Ser Arg Val Ile Gln Ile Arg Ala Ser Asp Ala 2825 2830 2835 Asp Ser Gly Thr Asn Gly Gln Val Met Tyr Ser Leu Asp Gln Ser 2840 2845 2850 Gln Ser Val Glu Val Ile Glu Ser Phe Ala Ile Asn Met Glu Thr 2855 2860 2865 Gly Trp Ile Thr Thr Leu Lys Glu Leu Asp His Glu Lys Arg Asp 2870 2875 2880 Asn Tyr Gln Ile Lys Val Val Ala Ser Asp His Gly Glu Lys Ile 2885 2890 2895 Gln Leu Ser Ser Thr Ala Ile Val Asp Val Thr Val Thr Asp Val 2900 2905 2910 Asn Asp Ser Pro Pro Arg Phe Thr Ala Glu Ile Tyr Lys Gly Thr 2915 2920 2925 Val Ser Glu Asp Asp Pro Gln Gly Gly Val Ile Ala Ile Leu Ser 2930 2935 2940 Thr Thr Asp Ala Asp Ser Glu Glu Ile Asn Arg Gln Val Thr Tyr 2945 2950 2955 Phe Ile Thr Gly Gly Asp Pro Leu Gly Gln Phe Ala Val Glu Thr 2960 2965 2970 Ile Gln Asn Glu Trp Lys Val Tyr Val Lys Lys Pro Leu Asp Arg 2975 2980 2985 Glu Lys Arg Asp Asn Tyr Leu Leu Thr Ile Thr Ala Thr Asp Gly 2990 2995 3000 Thr Phe Ser Ser Lys Ala Ile Val Glu Val Lys Val Leu Asp Ala 3005 3010 3015 Asn Asp Asn Ser Pro Val Cys Glu Lys Thr Leu Tyr Ser Asp Thr 3020 3025 3030 Ile Pro Glu Asp Val Leu Pro Gly Lys Leu Ile Met Gln Ile Ser 3035 3040 3045 Ala Thr Asp Ala Asp Ile Arg Ser Asn Ala Glu Ile Thr Tyr Thr 3050 3055 3060 Leu Leu Gly Ser Gly Ala Glu Lys Phe Lys Leu Asn Pro Asp Thr 3065 3070 3075 Gly Glu Leu Lys Thr Ser Thr Pro Leu Asp Arg Glu Glu Gln Ala 3080 3085 3090 Val Tyr His Leu Leu Val Arg Ala Thr Asp Gly Gly Gly Arg Phe 3095 3100 3105 Cys Gln Ala Ser Ile Val Val Thr Leu Glu Asp Val Asn Asp Asn 3110 3115 3120 Ala Pro Glu Phe Ser Ala Asp Pro Tyr Ala Ile Thr Val Phe Glu 3125 3130 3135 Asn Thr Glu Pro Gly Thr Leu Leu Thr Arg Val Gln Ala Thr Asp 3140 3145 3150 Ala Asp Ala Gly Leu Asn Arg Lys Ile Leu Tyr Ser Leu Ile Asp 3155 3160 3165 Ser Ala Asp Gly Gln Phe Ser Ile Asn Glu Leu Ser Gly Ile Ile 3170 3175 3180 Gln Leu Glu Lys Pro Leu Asp Arg Glu Leu Gln Ala Val Tyr Thr 3185 3190 3195 Leu Ser Leu Lys Ala Val Asp Gln Gly Leu Pro Arg Arg Leu Thr 3200 3205 3210 Ala Thr Gly Thr Val Ile Val Ser Val Leu Asp Ile Asn Asp Asn 3215 3220 3225 Pro Pro Val Phe Glu Tyr Arg Glu Tyr Gly Ala Thr Val Ser Glu 3230 3235 3240 Asp Ile Leu Val Gly Thr Glu Val Leu Gln Val Tyr Ala Ala Ser 3245 3250 3255 Arg Asp Ile Glu Ala Asn Ala Glu Ile Thr Tyr Ser Ile Ile Ser 3260 3265 3270 Gly Asn Glu His Gly Lys Phe Ser Ile Asp Ser Lys Thr Gly Ala 3275 3280 3285 Val Phe Ile Ile Glu Asn Leu Asp Tyr Glu Ser Ser His Glu Tyr 3290 3295 3300 Tyr Leu Thr Val Glu Ala Thr Asp Gly Gly Thr Pro Ser Leu Ser 3305 3310 3315 Asp Val Ala Thr Val Asn Val Asn Val Thr Asp Ile Asn Asp Asn 3320 3325 3330 Thr Pro Val Phe Ser Gln Asp Thr Tyr Thr Thr Val Ile Ser Glu 3335 3340 3345 Asp Ala Val Leu Glu Gln Ser Val Ile Thr Val Met Ala Asp Asp 3350 3355 3360 Ala Asp Gly Pro Ser Asn Ser His Ile His Tyr Ser Ile Ile Asp 3365 3370 3375 Gly Asn Gln Gly Ser Ser Phe Thr Ile Asp Pro Val Arg Gly Glu 3380 3385 3390 Val Lys Val Thr Lys Leu Leu Asp Arg Glu Thr Ile Ser Gly Tyr 3395 3400 3405 Thr Leu Thr Val Gln Ala Ser Asp Asn Gly Ser Pro Pro Arg Val 3410 3415 3420 Asn Thr Thr Thr Val Asn Ile Asp Val Ser Asp Val Asn Asp Asn 3425 3430 3435 Ala Pro Val Phe Ser Arg Gly Asn Tyr Ser Val Ile Ile Gln Glu 3440 3445 3450 Asn Lys Pro Val Gly Phe Ser Val Leu Gln Leu Val Val Thr Asp 3455 3460 3465 Glu Asp Ser Ser His Asn Gly Pro Pro Phe Phe Phe Thr Ile Val 3470 3475 3480 Thr Gly Asn Asp Glu Lys Ala Phe Glu Val Asn Pro Gln Gly Val 3485 3490 3495 Leu Leu Thr Ser Ser Ala Ile Lys Arg Lys Glu Lys Asp His Tyr 3500 3505 3510 Leu Leu Gln Val Lys Val Ala Asp Asn Gly Lys Pro Gln Leu Ser 3515 3520 3525 Ser Leu Thr Tyr Ile Asp Ile Arg Val Ile Glu Glu Ser Ile Tyr 3530 3535 3540 Pro Pro Ala Ile Leu Pro Leu Glu Ile Phe Ile Thr Ser Ser Gly 3545 3550 3555 Glu Glu Tyr Ser Gly Gly Val Ile Gly Lys Ile His Ala Thr Asp 3560 3565 3570 Gln Asp Val Tyr Asp Thr Leu Thr Tyr Ser Leu Asp Pro Gln Met 3575 3580 3585 Asp Asn Leu Phe Ser Val Ser Ser Thr Gly Gly Lys Leu Ile Ala 3590 3595 3600 His Lys Lys Leu Asp Ile Gly Gln Tyr Leu Leu Asn Val Ser Val 3605 3610 3615 Thr Asp Gly Lys Phe Thr Thr Val Ala Asp Ile Thr Val His Ile 3620 3625 3630 Arg Gln Val Thr Gln Glu Met Leu Asn His Thr Ile Ala Ile Arg 3635 3640 3645 Phe Ala Asn Leu Thr Pro Glu Glu Phe Val Gly Asp Tyr Trp Arg 3650 3655 3660 Asn Phe Gln Arg Ala Leu Arg Asn Ile Leu Gly Val Arg Arg Asn 3665 3670 3675 Asp Ile Gln Ile Val Ser Leu Gln Ser Ser Glu Pro His Pro His 3680 3685 3690 Leu Asp Val Leu Leu Phe Val Glu Lys Pro Gly Ser Ala Gln Ile 3695 3700 3705 Ser Thr Lys Gln Leu Leu His Lys Ile Asn Ser Ser Val Thr Asp 3710 3715 3720 Ile Glu Glu Ile Ile Gly Val Arg Ile Leu Asn Val Phe Gln Lys 3725 3730 3735 Leu Cys Ala Gly Leu Asp Cys Pro Trp Lys Phe Cys Asp Glu Lys 3740 3745 3750 Val Ser Val Asp Glu Ser Val Met Ser Thr His Ser Thr Ala Arg 3755 3760 3765 Leu Ser Phe Val Thr Pro Arg His His Arg Ala Ala Val Cys Leu 3770 3775 3780 Cys Lys Glu Gly Arg Cys Pro Pro Val His His Gly Cys Glu Asp 3785 3790 3795 Asp Pro Cys Pro Glu Gly Ser Glu Cys Val Ser Asp Pro Trp Glu 3800 3805 3810 Glu Lys His Thr Cys Val Cys Pro Ser Gly Arg Phe Gly Gln Cys 3815 3820 3825 Pro Gly Ser Ser Ser Met Thr Leu Thr Gly Asn Ser Tyr Val Lys 3830 3835 3840 Tyr Arg Leu Thr Glu Asn Glu Asn Lys Leu Glu Met Lys Leu Thr 3845 3850 3855 Met Arg Leu Arg Thr Tyr Ser Thr His Ala Val Val Met Tyr Ala 3860 3865 3870 Arg Gly Thr Asp Tyr Ser Ile Leu Glu Ile His His Gly Arg Leu 3875 3880 3885 Gln Tyr Lys Phe Asp Cys Gly Ser Gly Pro Gly Ile Val Ser Val 3890 3895 3900 Gln Ser Ile Gln Val Asn Asp Gly Gln Trp His Ala Val Ala Leu 3905 3910 3915 Glu Val Asn Gly Asn Tyr Ala Arg Leu Val Leu Asp Gln Val His 3920 3925 3930 Thr Ala Ser Gly Thr Ala Pro Gly Thr Leu Lys Thr Leu Asn Leu 3935 3940 3945 Asp Asn Tyr Val Phe Phe Gly Gly His Ile Arg Gln Gln Gly Thr 3950 3955 3960 Arg His Gly Arg Ser Pro Gln Val Gly Asn Gly Phe Arg Gly Cys 3965 3970 3975 Met Asp Ser Ile Tyr Leu Asn Gly Gln Glu Leu Pro Leu Asn Ser 3980 3985 3990 Lys Pro Arg Ser Tyr Ala His Ile Glu Glu Ser Val Asp Val Ser 3995 4000 4005 Pro Gly Cys Phe Leu Thr Ala Thr Glu Asp Cys Ala Ser Asn Pro 4010 4015 4020 Cys Gln Asn Gly Gly Val Cys Asn Pro Ser Pro Ala Gly Gly Tyr 4025 4030 4035 Tyr Cys Lys Cys Ser Ala Leu Tyr Ile Gly Thr His Cys Glu Ile 4040 4045 4050 Ser Val Asn Pro Cys Ser Ser Asn Pro Cys Leu Tyr Gly Gly Thr 4055 4060 4065 Cys Val Val Asp Asn Gly Gly Phe Val Cys Gln Cys Arg Gly Leu 4070 4075 4080 Tyr Thr Gly Gln Arg Cys Gln Leu Ser Pro Tyr Cys Lys Asp Glu 4085 4090 4095 Pro Cys Lys Asn Gly Gly Thr Cys Phe Asp Ser Leu Asp Gly Ala 4100 4105 4110 Val Cys Gln Cys Asp Ser Gly Phe Arg Gly Glu Arg Cys Gln Ser 4115 4120 4125 Asp Ile Asp Glu Cys Ser Gly Asn Pro Cys Leu His Gly Ala Leu 4130 4135 4140 Cys Glu Asn Thr His Gly Ser Tyr His Cys Asn Cys Ser His Glu 4145 4150 4155 Tyr Arg Gly Arg His Cys Glu Asp Ala Ala Pro Asn Gln Tyr Val 4160 4165 4170 Ser Thr Pro Trp Asn Ile Gly Leu Ala Glu Gly Ile Gly Ile Val 4175 4180 4185 Val Phe Val Ala Gly Ile Phe Leu Leu Val Val Val Phe Val Leu 4190 4195 4200 Cys Arg Lys Met Ile Ser Arg Lys Lys Lys His Gln Ala Glu Pro 4205 4210 4215 Lys Asp Lys His Leu Gly Pro Ala Thr Ala Phe Leu Gln Arg Pro 4220 4225 4230 Tyr Phe Asp Ser Lys Leu Asn Lys Asn Ile Tyr Ser Asp Ile Pro 4235 4240 4245 Pro Gln Val Pro Val Arg Pro Ile Ser Tyr Thr Pro Ser Ile Pro 4250 4255 4260 Ser Asp Ser Arg Asn Asn Leu Asp Arg Asn Ser Phe Glu Gly Ser 4265 4270 4275 Ala Ile Pro Glu His Pro Glu Phe Ser Thr Phe Asn Pro Glu Ser 4280 4285 4290 Val His Gly His Arg Lys Ala Val Ala Val Cys Ser Val Ala Pro 4295 4300 4305 Asn Leu Pro Pro Pro Pro Pro Ser Asn Ser Pro Ser Asp Ser Asp 4310 4315 4320 Ser Ile Gln Lys Pro Ser Trp Asp Phe Asp Tyr Asp Thr Lys Val 4325 4330 4335 Val Asp Leu Asp Pro Cys Leu Ser Lys Lys Pro Leu Glu Glu Lys 4340 4345 4350 Pro Ser Gln Pro Tyr Ser Ala Arg Glu Ser Leu Ser Glu Val Gln 4355 4360 4365 Ser Leu Ser Ser Phe Gln Ser Glu Ser Cys Asp Asp Asn Gly Tyr 4370 4375 4380 His Trp Asp Thr Ser Asp Trp Met Pro Ser Val Pro Leu Pro Asp 4385 4390 4395 Ile Gln Glu Phe Pro Asn Tyr Glu Val Ile Asp Glu Gln Thr Pro 4400 4405 4410 Leu Tyr Ser Ala Asp Pro Asn Ala Ile Asp Thr Asp Tyr Tyr Pro 4415 4420 4425 Gly Gly Tyr Asp Ile Glu Ser Asp Phe Pro Pro Pro Pro Glu Asp 4430 4435 4440 Phe Pro Ala Ala Asp Glu Leu Pro Pro Leu Pro Pro Glu Phe Ser 4445 4450 4455 Asn Gln Phe Glu Ser Ile His Pro Pro Arg Asp Met Pro Ala Ala 4460 4465 4470 Gly Ser Leu Gly Ser Ser Ser Arg Asn Arg Gln Arg Phe Asn Leu 4475 4480 4485 Asn Gln Tyr Leu Pro Asn Phe Tyr Pro Leu Asp Met Ser Glu Pro 4490 4495 4500 Gln Thr Lys Gly Thr Gly Glu Asn Ser Thr Cys Arg Glu Pro His 4505 4510 4515 Ala Pro Tyr Pro Pro Gly Tyr Gln Arg His Phe Glu Ala Pro Ala 4520 4525 4530 Val Glu Ser Met Pro Met Ser Val Tyr Ala Ser Thr Ala Ser Cys 4535 4540 4545 Ser Asp Val Ser Ala Cys Cys Glu Val Glu Ser Glu Val Met Met 4550 4555 4560 Ser Asp Tyr Glu Ser Gly Asp Asp Gly His Phe Glu Glu Val Thr 4565 4570 4575 Ile Pro Pro Leu Asp Ser Gln Gln His Thr Glu Val 4580 4585 4590 14 4590 PRT Homo sapiens 14 Met Gly Arg His Leu Ala Leu Leu Leu Leu Leu Leu Leu Leu Phe Gln 1 5 10 15 His Phe Gly Asp Ser Asp Gly Ser Gln Arg Leu Glu Gln Thr Pro Leu 20 25 30 Gln Phe Thr His Leu Glu Tyr Asn Val Thr Val Gln Glu Asn Ser Ala 35 40 45 Ala Lys Thr Tyr Val Gly His Pro Val Lys Met Gly Val Tyr Ile Thr 50 55 60 His Pro Ala Trp Glu Val Arg Tyr Lys Ile Val Ser Gly Asp Ser Glu 65 70 75 80 Asn Leu Phe Lys Ala Glu Glu Tyr Ile Leu Gly Asp Phe Cys Phe Leu 85 90 95 Arg Ile Arg Thr Lys Gly Gly Asn Thr Ala Ile Leu Asn Arg Glu Val 100 105 110 Lys Asp His Tyr Thr Leu Ile Val Lys Ala Leu Glu Lys Asn Thr Asn 115 120 125 Val Glu Ala Arg Thr Lys Val Arg Val Gln Val Leu Asp Thr Asn Asp 130 135 140 Leu Arg Pro Leu Phe Ser Pro Thr Ser Tyr Ser Val Ser Leu Pro Glu 145 150 155 160 Asn Thr Ala Ile Arg Thr Ser Ile Ala Arg Val Ser Ala Thr Asp Ala 165 170 175 Asp Ile Gly Thr Asn Gly Glu Phe Tyr Tyr Ser Phe Lys Asp Arg Thr 180 185 190 Asp Met Phe Ala Ile His Pro Thr Ser Gly Val Ile Val Leu Thr Gly 195 200 205 Arg Leu Asp Tyr Leu Glu Thr Lys Leu Tyr Glu Met Glu Ile Leu Ala 210 215 220 Ala Asp Arg Gly Met Lys Leu Tyr Gly Ser Ser Gly Ile Ser Ser Met 225 230 235 240 Ala Lys Leu Thr Val His Ile Glu Gln Ala Asn Glu Cys Ala Pro Val 245 250 255 Ile Thr Ala Val Thr Leu Ser Pro Ser Glu Leu Asp Arg Asp Pro Ala 260 265 270 Tyr Ala Ile Val Thr Val Asp Asp Cys Asp Gln Gly Ala Asn Gly Asp 275 280 285 Ile Ala Ser Leu Ser Ile Val Ala Gly Asp Leu Leu Gln Gln Phe Arg 290 295 300 Thr Val Arg Ser Phe Pro Gly Ser Lys Glu Tyr Lys Val Lys Ala Ile 305 310 315 320 Gly Asp Ile Asp Trp Asp Ser His Pro Phe Gly Tyr Asn Leu Thr Leu 325 330 335 Gln Ala Lys Asp Lys Gly Thr Pro Pro Gln Phe Ser Ser Val Lys Val 340 345 350 Ile His Val Thr Ser Pro Gln Phe Lys Ala Gly Pro Val Lys Phe Glu 355 360 365 Lys Asp Val Tyr Arg Ala Glu Ile Ser Glu Phe Ala Pro Pro Asn Thr 370 375 380 Pro Val Val Met Val Lys Ala Ile Pro Ala Tyr Ser His Leu Arg Tyr 385 390 395 400 Val Phe Lys Arg Thr Pro Gly Lys Ala Lys Phe Ser Leu Asn Tyr Asn 405 410 415 Thr Gly Leu Ile Ser Ile Leu Glu Pro Val Lys Arg Gln Gln Ala Ala 420 425 430 His Phe Glu Leu Glu Val Thr Thr Ser Asp Arg Lys Ala Ser Thr Lys 435 440 445 Val Leu Val Lys Val Leu Gly Ala Asn Ser Asn Pro Pro Glu Phe Thr 450 455 460 Gln Thr Ala Tyr Lys Ala Ala Phe Asp Glu Asn Val Pro Ile Gly Thr 465 470 475 480 Thr Ile Met Ser Leu Ser Ala Val Asp Pro Asp Glu Gly Glu Asn Gly 485 490 495 Tyr Val Thr Tyr Ser Ile Ala Asn Leu Asn His Val Pro Phe Ala Ile 500 505 510 Asp His Phe Thr Gly Ala Val Ser Thr Ser Glu Asn Leu Asp Tyr Glu 515 520 525 Leu Met Pro Arg Val Tyr Thr Leu Arg Ile Arg Ala Ser Asp Trp Gly 530 535 540 Leu Pro Tyr Arg Arg Glu Val Glu Val Leu Ala Thr Ile Thr Leu Asn 545 550 555 560 Asn Leu Asn Asp Asn Thr Pro Leu Phe Glu Lys Ile Asn Cys Glu Gly 565 570 575 Thr Ile Pro Arg Asp Leu Gly Val Gly Glu Gln Ile Thr Thr Val Ser 580 585 590 Ala Ile Asp Ala Asp Glu Leu Gln Leu Val Gln Tyr Gln Ile Glu Ala 595 600 605 Gly Asn Glu Leu Asp Leu Phe Ser Leu Asn Pro Asn Ser Gly Val Leu 610 615 620 Ser Leu Lys Arg Ser Leu Met Asp Gly Leu Gly Ala Lys Val Ser Phe 625 630 635 640 His Ser Leu Arg Ile Thr Ala Thr Asp Gly Glu Asn Phe Ala Thr Pro 645 650 655 Leu Tyr Ile Asn Ile Thr Val Ala Ala Ser His Lys Leu Val Asn Leu 660 665 670 Gln Cys Glu Glu Thr Gly Val Ala Lys Met Leu Ala Glu Lys Leu Leu 675 680 685 Gln Ala Asn Lys Leu His Asn Gln Gly Glu Val Glu Asp Ile Phe Phe 690 695 700 Asp Ser His Ser Val Asn Ala His Ile Pro Gln Phe Arg Ser Thr Leu 705 710 715 720 Pro Thr Gly Ile Gln Val Lys Glu Asn Gln Pro Val Gly Ser Ser Val 725 730 735 Ile Phe Met Asn Ser Thr Asp Leu Asp Thr Gly Phe Asn Gly Lys Leu 740 745 750 Val Tyr Ala Val Ser Gly Gly Asn Glu Asp Ser Cys Phe Met Ile Asp 755 760 765 Met Glu Thr Gly Met Leu Lys Ile Leu Ser Pro Leu Asp Arg Glu Thr 770 775 780 Thr Asp Lys Tyr Thr Leu Asn Ile Thr Val Tyr Asp Leu Gly Ile Pro 785 790 795 800 Gln Lys Ala Ala Trp Arg Leu Leu His Val Val Val Val Asp Ala Asn 805 810 815 Asp Asn Pro Pro Glu Phe Leu Gln Glu Ser Tyr Phe Val Glu Val Ser 820 825 830 Glu Asp Lys Glu Val His Ser Glu Ile Ile Gln Val Glu Ala Thr Asp 835 840 845 Lys Asp Leu Gly Pro Asn Gly His Val Thr Tyr Ser Ile Leu Thr Asp 850 855 860 Thr Asp Thr Phe Ser Ile Asp Ser Val Thr Gly Val Val Asn Ile Ala 865 870 875 880 Arg Pro Leu Asp Arg Glu Leu Gln His Glu His Ser Leu Lys Ile Glu 885 890 895 Ala Arg Asp Gln Ala Arg Glu Glu Pro Gln Leu Phe Ser Thr Val Val 900 905 910 Val Lys Val Ser Leu Glu Asp Val Asn Asp Asn Pro Pro Thr Phe Ile 915 920 925 Pro Pro Asn Tyr Arg Val Lys Val Arg Glu Asp Leu Pro Glu Gly Thr 930 935 940 Val Ile Met Trp Leu Glu Ala His Asp Pro Asp Leu Gly Gln Ser Gly 945 950 955 960 Gln Val Arg Tyr Ser Leu Leu Asp His Gly Glu Gly Asn Phe Asp Val 965 970 975 Asp Lys Leu Ser Gly Ala Val Arg Ile Val Gln Gln Leu Asp Phe Glu 980 985 990 Lys Lys Gln Val Tyr Asn Leu Thr Val Arg Ala Lys Asp Lys Gly Lys 995 1000 1005 Pro Val Ser Leu Ser Ser Thr Cys Tyr Val Glu Val Glu Val Val 1010 1015 1020 Asp Val Asn Glu Asn Leu His Pro Pro Val Phe Ser Ser Phe Val 1025 1030 1035 Glu Lys Gly Thr Val Lys Glu Asp Ala Pro Val Gly Ser Leu Val 1040 1045 1050 Met Thr Val Ser Ala His Asp Glu Asp Ala Gly Arg Asp Gly Glu 1055 1060 1065 Ile Arg Tyr Ser Ile Arg Asp Gly Ser Gly Val Gly Val Phe Lys 1070 1075 1080 Ile Gly Glu Glu Thr Gly Val Ile Glu Thr Ser Asp Arg Leu Asp 1085 1090 1095 Arg Glu Ser Thr Ser His Tyr Trp Leu Thr Val Phe Ala Thr Asp 1100 1105 1110 Gln Gly Val Val Pro Leu Ser Ser Phe Ile Glu Ile Tyr Ile Glu 1115 1120 1125 Val Glu Asp Val Asn Asp Asn Ala Pro Gln Thr Ser Glu Pro Val 1130 1135 1140 Tyr Tyr Pro Glu Ile Met Glu Asn Ser Pro Lys Asp Val Ser Val 1145 1150 1155 Val Gln Ile Glu Ala Phe Asp Pro Asp Ser Ser Ser Asn Asp Lys 1160 1165 1170 Leu Met Tyr Lys Ile Thr Ser Gly Asn Pro Gln Gly Phe Phe Ser 1175 1180 1185 Ile His Pro Lys Thr Gly Leu Ile Thr Thr Thr Ser Arg Lys Leu 1190 1195 1200 Asp Arg Glu Gln Gln Asp Glu His Ile Leu Glu Val Thr Val Thr 1205 1210 1215 Asp Asn Gly Ser Pro Pro Lys Ser Thr Ile Ala Arg Val Ile Val 1220 1225 1230 Lys Ile Leu Asp Glu Asn Asp Asn Lys Pro Gln Phe Leu Gln Lys 1235 1240 1245 Phe Tyr Lys Ile Arg Leu Pro Glu Arg Glu Lys Pro Asp Arg Glu 1250 1255 1260 Arg Asn Ala Arg Arg Glu Pro Leu Tyr Arg Val Ile Ala Thr Asp 1265 1270 1275 Lys Asp Glu Gly Pro Asn Ala Glu Ile Ser Tyr Ser Ile Glu Asp 1280 1285 1290 Gly Asn Glu His Gly Lys Phe Phe Ile Glu Pro Lys Thr Gly Val 1295 1300 1305 Val Ser Ser Lys Arg Phe Ser Ala Ala Gly Glu Tyr Asp Ile Leu 1310 1315 1320 Ser Ile Lys Ala Val Asp Asn Gly Arg Pro Gln Lys Ser Ser Thr 1325 1330 1335 Thr Arg Leu His Ile Glu Trp Ile Ser Lys Pro Lys Gln Ser Leu 1340 1345 1350 Glu Pro Ile Ser Phe Glu Glu Ser Phe Phe Thr Phe Thr Val Met 1355 1360 1365 Glu Ser Asp Pro Val Ala His Met Ile Gly Val Ile Ser Val Glu 1370 1375 1380 Pro Pro Gly Ile Pro Leu Trp Phe Asp Ile Thr Gly Gly Asn Tyr 1385 1390 1395 Asp Ser His Phe Asp Val Asp Lys Gly Thr Gly Thr Ile Ile Val 1400 1405 1410 Ala Lys Pro Leu Asp Ala Glu Gln Lys Ser Asn Tyr Asn Leu Thr 1415 1420 1425 Val Glu Ala Thr Asp Gly Thr Thr Thr Ile Leu Thr Gln Val Phe 1430 1435 1440 Ile Lys Val Ile Asp Thr Asn Asp His Arg Pro Gln Phe Ser Thr 1445 1450 1455 Ser Lys Tyr Glu Val Val Ile Pro Glu Asp Thr Ala Pro Glu Thr 1460 1465 1470 Glu Ile Leu Gln Ile Ser Ala Val Asp Gln Asp Glu Lys Asn Lys 1475 1480 1485 Leu Ile Tyr Thr Leu Gln Ser Ser Arg Asp Pro Leu Ser Leu Lys 1490 1495 1500 Lys Phe Arg Leu Asp Pro Ala Thr Gly Ser Leu Tyr Thr Ser Glu 1505 1510 1515 Lys Leu Asp His Glu Ala Val Ser Pro Ala His Leu Thr Val Met 1520 1525 1530 Val Arg Asp Gln Asp Val Pro Val Lys Arg Asn Phe Ala Arg Ile 1535 1540 1545 Val Val Asn Val Ser Asp Thr Asn Asp His Ala Pro Trp Phe Thr 1550 1555 1560 Ala Ser Ser Tyr Lys Gly Arg Val Tyr Glu Ser Ala Ala Val Gly 1565 1570 1575 Ser Val Val Leu Gln Val Thr Ala Leu Asp Lys Asp Lys Gly Lys 1580 1585 1590 Asn Ala Glu Val Leu Tyr Ser Ile Glu Ser Gly Asn Ile Gly Asn 1595 1600 1605 Ile Gly Asn Ser Phe Met Ile Asp Pro Val Leu Gly Ser Ile Lys 1610 1615 1620 Thr Ala Lys Glu Leu Asp Arg Ser Asn Gln Ala Glu Tyr Asp Leu 1625 1630 1635 Met Val Lys Ala Thr Asp Lys Gly Ser Pro Pro Met Ser Glu Ile 1640 1645 1650 Thr Ser Val Arg Ile Phe Val Thr Ile Ala Asp Asn Ala Ser Pro 1655 1660 1665 Lys Phe Thr Ser Lys Glu Tyr Ser Val Glu Leu Ser Glu Thr Val 1670 1675 1680 Ser Ile Gly Ser Phe Val Gly Met Val Thr Ala His Ser Gln Ser 1685 1690 1695 Ser Val Val Tyr Glu Ile Lys Asp Gly Asn Thr Gly Asp Ala Phe 1700 1705 1710 Asp Ile Asn Pro His Ser Gly Thr Ile Ile Thr Gln Lys Ala Leu 1715 1720 1725 Asp Phe Glu Thr Leu Pro Ile Tyr Thr Leu Ile Ile Gln Gly Thr 1730 1735 1740 Asn Met Ala Gly Leu Ser Thr Asn Thr Thr Val Leu Val His Leu 1745 1750 1755 Gln Asp Glu Asn Asp Asn Ala Pro Val Phe Met Gln Ala Glu Tyr 1760 1765 1770 Thr Gly Leu Ile Ser Glu Ser Ala Ser Ile Asn Ser Val Val Leu 1775 1780 1785 Thr Asp Arg Asn Val Pro Leu Val Ile Arg Ala Ala Asp Ala Asp 1790 1795 1800 Lys Asp Ser Asn Ala Leu Leu Val Tyr His Ile Val Glu Pro Ser 1805 1810 1815 Val His Thr Tyr Phe Ala Ile Asp Ser Ser Thr Gly Ala Ile His 1820 1825 1830 Thr Val Leu Ser Leu Asp Tyr Glu Glu Thr Ser Ile Phe His Phe 1835 1840 1845 Thr Val Gln Val His Asp Met Gly Thr Pro Arg Leu Phe Ala Glu 1850 1855 1860 Tyr Ala Ala Asn Val Thr Val His Val Ile Asp Ile Asn Asp Cys 1865 1870 1875 Pro Pro Val Phe Ala Lys Pro Leu Tyr Glu Ala Ser Leu Leu Leu 1880 1885 1890 Pro Thr Tyr Lys Gly Val Lys Val Ile Thr Val Asn Ala Thr Asp 1895 1900 1905 Ala Asp Ser Ser Ala Phe Ser Gln Leu Ile Tyr Ser Ile Thr Glu 1910 1915 1920 Gly Asn Ile Gly Glu Lys Phe Ser Met Asp Tyr Lys Thr Gly Ala 1925 1930 1935 Leu Thr Val Gln Asn Thr Thr Gln Leu Arg Ser Arg Tyr Glu Leu 1940 1945 1950 Thr Val Arg Ala Ser Asp Gly Arg Phe Ala Gly Leu Thr Ser Val 1955 1960 1965 Lys Ile Asn Val Lys Glu Ser Lys Glu Ser His Leu Lys Phe Thr 1970 1975 1980 Gln Asp Val Tyr Ser Ala Val Val Lys Glu Asn Ser Thr Glu Ala 1985 1990 1995 Glu Thr Leu Ala Val Ile Thr Ala Ile Gly Ser Pro Ile Asn Glu 2000 2005 2010 Pro Leu Phe Tyr His Ile Leu Asn Pro Asp Arg Arg Phe Lys Ile 2015 2020 2025 Ser Arg Thr Ser Gly Val Leu Ser Thr Thr Gly Thr Pro Phe Asp 2030 2035 2040 Arg Glu Gln Gln Glu Ala Phe Asp Val Val Val Glu Val Ile Glu 2045 2050 2055 Glu His Lys Pro Ser Ala Val Ala His Val Val Val Lys Val Ile 2060 2065 2070 Val Glu Asp Gln Asn Asp Asn Ala Pro Val Phe Val Asn Leu Pro 2075 2080 2085 Tyr Tyr Ala Val Val Lys Val Asp Thr Glu Val Gly His Val Ile 2090 2095 2100 Arg Tyr Val Thr Ala Val Asp Arg Asp Ser Gly Arg Asn Gly Glu 2105 2110 2115 Val His Tyr Tyr Leu Lys Glu His His Glu His Phe Gln Ile Gly 2120 2125 2130 Pro Leu Gly Glu Ile Ser Leu Lys Lys Gln Phe Glu Leu Asp Thr 2135 2140 2145 Leu Asn Lys Glu Tyr Leu Val Thr Val Val Ala Lys Asp Gly Gly 2150 2155 2160 Asn Pro Ala Phe Ser Ala Glu Val Ile Val Pro Ile Thr Val Met 2165 2170 2175 Asn Lys Ala Met Pro Val Phe Glu Lys Pro Phe Tyr Ser Ala Glu 2180 2185 2190 Ile Ala Glu Ser Ile Gln Val His Ser Pro Val Val His Val Gln 2195 2200 2205 Ala Asn Ser Pro Glu Gly Leu Lys Val Phe Tyr Ser Ile Thr Asp 2210 2215 2220 Gly Asp Pro Phe Ser Gln Phe Thr Ile Asn Phe Asn Thr Gly Val 2225 2230 2235 Ile Asn Val Ile Ala Pro Leu Asp Phe Glu Ala His Pro Ala Tyr 2240 2245 2250 Lys Leu Ser Ile Arg Ala Thr Asp Ser Leu Thr Gly Ala His Ala 2255 2260 2265 Glu Val Phe Val Asp Ile Ile Val Asp Asp Ile Asn Asp Asn Pro 2270 2275 2280 Pro Val Phe Ala Gln Gln Ser Tyr Ala Val Thr Leu Ser Glu Ala 2285 2290 2295 Ser Val Ile Gly Thr Ser Val Val Gln Val Arg Ala Thr Asp Ser 2300 2305 2310 Asp Ser Glu Pro Asn Arg Gly Ile Ser Tyr Gln Met Phe Gly Asn 2315 2320 2325 His Ser Lys Ser His Asp His Phe His Val Asp Ser Ser Thr Gly 2330 2335 2340 Leu Ile Ser Leu Leu Arg Thr Leu Asp Tyr Glu Gln Ser Arg Gln 2345 2350 2355 His Thr Ile Phe Val Arg Ala Val Asp Gly Gly Met Pro Thr Leu 2360 2365 2370 Ser Ser Asp Val Ile Val Thr Val Asp Val Thr Asp Leu Asn Gly 2375 2380 2385 Asn Pro Pro Leu Phe Glu Gln Gln Ile Tyr Glu Ala Arg Ile Ser 2390 2395 2400 Glu His Ala Pro His Gly His Phe Val Thr Cys Val Lys Ala Tyr 2405 2410 2415 Asp Ala Asp Ser Ser Asp Ile Asp Lys Leu Gln Tyr Ser Ile Leu 2420 2425 2430 Ser Gly Asn Asp His Lys His Phe Val Ile Asp Ser Ala Thr Gly 2435 2440 2445 Ile Ile Thr Leu Ser Asn Leu His Arg His Ala Leu Lys Pro Phe 2450 2455 2460 Tyr Ser Leu Asn Leu Ser Val Ser Asp Gly Val Phe Arg Ser Ser 2465 2470 2475 Thr Gln Val His Val Thr Val Ile Gly Gly Asn Leu His Ser Pro 2480 2485 2490 Ala Phe Leu Gln Asn Glu Tyr Glu Val Glu Leu Ala Glu Asn Ala 2495 2500 2505 Pro Leu His Thr Leu Val Met Glu Val Lys Thr Thr Asp Gly Asp 2510 2515 2520 Ser Gly Ile Tyr Gly His Val Thr Tyr His Ile Val Asn Asp Phe 2525 2530 2535 Ala Lys Asp Arg Phe Tyr Ile Asn Glu Arg Gly Gln Ile Phe Thr 2540 2545 2550 Leu Glu Lys Leu Asp Arg Glu Thr Pro Ala Glu Lys Val Ile Ser 2555 2560 2565 Val Arg Leu Met Ala Lys Asp Ala Gly Gly Lys Val Ala Phe Cys 2570 2575 2580 Thr Val Asn Val Ile Leu Thr Asp Asp Asn Asp Asn Ala Pro Gln 2585 2590 2595 Phe Arg Ala Thr Lys Tyr Glu Val Asn Ile Gly Ser Ser Ala Ala 2600 2605 2610 Lys Gly Thr Ser Val Val Lys Ser Ala Ser Asp Ala Asp Glu Gly 2615 2620 2625 Ser Asn Ala Asp Ile Thr Tyr Ala Ile Glu Ala Asp Ser Glu Ser 2630 2635 2640 Val Lys Glu Asn Leu Glu Ile Asn Lys Leu Ser Gly Val Ile Thr 2645 2650 2655 Thr Lys Glu Ser Leu Ile Gly Leu Glu Asn Glu Phe Phe Thr Phe 2660 2665 2670 Phe Val Arg Ala Val Asp Asn Gly Ser Pro Ser Lys Glu Ser Val 2675 2680 2685 Val Leu Val Tyr Val Lys Ile Leu Pro Pro Glu Met Gln Leu Pro 2690 2695 2700 Lys Phe Ser Glu Pro Phe Tyr Thr Phe Thr Val Ser Glu Asp Val 2705 2710 2715 Pro Val Gly Thr Glu Ile Asp Leu Ile Arg Ala Glu His Ser Gly 2720 2725 2730 Thr Val Leu Tyr Ser Leu Val Lys Gly Asn Thr Pro Glu Ser Asn 2735 2740 2745 Arg Asp Glu Ser Phe Val Ile Asp Arg Gln Ser Gly Arg Leu Lys 2750 2755 2760 Leu Glu Lys Ser Leu Asp His Glu Thr Thr Lys Trp Tyr Gln Phe 2765 2770 2775 Ser Ile Leu Ala Arg Cys Thr Gln Asp Asp His Glu Met Val Ala 2780 2785 2790 Ser Val Asp Val Ser Ile Gln Val Lys Asp Ala Asn Asp Asn Ser 2795 2800 2805 Pro Val Phe Glu Ser Ser Pro Tyr Glu Ala Phe Ile Val Glu Asn 2810 2815 2820 Leu Pro Gly Gly Ser Arg Val Ile Gln Ile Arg Ala Ser Asp Ala 2825 2830 2835 Asp Ser Gly Thr Asn Gly Gln Val Met Tyr Ser Leu Asp Gln Ser 2840 2845 2850 Gln Ser Val Glu Val Ile Glu Ser Phe Ala Ile Asn Met Glu Thr 2855 2860 2865 Gly Trp Ile Thr Thr Leu Lys Glu Leu Asp His Glu Lys Arg Asp 2870 2875 2880 Asn Tyr Gln Ile Lys Val Val Ala Ser Asp His Gly Glu Lys Ile 2885 2890 2895 Gln Leu Ser Ser Thr Ala Ile Val Asp Val Thr Val Thr Asp Val 2900 2905 2910 Asn Asp Ser Pro Pro Arg Phe Thr Ala Glu Ile Tyr Lys Gly Thr 2915 2920 2925 Val Ser Glu Asp Asp Pro Gln Gly Gly Val Ile Ala Ile Leu Ser 2930 2935 2940 Thr Thr Asp Ala Asp Ser Glu Glu Ile Asn Arg Gln Val Thr Tyr 2945 2950 2955 Phe Ile Thr Gly Gly Asp Pro Leu Gly Gln Phe Ala Val Glu Thr 2960 2965 2970 Ile Gln Asn Glu Trp Lys Val Tyr Val Lys Lys Pro Leu Asp Arg 2975 2980 2985 Glu Lys Arg Asp Asn Tyr Leu Leu Thr Ile Thr Ala Thr Asp Gly 2990 2995 3000 Thr Phe Ser Ser Lys Ala Ile Val Glu Val Lys Val Leu Asp Ala 3005 3010 3015 Asn Asp Asn Ser Pro Val Cys Glu Lys Thr Leu Tyr Ser Asp Thr 3020 3025 3030 Ile Pro Glu Asp Val Leu Pro Gly Lys Leu Ile Met Gln Ile Ser 3035 3040 3045 Ala Thr Asp Ala Asp Ile Arg Ser Asn Ala Glu Ile Thr Tyr Thr 3050 3055 3060 Leu Leu Gly Ser Gly Ala Glu Lys Phe Lys Leu Asn Pro Asp Thr 3065 3070 3075 Gly Glu Leu Lys Thr Ser Thr Pro Leu Asp Arg Glu Glu Gln Ala 3080 3085 3090 Val Tyr His Leu Leu Val Arg Ala Thr Asp Gly Gly Gly Arg Phe 3095 3100 3105 Cys Gln Ala Ser Ile Val Val Thr Leu Glu Asp Val Asn Asp Asn 3110 3115 3120 Ala Pro Glu Phe Ser Ala Asp Pro Tyr Ala Ile Thr Val Phe Glu 3125 3130 3135 Asn Thr Glu Pro Gly Thr Leu Leu Thr Arg Val Gln Ala Thr Asp 3140 3145 3150 Ala Asp Ala Gly Leu Asn Arg Lys Ile Leu Tyr Ser Leu Ile Asp 3155 3160 3165 Ser Ala Asp Gly Gln Phe Ser Ile Asn Glu Leu Ser Gly Ile Ile 3170 3175 3180 Gln Leu Glu Lys Pro Leu Asp Arg Glu Leu Gln Ala Val Tyr Thr 3185 3190 3195 Leu Ser Leu Lys Ala Val Asp Gln Gly Leu Pro Arg Arg Leu Thr 3200 3205 3210 Ala Thr Gly Thr Val Ile Val Ser Val Leu Asp Ile Asn Asp Asn 3215 3220 3225 Pro Pro Val Phe Glu Tyr Arg Glu Tyr Gly Ala Thr Val Ser Glu 3230 3235 3240 Asp Ile Leu Val Gly Thr Glu Val Leu Gln Val Tyr Ala Ala Ser 3245 3250 3255 Arg Asp Ile Glu Ala Asn Ala Glu Ile Thr Tyr Ser Ile Ile Ser 3260 3265 3270 Gly Asn Glu His Gly Lys Phe Ser Ile Asp Ser Lys Thr Gly Ala 3275 3280 3285 Val Phe Ile Ile Glu Asn Leu Asp Tyr Glu Ser Ser His Glu Tyr 3290 3295 3300 Tyr Leu Thr Val Glu Ala Thr Asp Gly Gly Thr Pro Ser Leu Ser 3305 3310 3315 Asp Val Ala Thr Val Asn Val Asn Val Thr Asp Ile Asn Asp Asn 3320 3325 3330 Thr Pro Val Phe Ser Gln Asp Thr Tyr Thr Thr Val Ile Ser Glu 3335 3340 3345 Asp Ala Val Leu Glu Gln Ser Val Ile Thr Val Met Ala Asp Asp 3350 3355 3360 Ala Asp Gly Pro Ser Asn Ser His Ile His Tyr Ser Ile Ile Asp 3365 3370 3375 Gly Asn Gln Gly Ser Ser Phe Thr Ile Asp Pro Val Arg Gly Glu 3380 3385 3390 Val Lys Val Thr Lys Leu Leu Asp Arg Glu Thr Ile Ser Gly Tyr 3395 3400 3405 Thr Leu Thr Val Gln Ala Ser Asp Asn Gly Ser Pro Pro Arg Val 3410 3415 3420 Asn Thr Thr Thr Val Asn Ile Asp Val Ser Asp Val Asn Asp Asn 3425 3430 3435 Ala Pro Val Phe Ser Arg Gly Asn Tyr Ser Val Ile Ile Gln Glu 3440 3445 3450 Asn Lys Pro Val Gly Phe Ser Val Leu Gln Leu Val Val Thr Asp 3455 3460 3465 Glu Asp Ser Ser His Asn Gly Pro Pro Phe Phe Phe Thr Ile Val 3470 3475 3480 Thr Gly Asn Asp Glu Lys Ala Phe Glu Val Asn Pro Gln Gly Val 3485 3490 3495 Leu Leu Thr Ser Ser Ala Ile Lys Arg Lys Glu Lys Asp His Tyr 3500 3505 3510 Leu Leu Gln Val Lys Val Ala Asp Asn Gly Lys Pro Gln Leu Ser 3515 3520 3525 Ser Leu Thr Tyr Ile Asp Ile Arg Val Ile Glu Glu Ser Ile Tyr 3530 3535 3540 Pro Pro Ala Ile Leu Pro Leu Glu Ile Phe Ile Thr Ser Ser Gly 3545 3550 3555 Glu Glu Tyr Ser Gly Gly Val Ile Gly Lys Ile His Ala Thr Asp 3560 3565 3570 Gln Asp Val Tyr Asp Thr Leu Thr Tyr Ser Leu Asp Pro Gln Met 3575 3580 3585 Asp Asn Leu Phe Ser Val Ser Ser Thr Gly Gly Lys Leu Ile Ala 3590 3595 3600 His Lys Lys Leu Asp Ile Gly Gln Tyr Leu Leu Asn Val Ser Val 3605 3610 3615 Thr Asp Gly Lys Phe Thr Thr Val Ala Asp Ile Thr Val His Ile 3620 3625 3630 Arg Gln Val Thr Gln Glu Met Leu Asn His Thr Ile Ala Ile Arg 3635 3640 3645 Phe Ala Asn Leu Thr Pro Glu Glu Phe Val Gly Asp Tyr Trp Arg 3650 3655 3660 Asn Phe Gln Arg Ala Leu Arg Asn Ile Leu Gly Val Arg Arg Asn 3665 3670 3675 Asp Ile Gln Ile Val Ser Leu Gln Ser Ser Glu Pro His Pro His 3680 3685 3690 Leu Asp Val Leu Leu Phe Val Glu Lys Pro Gly Ser Ala Gln Ile 3695 3700 3705 Ser Thr Lys Gln Leu Leu His Lys Ile Asn Ser Ser Val Thr Asp 3710 3715 3720 Ile Glu Glu Ile Ile Gly Val Arg Ile Leu Asn Val Phe Gln Lys 3725 3730 3735 Leu Cys Ala Gly Leu Asp Cys Pro Trp Lys Phe Cys Asp Glu Lys 3740 3745 3750 Val Ser Val Asp Glu Ser Val Met Ser Thr His Ser Thr Ala Arg 3755 3760 3765 Leu Ser Phe Val Thr Pro Arg His His Arg Ala Ala Val Cys Leu 3770 3775 3780 Cys Lys Glu Gly Arg Cys Pro Pro Val His His Gly Cys Glu Asp 3785 3790 3795 Asp Pro Cys Pro Glu Gly Ser Glu Cys Val Ser Asp Pro Trp Glu 3800 3805 3810 Glu Lys His Thr Cys Val Cys Pro Ser Gly Arg Phe Gly Gln Cys 3815 3820 3825 Pro Gly Ser Ser Ser Met Thr Leu Thr Gly Asn Ser Tyr Val Lys 3830 3835 3840 Tyr Arg Leu Thr Glu Asn Glu Asn Lys Leu Glu Met Lys Leu Thr 3845 3850 3855 Met Arg Leu Arg Thr Tyr Ser Thr His Ala Val Val Met Tyr Ala 3860 3865 3870 Arg Gly Thr Asp Tyr Ser Ile Leu Glu Ile His His Gly Arg Leu 3875 3880 3885 Gln Tyr Lys Phe Asp Cys Gly Ser Gly Pro Gly Ile Val Ser Val 3890 3895 3900 Gln Ser Ile Gln Val Asn Asp Gly Gln Trp His Ala Val Ala Leu 3905 3910 3915 Glu Val Asn Gly Asn Tyr Ala Arg Leu Val Leu Asp Gln Val His 3920 3925 3930 Thr Ala Ser Gly Thr Ala Pro Gly Thr Leu Lys Thr Leu Asn Leu 3935 3940 3945 Asp Asn Tyr Val Phe Phe Gly Gly His Ile Arg Gln Gln Gly Thr 3950 3955 3960 Arg His Gly Arg Ser Pro Gln Val Gly Asn Gly Phe Arg Gly Cys 3965 3970 3975 Met Asp Ser Ile Tyr Leu Asn Gly Gln Glu Leu Pro Leu Asn Ser 3980 3985 3990 Lys Pro Arg Ser Tyr Ala His Ile Glu Glu Ser Val Asp Val Ser 3995 4000 4005 Pro Gly Cys Phe Leu Thr Ala Thr Glu Asp Cys Ala Ser Asn Pro 4010 4015 4020 Cys Gln Asn Gly Gly Val Cys Asn Pro Ser Pro Ala Gly Gly Tyr 4025 4030 4035 Tyr Cys Lys Cys Ser Ala Leu Tyr Ile Gly Thr His Cys Glu Ile 4040 4045 4050 Ser Val Asn Pro Cys Ser Ser Asn Pro Cys Leu Tyr Gly Gly Thr 4055 4060 4065 Cys Val Val Asp Asn Gly Gly Phe Val Cys Gln Cys Arg Gly Leu 4070 4075 4080 Tyr Thr Gly Gln Arg Cys Gln Leu Ser Pro Tyr Cys Lys Asp Glu 4085 4090 4095 Pro Cys Lys Asn Gly Gly Thr Cys Phe Asp Ser Leu Asp Gly Ala 4100 4105 4110 Val Cys Gln Cys Asp Ser Gly Phe Arg Gly Glu Arg Cys Gln Ser 4115 4120 4125 Asp Ile Asp Glu Cys Ser Gly Asn Pro Cys Leu His Gly Ala Leu 4130 4135 4140 Cys Glu Asn Thr His Gly Ser Tyr His Cys Asn Cys Ser His Glu 4145 4150 4155 Tyr Arg Gly Arg His Cys Glu Asp Ala Ala Pro Asn Gln Tyr Val 4160 4165 4170 Ser Thr Pro Trp Asn Ile Gly Leu Ala Glu Gly Ile Gly Ile Val 4175 4180 4185 Val Phe Val Ala Gly Ile Phe Leu Leu Val Val Val Phe Val Leu 4190 4195 4200 Cys Arg Lys Met Ile Ser Arg Lys Lys Lys His Gln Ala Glu Pro 4205 4210 4215 Lys Asp Lys His Leu Gly Pro Ala Thr Ala Phe Leu Gln Arg Pro 4220 4225 4230 Tyr Phe Asp Ser Lys Leu Asn Lys Asn Ile Tyr Ser Asp Ile Pro 4235 4240 4245 Pro Gln Val Pro Val Arg Pro Ile Ser Tyr Thr Pro Ser Ile Pro 4250 4255 4260 Ser Asp Ser Arg Asn Asn Leu Asp Arg Asn Ser Phe Glu Gly Ser 4265 4270 4275 Ala Ile Pro Glu His Pro Glu Phe Ser Thr Phe Asn Pro Glu Ser 4280 4285 4290 Val His Gly His Arg Lys Ala Val Ala Val Cys Ser Val Ala Pro 4295 4300 4305 Asn Leu Pro Pro Pro Pro Pro Ser Asn Ser Pro Ser Asp Ser Asp 4310 4315 4320 Ser Ile Gln Lys Pro Ser Trp Asp Phe Asp Tyr Asp Thr Lys Val 4325 4330 4335 Val Asp Leu Asp Pro Cys Leu Ser Lys Lys Pro Leu Glu Glu Lys 4340 4345 4350 Pro Ser Gln Pro Tyr Ser Ala Arg Glu Ser Leu Ser Glu Val Gln 4355 4360 4365 Ser Leu Ser Ser Phe Gln Ser Glu Ser Cys Asp Asp Asn Gly Tyr 4370 4375 4380 His Trp Asp Thr Ser Asp Trp Met Pro Ser Val Pro Leu Pro Asp 4385 4390 4395 Ile Gln Glu Phe Pro Asn Tyr Glu Val Ile Asp Glu Gln Thr Pro 4400 4405 4410 Leu Tyr Ser Ala Asp Pro Asn Ala Ile Asp Thr Asp Tyr Tyr Pro 4415 4420 4425 Gly Gly Tyr Asp Ile Glu Ser Asp Phe Pro Pro Pro Pro Glu Asp 4430 4435 4440 Phe Pro Ala Ala Asp Glu Leu Pro Pro Leu Pro Pro Glu Phe Ser 4445 4450 4455 Asn Gln Phe Glu Ser Ile His Pro Pro Arg Asp Met Pro Ala Ala 4460 4465 4470 Gly Ser Leu Gly Ser Ser Ser Arg Asn Arg Gln Arg Phe Asn Leu 4475 4480 4485 Asn Gln Tyr Leu Pro Asn Phe Tyr Pro Leu Asp Met Ser Glu Pro 4490 4495 4500 Gln Thr Lys Gly Thr Gly Glu Asn Ser Thr Cys Arg Glu Pro His 4505 4510 4515 Ala Pro Tyr Pro Pro Gly Tyr Gln Arg His Phe Glu Ala Pro Ala 4520 4525 4530 Val Glu Ser Met Pro Met Ser Val Tyr Ala Ser Thr Ala Ser Cys 4535 4540 4545 Ser Asp Val Ser Ala Cys Cys Glu Val Glu Ser Glu Val Met Met 4550 4555 4560 Ser Asp Tyr Glu Ser Gly Asp Asp Gly His Phe Glu Glu Val Thr 4565 4570 4575 Ile Pro Pro Leu Asp Ser Gln Gln His Thr Glu Val 4580 4585 4590 15 4349 PRT Homo sapiens 15 Met Thr Ile Ala Leu Leu Gly Phe Ala Ile Phe Leu Leu His Cys Ala 1 5 10 15 Thr Cys Glu Lys Pro Leu Glu Gly Ile Leu Ser Ser Ser Ala Trp His 20 25 30 Phe Thr His Ser His Tyr Asn Ala Thr Ile Tyr Glu Asn Ser Ser Pro 35 40 45 Lys Thr Tyr Val Glu Ser Phe Glu Lys Met Gly Ile Tyr Leu Ala Glu 50 55 60 Pro Gln Trp Ala Val Arg Tyr Arg Ile Ile Ser Gly Asp Val Ala Asn 65 70 75 80 Val Phe Lys Thr Glu Glu Tyr Val Val Gly Asn Phe Cys Phe Leu Arg 85 90 95 Ile Arg Thr Lys Ser Ser Asn Thr Ala Leu Leu Asn Arg Glu Val Arg 100 105 110 Asp Ser Tyr Thr Leu Ile Ile Gln Ala Thr Glu Lys Thr Leu Glu Leu 115 120 125 Glu Ala Leu Thr Arg Val Val Val His Ile Leu Asp Gln Asn Asp Leu 130 135 140 Lys Pro Leu Phe Ser Pro Pro Ser Tyr Arg Val Thr Ile Ser Glu Asp 145 150 155 160 Met Pro Leu Lys Ser Pro Ile Cys Lys Val Thr Ala Thr Asp Ala Asp 165 170 175 Leu Gly Gln Asn Ala Glu Phe Tyr Tyr Ala Phe Asn Thr Arg Ser Glu 180 185 190 Met Phe Ala Ile His Pro Thr Ser Gly Val Val Thr Val Ala Gly Lys 195 200 205 Leu Asn Val Thr Trp Arg Gly Lys His Glu Leu Gln Val Leu Ala Val 210 215 220 Asp Arg Met Arg Lys Ile Ser Glu Gly Asn Gly Phe Gly Ser Leu Ala 225 230 235 240 Ala Leu Val Val His Val Glu Pro Ala Leu Arg Lys Pro Pro Ala Ile 245 250 255 Ala Ser Val Val Val Thr Pro Pro Asp Ser Asn Asp Gly Thr Thr Tyr 260 265 270 Ala Thr Val Leu Val Asp Ala Asn Ser Ser Gly Ala Glu Val Glu Ser 275 280 285 Val Glu Val Val Gly Gly Asp Pro Gly Lys His Phe Lys Ala Ile Lys 290 295 300 Ser Tyr Ala Arg Ser Asn Glu Phe Ser Leu Val Ser Val Lys Asp Ile 305 310 315 320 Asn Trp Met Glu Tyr Leu His Gly Phe Asn Leu Ser Leu Gln Ala Arg 325 330 335 Ser Gly Ser Gly Pro Tyr Phe Tyr Ser Gln Ile Arg Gly Phe His Leu 340 345 350 Pro Pro Ser Lys Leu Ser Ser Leu Lys Phe Glu Lys Ala Val Tyr Arg 355 360 365 Val Gln Leu Ser Glu Phe Ser Pro Pro Gly Ser Arg Val Val Met Val 370 375 380 Arg Val Thr Pro Ala Phe Pro Asn Leu Gln Tyr Val Leu Lys Pro Ser 385 390 395 400 Ser Glu Asn Val Gly Phe Lys Leu Asn Ala Arg Thr Gly Leu Ile Thr 405 410 415 Thr Thr Lys Leu Met Asp Phe His Asp Arg Ala His Tyr Gln Leu His 420 425 430 Ile Arg Thr Ser Pro Gly Gln Ala Ser Thr Val Val Val Ile Asp Ile 435 440 445 Val Asp Cys Asn Asn His Ala Pro Leu Phe Asn Arg Ser Ser Tyr Asp 450 455 460 Gly Thr Leu Asp Glu Asn Ile Pro Pro Gly Thr Ser Val Leu Ala Val 465 470 475 480 Thr Ala Thr Asp Arg Asp His Gly Glu Asn Gly Tyr Val Thr Tyr Ser 485 490 495 Ile Ala Gly Pro Lys Ala Leu Pro Phe Ser Ile Asp Pro Tyr Leu Gly 500 505 510 Ile Ile Ser Thr Ser Lys Pro Met Asp Tyr Glu Leu Met Lys Arg Ile 515 520 525 Tyr Thr Phe Arg Val Arg Ala Ser Asp Trp Gly Ser Pro Phe Arg Arg 530 535 540 Glu Lys Glu Val Ser Ile Phe Leu Gln Leu Arg Asn Leu Asn Asp Asn 545 550 555 560 Gln Pro Met Phe Glu Glu Val Asn Cys Thr Gly Ser Ile Arg Gln Asp 565 570 575 Trp Pro Val Gly Lys Ser Ile Met Thr Met Ser Ala Ile Asp Val Asp 580 585 590 Glu Leu Gln Asn Leu Lys Tyr Glu Ile Val Ser Gly Asn Glu Leu Glu 595 600 605 Tyr Phe Asp Leu Asn His Phe Ser Gly Val Ile Ser Leu Lys Arg Pro 610 615 620 Phe Ile Asn Leu Thr Ala Gly Gln Pro Thr Ser Tyr Ser Leu Lys Ile 625 630 635 640 Thr Ala Ser Asp Gly Lys Asn Tyr Ala Ser Pro Thr Thr Leu Asn Ile 645 650 655 Thr Val Val Lys Asp Pro His Phe Glu Val Pro Val Thr Cys Asp Lys 660 665 670 Thr Gly Val Leu Thr Gln Phe Thr Lys Thr Ile Leu His Phe Ile Gly 675 680 685 Leu Gln Asn Gln Glu Ser Ser Asp Glu Glu Phe Thr Ser Leu Ser Thr 690 695 700 Tyr Gln Ile Asn His Tyr Thr Pro Gln Phe Glu Asp His Phe Pro Gln 705 710 715 720 Ser Ile Asp Val Leu Glu Ser Val Pro Ile Asn Thr Pro Leu Ala Arg 725 730 735 Leu Ala Ala Thr Asp Pro Asp Ala Gly Phe Asn Gly Lys Leu Val Tyr 740 745 750 Val Ile Ala Asp Gly Asn Glu Glu Gly Cys Phe Asp Ile Glu Leu Glu 755 760 765 Thr Gly Leu Leu Thr Val Ala Ala Pro Leu Asp Tyr Glu Ala Thr Asn 770 775 780 Phe Tyr Ile Leu Asn Val Thr Val Tyr Asp Leu Gly Thr Pro Gln Lys 785 790 795 800 Ser Ser Trp Lys Leu Leu Thr Val Asn Val Lys Asp Trp Asn Asp Asn 805 810 815 Ala Pro Arg Phe Pro Pro Gly Gly Tyr Gln Leu Thr Ile Ser Glu Asp 820 825 830 Thr Glu Val Gly Thr Thr Ile Ala Glu Leu Thr Thr Lys Asp Ala Asp 835 840 845 Ser Glu Asp Asn Gly Arg Val Arg Tyr Thr Leu Leu Ser Pro Thr Glu 850 855 860 Lys Phe Ser Leu His Pro Leu Thr Gly Glu Leu Val Val Thr Gly His 865 870 875 880 Leu Asp Arg Glu Ser Glu Pro Arg Tyr Ile Leu Lys Val Glu Ala Arg 885 890 895 Asp Gln Pro Ser Lys Gly His Gln Leu Phe Ser Val Thr Asp Leu Ile 900 905 910 Ile Thr Leu Glu Asp Val Asn Asp Asn Ser Pro Gln Cys Ile Thr Glu 915 920 925 His Asn Arg Leu Lys Val Pro Glu Asp Leu Pro Pro Gly Thr Val Leu 930 935 940 Thr Phe Leu Asp Ala Ser Asp Pro Asp Leu Gly Pro Ala Gly Glu Val 945 950 955 960 Arg Tyr Val Leu Met Asp Gly Ala His Gly Thr Phe Arg Val Asp Leu 965 970 975 Met Thr Gly Ala Leu Ile Leu Glu Arg Glu Leu Asp Phe Glu Arg Arg 980 985 990 Ala Gly Tyr Asn Leu Ser Leu Trp Ala Ser Asp Gly Gly Arg Pro Leu 995 1000 1005 Ala Arg Arg Thr Leu Cys His Val Glu Val Ile Val Leu Asp Val 1010 1015 1020 Asn Glu Asn Leu His Pro Pro His Phe Ala Ser Phe Val His Gln 1025 1030 1035 Gly Gln Val Gln Glu Asn Ser Pro Ser Gly Thr Gln Val Ile Val 1040 1045 1050 Val Ala Ala Gln Asp Asp Asp Ser Gly Leu Asp Gly Glu Leu Gln 1055 1060 1065 Tyr Phe Leu Arg Ala Gly Thr Gly Leu Ala Ala Phe Ser Ile Asn 1070 1075 1080 Gln Asp Thr Gly Met Ile Gln Thr Leu Ala Pro Leu Asp Arg Glu 1085 1090 1095 Phe Ala Ser Tyr Tyr Trp Leu Thr Val Leu Ala Val Asp Arg Gly 1100 1105 1110 Ser Val Pro Leu Ser Ser Val Thr Glu Val Tyr Ile Glu Val Thr 1115 1120 1125 Asp Ala Asn Asp Asn Pro Pro Gln Met Ser Gln Ala Val Phe Tyr 1130 1135 1140 Pro Ser Ile Gln Glu Asp Ala Pro Val Gly Thr Ser Val Leu Gln 1145 1150 1155 Leu Asp Ala Trp Asp Pro Asp Ser Ser Ser Lys Gly Lys Leu Thr 1160 1165 1170 Phe Asn Ile Thr Ser Gly Asn Tyr Met Gly Phe Phe Met Ile His 1175 1180 1185 Pro Val Thr Gly Leu Leu Ser Thr Ala Gln Gln Leu Asp Arg Glu 1190 1195 1200 Asn Lys Asp Glu His Ile Leu Glu Val Thr Val Leu Asp Asn Gly 1205 1210 1215 Glu Pro Ser Leu Lys Ser Thr Ser Arg Val Val Val Gly Ile Leu 1220 1225 1230 Asp Val Asn Asp Asn Pro Pro Ile Phe Ser His Lys Leu Phe Asn 1235 1240 1245 Val Arg Leu Pro Glu Arg Leu Ser Pro Val Ser Pro Gly Pro Val 1250 1255 1260 Tyr Arg Leu Val Ala Ser Asp Leu Asp Glu Gly Leu Asn Gly Arg 1265 1270 1275 Val Thr Tyr Ser Ile Glu Asp Ser Tyr Glu Glu Ala Phe Ser Ile 1280 1285 1290 Asp Leu Val Thr Gly Val Val Ser Ser Asn Ser Thr Phe Thr Ala 1295 1300 1305 Gly Glu Tyr Asn Ile Leu Thr Ile Lys Ala Thr Asp Ser Gly Gln 1310 1315 1320 Pro Pro Leu Ser Ala Ser Val Arg Leu His Ile Glu Trp Ile Pro 1325 1330 1335 Trp Pro Arg Pro Ser Ser Ile Pro Leu Ala Phe Asp Glu Thr Tyr 1340 1345 1350 Tyr Ser Phe Thr Val Met Glu Thr Asp Pro Val Asn His Met Val 1355 1360 1365 Gly Val Ile Ser Val Glu Gly Arg Pro Gly Leu Phe Trp Phe Asn 1370 1375 1380 Ile Ser Gly Gly Asp Lys Asp Met Asp Phe Asp Ile Glu Lys Thr 1385 1390 1395 Thr Gly Ser Ile Val Ile Ala Arg Pro Leu Asp Thr Arg Arg Arg 1400 1405 1410 Ser Asn Tyr Asn Leu Thr Val Glu Val Thr Asp Gly Ser Arg Thr 1415 1420 1425 Ile Ala Thr Gln Val His Ile Phe Met Ile Ala Asn Ile Asn His 1430 1435 1440 His Arg Pro Gln Phe Leu Glu Thr Arg Tyr Glu Val Arg Val Pro 1445 1450 1455 Gln Asp Thr Val Pro Gly Val Glu Leu Leu Arg Val Gln Ala Ile 1460 1465 1470 Asp Gln Asp Lys Gly Lys Ser Leu Ile Tyr Thr Ile His Gly Ser 1475 1480 1485 Gln Asp Pro Gly Ser Ala Ser Leu Phe Gln Leu Asp Pro Ser Ser 1490 1495 1500 Gly Val Leu Val Thr Val Gly Lys Leu Asp Leu Gly Ser Gly Pro 1505 1510 1515 Ser Gln His Thr Leu Thr Val Met Val Arg Asp Gln Glu Ile Pro 1520 1525 1530 Ile Lys Arg Asn Phe Val Trp Val Thr Ile His Val Glu Asp Gly 1535 1540 1545 Asn Leu His Pro Pro Arg Phe Thr Gln Leu His Tyr Glu Ala Ser 1550 1555 1560 Val Pro Asp Thr Ile Ala Pro Gly Thr Glu Leu Leu Gln Val Arg 1565 1570 1575 Ala Met Asp Ala Asp Arg Gly Val Asn Ala Glu Val His Tyr Ser 1580 1585 1590 Leu Leu Lys Gly Asn Ser Glu Gly Phe Phe Asn Ile Asn Ala Leu 1595 1600 1605 Leu Gly Ile Ile Thr Leu Ala Gln Lys Leu Asp Gln Ala Asn His 1610 1615 1620 Ala Pro His Thr Leu Thr Val Lys Ala Glu Asp Gln Gly Ser Pro 1625 1630 1635 Gln Trp His Asp Leu Ala Thr Val Ile Ile His Val Tyr Pro Ser 1640 1645 1650 Asp Arg Ser Ala Pro Ile Phe Ser Lys Ser Glu Tyr Phe Val Glu 1655 1660 1665 Ile Pro Glu Ser Ile Pro Val Gly Ser Pro Ile Leu Leu Val Ser 1670 1675 1680 Ala Met Ser Pro Ser Glu Val Thr Tyr Glu Leu Arg Glu Gly Asn 1685 1690 1695 Lys Asp Gly Val Phe Ser Met Asn Ser Tyr Ser Gly Leu Ile Ser 1700 1705 1710 Thr Gln Lys Lys Leu Asp His Glu Lys Ile Ser Ser Tyr Gln Leu 1715 1720 1725 Lys Ile Arg Gly Ser Asn Met Ala Gly Ala Phe Thr Asp Val Met 1730 1735 1740 Val Val Val Asp Ile Ile Asp Glu Asn Asp Asn Ala Pro Met Phe 1745 1750 1755 Leu Lys Ser Thr Phe Val Gly Gln Ile Ser Glu Ala Ala Pro Leu 1760 1765 1770 Tyr Ser Met Ile Met Asp Lys Asn Asn Asn Pro Phe Val Ile His 1775 1780 1785 Ala Ser Asp Ser Asp Lys Glu Ala Asn Ser Leu Leu Val Tyr Lys 1790 1795 1800 Ile Leu Glu Pro Glu Ala Leu Lys Phe Phe Lys Ile Asp Pro Ser 1805 1810 1815 Met Gly Thr Leu Thr Ile Val Ser Glu Met Asp Tyr Glu Ser Met 1820 1825 1830 Pro Ser Phe Gln Phe Cys Val Tyr Val His Asp Gln Gly Ser Pro 1835 1840 1845 Val Leu Phe Ala Pro Arg Pro Ala Gln Val Ile Ile His Val Arg 1850 1855 1860 Asp Val Asn Asp Ser Pro Pro Arg Phe Ser Glu Gln Ile Tyr Glu 1865 1870 1875 Val Ala Ile Val Gly Pro Ile His Pro Gly Met Glu Leu Leu Met 1880 1885 1890 Val Arg Ala Ser Asp Glu Asp Ser Glu Val Asn Tyr Ser Ile Lys 1895 1900 1905 Thr Gly Asn Ala Asp Glu Ala Val Thr Ile His Pro Val Thr Gly 1910 1915 1920 Ser Ile Ser Val Leu Asn Pro Ala Phe Leu Gly Leu Ser Arg Lys 1925 1930 1935 Leu Thr Ile Arg Ala Ser Asp Gly Leu Tyr Gln Asp Thr Ala Leu 1940 1945 1950 Val Lys Ile Ser Leu Thr Gln Val Leu Asp Lys Ser Leu Gln Phe 1955 1960 1965 Asp Gln Asp Val Tyr Trp Ala Ala Val Lys Glu Asn Leu Gln Asp 1970 1975 1980 Arg Lys Ala Leu Val Ile Leu Gly Ala Gln Gly Asn His Leu Asn 1985 1990 1995 Asp Thr Leu Ser Tyr Phe Leu Leu Asn Gly Thr Asp Met Phe His 2000 2005 2010 Met Val Gln Ser Ala Gly Val Leu Gln Thr Arg Gly Val Ala Phe 2015 2020 2025 Asp Arg Glu Gln Gln Asp Thr His Glu Leu Ala Val Glu Val Arg 2030 2035 2040 Asp Asn Arg Thr Pro Gln Arg Val Ala Gln Gly Leu Val Arg Val 2045 2050 2055 Ser Ile Glu Asp Val Asn Asp Asn Pro Pro Lys Phe Lys His Leu 2060 2065 2070 Pro Tyr Tyr Thr Ile Ile Gln Asp Gly Thr Glu Pro Gly Asp Val 2075 2080 2085 Leu Phe Gln Val Ser Ala Thr Asp Glu Asp Leu Gly Thr Asn Gly 2090 2095 2100 Ala Val Thr Tyr Glu Phe Ala Glu Asp Tyr Thr Tyr Phe Arg Ile 2105 2110 2115 Asp Pro Tyr Leu Gly Asp Ile Ser Leu Lys Lys Pro Phe Asp Tyr 2120 2125 2130 Gln Ala Leu Asn Lys Tyr His Leu Lys Val Ile Ala Arg Asp Gly 2135 2140 2145 Gly Thr Pro Ser Leu Gln Ser Glu Glu Glu Val Leu Val Thr Val 2150 2155 2160 Arg Asn Lys Ser Asn Pro Leu Phe Gln Ser Pro Tyr Tyr Lys Val 2165 2170 2175 Arg Val Pro Glu Asn Ile Thr Leu Tyr Thr Pro Ile Leu His Thr 2180 2185 2190 Gln Ala Arg Ser Pro Glu Gly Leu Arg Leu Ile Tyr Asn Ile Val 2195 2200 2205 Glu Glu Glu Pro Leu Met Leu Phe Thr Thr Asp Phe Lys Thr Gly 2210 2215 2220 Val Leu Thr Val Thr Gly Pro Leu Asp Tyr Glu Ser Lys Thr Lys 2225 2230 2235 His Val Phe Thr Val Arg Ala Thr Asp Thr Ala Leu Gly Ser Phe 2240 2245 2250 Ser Glu Ala Thr Val Glu Val Leu Val Glu Asp Val Asn Asp Asn 2255 2260 2265 Pro Pro Thr Phe Ser Gln Leu Val Tyr Thr Thr Ser Ile Ser Glu 2270 2275 2280 Gly Leu Pro Ala Gln Thr Pro Val Ile Gln Leu Leu Ala Ser Asp 2285 2290 2295 Gln Asp Ser Gly Arg Asn Arg Asp Val Ser Tyr Gln Ile Val Glu 2300 2305 2310 Asp Gly Ser Asp Val Ser Lys Phe Phe Gln Ile Asn Gly Ser Thr 2315 2320 2325 Gly Glu Met Ser Thr Val Gln Glu Leu Asp Tyr Glu Ala Gln Gln 2330 2335 2340 His Phe His Val Lys Val Arg Ala Met Asp Lys Gly Asp Pro Pro 2345 2350 2355 Leu Thr Gly Glu Thr Leu Val Val Val Asn Val Ser Asp Ile Asn 2360 2365 2370 Asp Asn Pro Pro Glu Phe Arg Gln Pro Gln Tyr Glu Ala Asn Val 2375 2380 2385 Ser Glu Leu Ala Thr Cys Gly His Leu Val Leu Lys Val Gln Ala 2390 2395 2400 Ile Asp Pro Asp Ser Arg Asp Thr Ser Arg Leu Glu Tyr Leu Ile 2405 2410 2415 Leu Ser Gly Asn Gln Asp Arg His Phe Phe Ile Asn Ser Ser Ser 2420 2425 2430 Gly Ile Ile Ser Met Phe Asn Leu Cys Lys Lys His Leu Asp Ser 2435 2440 2445 Ser Tyr Asn Leu Arg Val Gly Ala Ser Asp Gly Val Phe Arg Ala 2450 2455 2460 Thr Val Pro Val Tyr Ile Asn Thr Thr Asn Ala Asn Lys Tyr Ser 2465 2470 2475 Pro Glu Phe Gln Gln His Leu Tyr Glu Ala Glu Leu Ala Glu Asn 2480 2485 2490 Ala Met Val Gly Thr Lys Val Ile Asp Leu Leu Ala Ile Asp Lys 2495 2500 2505 Asp Ser Gly Pro Tyr Gly Thr Ile Asp Tyr Thr Ile Ile Asn Lys 2510 2515 2520 Leu Ala Ser Glu Lys Phe Ser Ile Asn Pro Asn Gly Gln Ile Ala 2525 2530 2535 Thr Leu Gln Lys Leu Asp Arg Glu Asn Ser Thr Glu Arg Val Ile 2540 2545 2550 Ala Ile Lys Val Met Ala Arg Asp Gly Gly Gly Arg Val Ala Phe 2555 2560 2565 Cys Thr Val Lys Ile Ile Leu Thr Asp Glu Asn Asp Asn Pro Pro 2570 2575 2580 Gln Phe Lys Ala Ser Glu Tyr Thr Val Ser Ile Gln Ser Asn Val 2585 2590 2595 Ser Lys Asp Ser Pro Val Ile Gln Val Leu Ala Tyr Asp Ala Asp 2600 2605 2610 Glu Gly Gln Asn Ala Asp Val Thr Tyr Ser Val Asn Pro Glu Asp 2615 2620 2625 Leu Val Lys Asp Val Ile Glu Ile Asn Pro Val Thr Gly Val Val 2630 2635 2640 Lys Val Lys Asp Ser Leu Val Gly Leu Glu Asn Gln Thr Leu Asp 2645 2650 2655 Phe Phe Ile Lys Ala Gln Asp Gly Gly Pro Pro His Trp Asn Ser 2660 2665 2670 Leu Val Pro Val Arg Leu Gln Val Val Pro Lys Lys Val Ser Leu 2675 2680 2685 Pro Lys Phe Ser Glu Pro Leu Tyr Thr Phe Ser Ala Pro Glu Asp 2690 2695 2700 Leu Pro Glu Gly Ser Glu Ile Gly Ile Val Lys Ala Val Ala Ala 2705 2710 2715 Gln Asp Pro Val Ile Tyr Ser Leu Val Arg Gly Thr Thr Pro Glu 2720 2725 2730 Ser Asn Lys Asp Gly Val Phe Ser Leu Asp Pro Asp Thr Gly Val 2735 2740 2745 Ile Lys Val Arg Lys Pro Met Asp His Glu Ser Thr Lys Leu Tyr 2750 2755 2760 Gln Ile Asp Val Met Ala His Cys Leu Gln Asn Thr Asp Val Val 2765 2770 2775 Ser Leu Val Ser Val Asn Ile Gln Val Gly Asp Val Asn Asp Asn 2780 2785 2790 Arg Pro Val Phe Glu Ala Asp Pro Tyr Lys Ala Val Leu Thr Glu 2795 2800 2805 Asn Met Pro Val Gly Thr Ser Val Ile Gln Val Thr Ala Ile Asp 2810 2815 2820 Lys Asp Thr Gly Arg Asp Gly Gln Val Ser Tyr Arg Leu Ser Ala 2825 2830 2835 Asp Pro Gly Ser Asn Val His Glu Leu Phe Ala Ile Asp Ser Glu 2840 2845 2850 Ser Gly Trp Ile Thr Thr Leu Gln Glu Leu Asp Cys Glu Thr Cys 2855 2860 2865 Gln Thr Tyr His Phe His Val Val Ala Tyr Asp His Gly Gln Thr 2870 2875 2880 Ile Gln Leu Ser Ser Gln Ala Leu Val Gln Val Ser Ile Thr Asp 2885 2890 2895 Glu Asn Asp Asn Ala Pro Arg Phe Ala Ser Glu Glu Tyr Arg Gly 2900 2905 2910 Ser Val Val Glu Asn Ser Glu Pro Gly Glu Leu Val Ala Thr Leu 2915 2920 2925 Lys Thr Leu Asp Ala Asp Ile Ser Glu Gln Asn Arg Gln Val Thr 2930 2935 2940 Cys Tyr Ile Thr Glu Gly Asp Pro Leu Gly Gln Phe Gly Ile Ser 2945 2950 2955 Gln Val Gly Asp Glu Trp Arg Ile Ser Ser Arg Lys Thr Leu Asp 2960 2965 2970 Arg Glu His Thr Ala Lys Tyr Leu Leu Arg Val Thr Ala Ser Asp 2975 2980 2985 Gly Lys Phe Gln Ala Ser Val Thr Val Glu Ile Phe Val Leu Asp 2990 2995 3000 Val Asn Asp Asn Ser Pro Gln Cys Ser Gln Leu Leu Tyr Thr Gly 3005 3010 3015 Lys Val His Glu Asp Val Phe Pro Gly His Phe Ile Leu Lys Val 3020 3025 3030 Ser Ala Thr Asp Leu Asp Thr Asp Thr Asn Ala Gln Ile Thr Tyr 3035 3040 3045 Ser Leu His Gly Pro Gly Ala His Glu Phe Lys Leu Asp Pro His 3050 3055 3060 Thr Gly Glu Leu Thr Thr Leu Thr Ala Leu Asp Arg Glu Arg Lys 3065 3070 3075 Asp Val Phe Asn Leu Val Ala Lys Ala Thr Asp Gly Gly Gly Arg 3080 3085 3090 Ser Cys Gln Ala Asp Ile Thr Leu His Val Glu Asp Val Asn Asp 3095 3100 3105 Asn Ala Pro Arg Phe Phe Pro Ser His Cys Ala Val Ala Val Phe 3110 3115 3120 Asp Asn Thr Thr Val Lys Thr Pro Val Ala Val Val Phe Ala Arg 3125 3130 3135 Asp Pro Asp Gln Gly Ala Asn Ala Gln Val Val Tyr Ser Leu Pro 3140 3145 3150 Asp Ser Ala Glu Gly His Phe Ser Ile Asp Ala Thr Thr Gly Val 3155 3160 3165 Ile Arg Leu Glu Lys Pro Leu Gln Val Arg Pro Gln Ala Pro Leu 3170 3175 3180 Glu Leu Thr Val Arg Ala Ser Asp Leu Gly Thr Pro Ile Pro Leu 3185 3190 3195 Ser Thr Leu Gly Thr Val Thr Val Ser Val Val Gly Leu Glu Asp 3200 3205 3210 Tyr Leu Pro Val Phe Leu Asn Thr Glu His Ser Val Gln Val Pro 3215 3220 3225 Glu Asp Ala Pro Pro Gly Thr Glu Val Leu Gln Leu Ala Thr Leu 3230 3235 3240 Thr Arg Pro Gly Ala Glu Lys Thr Gly Tyr Arg Val Val Ser Gly 3245 3250 3255 Asn Glu Gln Gly Arg Phe Arg Leu Asp Ala Arg Thr Gly Ile Leu 3260 3265 3270 Tyr Val Asn Ala Ser Leu Asp Phe Glu Thr Ser Pro Lys Tyr Phe 3275 3280 3285 Leu Ser Ile Glu Cys Ser Arg Lys Ser Ser Ser Ser Leu Ser Asp 3290 3295 3300 Val Thr Thr Val Met Val Asn Ile Thr Asp Val Asn Glu His Arg 3305 3310 3315 Pro Gln Phe Pro Gln Asp Pro Tyr Ser Thr Arg Val Leu Glu Asn 3320 3325 3330 Ala Leu Val Gly Asp Val Ile Leu Thr Val Ser Ala Thr Asp Glu 3335 3340 3345 Asp Gly Pro Leu Asn Ser Asp Ile Thr Tyr Ser Leu Ile Gly Gly 3350 3355 3360 Asn Gln Leu Gly His Phe Thr Ile His Pro Lys Lys Gly Glu Leu 3365 3370 3375 Gln Val Ala Lys Ala Leu Asp Arg Glu Gln Ala Ser Ser Tyr Ser 3380 3385 3390 Leu Lys Leu Arg Ala Thr Asp Ser Gly Gln Pro Pro Leu His Glu 3395 3400 3405 Asp Thr Asp Ile Ala Ile Gln Val Ala Asp Val Asn Asp Asn Pro 3410 3415 3420 Pro Arg Phe Phe Gln Leu Asn Tyr Ser Thr Thr Val Gln Glu Asn 3425 3430 3435 Ser Pro Ile Gly Ser Lys Val Leu Gln Leu Ile Leu Ser Asp Pro 3440 3445 3450 Asp Ser Pro Glu Asn Gly Pro Pro Tyr Ser Phe Arg Ile Thr Lys 3455 3460 3465 Gly Asn Asn Gly Ser Ala Phe Arg Val Thr Pro Asp Gly Trp Leu 3470 3475 3480 Val Thr Ala Glu Gly Leu Ser Arg Arg Ala Gln Glu Trp Tyr Gln 3485 3490 3495 Leu Gln Ile Gln Ala Ser Asp Ser Gly Ile Pro Pro Leu Ser Ser 3500 3505 3510 Leu Thr Ser Val Arg Val His Val Thr Glu Gln Ser His Tyr Ala 3515 3520 3525 Pro Ser Ala Leu Pro Leu Glu Ile Phe Ile Thr Val Gly Glu Asp 3530 3535 3540 Glu Phe Gln Gly Gly Met Val Gly Lys Ile His Ala Thr Asp Arg 3545 3550 3555 Asp Pro Gln Asp Thr Leu Thr Tyr Ser Leu Ala Glu Glu Glu Thr 3560 3565 3570 Leu Gly Arg His Phe Ser Val Gly Ala Pro Asp Gly Lys Ile Ile 3575 3580 3585 Ala Ala Gln Gly Leu Pro Arg Gly His Tyr Ser Phe Asn Val Thr 3590 3595 3600 Val Ser Asp Gly Thr Phe Thr Thr Thr Ala Gly Val His Val Tyr 3605 3610 3615 Val Trp His Val Gly Gln Glu Ala Leu Gln Gln Ala Met Trp Met 3620 3625 3630 Gly Phe Tyr Gln Leu Thr Pro Glu Glu Leu Val Ser Asp His Trp 3635 3640 3645 Arg Asn Leu Gln Arg Phe Leu Ser His Lys Leu Asp Ile Lys Arg 3650 3655 3660 Ala Asn Ile His Leu Ala Ser Leu Gln Pro Ala Glu Ala Val Ala 3665 3670 3675 Gly Val Asp Val Leu Leu Val Phe Glu Gly His Ser Gly Thr Phe 3680 3685 3690 Tyr Glu Phe Gln Glu Leu Ala Ser Ile Ile Thr His Ser Ala Lys 3695 3700 3705 Glu Met Glu His Ser Val Gly Val Gln Met Arg Ser Ala Met Pro 3710 3715 3720 Met Val Pro Cys Gln Gly Pro Thr Cys Gln Gly Gln Ile Cys His 3725 3730 3735 Asn Thr Val His Leu Asp Pro Lys Val Gly Pro Thr Tyr Ser Thr 3740 3745 3750 Ala Arg Leu Ser Ile Leu Thr Pro Arg His His Leu Gln Arg Ser 3755 3760 3765 Cys Ser Cys Asn Gly Thr Ala Thr Arg Phe Ser Gly Gln Ser Tyr 3770 3775 3780 Val Arg Tyr Arg Ala Pro Ala Ala Arg Asn Trp His Ile His Phe 3785 3790 3795 Tyr Leu Lys Thr Leu Gln Pro Gln Ala Ile Leu Leu Phe Thr Asn 3800 3805 3810 Glu Thr Ala Ser Val Ser Leu Lys Leu Ala Ser Gly Val Pro Gln 3815 3820 3825 Leu Glu Tyr His Cys Leu Gly Gly Phe Tyr Gly Asn Leu Ser Ser 3830 3835 3840 Gln Arg His Val Asn Asp His Glu Trp His Ser Ile Leu Val Glu 3845 3850 3855 Glu Met Asp Ala Ser Ile Arg Leu Met Val Asp Ser Met Gly Asn 3860 3865 3870 Thr Ser Leu Val Val Pro Glu Asn Cys Arg Gly Leu Arg Pro Glu 3875 3880 3885 Arg His Leu Leu Leu Gly Gly Leu Ile Leu Leu His Ser Ser Ser 3890 3895 3900 Asn Val Ser Gln Gly Phe Glu Gly Cys Leu Asp Ala Val Val Val 3905 3910 3915 Asn Glu Glu Ala Leu Asp Leu Leu Ala Pro Gly Lys Thr Val Ala 3920 3925 3930 Gly Leu Leu Glu Thr Gln Ala Leu Thr Gln Cys Cys Leu His Ser 3935 3940 3945 Asp Tyr Cys Ser Gln Asn Thr Cys Leu Asn Gly Gly Lys Cys Ser 3950 3955 3960 Trp Thr His Gly Ala Gly Tyr Val Cys Lys Cys Pro Pro Gln Phe 3965 3970 3975 Ser Gly Lys His Cys Glu Gln Gly Arg Glu Asn Cys Thr Phe Ala 3980 3985 3990 Pro Cys Leu Glu Gly Gly Thr Cys Ile Leu Ser Pro Lys Gly Ala 3995 4000 4005 Ser Cys Asn Cys Pro His Pro Tyr Thr Gly Asp Arg Cys Glu Met 4010 4015 4020 Glu Ala Arg Gly Cys Ser Glu Gly His Cys Leu Val Thr Pro Glu 4025 4030 4035 Ile Gln Arg Gly Asp Trp Gly Gln Gln Glu Leu Leu Ile Ile Thr 4040 4045 4050 Val Ala Val Ala Phe Ile Ile Ile Ser Thr Val Gly Leu Leu Phe 4055 4060 4065 Tyr Cys Arg Arg Cys Lys Ser His Lys Pro Val Ala Met Glu Asp 4070 4075 4080 Pro Asp Leu Leu Ala Arg Ser Val Gly Val Asp Thr Gln Ala Met 4085 4090 4095 Pro Ala Ile Glu Leu Asn Pro Leu Ser Ala Ser Ser Cys Asn Asn 4100 4105 4110 Leu Asn Gln Pro Glu Pro Ser Lys Ala Ser Val Pro Asn Glu Leu 4115 4120 4125 Val Thr Phe Gly Pro Asn Ser Lys Gln Arg Pro Val Val Cys Ser 4130 4135 4140 Val Pro Pro Arg Leu Pro Pro Ala Ala Val Pro Ser His Ser Asp 4145 4150 4155 Asn Glu Pro Val Ile Lys Arg Thr Trp Ser Ser Glu Glu Met Val 4160 4165 4170 Tyr Pro Gly Gly Ala Met Val Trp Pro Pro Thr Tyr Ser Arg Asn 4175 4180 4185 Glu Arg Trp Glu Tyr Pro His Ser Glu Val Thr Gln Gly Pro Leu 4190 4195 4200 Pro Pro Ser Ala His Arg His Ser Thr Pro Val Val Met Pro Glu 4205 4210 4215 Pro Asn Gly Leu Tyr Gly Gly Phe Pro Phe Pro Leu Glu Met Glu 4220 4225 4230 Asn Lys Arg Ala Pro Leu Pro Pro Arg Tyr Ser Asn Gln Asn Leu 4235 4240 4245 Glu Asp Leu Met Pro Ser Arg Pro Pro Ser Pro Arg Glu Arg Leu 4250 4255 4260 Val Ala Pro Cys Leu Asn Glu Tyr Thr Ala Ile Ser Tyr Tyr His 4265 4270 4275 Ser Gln Phe Arg Gln Gly Gly Gly Gly Pro Cys Leu Ala Asp Gly 4280 4285 4290 Gly Tyr Lys Gly Val Gly Met Arg Leu Ser Arg Ala Gly Pro Ser 4295 4300 4305 Tyr Ala Val Cys Glu Val Glu Gly Ala Pro Leu Ala Gly Gln Gly 4310 4315 4320 Gln Pro Arg Val Pro Pro Asn Tyr Glu Gly Ser Asp Met Val Glu 4325 4330 4335 Ser Asp Tyr Gly Ser Cys Glu Glu Val Met Phe 4340 4345 16 3298 PRT Homo sapiens 16 Met Gln Lys Glu Leu Gly Ile Val Pro Ser Cys Pro Gly Met Lys Ser 1 5 10 15 Pro Arg Pro His Leu Leu Leu Pro Leu Leu Leu Leu Leu Leu Leu Leu 20 25 30 Leu Gly Ala Gly Val Pro Gly Ala Trp Gly Gln Ala Gly Ser Leu Asp 35 40 45 Leu Gln Ile Asp Glu Glu Gln Pro Ala Gly Thr Leu Ile Gly Asp Ile 50 55 60 Ser Ala Gly Leu Pro Ala Gly Thr Ala Ala Pro Leu Met Tyr Phe Ile 65 70 75 80 Ser Ala Gln Glu Gly Ser Gly Val Gly Thr Asp Leu Ala Ile Asp Glu 85 90 95 His Ser Gly Val Val Arg Thr Ala Arg Val Leu Asp Arg Glu Gln Arg 100 105 110 Asp Arg Tyr Arg Phe Thr Ala Val Thr Pro Asp Gly Ala Thr Val Glu 115 120 125 Val Thr Val Arg Val Ala Asp Ile Asn Asp His Ala Pro Ala Phe Pro 130 135 140 Gln Ala Arg Ala Ala Leu Gln Val Pro Glu His Thr Ala Phe Gly Thr 145 150 155 160 Arg Tyr Pro Leu Glu Pro Ala Arg Asp Ala Asp Ala Gly Arg Leu Gly 165 170 175 Thr Gln Gly Tyr Ala Leu Ser Gly Asp Gly Ala Gly Glu Thr Phe Arg 180 185 190 Leu Glu Thr Arg Pro Gly Pro Asp Gly Thr Pro Val Pro Glu Leu Val 195 200 205 Val Thr Gly Glu Leu Asp Arg Glu Asn Arg Ser His Tyr Met Leu Gln 210 215 220 Leu Glu Ala Tyr Asp Gly Gly Ser Pro Pro Arg Arg Ala Gln Ala Leu 225 230 235 240 Leu Asp Val Thr Leu Leu Asp Ile Asn Asp His Ala Pro Ala Phe Asn 245 250 255 Gln Ser Arg Tyr His Ala Val Val Ser Glu Ser Leu Ala Pro Gly Ser 260 265 270 Pro Val Leu Gln Val Phe Ala Ser Asp Ala Asp Ala Gly Val Asn Gly 275 280 285 Ala Val Thr Tyr Glu Ile Asn Arg Arg Gln Ser Glu Gly Asp Gly Pro 290 295 300 Phe Ser Ile Asp Ala His Thr Gly Leu Leu Gln Leu Glu Arg Pro Leu 305 310 315 320 Asp Phe Glu Gln Arg Arg Val His Glu Leu Val Val Gln Ala Arg Asp 325 330 335 Gly Gly Ala His Pro Glu Leu Gly Ser Ala Phe Val Thr Val His Val 340 345 350 Arg Asp Ala Asn Asp Asn Gln Pro Ser Met Thr Val Ile Phe Leu Ser 355 360 365 Ala Asp Gly Ser Pro Gln Val Ser Glu Ala Ala Pro Pro Gly Gln Leu 370 375 380 Val Ala Arg Ile Ser Val Ser Asp Pro Asp Asp Gly Asp Phe Ala His 385 390 395 400 Val Asn Val Ser Leu Glu Gly Gly Glu Gly His Phe Ala Leu Ser Thr 405 410 415 Gln Asp Ser Val Ile Tyr Leu Val Cys Val Ala Arg Arg Leu Asp Arg 420 425 430 Glu Glu Arg Asp Ala Tyr Asn Leu Arg Val Thr Ala Thr Asp Ser Gly 435 440 445 Ser Pro Pro Leu Arg Ala Glu Ala Ala Phe Val Leu His Val Thr Asp 450 455 460 Val Asn Asp Asn Ala Pro Ala Phe Asp Arg Gln Leu Tyr Arg Pro Glu 465 470 475 480 Pro Leu Pro Glu Val Ala Leu Pro Gly Ser Phe Val Val Arg Val Thr 485 490 495 Ala Arg Asp Pro Asp Gln Gly Thr Asn Gly Gln Val Thr Tyr Ser Leu 500 505 510 Ala Pro Gly Ala His Thr His Trp Phe Ser Ile Asp Pro Thr Ser Gly 515 520 525 Ile Ile Thr Thr Ala Ala Ser Leu Asp Tyr Glu Leu Glu Pro Gln Pro 530 535 540 Gln Leu Ile Val Val Ala Thr Asp Gly Gly Leu Pro Pro Leu Ala Ser 545 550 555 560 Ser Ala Thr Val Ser Val Ala Leu Gln Asp Val Asn Asp Asn Glu Pro 565 570 575 Gln Phe Gln Arg Thr Phe Tyr Asn Ala Ser Leu Pro Glu Gly Thr Gln 580 585 590 Pro Gly Thr Cys Phe Leu Gln Val Thr Ala Thr Asp Ala Asp Ser Gly 595 600 605 Pro Phe Gly Leu Leu Ser Tyr Ser Leu Gly Ala Gly Leu Gly Ser Ser 610 615 620 Gly Ser Pro Pro Phe Arg Ile Asp Ala His Ser Gly Asp Val Cys Thr 625 630 635 640 Thr Arg Thr Leu Asp Arg Asp Gln Gly Pro Ser Ser Phe Asp Phe Thr 645 650 655 Val Thr Ala Val Asp Gly Gly Gly Leu Lys Ser Met Val Tyr Val Lys 660 665 670 Val Phe Leu Ser Asp Glu Asn Asp Asn Pro Pro Gln Phe Tyr Pro Arg 675 680 685 Glu Tyr Ala Ala Ser Ile Ser Ala Gln Ser Pro Pro Gly Thr Ala Val 690 695 700 Leu Arg Leu Arg Ala His Asp Pro Asp Gln Gly Ser His Gly Arg Leu 705 710 715 720 Ser Tyr His Ile Leu Ala Gly Asn Ser Pro Pro Leu Phe Thr Leu Asp 725 730 735 Glu Gln Ser Gly Leu Leu Thr Val Ala Trp Pro Leu Ala Arg Arg Ala 740 745 750 Asn Ser Val Val Gln Leu Glu Ile Gly Ala Glu Asp Gly Gly Gly Leu 755 760 765 Gln Ala Glu Pro Ser Ala Arg Val Asp Ile Ser Ile Val Pro Gly Thr 770 775 780 Pro Thr Pro Pro Ile Phe Glu Gln Leu Gln Tyr Val Phe Ser Val Pro 785 790 795 800 Glu Asp Val Ala Pro Gly Thr Ser Val Gly Ile Val Gln Ala His Asn 805 810 815 Pro Pro Gly Arg Leu Ala Pro Val Thr Leu Ser Leu Ser Gly Gly Asp 820 825 830 Pro Arg Gly Leu Phe Ser Leu Asp Ala Val Ser Gly Leu Leu Gln Thr 835 840 845 Leu Arg Pro Leu Asp Arg Glu Leu Leu Gly Pro Val Leu Glu Leu Glu 850 855 860 Val Arg Ala Gly Ser Gly Val Pro Pro Ala Phe Ala Val Ala Arg Val 865 870 875 880 Arg Val Leu Leu Asp Asp Val Asn Asp Asn Ser Pro Ala Phe Pro Ala 885 890 895 Pro Glu Asp Thr Val Leu Leu Pro Pro Asn Thr Ala Pro Gly Thr Pro 900 905 910 Ile Tyr Thr Leu Arg Ala Leu Asp Pro Asp Ser Gly Val Asn Ser Arg 915 920 925 Val Thr Phe Thr Leu Leu Ala Gly Gly Gly Gly Ala Phe Thr Val Asp 930 935 940 Pro Thr Thr Gly His Val Arg Leu Met Arg Pro Leu Gly Pro Ser Gly 945 950 955 960 Gly Pro Ala His Glu Leu Glu Leu Glu Ala Arg Asp Gly Gly Ser Pro 965 970 975 Pro Arg Thr Ser His Phe Arg Leu Arg Val Val Val Gln Asp Val Gly 980 985 990 Thr Arg Gly Leu Ala Pro Arg Phe Asn Ser Pro Thr Tyr Arg Val Asp 995 1000 1005 Leu Pro Ser Gly Thr Thr Ala Gly Thr Gln Val Leu Gln Val Gln 1010 1015 1020 Ala Gln Ala Pro Asp Gly Gly Pro Ile Thr Tyr His Leu Ala Ala 1025 1030 1035 Glu Gly Ala Ser Ser Pro Phe Gly Leu Glu Pro Gln Ser Gly Trp 1040 1045 1050 Leu Trp Val Arg Ala Ala Leu Asp Arg Glu Ala Gln Glu Leu Tyr 1055 1060 1065 Ile Leu Lys Val Met Ala Val Ser Gly Ser Lys Ala Glu Leu Gly 1070 1075 1080 Gln Gln Thr Gly Thr Ala Thr Val Arg Val Ser Ile Leu Asn Gln 1085 1090 1095 Asn Glu His Ser Pro Arg Leu Ser Glu Asp Pro Thr Phe Leu Ala 1100 1105 1110 Val Ala Glu Asn Gln Pro Pro Gly Thr Ser Val Gly Arg Val Phe 1115 1120 1125 Ala Thr Asp Arg Asp Ser Gly Pro Asn Gly Arg Leu Thr Tyr Ser 1130 1135 1140 Leu Gln Gln Leu Ser Glu Asp Ser Lys Ala Phe Arg Ile His Pro 1145 1150 1155 Gln Thr Gly Glu Val Thr Thr Leu Gln Thr Leu Asp Arg Glu Gln 1160 1165 1170 Gln Ser Ser Tyr Gln Leu Leu Val Gln Val Gln Asp Gly Gly Ser 1175 1180 1185 Pro Pro Arg Ser Thr Thr Gly Thr Val His Val Ala Val Leu Asp 1190 1195 1200 Leu Asn Asp Asn Ser Pro Thr Phe Leu Gln Ala Ser Gly Ala Ala 1205 1210 1215 Gly Gly Gly Leu Pro Ile Gln Val Pro Asp Arg Val Pro Pro Gly 1220 1225 1230 Thr Leu Val Thr Thr Leu Gln Ala Lys Asp Pro Asp Glu Gly Glu 1235 1240 1245 Asn Gly Thr Ile Leu Tyr Thr Leu Thr Gly Pro Gly Ser Glu Leu 1250 1255 1260 Phe Ser Leu His Pro His Ser Gly Glu Leu Leu Thr Ala Ala Pro 1265 1270 1275 Leu Ile Arg Ala Glu Arg Pro His Tyr Val Leu Thr Leu Ser Ala 1280 1285 1290 His Asp Gln Gly Ser Pro Pro Arg Ser Ala Ser Leu Gln Leu Leu 1295 1300 1305 Val Gln Val Leu Pro Ser Ala Arg Leu Ala Glu Pro Pro Pro Asp 1310 1315 1320 Leu Ala Glu Arg Asp Pro Ala Ala Pro Val Pro Val Val Leu Thr 1325 1330 1335 Val Thr Ala Ala Glu Gly Leu Arg Pro Gly Ser Leu Leu Gly Ser 1340 1345 1350 Val Ala Ala Pro Glu Pro Ala Gly Val Gly Ala Leu Thr Tyr Thr 1355 1360 1365 Leu Val Gly Gly Ala Asp Pro Glu Gly Thr Phe Ala Leu Asp Ala 1370 1375 1380 Ala Ser Gly Arg Leu Tyr Leu Ala Arg Pro Leu Asp Phe Glu Ala 1385 1390 1395 Gly Pro Pro Trp Arg Ala Leu Thr Val Arg Ala Glu Gly Pro Gly 1400 1405 1410 Gly Ala Gly Ala Arg Leu Leu Arg Val Gln Val Gln Val Gln Asp 1415 1420 1425 Glu Asn Glu His Ala Pro Ala Phe Ala Arg Asp Pro Leu Ala Leu 1430 1435 1440 Ala Leu Pro Glu Asn Pro Glu Pro Gly Ala Ala Leu Tyr Thr Phe 1445 1450 1455 Arg Ala Ser Asp Ala Asp Gly Pro Gly Pro Asn Ser Asp Val Arg 1460 1465 1470 Tyr Arg Leu Leu Arg Gln Glu Pro Pro Val Pro Ala Leu Arg Leu 1475 1480 1485 Asp Ala Arg Thr Gly Ala Leu Ser Ala Pro Arg Gly Leu Asp Arg 1490 1495 1500 Glu Thr Thr Pro Ala Leu Leu Leu Leu Val Glu Ala Thr Asp Arg 1505 1510 1515 Pro Ala Asn Ala Ser Arg Arg Arg Ala Ala Arg Val Ser Ala Arg 1520 1525 1530 Val Phe Val Thr Asp Glu Asn Asp Asn Ala Pro Val Phe Ala Ser 1535 1540 1545 Pro Ser Arg Val Arg Leu Pro Glu Asp Gln Pro Pro Gly Pro Ala 1550 1555 1560 Ala Leu His Val Val Ala Arg Asp Pro Asp Leu Gly Glu Ala Ala 1565 1570 1575 Arg Val Ser Tyr Arg Leu Ala Ser Gly Gly Asp Gly His Phe Arg 1580 1585 1590 Leu His Ser Ser Thr Gly Ala Leu Ser Val Val Arg Pro Leu Asp 1595 1600 1605 Arg Glu Gln Arg Ala Glu His Val Leu Thr Val Val Ala Ser Asp 1610 1615 1620 His Gly Ser Pro Pro Arg Ser Ala Thr Gln Val Leu Thr Val Ser 1625 1630 1635 Val Ala Asp Val Asn Asp Glu Ala Pro Thr Phe Gln Gln Gln Glu 1640 1645 1650 Tyr Ser Val Leu Leu Arg Glu Asn Asn Pro Pro Gly Thr Ser Leu 1655 1660 1665 Leu Thr Leu Arg Ala Thr Asp Pro Asp Val Gly Ala Asn Gly Gln 1670 1675 1680 Val Thr Tyr Gly Gly Val Ser Ser Glu Ser Phe Ser Leu Asp Pro 1685 1690 1695 Asp Thr Gly Val Leu Thr Thr Leu Arg Ala Leu Asp Arg Glu Glu 1700 1705 1710 Gln Glu Glu Ile Asn Leu Thr Val Tyr Ala Gln Asp Arg Gly Ser 1715 1720 1725 Pro Pro Gln Leu Thr His Val Thr Val Arg Val Ala Val Glu Asp 1730 1735 1740 Glu Asn Asp His Ala Pro Thr Phe Gly Ser Ala His Leu Ser Leu 1745 1750 1755 Glu Val Pro Glu Gly Gln Asp Pro Gln Thr Leu Thr Met Leu Arg 1760 1765 1770 Ala Ser Asp Pro Asp Val Gly Ala Asn Gly Gln Leu Gln Tyr Arg 1775 1780 1785 Ile Leu Asp Gly Asp Pro Ser Gly Ala Phe Val Leu Asp Leu Ala 1790 1795 1800 Ser Gly Glu Phe Gly Thr Met Arg Pro Leu Asp Arg Glu Val Glu 1805 1810 1815 Pro Ala Phe Gln Leu Arg Ile Glu Ala Arg Asp Gly Gly Gln Pro 1820 1825 1830 Ala Leu Ser Ala Thr Leu Leu Leu Thr Val Thr Val Leu Asp Ala 1835 1840 1845 Asn Asp His Ala Pro Ala Phe Pro Val Pro Ala Tyr Ser Val Glu 1850 1855 1860 Val Pro Glu Asp Val Pro Ala Gly Thr Leu Leu Leu Gln Leu Gln 1865 1870 1875 Ala His Asp Pro Asp Ala Gly Ala Asn Gly His Val Thr Tyr Tyr 1880 1885 1890 Leu Gly Ala Gly Thr Ala Gly Ala Phe Leu Leu Glu Pro Ser Ser 1895 1900 1905 Gly Glu Leu Arg Thr Ala Ala Ala Leu Asp Arg Glu Gln Cys Pro 1910 1915 1920 Ser Tyr Thr Phe Ser Val Ser Ala Val Asp Gly Ala Ala Ala Gly 1925 1930 1935 Pro Leu Ser Thr Thr Val Ser Val Thr Ile Thr Val Arg Asp Val 1940 1945 1950 Asn Asp His Ala Pro Thr Phe Pro Thr Ser Pro Leu Arg Leu Arg 1955 1960 1965 Leu Pro Arg Pro Gly Pro Ser Phe Ser Thr Pro Thr Leu Ala Leu 1970 1975 1980 Ala Thr Leu Arg Ala Glu Asp Arg Asp Ala Gly Ala Asn Ala Ser 1985 1990 1995 Ile Leu Tyr Arg Leu Ala Gly Thr Pro Pro Pro Gly Thr Thr Val 2000 2005 2010 Asp Ser Tyr Thr Gly Glu Ile Arg Val Ala Arg Ser Pro Val Ala 2015 2020 2025 Leu Gly Pro Arg Asp Arg Val Leu Phe Ile Val Ala Thr Asp Leu 2030 2035 2040 Gly Arg Pro Ala Arg Ser Ala Thr Gly Val Ile Ile Val Gly Leu 2045 2050 2055 Gln Gly Glu Ala Glu Arg Gly Pro Arg Phe Pro Arg Ala Ser Ser 2060 2065 2070 Glu Ala Thr Ile Arg Glu Asn Ala Pro Pro Gly Thr Pro Ile Val 2075 2080 2085 Ser Pro Arg Ala Val His Ala Gly Gly Thr Asn Gly Pro Ile Thr 2090 2095 2100 Tyr Ser Ile Leu Ser Gly Asn Glu Lys Gly Thr Phe Ser Ile Gln 2105 2110 2115 Pro Ser Thr Gly Ala Ile Thr Val Arg Ser Ala Glu Gly Leu Asp 2120 2125 2130 Phe Glu Val Ser Pro Arg Leu Arg Leu Val Leu Gln Ala Glu Ser 2135 2140 2145 Gly Gly Ala Phe Ala Phe Thr Val Leu Thr Leu Thr Leu Gln Asp 2150 2155 2160 Ala Asn Asp Asn Ala Pro Arg Phe Leu Arg Pro His Tyr Val Ala 2165 2170 2175 Phe Leu Pro Glu Ser Arg Pro Leu Glu Gly Pro Leu Leu Gln Val 2180 2185 2190 Glu Ala Asp Asp Leu Asp Gln Gly Ser Gly Gly Gln Ile Ser Tyr 2195 2200 2205 Ser Leu Ala Ala Ser Gln Pro Ala Arg Gly Leu Phe His Val Asp 2210 2215 2220 Pro Thr Thr Gly Thr Ile Thr Thr Thr Ala Ile Leu Asp Arg Glu 2225 2230 2235 Ile Trp Ala Glu Thr Arg Leu Val Leu Met Ala Thr Asp Arg Gly 2240 2245 2250 Ser Pro Ala Leu Val Gly Ser Ala Thr Leu Thr Val Met Val Ile 2255 2260 2265 Asp Thr Asn Asp Asn Arg Pro Thr Ile Pro Gln Pro Trp Glu Leu 2270 2275 2280 Arg Val Ser Glu Asp Ala Leu Leu Gly Ser Glu Ile Ala Gln Val 2285 2290 2295 Thr Gly Asn Asp Val Asp Ser Gly Pro Val Leu Trp Tyr Val Leu 2300 2305 2310 Ser Pro Ser Gly Pro Gln Asp Pro Phe Ser Val Gly Arg Tyr Gly 2315 2320 2325 Gly Arg Val Ser Leu Thr Gly Pro Leu Asp Phe Glu Gln Cys Asp 2330 2335 2340 Arg Tyr Gln Leu Gln Leu Leu Ala His Asp Gly Pro His Glu Gly 2345 2350 2355 Arg Ala Asn Leu Thr Val Leu Val Glu Asp Val Asn Asp Asn Ala 2360 2365 2370 Pro Ala Phe Ser Gln Ser Leu Tyr Gln Val Met Leu Leu Glu His 2375 2380 2385 Thr Pro Pro Gly Ser Ala Ile Leu Ser Val Ser Ala Thr Asp Arg 2390 2395 2400 Asp Ser Gly Ala Asn Gly His Ile Ser Tyr His Leu Ala Ser Pro 2405 2410 2415 Ala Asp Gly Phe Ser Val Asp Pro Asn Asn Gly Thr Leu Phe Thr 2420 2425 2430 Ile Val Gly Thr Val Ala Leu Gly His Asp Gly Ser Gly Ala Val 2435 2440 2445 Asp Val Val Leu Glu Ala Arg Asp His Gly Ala Pro Gly Arg Ala 2450 2455 2460 Ala Arg Ala Thr Val His Val Gln Leu Gln Asp Gln Asn Asp His 2465 2470 2475 Ala Pro Ser Phe Thr Leu Ser His Tyr Arg Val Ala Val Thr Glu 2480 2485 2490 Asp Leu Pro Pro Gly Ser Thr Leu Leu Thr Leu Glu Ala Thr Asp 2495 2500 2505 Ala Asp Gly Ser Arg Ser His Ala Ala Val Asp Tyr Ser Ile Ile 2510 2515 2520 Ser Gly Asn Trp Gly Arg Val Phe Gln Leu Glu Pro Arg Leu Ala 2525 2530 2535 Glu Ala Gly Glu Ser Ala Gly Pro Gly Pro Arg Ala Leu Gly Cys 2540 2545 2550 Leu Val Leu Leu Glu Pro Leu Asp Phe Glu Ser Leu Thr Gln Tyr 2555 2560 2565 Asn Leu Thr Val Ala Ala Ala Asp Arg Gly Gln Pro Pro Gln Ser 2570 2575 2580 Ser Val Val Pro Val Thr Val Thr Val Leu Asp Val Asn Asp Asn 2585 2590 2595 Pro Pro Val Phe Thr Arg Ala Ser Tyr Arg Val Thr Val Pro Glu 2600 2605 2610 Asp Thr Pro Val Gly Ala Glu Leu Leu His Val Glu Ala Ser Asp 2615 2620 2625 Ala Asp Pro Gly Pro His Gly Leu Val Arg Phe Thr Val Ser Ser 2630 2635 2640 Gly Asp Pro Ser Gly Leu Phe Glu Leu Asp Glu Ser Ser Gly Thr 2645 2650 2655 Leu Arg Leu Ala His Ala Leu Asp Cys Glu Thr Gln Ala Arg His 2660 2665 2670 Gln Leu Val Val Gln Ala Ala Asp Pro Ala Gly Ala His Phe Ala 2675 2680 2685 Leu Ala Pro Val Thr Ile Glu Val Gln Asp Val Asn Asp His Gly 2690 2695 2700 Pro Ala Phe Pro Leu Asn Leu Leu Ser Thr Ser Val Ala Glu Asn 2705 2710 2715 Gln Pro Pro Gly Thr Leu Val Thr Thr Leu His Ala Ile Asp Gly 2720 2725 2730 Asp Ala Gly Ala Phe Gly Arg Leu Arg Tyr Ser Leu Leu Glu Ala 2735 2740 2745 Gly Pro Gly Pro Glu Gly Arg Glu Ala Phe Ala Leu Asn Ser Ser 2750 2755 2760 Thr Gly Glu Leu Arg Ala Arg Val Pro Phe Asp Tyr Glu His Thr 2765 2770 2775 Glu Ser Phe Arg Leu Leu Val Gly Ala Ala Asp Ala Gly Asn Leu 2780 2785 2790 Ser Ala Ser Val Thr Val Ser Val Leu Val Thr Gly Glu Asp Glu 2795 2800 2805 Tyr Asp Pro Val Phe Leu Ala Pro Ala Phe His Phe Gln Val Pro 2810 2815 2820 Glu Gly Ala Arg Arg Gly His Ser Leu Gly His Val Gln Ala Thr 2825 2830 2835 Asp Glu Asp Gly Gly Ala Asp Gly Leu Val Leu Tyr Ser Leu Ala 2840 2845 2850 Thr Ser Ser Pro Tyr Phe Gly Ile Asn Gln Thr Thr Gly Ala Leu 2855 2860 2865 Tyr Leu Arg Val Asp Ser Arg Ala Pro Gly Ser Gly Thr Ala Thr 2870 2875 2880 Ser Gly Gly Gly Gly Arg Thr Arg Arg Glu Ala Pro Arg Glu Leu 2885 2890 2895 Arg Leu Glu Val Ile Ala Arg Gly Pro Leu Pro Gly Ser Arg Ser 2900 2905 2910 Ala Thr Val Pro Val Thr Val Asp Ile Thr His Thr Ala Leu Gly 2915 2920 2925 Leu Ala Pro Asp Leu Asn Leu Leu Leu Val Gly Ala Val Ala Ala 2930 2935 2940 Ser Leu Gly Val Val Val Val Leu Ala Leu Ala Ala Leu Val Leu 2945 2950 2955 Gly Leu Val Arg Ala Arg Ser Arg Lys Ala Glu Ala Ala Pro Gly 2960 2965 2970 Pro Met Ser Gln Ala Ala Pro Leu Ala Ser Asp Ser Leu Gln Lys 2975 2980 2985 Leu Gly Arg Glu Pro Pro Ser Pro Pro Pro Ser Glu His Leu Tyr 2990 2995 3000 His Gln Thr Leu Pro Ser Tyr Gly Gly Pro Gly Ala Gly Gly Pro 3005 3010 3015 Tyr Pro Arg Gly Gly Ser Leu Asp Pro Ser His Ser Ser Gly Arg 3020 3025 3030 Gly Ser Ala Glu Ala Ala Glu Asp Asp Glu Ile Arg Met Ile Asn 3035 3040 3045 Glu Phe Pro Arg Val Ala Ser Val Ala Ser Ser Leu Ala Ala Arg 3050 3055 3060 Gly Pro Asp Ser Gly Ile Gln Gln Asp Ala Asp Gly Leu Ser Asp 3065 3070 3075 Thr Ser Cys Glu Pro Pro Ala Pro Asp Thr Trp Tyr Lys Gly Arg 3080 3085 3090 Lys Ala Gly Leu Leu Leu Pro Gly Ala Gly Ala Thr Leu Tyr Arg 3095 3100 3105 Glu Glu Gly Pro Pro Ala Thr Ala Thr Ala Phe Leu Gly Gly Cys 3110 3115 3120 Gly Leu Ser Pro Ala Pro Thr Gly Asp Tyr Gly Phe Pro Ala Asp 3125 3130 3135 Gly Lys Pro Cys Val Ala Gly Ala Leu Thr Ala Ile Val Ala Gly 3140 3145 3150 Glu Glu Glu Leu Arg Gly Ser Tyr Asn Trp Asp Tyr Leu Leu Ser 3155 3160 3165 Trp Cys Pro Gln Phe Gln Pro Leu Ala Ser Val Phe Thr Glu Ile 3170 3175 3180 Ala Arg Leu Lys Asp Glu Ala Arg Pro Cys Pro Pro Ala Pro Arg 3185 3190 3195 Ile Asp Pro Pro Pro Leu Ile Thr Ala Val Ala His Pro Gly Ala 3200 3205 3210 Lys Ser Val Pro Pro Lys Pro Ala Asn Thr Ala Ala Ala Arg Ala 3215 3220 3225 Ile Phe Pro Pro Ala Ser His Arg Ser Pro Ile Ser His Glu Gly 3230 3235 3240 Ser Leu Ser Ser Ala Ala Met Ser Pro Ser Phe Ser Pro Ser Leu 3245 3250 3255 Ser Pro Leu Ala Ala Arg Ser Pro Val Val Ser Pro Phe Gly Val 3260 3265 3270 Ala Gln Gly Pro Ser Ala Ser Ala Leu Ser Ala Glu Ser Gly Leu 3275 3280 3285 Glu Pro Pro Asp Asp Thr Glu Leu His Ile 3290 3295

Claims

What is claimed is:

1. A method of identifying a candidate p53 pathway modulating agent, said method comprising the steps of:

(a) providing an assay system comprising a purified CAD polypeptide or nucleic acid or a functionally active fragment or derivative thereof;

(b) contacting the assay system with a test agent under conditions whereby, but for the presence of the test agent, the system provides a reference activity; and

(c) detecting a test agent-biased activity of the assay system, wherein a difference between the test agent-biased activity and the reference activity identifies the test agent as a candidate p53 pathway modulating agent.

2. The method of claim 1 wherein the assay system comprises cultured cells that express the CAD polypeptide.

3. The method of claim 2 wherein the cultured cells additionally have defective p53 function.

4. The method of claim 1 wherein the assay system includes a screening assay comprising a CAD polypeptide, and the candidate test agent is a small molecule modulator.

5. The method of claim 4 wherein the assay is an adhesion assay.

6. The method of claim 1 wherein the assay system is selected from the group consisting of an apoptosis assay system, a cell proliferation assay system, an angiogenesis assay system, and a hypoxic induction assay system.

7. The method of claim 1 wherein the assay system includes a binding assay comprising a CAD polypeptide and the candidate test agent is an antibody.

8. The method of claim 1 wherein the assay system includes an expression assay comprising a CAD nucleic acid and the candidate test agent is a nucleic acid modulator.

9. The method of claim 8 wherein the nucleic acid modulator is an antisense oligomer.

10. The method of claim 8 wherein the nucleic acid modulator is a PMO.

11. The method of claim 1 additionally comprising:

(d) administering the candidate p53 pathway modulating agent identified in (c) to a model system comprising cells defective in p53 function and, detecting a phenotypic change in the model system that indicates that the p53 function is restored.

12. The method of claim 11 wherein the model system is a mouse model with defective p53 function.

13. A method for modulating a p53 pathway of a cell comprising contacting a cell defective in p53 function with a candidate modulator that specifically binds to a CAD polypeptide comprising an amino acid sequence selected from group consisting of SEQ ID NOs:11, 12, 13, 14, 15, and 16, whereby p53 function is restored.

14. The method of claim 13 wherein the candidate modulator is administered to a vertebrate animal predetermined to have a disease or disorder resulting from a defect in p53 function.

15. The method of claim 13 wherein the candidate modulator is selected from the group consisting of an antibody and a small molecule.

16. The method of claim 1, comprising the additional steps of:

(d) providing a secondary assay system comprising cultured cells or a non-human animal expressing CAD,

(e) contacting the secondary assay system with the test agent of (b) or an agent derived therefrom under conditions whereby, but for the presence of the test agent or agent derived therefrom, the system provides a reference activity; and

(f) detecting an agent-biased activity of the second assay system, wherein a difference between the agent-biased activity and the reference activity of the second assay system confirms the test agent or agent derived therefrom as a candidate p53 pathway modulating agent, and wherein the second assay detects an agent-biased change in the p53 pathway.

17. The method of claim 16 wherein the secondary assay system comprises cultured cells.

18. The method of claim 16 wherein the secondary assay system comprises a non-human animal.

19. The method of claim 18 wherein the non-human animal mis-expresses a p53 pathway gene.

20. A method of modulating p53 pathway in a mammalian cell comprising contacting the cell with an agent that specifically binds a CAD polypeptide or nucleic acid.

21. The method of claim 20 wherein the agent is administered to a mammalian animal predetermined to have a pathology associated with the p53 pathway.

22. The method of claim 20 wherein the agent is a small molecule modulator, a nucleic acid modulator, or an antibody.

23. A method for diagnosing a disease in a patient comprising:

(a) obtaining a biological sample from the patient;

(b) contacting the sample with a probe for CAD expression;

(c) comparing results from step (b) with a control;

(d) determining whether step (c) indicates a likelihood of disease.

24. The method of claim 23 wherein said disease is cancer.

25. The method according to claim 24, wherein said cancer is a cancer as shown in Table 1 as having >25% expression level.