CA2351361A1 - Gtpase associated proteins - Google Patents

Abstract

The invention provides human GTPase associated proteins (GTPAP) and polynucleotides which identify and encode GTPAP. The invention also provides expression vectors, host cells, antibodies, agonist, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with expression of GTPAP.

Description

GTPASE ASSOCIATED PROTEINS
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of GTPase associated proteins and to the use of these sequences in the diagnosis, treatment, and prevention of cell proliferative, autoimmune/inflammatory, and immune system disorders.
BACKGROUND OF THE INVENTION
Guanine nucleotide binding proteins (GTP-binding proteins) participate in a wide range of regulatory functions in all eukaryotic cells, including metabolism, cellular growth, differentiation, signal transduction, cytoskeletal organization, and intracellular vesicle transport and secretion. In higher organisms they are involved in signaling that regulates such processes as the immune response (Aussel, C. et al {1988) J. Immunol. 140:215-220), apoptosis, differentiation, and cell proliferation including oncogenesis (Dhanasekaran, N. et al. (1998) Oncogene 17:1383-1394).
Exchange of bound GDP for GTP followed by hydrolysis of GTP to GDP provides the energy that enables GTP-binding proteins to alter their conformation and interact with other cellular components. The superfamily of GTP-binding proteins consists of several families and may be grouped as translational factors, heterotrimeric GTP-binding proteins involved in transmembrane signaling processes (also called G-proteins), and low molecular weight GTP-binding proteins including the proto-oncogene Ras proteins and products of rab, rap, rho, rac, smg2l, smg25, YPT, SEC4, and ARF genes, and tubulins (Kaziro, Y. et al. (1991) Ann. Rev. Biochem. 60:349-400). In all cases, the GTPase activity is regulated through interactions with other proteins.
GTP-binding proteins involved in protein biosynthesis include initiation factor 2 (IF-2), elongation factor 2 (EF-Tu), and elongation factor G (EF-G), observed in prokaryotes; and initiation factor 2 (eIF-2}, elongation factor Ia (EF-Ia) and elongation factor 2 (EF-2) observed in eukaryotes (Kaziro, supra). IF-2 promotes the GTP-dependent binding of the tRNA to the small subunit of the ribosome, the step that initiates protein translation. Similarly, elongation factors promote the binding of tRNA and GTP and the displacement of GDP after hydrolysis as protein biosynthesis proceeds.
Heterotrimeric GTP-binding proteins are composed of 3 subunits (a, ~i and y) which, in their inactive conformation, associate as a trimer at the inner face of the plasma membrane. G« binds GDP
or GTP and contains the GTPase activity. The (3y complex enhances binding of G« to a receptor.
Gy is necessary for the folding and activity of G~3. (Neer, E.J. et al. {1994) Nature 371:297-300.) Multiple homologs of each subunit have been identified in mammalian tissues, and different combinations of subunits have specific functions and tissue specificities.
(Spiegel, A.M. (1997) J.

Inher. Metab. Dis. 20:113-121.) G protein activity is triggered by seven-transmembrane cell surface receptors (G-protein coupled receptors) which respond to lipid analogs, amino acids and their derivatives, peptides, cytokines, and specialized stimuli such as light, taste, and odor. Activation of the receptor by its stimulus causes the replacement of the G protein-bound GDP
with GTP. G«-GTP
S dissociates from the receptor/(3y complex and each of these separated components can interact with and regulate downstream effectors. The signaling stops when G« hydrolyzes its bound GTP to GDP
and reassociates with the ~iy complex (Veer, supra).
The alpha subunits of heterotrimeric G proteins can be divided into four distinct classes. The a-s class is sensitive to ADP-ribosylation by pertussis toxin which uncouples the receptor:G-protein interaction. This uncoupling blocks signal transduction to receptors that decrease cAMP levels which normally regulate ion channels and activate phospholipases. The inhibitory a-I
class is also susceptible to modification by pertussis toxin which prevents a-I from lowering cAMP levels. Two novel classes of a subunits refractory to pertussis toxin modification are a-q, which activates phospholipase C, and a-12, which has sequence homology with the Drosophila gene concertina and 1S may contribute to the regulation afembryonic development (Simon, M.I.
(1991) Science 252:802-808).
The mammalian G~3 and Gy subunits, each about 340 amino acids long, share more than 80%
homology. The G~3 subunit (also called transducin) contains seven repeating units, each about 43 amino acids long. The activity of both subunits may be regulated by other proteins such as calmodulin and phosducin or the neural protein GAP 43 (D. Clapham and E. Neer, 1993, Nature 365:403-406). The (3 and y subunits are tightly associated. The ~3 subunit sequences are highly conserved between species, implying that they perform a fundamentally important role in the organization and function of G-protein linked systems (Van der Voorn L. (1992) Febs. Lett. 307 (2):131-134). They contain seven tandem repeats of the WD-repeat sequence motif, a motif found in 2S many proteins with regulatory functions. WD-repeat proteins contain from four to eight copies of a loosely conserved repeat of approximately 40 amino acids which participates in protein-protein interactions. Mutations and variant expression of ~i transducin proteins are linked with various disorders. Mutations in LIS 1. a subunit of the human platelet activating factor acetylhydrolase, cause Miller-Dieker lissencephaly. RACK1 binds activated protein kinase C, and RbAp48 binds retinoblastoma protein. CstF is required for polyadenylation of mammalian pre-mRNA in vitro and associates with subunits of cleavage-stimulating factor. Defects in the regulation of ~3-catenin contribute to the neoplastic transformation of human cells. The WD40 repeats of the human F-box protein (3TrCP mediate binding to (3-catenin, thus regulating the targeted degradation of (3-catenin by ubiquitin ligase (Veer, supra; Hart, M. et al (1999) Curr. Biol. 9:207-210).
The y subunit primary structures are more variable than those of the (3 subunits. They are often post-translationally modified by isoprenylation arid carboxyl-methylation of a cysteine residue four amino acids from the C-terminus; this appears to be necessary for the interaction of the ~i~y subunit with the membrane and with other GTP-binding proteins. The (iy subunit has been shown to modulate the activity of isoforms of adenylyl cyclase, phospholipase C, and some ion channels. It is involved in receptor phosphorylation via specific kinases, and has been implicated in the p21 ras-dependent activation of the MAP kinase cascade and the recognition of specific receptors by GTP-binding proteins. (Clapham and Neer, supra).
G-proteins interact with a variety of effectors including adenylyl cyclase (Clapham and Neer, su ra . The signaling pathway mediated by CAMP is mitogenic in hormone-dependent endocrine tissues such as adrenal cortex, thyroid, ovary, pituitary, and testes. Cancers in these tissues have been related to a mutationalIy activated form of a Gas known as the gsp (Gs protein) oncogene (Dhanasekaran, su ra . Another effector is phosducin, a retinal phosphoprotein, which forms a specific complex with retinal G~3 and Gy (G(3y) and modulates the ability of G~iy to interact with retinal G« (Clapham and Neer, su ra).
Irregularities in the GTP-binding protein signaling cascade may result in abnormal activation of leukocytes and lymphocytes, leading to the tissue damage and destruction seen in many inflammatory and autoimmune diseases such as rheumatoid arthritis, biliary cirrhosis, hemolytic anemia, lupus erythematosus, and thyroiditis. Abnormal cell proliferation, including cyclic AMP
stimulation of brain, thyroid, adrenal, and gonadal tissue proliferation is regulated by G proteins.
Mutations in G« subunits have been found in growth-hormone-secreting pituitary somatotroph tumors, hyperfunctioning thyroid adenomas, and ovarian and adrenal neoplasms (Meij, J.T.A. (1996) Mol. Cell. Biochem. 157:31-38; Aussel, supra).
LMW GTP-binding proteins are GTPases which regulate cell growth, cell cycle control, protein secretion, and intracellular vesicle interaction. They consist of single polypeptides which, like the alpha subunit of the heterotrimeric GTP-binding proteins, are able to bind to and hydrolyze GTP, thus cycling between an inactive and an active state. LMW GTP-binding proteins respond to extracellular signals from receptors and activating proteins by transducing mitogenic signals involved in various cell functions. The binding and hydrolysis of GTP regulates the response of LMW GTP-binding proteins and acts as an energy source during this process (Bokoch, G.
M. and Der, C. J.
(1993) FASEB J. 7:750-759).
At least sixty members of the LMW GTP-binding protein superfamily have been identified _ WO 00!31263 PCT/US99/28013 and are currently grouped into the ras, rho, arf, sari, ran, and rab subfamilies. Activated ras genes were initially found in human cancers, and subsequent studies conformed that ras function is critical in determining whether cells continue to grow or become differentiated. Rasl and Ras2 proteins stimulate adenylate cyclase (Kaziro, su ra), affecting a broad array of cellular processes. Stimulation of cell surface receptors activates Ras which, in turn, activates cytopiasmic kinases. These kinases translocate to the nucleus and activate key transcription factors that control gene expression and protein synthesis (Barbacid, M. (1987) Ann. Rev Biochem. 56:779-827, Treisman, R. {1994) Curr.
Opin.Genet. Dev. 4:96-98). Other members of the LMW GTP-binding protein superfamily have roles in signal transduction that vary with the function of the activated genes and the locations of the GTP-binding proteins that initiate the activity. Rho GTP-binding proteins control signal transduction pathways that link growth factor receptors to actin polymerization, which is necessary for normal cellular growth and division. The rab, arf, and sari families of proteins control the translocation of vesicles to and from membranes for protein processing, localization, and secretion. Vesicle- and target- specific identifiers (v-SNARES and t-SNAREs) bind to each other and dock the vesicle to the IS acceptor membrane. The budding process is regulated by the closely related ADP ribosylation factors (ARFs) and SAR proteins, while rab proteins allow assembly of SNARE complexes and may play a role in removal of defective complexes {J. Rothman and F. Wieland (1996) Science 272:227-234).
Ran GTP-binding proteins are located in the nucleus of cells and have a key role in nuclear protein import, the control of DNA synthesis; and cell-cycle progression (Hall, A.
(1990) Science 249:635-640; Barbacid, M. (1987) Ann. Rev Biochem. 56:779-827; Ktistakis, N. (1998) BioEssays 20:495-504; and Sasaki, T. and Takai, Y. (1998) Biochem. Biophys. Res. Commun.
245:641-645).
The cycling of LMW GTP-binding proteins between the GTP-bound active form and the GDP-bound inactive form is regulated by additional proteins. Guanosine nucleotide exchange factors (GEFs) increase the rate of nucleotide dissociation by several orders of magnitude, thus facilitating release of GDP and loading with GTP. The best characterized is the mammalian homologue of the Drosophila Son-of Sevenless protein. Certain Ras-family proteins are also regulated by guanine nucleotide dissociation inhibitors (GDIs), which inhibit GDP dissociation. The intrinsic rate of GTP
hydrolysis of the LMW GTP-binding proteins is typically very slow, but it can be stimulated by several orders of magnitude by GTPase-activating proteins (GAPS) (Geyer, M.
and Wittinghofer, A.
(1997) Curr. Opin. Struct. Biol. 7:786-792). Both GEF and GAP activity may be controlled in response to extracellular stimuli and modulated by accessory proteins such as RaIBP 1 and POB 1.
Mutant Ras-family proteins, which bind but can not hydrolyze GTP, are permanently activated, and cause cell proliferation or cancer, as do GEFs that inappropriately activate LMW GTP-binding proteins, such as the human oncogene NET1, a Rho-GEF (Drivas, G. T. et al.
(1990) Moi. Cell. Biol -WO 00131263 PCT/US99/2$013 10:1793-1798; Aiberts,.A. S. and Treisman, R. (1998) EMBO J. 14:4075-4085).
A novel group of GTP-binding proteins is the GTP1/OBG family, which are found in species' ranging from bacteria to yeast to humans. These proteins contain characteristic GTP- binding motifs and are similar to one another but do not show sequence homology to other GTP-binding proteins.
The exact functions of these proteins are as yet uncertain, but they have been shown to be important for regulation of cell differentiation and development (Okamoto, S. and Ochi, K. (1998). Mol.
Microbiol 30:107-119; Sazaka, T. et al. (1992) Biochem. Biophys. Res. Common.
189:363-370).
The discovery of new GTPase associated proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of cell proliferative, autoimmunelinflammatory, and immune system disorders.
SUMMARY OF THE INVENTION
The invention features substantially purif;ed polypeptides, GTPase associated proteins, referred to collectively as "GTPAP" and individually as "GTPAP-1," "GTPAP-2,"
"GTPAP-3,"
"GTPAP-4," "GTPAP-S," ''GTPAP-6," "GTPAP-7," "GTPAP-8," "GTPAP-9," "GTPAP-10,"
"GTPAP-11," "GTPAP-12," ''GTPAP-13," "GTPAP-14," "GTPAP-15," "GTPAP-16,"
"GTPAP-17,"
"GTPAP-18," "GTPAP-19," ''GTPAP-20," "GTPAP-21," "GTPAP-22," "GTPAP-23,"
"GTPAP-24,"
"GTPAP-25," "GTPAP-26," "GTPAP-27," "GTPAP-28," and "GTPAP-29." In one aspect, the invention provides a substantially purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: I-29 and fragments thereof. The invention also includes a polypeptide comprising an amino acid sequence that differs by one or more conservative amino acid substitutions from an amino acid sequence selected from the group consisting of SEQ ID NO:1-29.
The invention further provides a substantially purified variant having at least 90% amino acid identity to at least one of the amino acid sequences selected from the group consisting of SEQ ID
NO:1-29 and fragments thereof. The invention also provides an isolated and purified polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: I-29 and fragments thereof. The invention also includes an isolated and purified polynucleotide variant having at least 90% polynucleotide sequence identity to the polynucieotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-29 and fragments thereof.
Additionally, the invention provides an isolated and purified polynucleotide which hybridizes under stringent conditions to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-29 and fragments thereof. The invention also provides an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide encoding the polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1-29 and fragments thereof.
The invention also provides a method for detecting a polynucleotide in a sample containing nucleic acids, the method comprising the steps of: (a) hybridizing the complement of the polynucleotide sequence to at least one of the polynucleotides of the sample, thereby forming a hybridization complex; and {b) detecting the hybridization complex, wherein the presence of the hybridization complex correlates with the presence of a polynucleotide in the sample. In one aspect, the method further comprises amplifying the polynucleotide prior to hybridization.
The invention also provides an isolated and purified polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:30-58 and fragments thereof. The invention further provides an isolated and purified polynucleotide variant having at least 90% polynucleotide sequence identity to the polynucleotide sequence selected from the group consisting of SEQ ID N0:30-58 and fragments thereof. The invention also provides an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:30-58 and fragments thereof.
The invention further provides an expression vector containing at least a fragment of the polynucleotide encoding the poiypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:l-29. In another aspect, the expression vector is contained within a host cell.
The invention also provides a method for producing a polypeptide, the method comprising the steps of: {a) culturing the host cell containing an expression vector containing a polynucleotide of the invention under conditions suitable for the expression of the polypeptide; and (b) recovering the polypeptide from the host cell culture.
The invention also provides a pharmaceutical composition comprising a substantially purified polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO:I-29 and fragments thereof, in conjunction with a suitable pharmaceutical carrier.
The invention further includes a purified antibody which binds to a polypeptide selected from the group consisting of SEQ ID NO:1-29 and fragments thereof. The invention also provides a purified agonist and a purified antagonist to the polypeptide.
The invention also provides a method far treating or preventing a disorder associated with decreased expression or activity of GTPAP, the method comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition comprising a substantially WO 00/31x63 PCT/US99/28013 purified polypeptide having the amino acid sequence selected from the group consisting of SEQ ID
NO:I-29 and fragments thereof, in conjunction with a suitable pharmaceutical carrier.
The invention also provides a method for treating or preventing a disorder associated with increased expression or activity of GTPAP, the method comprising administering to a subject in need of such treatment an effective amount of an antagonist of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-29 and fragments thereof.
BRIEF DESCRIPTION OF THE TABLES
Table I shows polypeptide and nucleotide sequence identification numbers (SEQ
ID NOs), clone identification numbers (clone IDs), cDNA libraries, and cDNA fragments used to assemble full-length sequences encoding GTPAP.
Table 2 shows features of each polypeptide sequence, including potential motifs, homologous sequences, and methods, algorithms, and searchable databases used for analysis of GTPAP.
Table 3 shows selected fragments of each nucleic acid sequence; the tissue-specific expression patterns of each nucleic acid sequence as determined by northern analysis; diseases, disorders, or conditions associated with these tissues; and the vector into which each. cDNA was cloned.
Table 4 describes the tissues used to construct the cDNA libraries from which cDNA clones encoding GTPAP were isolated.
Table S shows the tools, programs, and algorithms used to analyze GTPAP, along with applicable descriptions, references, and threshold parameters.
DESCRIPTION OF THE INVENTION
Before the present proteins, nucleotide sequences, and methods are described, it is understood that this invention is not limited to the particular machines, materials and methods described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
It must be noted that as used herein and in the appended claims, the singular forms "a," "an,"
and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to ''a host cell" includes a plurality of such host cells, and a reference to "an antibody" is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.
Although any machines, materials, and methods similar or equivalent to those described herein can be used to practice or test the present invention, the preferred machines, materials and methods are now described. All publications mentioned herein are cited for the purpose of describing and disclosing the cell lines, protocols, reagents and vectors which are reported in the publications and which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
DEFINITIONS
"GTPAP" refers to the amino acid sequences of substantially purified GTPAP
obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, murine, equine, and human, and from any source, whether natural, synthetic, semi-synthetic, or recombinant.
The term "agonist" refers to a molecule which intensifies or mimics the biological activity of GTPAP. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of GTPAP either by directly interacting with GTPAP or by acting on components of the biological pathway in which GTPAP
participates.
An "allelic variant" is an alternative form of the gene encoding GTPAP.
Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. A gene may have none, one, or many allelic variants of its naturally occurring form. Common mutational changes which give rise to allelic variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides.
Each of these types of changes may occur alone, or in combination with the others, one or more times m a given sequence.
"Altered" nucleic acid sequences encoding GTPAP include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as GTPAP or a polypeptide with at least one functional characteristic of GTPAP. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding GTPAP, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence encoding GTPAP. The encoded protein may also be "altered," and may contain deletions, insertions, or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent GTPAP. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological .activity of GTPAP is retained. For example, negatively charged amino acids may include aspartic acid and glutamic acid, and positively charged -amino acids may include lysine and arginine. Amino acids with uncharged polar side chains having similar hydrophilicity values may include: asparagine and glutamine; and serine and threonine.
Amino acids with uncharged side chains having similar hydrophilicity values may include: leucine, isoleucine, and valine; glycine and alanine; and phenylalanine and tyrosine.
The terms "amino acid" and "amino acid sequence" refer to an oligopeptide, peptide, poiypeptide, or protein sequence, or a fragment of any of these, and to naturally occurring or synthetic molecules. Where "amino acid sequence" is recited to refer to an amino acid sequence of a naturally occurring protein molecule, "amino acid sequence" and like terms are not meant to limit the amino acid sequence to the complete native amino acid sequence associated with the recited protein molecule.
"Amplification" relates to the production of additional copies of a nucleic acid sequence.
Amplification is generally carried out using polymerase chain reaction {PCR) technologies well known in the art.
The term "antagonist'' refers to a molecule which inhibits or attenuates the biological activity of GTPAP. Antagonists may include proteins such as antibodies, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of CrTPAP either by directly interacting with GTPAP or by acting on components of the biological pathway in which GTPAP participates.
The term "antibody'' refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab; F{ab')=. and Fv fragments, which are capable of binding an epitopic determinant.
Antibodies that bind GTPAP polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired.
Commonly used carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (ICi.H). The coupled peptide is then used to immunize the animal.
The term "antigenic determinant" refers to that region of a molecule (i.e., an epitope) that makes contact with a particular antibody. When a protein or a fragment of a protein is used to immunize a host animal, numerous regions of the protein may induce the production of antibodies which bind specifically to antigenic determinants (particular regions or three-dimensional structures on the protein). An antigenic determinant may compete with the intact antigen (i.e., the immunogen used to elicit the immune response) for binding to an antibody.
The term "antisense" refers to any composition containing a nucleic acid sequence which is WO OOI312b3 PCT/EJS99/28013 complementary to the "sense" strand of a specific nucleic acid sequence.
Antisense molecules may be produced by any method including synthesis or transcription. Once introduced into a cell, the complementary nucleotides combine with natural sequences produced by the cell to form duplexes and to block either transcription or translation. The designation "negative"
or "minus" can refer to the antisense strand, and the designation "positive" or "plus" can refer to the sense strand.
The term "biologically active" refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, "immunologically active" refers to the capability of the natural, recombinant, or synthetic GTPAP, or of any oIigopeptide thereof, to induce a specifc immune response in appropriate animals or cells and to bind with specific antibodies.
The terms "complementary" and "complernentarity" refer to the natural binding of polynucleotides by base pairing. For example, the sequence "5' A-G-T 3"' bonds to the complementary sequence "3' T-C-A 5'." Complementarity between two single-stranded molecules may be "partial," such that only some of the nucleic acids bind, or it may be "complete," such that total complementarity exists between the single stranded molecules. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of the hybridization between the nucleic acid strands. This is of particular importance in amplification reactions, which depend upon binding beriveen nucleic acid strands, and in the design and use of peptide nucleic acid (PNA) molecules.
A "composition comprising a given polynucleotide sequence" and a "composition comprising a given amino acid sequence" refer broadly to any composition containing the given polynucleotide or amino acid sequence. The composition may comprise a dry formulation or an aqueous solution.
Compositions comprising polynucleotide sequences encoding GTPAP or fragments of GTPAP may be employed as hybridization probes. The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e.g., NaCI), detergents (e.g., sodium dodecyl sulfate; SDS), and other components {e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).
"Consensus sequence" refers to a nucleic acid sequence which has been resequenced to resolve uncalled bases, extended using the XL-PCR kit (Perkin-Elmer, Norwalk CT) in the 5' and/or the 3' direction, and resequenced, or which has been assembled from the overlapping sequences of one or more Incyte Clones and, in some cases, one or more public domain ESTs, using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (GCG, Madison WI). Some sequences have been both extended and assembled to produce the consensus sequence.
"Conservative amino acid substitutions" are those substitutions that, when made, least interfere with the properties of the original protein, i.e., the structure and especially the function of tie protein is conserved and not significantly changed by such substitutions. The table below shows amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative amino acid substitutions.
Original Residue Conservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, His Asp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly Ala His Asn, Arg, Gln, Glu Iie Leu, Val Leu Ile, Val Lys Arg, G(n, Glu Met Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Vat Trp Phe; Tyr Tyr His, Phe, Trp Vat Ile, Leu, Thr Conservative amino acid substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the site of the substitution, and/or (c) the bulk of the side chain.
A "deletion" refers to a change in the amino acid or nucleotide sequence that results in the absence of one or more amino acid residues or nucleotides.
The term "derivative"refers to the chemical modification of a polypeptide sequence, or a polynucleotide sequence. Chemical modifications of a polynucleotide sequence can include, for example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group.
A derivative polynucleotide encodes a polypeptide which retains at least one biological or immunological function of the natural molecule. A derivative polypeptide is one modified by glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the polypeptide from which it was derived.
A "fragment" is a unique portion of GTPAP or the polynucleotide encoding GTPAP
which is identical in sequence to but shorter in length than the parent sequence. A
fragment may comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue. For example, a fragment may comprise from 5 to 1000 contiguous nucleotides or amino acid residues. A fragment used as a probe, primer, antigen, therapeutic molecule. or for other purposes, may be at least 5, 10, I5, 20, 25, 30, 40, 50, 60, 7S, 100, 150, 250 or at least 500 contiguous nucleotides or amino acid residues in Length. Fragments may be preferentially selected from certain regions of a molecule. For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or 500 amino acids (or first 25% or 50% of a polypeptide) as shown in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing, tables, and figures, may be encompassed by the present embodiments.
A fragment of SEQ 1D N0:30-58 comprises a region of unique polynucleotide sequence that specifically identifies SEQ ID N0:30-58, for example, as distinct from any other sequence in the same genome. A fragment of SEQ ID N0:30-58 is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID
N0:30-58 from related polynucleotide sequences. The precise length of a fragment of SEQ ID N0:30-58 and the region of SEQ 1D N0:30-S8 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.
A fragment of SEQ ID NO:1-29 is encoded by a fragment of SEQ ID N0:30-58. A
fragment of SEQ ID NO:1-29 comprises a region of unique amino acid sequence that specifically identifies SEQ ID NO:1-29. For example, a fragment of SEQ ID NO:I-29 is useful as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO:1-29.
The precise length of a fragment of SEQ ID NO:1-29 and the region of SEQ ID NO:1-29 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.
The term "similarity" refers to a degree of complementarity. There rnay be partial similarity or complete similarity. The word "identity" may substitute for the word "similarity." A partially complementary sequence that at least partially inhibits an identical sequence from hybridizing to a target nucleic acid is referred to as "substantially similar." The inhibition of hybridization of the completely complementary sequence to the target sequence may be examined using a hybridization assay (Southern or northern blot, solution hybridization, and the like) under conditions of reduced stringency. A substantially similar sequence or hybridization probe will compete for and inhibit the binding of a completely similar (identical) sequence to the target sequence under conditions of reduced stringency. This is not to say that conditions of reduced stringency are such that non-specific binding is permitted, as reduced stringency conditions require that the binding of two sequences to one another be a specific (i.e.. a selective) interaction. The absence of non-specific binding may be tested by the use of a second target sequence which lacks even a partial degree of complementarity (e.g., less than about 30% similarity or identity). In the absence of non-specific binding, the ' substantially similar sequence or probe will not hybridize to the second non-complementary target sequence.
The phrases "percent identity" and "% identity," as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two poIynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.
Percent identity between polynucleotide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison WI}. CLUSTAL V is described in Higgins, D.G. and P.M. Sharp {1989) CABIOS 5:151-153 and in Higgins, D.G. et al. (1992) CABIOS
8:189-191. For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: Ktuple=2, gap penalty=5, window=4, and "diagonals saved"=4. The "weighted" residue weight table is selected as the default. Percent identity is reported by CLUSTAL V as the "percent similarity" between aligned polynucleotide sequence pairs.
Alternatively, a suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410), which is available from several sources, including the NCBI, Bethesda, MD, and on the Internet at http:/Iwww.ncbi.nlm.nih.gov/BLAST/. The BLAST software suite includes various sequence analysis programs including "biastn," that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called "BLAST 2 Sequences" that is used for direct pairwise comparison of two nucleotide sequences. "BLAST 2 Sequences" can be accessed and used interactively at http:l/www.ncbi.nlm.nih.govlgorf/bl2.html. The "BLAST 2 Sequences''' tool can be used for both blastn and blastp (discussed below). BLAST
programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such default parameters may be, for example:
Matrix: BLOSUM62 Reward for match: 1 Penalty for mismatch: -2 Open Gap: ~ arrd Extension Gap: 2 penalties Gap x drop-off ~ 0 WO 00/31263 ' PCT/US99/28013 Expect: ! 0 Word Size: l l Filter: on Percent identity may be measured over the length of an entire defined sequence, for example, as defned by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at feast 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures, or Sequence Listing, may be used to describe a i0 length over which percentage identity may be measured.
Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.
The phrases "percent identity" and "% identity," as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions.
Such conservative substitutions, explained in more detail above, generally preserve the hydrophobicity and acidity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide.
Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: Ktuple=1, gap penalty=3, window=5, and "diagonals saved"=5. The PAM250 matrix is selected as the default residue weight table. As with polynucleotide alignments, the percent identity is reported by CLUSTAL V as the "percent similarity" between aligned polypeptide sequence pairs.
Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two poiypeptide sequences, one may use the "BLAST 2 Sequences"
tool Version 2Ø9 (May-07-1999) with blastp set at default parameters. Such default parameters may be, for example:
Matrix: BL4SUM62 Open Gap: 11 and Extension Gap: 1 penalties Gap x drop-off: ~0 .
Expect: l0 Word Size: 3 Filter: on Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 1S, at least 20, at least 30, at least 40, at least S0, at least 70 or at least 1S0 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
"Human artiEcial chromosomes" (HACs) are linear microchromosomes which may contain DNA sequences of about 6 kb to 10 Mb in size, and which contain all of the elements required for stable mitotic chromosome segregation and maintenance.
The term "humanized antibody" refers to antibody molecules in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely 1S resembles a human antibody, and still retains its original binding ability.
"Hybridization" refers to the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of identity. Specific hybridization complexes form under permissive annealing conditions and remain hybridized after the ''washing" step(s). The washing steps) is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i.e., binding between pairs of nucleic acid strands that are not perfectly matched.
Permissive conditions for annealing of nucleic acid sequences are routinely determinable by one of ordinary skit! in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among 2S experiments to achieve the desired stringency, and therefore hybridization specificity. Permissive annealing conditions occur, for example, at 68°C in the presence of about b x SSC, about 1% (w/v) SDS, and about 100 pg/ml denatured salmon sperm DNA.
Generally, stringency of hybridization is expressed, in part, with reference to the temperature under which the wash step is carried out. Generally, such wash temperatures are selected to be about S°C to 20°C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The T,~ is the temperature (under defined ionic strength and pH) at which SO% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions far nucleic acid hybridization are well known and can be found in Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, 2°d ed., vol. 1-3, Cold Spring Harbor Press, Plainview N1';

specifically see volume.2, chapter 9.
High stringency conditions for hybridization between polynucleotides of the present invention include wash conditions of 68°C in the presence of about 0.2 x SSC and about 0.1% SDS, for 1 hour.
Alternatively, temperatures of about 65°C, 60°C, 55°C, or 42°C may be used. SSC concentration may be varied from about 0.1 to 2 x SSC, with SDS being present at about 0.1%.
Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, denatured salmon sperm DNA at about 100-200 pg/ml. Organic solvent, such as formamide at a concentration of about 35-50% vlv,~may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their encoded polypeptides.
The term "hybridization complex" refers to a complex formed between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary bases. A
hybridization complex may be formed in solution (e.g., C°t or R°t analysis) or formed between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed).
The words "insertion" and "addition" refer to changes in an amino acid or nucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively.
"Immune response" can refer to conditions associated with inflammation, trauma, immune disorders, or infectious or genetic disease, etc. These conditions can be characterized by expression of various factors, e.g., cytokines, chemokines, and other signaling molecules, which may affect cellular and systemic defense systems.
The term "microarray" refers to an arrangement of distinct polynucleotides on a substrate.
The terms "element" and "array element" in a microarray context, refer to hybridizable polynucleotides arranged on the surface of a substrate.
The term "modulate" refers to a change in the activity of GTPAP. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of GTPAP.
The phrases "nucleic acid" and "nucleic acid sequence" refer to a nucleotide, oligonucleotide, polynucleotide, or any fragment thereof. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like material. ' WO 00!31263 PCT/US99/28013 "Operably linked" refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.
"Peptide nucleic acid" (PNA} refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition.
PNAs preferentially bind complementary single stranded DNA or RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell.
"Probe" refers to nucleic acid sequences encoding GTPAP, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acid sequences. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule.
Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes.
"Primers" are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid sequence, e.g., by the poiymerase chain reaction (PCR).
Probes and primers as used in the present invention typically comprise at least I 5 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Probes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the tables, figures, and Sequence Listing, may be used.
Methods for preparing and using probes and primers are described in the references, for example Sambrook et al., 1989, Molecular Clonin~A Laboratory Manual, 2°d ed., vol. I-3, Cold Spring Harbor Press, Plainview NY; Ausubel et al.,1987, Current Protocols in Molecular Biolosv, Greene Publ. Assoc. & Wiley-Intersciences, New York NY; Innis et al., 1990, PCR Protocols. A
Guide to Methods and Applications, Academic Press, San Diego CA. PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.~. 1991, Whitehead Institute for Biomedical Research, Cambridge MA}.
Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR
primer pairs of up to 100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to -5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases.
Similar primer selection programs have incorporated additional features for expanded capabilities. For example, the PrimOU primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas TX) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead Institute/MIT
Center for Genome Research, Cambridge MA) allows the user to input a "mispriming library," in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful, in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs.) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.
A "recombinant nucleic acid" is a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence.
This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques such as those described in Sambrook, suQra. The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence. Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.
Alternatively, such recombinant nucleic acids may be part of a viral vector, e.g., based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.
The term "sample" is used in its broadest sense. A sample suspected of containing nucleic acids encoding GTPAP, or fragments thereof, or GTPAP itself, may comprise a bodily fluid; an extract from a cell. chromosome, organelle, or membrane isolated from a cell;
a cell; genornic DNA,-WO 00/312b3 PCT/US99128013 RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print;
etc.
The terms "specific binding" and "specifically binding" refer to that interaction between a protein or peptide and an agonist, an antibody, an antagonist, a small molecule, or any natural or synthetic binding composition. The interaction is dependent upon the presence of a particular structure of the protein, e.g., the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope "A," the presence of a polypeptide containing the epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A
and the antibody will reduce the amount of labeled A that binds to the antibody.
The term "substantial ly purified" refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least about 60% free, preferably about 75% free, and most preferably about 90% free from other components with which they are naturally associated.
A "substitution" refers to the replacement of one or more amino acids or nucleotides by different amino acids or nucleotides, respectively.
IS "Substrate" refers to any suitable rigid or semi-rigid support including membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles and capillaries. The substrate can have a variety of surface forms such as wells, trenches, pins, channels and pores, to which polynucleotides or polypeptides are bound.
"Transformation" describes a process by which exogenous DNA enters and changes a recipient cell. Transformation may occur under natural or artificial conditions according to various methods well known in the art, and may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method for transformation is selected based on the type of host cell being transformed and may include, but is not limited to, viral infection, electroporation, heat shock, lipofection, and particle bombardment. The term "transformed" cells includes stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as transiently transformed cells which express the inserted DNA or RNA for limited periods of time.
A "variant" of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 40% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least, 90%, at least 95% or at least 98% or greater sequence identity over a certain defined length. A variant may be described as, for example, an ''allelic" (as defined above), "splice," "species," or "polymorphic"
variant. A splice variant may WO 00!31263 PCT/US99I28013 have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule. Species variants are polynucleotide sequences that vary from one species to another. The resulting poiypeptides generally will have significant amino acid identity relative to each other. A polymorphic variant is a variation in the polynucieotide sequence of a particular gene between individuals of a given species. Polymorphic variants also may encompass "single nucleotide polymorphisms" (SNPs) in which the polynucleotide sequence varies by one nucleotide base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.
A "variant" of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at least 70%; at least 80%, at least 90%, at least 95%, or at least 98% or greater sequence identity over a certain defined length of one of the polypeptides.
THE INVENTION
The invention is based on the discovery of new human GTPase associated proteins (GTPAP), the polynucleotides encoding GTPAP, and the use of these compositions for the diagnosis, treatment, or prevention of cell proliferative, autoimmune/inflammatory, and immune system disorders.
Table 1 lists the Incyte clones used to assemble full length nucleotide sequences encoding GTPAP. Columns 1 and 2 show the sequence identification numbers (SEQ ID NOs) of the polypeptide and nucleotide sequences, respectively. Column 3 shows the clone IDs of the Incyte clones in which nucleic acids encoding each GTPAP were identified, and column 4 shows the cDNA
libraries from which these clones were isolated. Column 5 shows lncyte clones and their corresponding cDNA libraries. Clones for which cDNA libraries are not indicated were derived from pooled cDNA libraries. The Incyte clones in column 5 were used to assemble the consensus nucleotide sequence of each GTPAP and are useful as fragments in hybridization technologies.
The columns of Table 2 show various properties of each of the polypeptides of the invention:
column 1 references the SEQ ID NO; column 2 shows the number of amino acid residues in each polypeptide; column 3 shows potential phosphorylation sites; column 4 shows potential glycosylation sites; column 5 shows the amino acid residues comprising signature sequences and motifs; column 6 shows homologous sequences as identified by BLAST analysis; and column 7 shows analytical -WO 00/31263 PCT/US99/2$013 methods and in some cases, searchable databases to which the analytical methods were applied. The methods of column 7 were used to characterize each polypeptide through sequence homology and protein motifs.
The columns of Table 3 show the tissue-specificity and diseases, disorders, or conditions associated with nucleotide sequences encoding GTPAP. The first column of Table 3 lists the nucleotide SEQ ID NOs. Column 2 lists fragments of the nucleotide sequences of column 1. These fragments are useful, for example, in hybridization or amplification technologies to identify SEQ ID
N0:30-58 and to distinguish between SEQ ID N0:30-58 and related polynucleotide sequences. The polypeptides encoded by these fragments are useful, for example, as immunogenic peptides. Column 3 lists tissue categories which express GTPAP as a fraction of total tissues expressing GTPAP.
Column 4 lists diseases, disorders, or conditions associated with those tissues expressing GTPAP as a fraction of total tissues expressing GTPAP. Column 5 lists the vectors used to subclone each cDNA
library. Of particular note is the specific expression of SEQ ID N0:43 in only one library, a human testis tissue library; the specific expression of SEQ ID N0:49 in only 4 libraries, one of which is associated with cell proliferation and 3 of which are associated with inflammation; and the specific expression of SEQ ID N0:40 in only 5 libraries, 3 of which are associated with cell proliferation and one of which is associated with inflammation.
The columns of Table 4 show descriptions of the tissues used to construct the cDNA libraries from which cDNA clones encoding GTPAP were isolated. Column 1 references the nucleotide SEQ
ID NOs, column 2 shows the cDNA libraries from which these clones were isolated, and column 3 shows the tissue origins and other descriptive information relevant to the cDNA libraries in column 2.
The invention also encompasses GTPAP variants. A preferred GTPAP variant is one which has at least about 80%, or alternatively at least about 90%, or even at least about 95% amino acid sequence identity to the GTPAP amino acid sequence, and which contains at least one functional or structural characteristic of GTPAP.
The invention also encompasses polynucleotides which encode GTPAP. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID N0:30-58, which encodes GTPAP.
The invention also encompasses a variant of a polynucleotide sequence encoding GTPAP. In particular, such a variant polynucleotide sequence will have at least about 70%, or alternatively at least about 90%, or even at feast about 95% polynucleotide sequence identity to the polynucleotide sequence encoding GTPAP. A particular aspect of the invention encompasses a variant of a polynucteotide sequence comprising a sequence selected from the group consisting of SEQ ID
N0:30-58 which has at least about 70%, or alternatively at least about 90%, or even at least about ' 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID N0:30-58. Any one of the palynucleotide variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of GTPAP.
It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code, a multitude of polynucleotide sequences encoding GTPAP, some bearing minimal similarity to the polynucleotide sequences of any known and naturally occurring gene, may be produced. Thus, the invention contemplates each and every possible variation of polynucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the polynucleotide sequence of naturally occurring GTPAP, and all such variations are to be considered as being specifically disclosed.
Although nucleotide sequences which encode GTPAP and its variants are generally capable of hybridizing to the nucleotide sequence of the naturally occurring GTPAP
under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding GTPAP or its derivatives possessing a substantially different codon usage, e.g., inclusion of non-naturally occurring codons. Codons may be selected to increase the rate at which expression of the peptide occurs in a particular prokaryotic or eukaryotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding GTPAP and its derivatives without altering the encoded amino acid sequences include the production of RNA transcripts having more desirable properties, such as a greater half life, than transcripts produced from the naturally occurring sequence.
The invention also encompasses production of DNA sequences which encode GTPAP
and GTPAP derivatives, or fragments thereof, entirely by synthetic chemistry.
After production, the synthetic sequence may be inserted into any of the many available expression vectors and cell systems using reagents well known in the art. Moreover, synthetic chemistry may be used to introduce mutations into a sequence encoding GTPAP or any fragment thereof.
Also encompassed by the invention are polynucleotide sequences that are capable of hybridizing to the claimed polynucleotide sequences, and, in particular, to those shown in SEQ ID
N0:30-58 and fragments thereof under various conditions of stringency. (See, e.g., Wahl, G.M. and S.L. Berger (1987) Methods Enzymol. 152:399-407; Kimmel, A.R. (1987) Methods Enzymol.
152:507-511.) Hybridization conditions, including annealing and wash conditions; are described in "Definitions."
Methods for DNA sequencing are well known in the art and may be used to practice any of the embodiments of the invention. The methods may employ such enzymes as the Klenow fragment' of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase {Perkin-Elmer), thermostable T7 polymerase (Amersham Pharmacia Biotech, Piscataway NJ), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE
amplification system {Life Technologies, Gaithersburg MD). Preferably, sequence preparation is automated with machines such as the MICROLAB 2200 liquid transfer system (Hamilton, Reno NV), PTC200 thermal cycier (MJ Research, Watertown MA) and ABI CATALYST 800 thermal cycler (Perkin-Elmer). Sequencing is then carried out using either the ABI 373 or 377 DNA sequencing system (Perkin-Elmer), the MEGABACE 1000 DNA sequencing system (Molecular Dynamics, Sunnyvale CA), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art. (See, e.g., Ausubel, F.M. (1997) Short Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY, unit 7.7;
Meyers, R.A. (1995) Molecular BioloQ;y and Biotechnolo~y, Wiley VCH, New York NY, pp. 856-853.) The nucleic acid sequences encoding GTPAP may be extended utilizing a partial nucleotide sequence and employing various PCR-based methods known in the art to detect upstream sequences, such as promoters and regulatory elements. For example, one method which may be employed, restriction-site PCR, uses universal and nested primers to amplify unknown sequence from genomic DNA within a cloning vector. (See, e.g., Sarkar, G. (1993) PCR Methods Applic.
2:318-322.) Another method, inverse PCR, uses primers that extend in divergent directions to amplify unknown sequence from a circularized template. The template is derived from restriction fragments comprising a known genomic locus and surrounding sequences. (See, e.g., Triglia, T. et al. ( 1988) Nucleic Acids Res. 16:8186.) A third method, capture PCR, involves PCR amplification of DNA
fragments adjacent to known sequences in human and yeast artificial chromosome DNA. (See, e.g., Lagerstrom, M. et al.
(1991 ) PCR Methods Applic. 1:111-119.) 1n this method, multiple restriction enzyme digestions and ligations may be used to insert an engineered double-stranded sequence into a region of unknown sequence before performing PCR. Other methods which may be used to retrieve unknown sequences are known in the art. (See, e.g., Parker, J.D. et al. ( 1991 ) Nucleic Acids Res. 19:3055-3060).
Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries (Clontech, Palo Alto CA) to walk genomic DNA. This procedure avoids the need to screen libraries and is useful in finding intron/exon junctions. For all PCR-based methods, primers may be designed using commercially available software, such as OLIGO 4.06 Primer Analysis software (National Biosciences, Plymouth MN) or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the template at temperatures of about 68°C to 72°C.
When screening for full-length cDNAs, it is preferable to use libraries that have been ' size-selected to include larger cDNAs. In addition, random-primed libraries, which often include sequences containing the 5' regions of genes, are preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genvmic libraries may be useful for extension of sequence into 5' non-transcribed regulatory regions.
Capillary electrophoresis systems which are commercially available may be used to analyze the size or confirm the nucleotide sequence of sequencing or PCR products. In particular, capillary sequencing may employ flowable polymers for electrophoretic separation, four different nucleotide-specific, laser-stimulated fluorescent dyes, and a charge coupled device camera for detection of the emitted wavelengths. Output/light intensity may be converted tv electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Perkin-Eimer), and the entire process from loading of samples to computer analysis and electronic data display may be computer controlled.
Capillary electrophoresis is especially preferable for sequencing small DNA
fragments which may be present in limited amounts in a particular sample.
In another embodiment of the invention, polynucleotide sequences or fragments thereof which encode GTPAP may be cloned in recombinant DNA molecules that direct expression of GTPAP, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be produced and used to express GTPAP.
The nucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter GTPAP-encoding sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and/or expression of the gene product. DNA
shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oligonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.
In another embodiment, sequences encoding GTPAP may be synthesized, in whole or in part, using chemical methods well known in the art. (See, e.g., Caruthers, M.H. et al. ( 1980) Nucleic Acids Symp. Ser. 7:215-223; and Horn, T. et al. (1980) Nucleic Acids Symp. Ser.
7:225-232.) Alternatively, GTPAP itself or a fragment thereof may be synthesized using chemical methods. For example, peptide synthesis can be performed using various solid-phase techniques. (See, e.g., Roberge, J.Y. et al. (1995) Science 269:202-204.) Automated synthesis may be achieved using the ABI 431 A peptide synthesizer (Perkin-Elmer). Additionally, the amino acid sequence of GTPAP, or any part thereof, may be altered during direct synthesis andlor combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide.

The peptide may be substantially purified by preparative high performance liquid chromatography. (See, e.g., Chiez, R.M. and F.Z. Regnier {1990) Methods Enzymol. 182:392-421.) The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing.
(See, e.g., Creighton, T. {1984) Proteins. Structures and Molecular Properties, WH Freeman, New York NY.) In order to express a biologically active GTPAP, the nucleotide sequences encoding GTPAP
or derivatives thereof may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. These elements include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5' and 3' untranslated regions in the vector and in polynucleotide sequences encoding GTPAP. Such elements may vary in their strength and specificity. Specific initiation signals may also be used to achieve more efficient translation of sequences encoding GTPAP. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding GTPAP and its initiation codon and upstream regulatory sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed. However, in cases where only coding sequence, or a fragment thereof, is inserted, exogenous translational control signals including an in-frame ATG initiation codon should be provided by the vector. Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of enhancers appropriate for the particular host cell system used.
{See, e.g., Scharf, D. et al. (1994) Results Probl. Cell Differ. 20:125-162.) Methods which are well known to those skilled in the art may be used to construct expression vectors containing sequences encoding GTPAP and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. (See, e.g., Sambrook, J. et al. (1989) Molecular Clonin ,~A
Laboratory Manual, Cold Spring Harbor Press, Plainview NY, ch: 4, 8, and 16-17; Ausubel, F.M. et al. {1995) Current Protocols in Molecular Bioloey, John Wiley & Sons, New York NY, ch. 9, 13, and 16.) A variety of expression vector/host systems may be utilized to contain and express sequences encoding GTPAP. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors;
yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e.g., baculovirus);
plant cell systems transformed with viral expression vectors (e.g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g.. Ti or pBR322 plasmids); or animal cell systems. The invention is not limited by the host cell employed.
In bacterial systems. a number of cloning and expression vectors may be selected depending upon the use intended for polynucleotide sequences encoding GTPAP. For example; routine cloning, subcloning, and propagation of polynucleotide sequences encoding GTPAP can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla CA) or PSPORT1 plasmid (Life Technologies). Ligation of sequences encoding GTPAP into the vector's multiple cloning site disrupts the lacZ gene, allowing a colorimetric screening procedure for identification of transformed bacteria containing recombinant molecules. In addition, these vectors may be useful for in vitro transcription, dideoxy sequencing, single strand rescue with helper phage, and creation of nested deletions in the cloned sequence. (See, e.g., Van Heeke, G. and S.M.
Schuster (1989) J. Biol.
Chem. 264:5543-5509.) When large quantities of GTPAP are needed, e.g. for the production of antibodies, vectors which direct high level expression of GTPAP may be used.
For example, vectors containing the strong, inducible TS or T7 bacteriophage promoter may be used.
Yeast expression systems may be used for production of GTPAP. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH
promoters, may be used in the yeast Saccharomyces cerevisiae or Pichia pastoris. In addition, such vectors direct either the secretion or intracellular retention of expressed proteins and enable integration of foreign sequences into the host genome for stable propagation.
(See, e.g., Ausubel, 1995, su ra; Bitter, G.A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C.A. et al. (1994) Bio/Technology 12:181-184.) Plant systems may also be used for expression of GTPAP. Transcription of sequences encoding GTPAP may be driven viral promoters, e.g., the35S and 19S promoters of CaMV used alone or in combination with the omega leader sequence from TMV (Takamatsu, N.
{1987) EMBO J.
6:307-311). Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used. (See. e.g., Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Brogue, R. et al.
(1984} Science 224:838-843: and Winter, J. et al. {1991) Results Probl. Cell Differ. 17:85-105.) These constructs can be introduced into plant cells by direct DNA
transformation or pathogen-mediated transfection. (See, e.g., The McGraw Hill Yearbook of Science and TechnoloQy (1992) McGraw Hill, New York NY, pp. 191-196.) In mammalian cells. a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, sequences encoding GTPAP
may be ligated into an adenovirus transcriptionltranslation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential E I or E3 region of the viral genome may be used to obtain infective virus which expresses GTPAP in host cells. (See, e.g., Logan, J. and T. Shenk (1984) Proc.
Natl. Acad. Sci. USA 81:3655-3659.) In addition, transcription enhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells. SV40 or EBV-based vectors may also be used for high-level protein expression.
Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb to 10 Mb are constructed and delivered via conventional delivery methods {liposomes, polycationic amino polymers, or vesicles) for therapeutic purposes: (See, e.g., Harrington, J.J.
et al. ( 1997) Nat. Genet.
15:345-355.) For long term production of recombinant proteins in mammalian systems, stable expression of GTPAP in cell lines is preferred. For example, sequences encoding GTPAP can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells may be allowed to grow for about 1 to 2 days in enriched media before being switched to selective media. The purpose of the selectable marker is to confer resistance to a selective agent, and its presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be propagated using tissue culture techniques appropriate to the cell type.
Any number of selection systems may be used to recover transformed cell lines.
These include, but are not limited to, the herpes simplex virus thymidine kinase and adenine phosphoribosyltransferase genes, for use in tk and apr' cells, respectively.
(See, e.g., Wigler, M, et al. (1977) Cell I 1:223-232: Lowy, I. et al. (1980) Cel( 22:817-823.) Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dhfr confers resistance to methotrexate; neo confers resistance to the aminoglycosides neomycin and G-418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively. (See, e.g., Wigier, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14.) Additional selectable genes have been described, e.g., trpB and hisD, which alter cellular requirements for metabolites. (See, e.g., Hartman, S.C. and R.C. Mulligan (1988) Proc.
Natl. Acad. Sci. USA 85:8047-8051.) Visible markers, e.g., anthocyanins, green fluorescent proteins (GFP; Clontech), !3 glucuronidase and its substrate !3-glucuronide, or luciferase and its substrate luciferin may be used. These markers can be used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system.

(See, e.g., Rhodes, C.A. (1995) Methods Mol. Biol. 55:121-131.) Although the presence/absence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding GTPAP is inserted within a marker gene sequence, transformed cells containing sequences encoding GTPAP can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding GTPAP under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
In general, host cells that contain the nucleic acid sequence encoding GTPAP
and that express GTPAP may be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations, PCR
amplification, and protein bioassay or immunoassay techniques which include membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein sequences.
immunological methods for detecting and measuring the expression of GTPAP
using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include enzyme-linked immunosorbent assays (ELISAs}, radioimmunoassays (RIAs), and fluorescence activated cell sorting (FAGS}. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on GTPAP is preferred, but a competitive binding assay maybe employed. These and other assays are well known in the art. (See, e.g., Hampton, R. et al. (1990) Serolo ical Methods. a Laboratory Manual, APS
Press, St. Paul MN, Sect. IV; Coligan, J.E. et al. (1997) Current Protocols in Immunolo~y, Greene Pub. Associates and Wiley-Interscience, New York NY; and Pound, J.D. (199$) Immunochemical Protocols, Humana Press, Totowa NJ.) A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to poiynucleotides encoding GTPAP
include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.
Alternatively, the sequences encoding GTPAP, or any fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits, such as those provided by Amersham Pharmacia Biotech, Promega {Madison WI), and US Biochemical. Suitable reporter molecules or labels which may be used for WO 00131263 PCT/US99l28013 ease ofdetection include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the like.
Host cells transformed with nucleotide sequences encoding GTPAP may be cultured under conditions suitable for the expression and recovery of the protein from cell culture. The protein produced by a transformed cell may be secreted or retained intracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucIeotides which encode GTPAP may be designed to contain signal sequences which direct secretion of GTPAP through a prokaryotic or eukaryotic cell membrane.
In addition, a host cell strain may be chosen for its ability to modulate expression of the inserted sequences or to process the expressed protein in the desired fashion.
Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translational processing which cleaves a "prepro" or "pro" form of the protein may also be used to specify protein targeting, folding, and/or activity.
Different host cells which have specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type Culture Collection (ATCC, Manassas VA) and may be chosen to ensure the correct modification and processing of the foreign protein.
In another embodiment of the invention, natural, modified, or recombinant nucleic acid sequences encoding GTPAP may be ligated to a heterologous sequence resulting in translation of a fusion protein in any of the aforementioned host systems. For example, a chimeric GTPAP protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of GTPAP
activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable purification of their cognate fusion proteins on immobilized glutathione, maltose, phenylarsine oxide, calmodulin, and metal-chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA) enable immunoaffinity purification of fusion proteins using commercially available monoclonal and polyclonal antibodies that specifically recognize these epitope tags. A fusion protein may also be engineered to contain a proteolytic cleavage site located between the GTPAP encoding sequence and the heterologous protein sequence, so that GTPAP may be cleaved away from the heterologous moiety following purification.
Methods for fusion protein expression and purification are discussed in Ausubel (1995, supra, ch. 10).

A variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.
In a further embodiment of the invention, synthesis of radiolabeled GTPAP may be achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system (Promega}. These systems couple transcription and translation of protein-coding sequences operably associated with the T7, T3, or SP6 promoters. Translation takes place in the presence of a radiolabeled amino acid precursor, for example, 'SS-methionine.
Fragments of GTPAP may be produced not only by recombinant means, but also by direct peptide synthesis using solid-phase techniques. (See, e.g., Creighton, supra, pp. 55-60.) Protein synthesis may be performed by manual techniques or by automation. Automated synthesis may be achieved; for example, using the ABI 431A peptide synthesizer (Perkin-Elmer).
Various fragments of GTPAP may be synthesized separately and then combined to produce the full length molecule.
THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of GTPAP and GTPase associated proteins. In addition, the expression of GTPAP is closely associated with proliferating tissues associated with cancer and fetal development, inflamed tissues, and tissues invovled in the immune response. Therefore, GTPAP appears to play a role in cell proliferative, autoimmune/inflammatory, and immune system disorders. In the treatment of disorders associated with increased GTPAP expression or activity, it is desirable to decrease the expression or activity of GTPAP. In the treatment of disorders associated with decreased GTPAP
expression or activity, it is desirable to increase the expression or activity of GTPAP.
Therefore, in one embodiment, GTPAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of GTPAP. Examples of such disorders include, but are not limited to, a cell proliferative disorder, such as actinic keratosis, arteriosclerosis. atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin. spleen, testis, thymus, thyroid, and uterus; an autaimmune/inflammatory disorder, such as acquired immunodeficiency syndrome (AIDS}, Addison's disease, adult respiratory distress syndrome, allergies. ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED); bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjtigren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; and an immune system disorder, such as acquired immunodeficiency syndrome (AIDS); X-linked agammaglobinemia of Bruton, common variable immunodelzciency (CVI), DiGeorge's syndrome (thymic hypoplasia), thymic dysplasia, isolated IgA deficiency, severe combined immunodeficiency disease (SCID), IS immunodeficiency with thrombocytopenia and eczema (Wiskott-Aldrich syndrome), Chediak-Higashi syndrome, chronic granulomatous diseases, hereditary angioneurotic edema, and immunodeficiency associated with Cushing's disease, leukemias such as multiple myeloma, and lymphomas such as Hodgkin's disease.
In another embodiment, a vector capable of expressing GTPAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of GTPAP including, but not limited to, those described above.
In a further embodiment, a pharmaceutical composition comprising a substantially purified GTPAP in conjunction with a suitable pharmaceutical carrier may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of GTPAP including, but not limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of GTPAP
may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of GTPAP including, but not limited to; those listed above.
In a further embodiment, an antagonist of GTPAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of GTPAP.
Examples of such disorders include, but are not limited to, those cell proliferative, autoimmunelinflammatory, and immune system disorders described above. In one aspect, an antibody which specifically binds GTPAP may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express GTPAP.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding GTPAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of GTPAP including, but not limited to, those described above.
In other embodiments, any of the proteins, antagonists, antibodies, agonists, complementary sequences, or vectors of the invention may be administered in combination with other appropriate therapeutic agents. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
An antagonist of GTPAP may be produced using methods which are generally known in the art. In particular, purified GTPAP may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind GTPAP.
Antibodies to GTPAP may also be generated using methods that are well known in the art. .Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies (i.e., those which inhibit dimer formation) are generally preferred for therapeutic use.
For the production of antibodies, various hosts including goats, rabbits, rats, mice, humans, and others may be immunized by injection with GTPAP or with any fragment or oligopeptide thereof which has immunogenic properties. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, KLH, and dinitrophenol. Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Cor~rnebacterium parvum are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to GTPAP have an amino acid sequence consisting of at least about 5 amino acids, and generally will consist of at least about 10 amino acids. It is also preferable that these oligopeptides, peptides, or fragments are identical to a portion of the amino acid sequence of the natural protein and contain the entire amino acid sequence of a small, naturally occurring molecule. Short stretches of GTPAP
amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.
Monoclonal antibodies to GTPAP may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture.
These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique. (See, e.g., Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D.
et al. (1985) J.
Immunol. Methods 81:31-42; Cote, R.J. et al. (i983) Proc. Natl. Acad. Sci. USA
80:2026-2030; and Cole, S.P. et al. (1984) Mol. Cell Biol. 62:109-120.) In addition, techniques developed for the production of "chimeric antibodies,"
such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used. (See, e.g., Morrison, S.L. et al. (1984) Proc.
Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M.S. et al. (1984) Nature 312:604-608; and Takeda, S. et al. ( 1985) Nature 314:42-454.) Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce GTPAP-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries. (See, e.g., Burton, D.R. (1991) Proc. Natl. Acad. Sci. USA 88:10134-10137.) IS Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed in the literature. (See, e.g., Orlandi, R. et al. ( 1989) Proc.
Natl. Acad. Sci. USA
86:3833-3837; Winter, G. et al. (1991) Nature 349:293-299.) Antibody fragments which contain specific binding sites for GTPAP may also be generated.
For example, such fragments include, but are not limited to, F(ab'), fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F(ab')2 fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.
(See, e.g., Huse, W.D.
et al. (1989) Science 246:127-1281.) Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between GTPAP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering GTPAP epitopes is generally used, but a competitive binding assay may also be employed (Pound, supra).
Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for GTPAP.
Affinity is expressed as an association constant, Ka, .which is defined as the molar concentration of GTPAP-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions.
The Ka determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple GTPAP epitopes, represents the average affinity, or avidity, of the antibodies for GTPAP. The Ka determined for a preparation of monoclonal antibodies, which are monospeciflc for a particular GTPAP epitope, represents a true measure of affinity. High-affinity antibody preparations with Ka ranging from about 109 to 10'z L/mole are preferred for use in immunoassays in which the GTPAP-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with Ka ranging from about 106 to 10' Llmole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of GTPAP, preferably in active form, from the antibody (Catty, D. ( 1988) Antibodies, Volume I: A Practical Approach, IRL Press, Washington, DC; Liddell, J.E. and Cryer, A. (1991) A
Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a poIyclonal antibody preparation containing at least 1-2 mg specific antibodylml, preferably 5-10 mg specific antibodylml, is generally employed in procedures requiring precipitation of GTPAP-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available. {See, e.g., Catty, supra, and Coiigan et al. supra.) In another embodiment of the invention, the polynucleotides encoding GTPAP, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, the complement of the polynucleotide encoding GTPAP may be used in situations in which it would be desirable to block the transcription of the mRNA. In particular, cells may be transformed with sequences complementary to polynucleotides encoding GTPAP. Thus, complementary molecules or fragments may be used to modulate GTPAP activity, or to achieve regulation of gene function. Such technology is now well known in the art, and sense or antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding GTPAP.
Expression vectors derived from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of nucleotide sequences to the targeted organ, tissue, or cell population. Methods which are well known to those skilled in the art can be used to construct vectors to express nucleic acid sequences complementary to the polynucleotides encoding GTPAP. (See; e.g., Sambrook, supra; Ausubel, 1995, supra.) Genes encoding GTPAP can be turned off by transforming a cell or tissue with expression vectors which express high levels of a polynucleotide, or fragment thereof, encoding GTPAP. Such constructs may be used to introduce untranslatable sense or antisense sequences into a cell. .Even in the absence of integration into the DNA, such vectors may continue to transcribe RNA molecules until they are disabled by endogenous nucleases. Transient expression may last for a month or more with a non-replicating vector, and may last even longer if appropriate replication elements are part of the vector system.
As mentioned above, modifications of gene expression can be obtained by designing complementary sequences or antisense molecules (DNA, RNA, or PNA) to the control, 5', or regulatory regions of the gene encoding GTPAP. Oligonucleotides derived from the transcription initiation site, e.g., between about positions -10 and +10 from the start site, may be employed.
Similarly, inhibition can be achieved using triple helix base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules.
Recent therapeutic advances using triplex DNA have been described in the literature. (See, e:g., Gee, J.E. et al. (1994) in Huber, B.E. and B.I. Carr, Molecular and Immunolo. ig c Approaches, Futura Publishing, Mt. Kisco NY, pp. 163-177.) A complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.
Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
For example, engineered hammerhead motif ribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding GTPAP.
Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, including the following sequences; GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides, corresponding to the region ofthe target gene containing the cleavage site, may be evaluated for secondary structural features which may render the oligonucleotide inoperable.
The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.
Complementary ribonucleic acid molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of nucleic acid molecules.
These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis.
Alternativeiy, RNA molecules may be generated by in vitro and in vivo transcription of DNA
sequences encoding GTPAP. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6.
Alternatively, these cDNA
constructs that synthesize complementary RNA, constitutively or inducibly, can be introduced into cell lines, cells, or tissues.
RNA molecules may be modified to increase intracellular stability and half life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine which are novas easily recognized by endogenous endonucieases.
IS Many methods for introducing vectors into cells or tissues are available and equally suitable for use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient.
Delivery by transfection, by fiposome injections, or by polycationic amino polymers may be achieved using methods which are welt known in the art. (See, e.g., Goldrnan, C.K. et al. (1997) Nat.
Biotechno1.15:462-466.) Any of the therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as humans, dogs, cats, cows, horses, rabbits, and monkeys.
An additional embodiment of the invention relates to the administration of a pharmaceutical or sterile composition, in conjunction with a pharmaceutically acceptable carrier, for any of the therapeutic effects discussed above. Such pharmaceutical compositions may consist of GTPAP, antibodies to GTPAP, and mimetics, agonists, antagonists, or inhibitors of GTPAP. The compositions may be administered alone or in combination with at least one other agent, such as a stabilizing compound, which may be administered in any sterile, biocompatible pharmaceutical carrier including, but not limited to, saline, buffered saline, dextrose, and water. The compositions may be administered to a patient alone, or in combination with other agents, drugs, or hormones.
The pharmaceutical compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intro-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.
In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically-acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
Further details on techniques for formulation and administration may be found in the latest edition of Remin~t, on's Pharmaceutical Sciences {Maack Publishing, Euston PA).
Pharmaceutical compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration.
Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
Pharmaceutical preparations for oral use can be obtained through combining active compounds with solid excipient and processing the resultant mixture of granules {optionally, after grinding) to obtain tablets or dragee cores. Suitable auxiliaries can be added, if desired. Suitable excipients include carbohydrate or protein fillers, such as sugars, including lactose, sucrose, mannitol, and sorbitol; starch from corn. wheat, rice, potato, or other plants;
cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; gums, including arabic and tragacanth; and proteins, such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, and alginic acid or a salt thereof, such as sodium alginate.
Dragee cores may be used in conjunction with suitable coatings, such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments maybe added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, i.e., dosage.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating, such as glycerol or sorbitol.
Push-fit capsules can contain active ingredients mixed with fillers or binders, such as lactose or starches, lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid, or liquid polyethylene glycol with or without stabilizers:
Pharmaceutical formulations suitable for parenteral administration may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologica.liy buffered saline. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable Iipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides, or liposomes. Non-lipid polycationic amino polymers may also be used for delivery. Optionally, the suspension may also contain suitable stabilizers or agents to increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
For topical or nasal administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
The pharmaceutical compositions of the present invention may be manufactured in a manner that is known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
The pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, and succinic acids. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder which may contain any or all of the following: 1 mM to 50 mM histidine, 0.l% to 2% sucrose, and 2%
to 7% mannitol, at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of GTPAP, such labeling would include amount, frequency, and method of administration.
Pharmaceutical compositions suitable for use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models such as mice, rats, rabbits, dogs, or pigs.
An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
A therapeutically effective dose refers to that amount of active ingredient, for example GTPAP or fragments thereof, antibodies of GTPAP, and agonists, antagonists or inhibitors of GTPAP, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the EDS° (the dose therapeutically effective in 50%
of the population) or LDS° (the dose lethal to 50% of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LDS°/EDS°
ratio. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used to formulate a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that includes the EDS° with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.
The exact dosage will be determined by the practitioner, in light of factors related to the subject requiring treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, time and frequency of administration, drug combination(s), reaction sensitivities, and response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or biweekly depending on the half life and clearance rate of the particular formulation.
Normal dosage amounts may vary from about 0.1 ~cg to 100,000 ~cg, up to a total dose of about 1 gram, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.
DIAGNOSTICS
In another embodiment, antibodies which specifically bind GTPAP may be used for the diagnosis of disorders characterized by expression of GTPAP, or in assays to monitor patients being treated with GTPAP or agonists, antagonists, or inhibitors of GTPAP.
Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics.
Diagnostic assays for GTPAP include methods which utilize the antibody and a label to detect GTPAP in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and may be labeled by covalent or non-covalent attachment of a reporter molecule. A wide variety of reporter molecules, several of which are described above, are known in the art and may be used.

A variety of protocols for measuring GTPAP, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of GTPAP expression.
Normal or standard values for GTPAP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibody to GTPAP under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means.
Quantities of GTPAP
expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.
In another embodiment of the invention, the polynucleotides encoding GTPAP may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotide sequences, complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used to detect and quantify gene expression in biopsied tissues in which expression of GTPAP
may be correlated with disease. The diagnostic assay may be used to determine absence; presence, and excess expression of GTPAP, and to monitor regulation of GTPAP levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding GTPAP or closely related molecules may be used to identify nucleic acid sequences which encode GTPAP. The specificity of the probe, whether it is made from a highiy specific region, e.g., the 5' regulatory region, or from a less specific region, e.g., a conserved motif, and the stringency of the hybridization or amplification wil I determine whether the probe identifies only naturally occurring sequences encoding GTPAP, allelic variants, or related sequences.
Probes may also be used for the detection of related sequences, and may have at least 50%
sequence identity to any of the GTPAP encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID
N0:30-58 or from genomic sequences including promoters, enhancers, and introns of the GTPAP
gene.
Means for producing specific hybridization probes for DNAs encoding GTPAP
include the cloning of polynucleotide sequences encoding GTPAP or GTPAP derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA
polyrnerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as 3'-P or'SS, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.

Polynucieotide sequences encoding GTPAP may be used for the diagnosis of disorders associated with expression of GTPAP. Examples of such disorders include, but are not limited to, a cell proliferative disorder, such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofcbrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; an autoimmune/inflammatory disorder, such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED}, bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis. Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia. irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome. rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; and an immune system disorder, such as acquired immunodeficiency syndrome (AIDS), X-linked agammagiobinemia of Bruton. common variable immunodeficiency (CVI), DiGeorge's syndrome (thymic hypoplasia), thymic dysplasia, isolated IgA deficiency, severe combined immunodeficiency disease (SCID), immunodeficiency with thrornbocytopenia and eczema (Wiskott-Aldrich syndrome), Chediak-Higashi syndrome, chronic granulomatous diseases, hereditary angioneurotic edema, and immunodeficiency associated with Cushing's disease, leukemias such as multiple myeloma, and lymphomas such as Hodgkin's disease. The polynucleotide sequences encoding GTPAP may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR
technologies; in dipstick, pin. and multiforrnat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered GTPAP expression. Such qualitative or quantitative methods are well known in the art.

In a particular aspect, the nucleotide sequences encoding GTPAP may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding GTPAP may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample is washed and the signal is quantified and compared with a standard value. If the amount of signal in the patient sample is significantly altered in comparison to a control sample then the presence of altered levels of nucleotide sequences encoding GTPAP in the sample indicates the presence of the associated disorder. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or to t0 monitor the treatment of an individual patient.
In order to provide a basis for the diagnosis of a disorder associated with expression of GTPAP, a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding GTPAP, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained in this manner may be compared with values obtained from samples from patients who are symptomatic for a disorder.
Deviation from standard values is used to establish the presence of a disorder.
Once the presence of a disorder is established and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to determine if the level of expression in the patient begins to approximate that which is observed in the normal subject.
The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.
With respect to cancer, the presence of an abnormal amount of transcript (either under- or overexpressed) in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.
Additional diagnostic uses for oligonucleotides designed from the sequences encoding GTPAP may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically. or produced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding GTPAP, or a fragment of a polynucleotide complementary to the polynucleotide encoding GTPAP, and will be employed under optimized conditions for identification of a specific gene or condition. Oligomers may also be employed under less stringent conditions for detection or quantification of closely related DNA or RNA sequences.
Methods which may also be used to quantify the expression of GTPAP include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves. (See, e.g., Melby, P.C. et al. (1993) J. Immunol. Methods 159:235-244; Duplaa, C.
et al. (1993) Anal. Biochem. 212:229-236.) The speed of quantitation of multiple samples may be accelerated by running the assay in a high-throughput format where the oligomer of interest is presented in various dilutions and a spectrophotometric ar colorimetric response gives rapid quantitation.
In further embodiments, oligonucleotides or longer fragments derived from any of the polynucleotide sequences described herein may be used as targets in a microarray. The microarray can be used to monitor the expression level of large numbers of genes simultaneously and to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disorder, to diagnose a disorder, and to develop and monitor the activities of therapeutic agents.
Microarrays may be prepared, used, and analyzed using methods known in the art. (See, e.g., Brennan, T.M. et al. ( 199S) U.S. Patent No. 5,474,796; Schena, M. et al. {
1996) Proc. Natl. Acad. Sci.
USA 93:10614-10619; Ba(deschweiler et al. (1995) PCT application W09S/2S1116;
Shalon, D. et al.
(1995) PCT application W09S/3SSOS; Heller, R.A. et al. (1997) Proc. Natl.
Acad. Sci. USA 94:2150-21SS; and Heller, M.J. et al. (1997) U.S. Patent No. S,60S,662.) in another embodiment of the invention, nucleic acid sequences encoding GTPAP
may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence.
The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e.g., human artificial chromosomes (NACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial PI
constructions, or single chromosome cDNA libraries. (See, e.g., Harrington, J.J. et al. (1997) Nat.
Genet. 15:345-3SS; Price, C.M. (1993) Blood Rev. 7:127-134; and Trask, B.J. (1991) Trends Genet. 7:149-IS4.) Fluorescent in situ hybridization (FISH) may be correlated with other physical chromosome mapping techniques and genetic map data. (See, e.g., Heinz-Ulrich, et al.
(1995) in Meyers, supra, pp. 965-968.) Examples of genetic map data can be found in various scientific journals or at the Online Mendelian inheritance in Man (OMIM) World Wide Web site. Correlation between the WO OOI31263 PCT/US99l28013 location of the gene encoding GTPAP on a physical chromosomal map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA
associated with that disorder. The nucleotide sequences of the invention may be used to detect differences in gene sequences among normal, carrier, and affected individuals.
In situ hybridization of chromosomal preparations and physical mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending genetic maps.
Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the number or arm of a particular human chromosome is not known. New sequences can be assigned to chromosomal arms by physical mapping.
This provides valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the disease or syndrome has been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to I 1q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation. (See, e.g., Gatti, R.A. et al. (1988) Nature 336:577-580.) The nucleotide sequence of the subject invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., among normal, carrier, or affected individuals.
In another embodiment of the invention, GTPAP, its catalytic or immunogenic fragments, or oIigopeptides thereof can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such screening may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between GTPAP and the agent being tested may be measured.
Another technique for drug screening provides for high throughput screening of compounds having suitable binding affinity to the protein of interest. (See, e.g., Geysen, et al. (1984) PCT
application W084/03564.) In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with GTPAP, or fragments thereof, and washed. Bound GTPAP is then detected by methods well known in the art.
Purified GTPAP can also be coated directly onto plates for use in the aforementioned drug screening techniques.
Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.
In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding GTPAP specifically compete with a test compound for binding GTPAP. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with GTPAP.

WO 00/312b3 PCT/US99/28013 In additional embodiments, the nucleotide sequences which encode GTPAP may be used in any molecular biology techniques that have yet to be developed, provided the new techniques rely on properties of nucleotide sequences that are currently known, including, but not limited to, such properties as the triplet genetic code and specific base pair interactions.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as mereiy illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The disclosures of all patents, applications, and publications mentioned above and below, in particular U.S. Ser. Nos. 60/109,592, 60/I 18,610, and 60/127,990 are hereby expressly incorporated by reference.
EXAMPLES
I. Construction of cDNA Libraries RNA was purchased from Clontech or isolated from tissues described in Table 4.
Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL
(Life Technologies), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCI cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.
Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA
purity. In some cases, RNA was treated with DNase. For most libraries, poly(A+) RNA was isolated using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX latex particles (QIAGEN, Chatsworth CA}, or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively, RNA was isolated directly from tissue lysates using other RNA isolation kits, e.g., the POLY(A)PURE mRNA
purification kit (Ambion, Austin TX).
In some cases, Strataaene was provided with RNA and constructed the corresponding cDNA
libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP
vector system (Stratagene) or SUPERSCRIPT plasmid system (Life Technologies), using the recommended procedures or similar methods known in the art. (See, e.g., Ausubel, 1997, sutra, units 5.1-6.6.) Reverse transcription was initiated using oligo d{T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA
was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL S 1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Pharmacia Biotech) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORTI plasmid (Life Technologies), or pINCY (Incyte Pharmaceuticals, Palo Alto CA). Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XLl-BIueMRF, or SOLR from Stratagene or DHSa, DHIOB, or ElectroMAX DH 1 OB from Life Technologies.
II. Isolation of cDNA Clones Plasmids were recovered from host cells by in vivo excision using the UNIZAP
vector system (Stratagene) or by cell lysis. Plasmids were purified using at least one of the following: a Magic or WIZARD Minipreps DNA purification system (Promega); an AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg MD); and QIAWELL 8 Plasmid, QIAWELL 8 Plus Plasmid, QIAWELL 8 Uitra Plasmid purification systems or the R.E.A.L. PREP 96.plasmid purification kit from QIAGEN. Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without Iyophilization, at 4°C.
Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format (Rao, V.B. (1994) Anal. Biochem. 216:1-14). Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified pIasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Eugene OR) and a FLUOROSKAN II
fluorescence scanner (Labsystems Oy, Helsinki, Finland).
III. Sequencing and Analysis cDNA sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Perkin-Elmer) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser {Robbins Scientific) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions were prepared using reagents provided by Amersham Pharmacia Biotech or supplied in ABI sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Perkin-Elmer). Electrophoretic separation of cDNA sequencing reactions and detection of labeled WO 00131263 PCT/US991280t3 polynucleotides were carried out using the MEGABACE l 000 DNA sequencing system (Molecular Dynamics); the ABI PR1SM 373 or 377 sequencing system (Perkin-Elmer) in conjunction with standard ABI protocols and base calling software; or other sequence analysis systems known in the art. Reading frames within the cDNA sequences were identified using standard methods (reviewed in Ausubel, 1997, supra, unit 7.7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example V.
The polynucleotide sequences derived from cDNA sequencing were assembled and analyzed using a combination of software programs which utilize algorithms well known to those skilled in the art. Table 5 summarizes the tools, programs, and algorithms used and provides applicable descriptions, references, and threshold parameters. The first column of Table 5 shows the tools, programs, and algorithms used, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score, the greater the homology between two sequences). Sequences were analyzed using MACDNASIS PRO
software (Hitachi Software Engineering, South San Francisco CA) and LASERGENE
software (DNASTAR). Polynucleotide and polypeptide sequence alignments were generated using the default parameters specified by the clustal algorithm as incorporated into the MEGALIGN multisequence alignment program (DNASTAR), which also calculates the percent identity between aligned sequences.
The polynucleotide sequences were validated by removing vector, linker, and polyA
sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programing, and dinucleotide nearest neighbor analysis. The sequences were then queried against a selection of public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS, DOMO, PRODOM, and PFAM to acquire annotation using programs based on BLAST, FASTA, and BLIMPS. The sequences were assembled into full length polynucleotide sequences using programs based on Phred, Phrap, and Consed, and were screened for open reading frames using programs based on GeneMark, BLAST, and FASTA.
The full length polynucleotide sequences were translated to derive the corresponding full length amino acid sequences, and these full length sequences were subsequently analyzed by querying against databases such as the GenBank databases (described above}, SwissProt, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, and Hidden Markov Model (HMM)-based protein family databases such as PFAM. HMM is a probabilistic approach which analyzes consensus primary structures of gene families. (See, e.g., Eddy, S.R. (1996) Curr. Opin. Struct. Biol. 6:361-365.) The programs described above for the assembly and analysis of full length poiynucleotide and amino acid sequences were also used to identify polynucleotide sequence fragments from SEQ
ID N0:30-58. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies were described in The Invention section above.
IV. Northern Analysis Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound. (See, e.g., Sambrook, s" unra, ch. 7; Ausubel, 1995, su ra, ch. 4 and 16.) Analogous computer techniques applying BLAST were used to search for identical or related molecules in nucleotide databases such as Genl3ank or LIFESEQ (Incyte Pharmaceuticals). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as IS exact or similar. The basis ofthe search is the product score, which is defined as:
sequence identity % maximum BLAST score The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. For example, with a product score of 40, the match will be exact within a 1% to 2% error, and. with a product score of 70, the match will be exact. Similar molecules are usually identified by selecting those which show product scores between 15 and 40, although lower scores may identify related molecules.
The results of northern analyses are reported as a percentage distribution of libraries in which the transcript encoding GTPAP occurred. Analysis involved the categorization of cDNA libraries by organ/tissue and disease. The organltissue categories included cardiovascular, dermatologic, developmental, endocrine, gastrointestinal, hematopoietic/immune, musculoskeietal, nervous, reproductive, and urologic. The disease/condition categories included cancer, inflammation, trauma, cell proliferation, neurological. and pooled. For each category, the number of libraries expressing the sequence of interest was counted and divided by the total number of libraries across all categories.
Percentage values of tissue-specific and disease- or condition-specific expression are reported in Table 3.
V. Extension of GTPAP Encoding Polynucleotides The full length nucleic acid sequences of SEQ ID N0:30-58 were produced by extension of an appropriate fragment of the full length molecule using oligonucleotide primers designed from this fragment. One primer was synthesized to initiate 5' extension of the known fragment, and the other primer, to initiate 3' extension of the known fragment. The initial primers were designed using OLIGO 4.06 software {National Biosciences), or another appropriate program, to be about 22 to 30 S nucleotides in length, to have a GC content of about S0% or more, and to anneal to the target sequence at temperatures of about 68°C to about 72°C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.
Selected human cDNA libraries were used to extend the sequence. If more than one extension was necessary or desired, additional or nested sets of primers were designed.
High fidelity amplification was obtained by PCR using methods well known in the art. PCR
was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc.}. The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing Mg'-+, (NHQ)zS04, and j3-mercaptoethanol, Taq DNA polymerase (Amersham Pharmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerase {Stratagene), with the following parameters for primer 1S pair PCI A and PCI B: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 60°C, 1 min; Step 4: 68°C, 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68°C, S
min; Step 7: storage at 4°C. In the alternative, the parameters for primer pair T7 and SK+ were as follows: Step 1: 94°C, 3 min; Step 2:
94°C, 15 sec; Step 3: S7°C, 1 min; Step 4: 68°C, 2 min;
Step 5: Steps 2, 3, and 4 repeated 20 times;
Step 6: 68°C, 5 min; Step 7: storage at 4°C.
The concentration of DNA in each well was determined by dispensing 100 pl PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1X TE
and 0.5 pl of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan II
(Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A S ul to 10 ~cl aliquot of the reaction mixture was analyzed by electrophoresis on a 1 % agarose mini-gel to determine which reactions were successful in extending the sequence.
The extended nucleotides were desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease {Molecular Biology Research, Madison WI), and sonicated or sheared prior to religation into pUC 18 vector (Amersham Pharmacia Biotech). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE
(Promega). Extended clones were religated using T4 ligase (New England Biolabs, Beverly MA) into pUC 18 vector {Amersham Pharmacia Biotech), treated with Pfu DNA polymerise (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, individual colonies were picked and cultured overnight at 37°C in 384 well plates in LB/2x cart liquid media.
The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerise (Amersham Pharmacia Biotech) and Pfu DNA polymerise (Stratagene) with the following parameters: Step 1: 94°C, 3 min; Step 2: 94°C, 1S sec; Step 3:
60°C, 1 min; Step 4: 72°C, 2 min;
Step S: steps 2, 3, and 4 repeated 29 times; Step 6: 72°C, 5 min; Step 7: storage at 4°G. DNA was quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA
recoveries were reamplified using the same conditions as described above.
Samples were diluted with 20% dimethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Pharmacia Biotech) or the ABI
PRISM
BIGDYE Terminator cycle sequencing ready reaction kit (Perkin-Elmer).
In like manner, the nucleotide sequences of SEQ ID N0:30-S8 are used to obtain S' regulatory sequences using the procedure above, oligonucleotides designed for such extension, and an appropriate genomic library.
VI. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID N0:30-S8 are employed to screen cDNAs, genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting of about 20 base pairs, is specifically described, essentially the same procedure is used with larger nucleotide fragments. Otigonucleotides are designed using state-of the-art software such as OLIGO 4.06 software (National Biosciences) and labeled by combining SO pmol of each oligomer, 250 ~Ci of [y-32P] adenosine triphosphate (Amersham Pharmacia Biotech), and T4 polynucleotide kinase (DuPont NEN, Boston MA). The labeled oligonucleotides are substantially purified using a SEPHADEX G-2S superfine size exclusion dextrin bead column (Amersham Pharmacia Biotech).
An aliquot containing 10' counts per minute of the labeled probe is used in a typical membrane-based hybridization analysis of human genomic DNA digested with one of the following endonucleases:
Ase I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).
The DNA from each digest is fractionated on a 0.7% agarose gel and transferred to nylon membranes (Nytran Pius, Schleicher & Schuell, Durham NH). Hybridization is carried out for 16 hours at 40°C. To remove nonspecific signals, blots are sequentially washed at room temperature under conditions of up to, for example, 0.1 x saline sodium citrate and O.S%
sodium dodecyl sulfate.
Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.
VII. Microarrays A chemical coupling procedure and an ink jet device can be used to synthesize array elements on the surface of a substrate. (See, e.g., Baldeschweiler, supra.) An array analogous to a dot or slot blot may also be used to arrange and link elements to the surface of a substrate using thermal, UV, chemical, or mechanical bonding procedures. A typical array may be produced by hand or using available methods and machines and contain any appropriate number of elements. After hybridization, nanhybridized probes are removed and a scanner used to determine the levels and patterns of fluorescence. The degree of complementarity and the relative abundance of each probe which hybridizes to an element on the microarray may be assessed through analysis of the scanned images.
Full-length cDNAs, Expressed Sequence Tags (ESTs), or fragments thereof may comprise the elements of the microarray. Fragments suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). Full-length cDNAs, ESTs, or I S fragments thereof corresponding to one of the nucleotide sequences of the present invention, or selected at random from a cDNA library relevant to the present invention, are arranged on an appropriate substrate, e.g., a glass slide. The cDNA is fixed to the slide using, e.g., UV cross-linking followed by thermal and chemical treatments and subsequent drying. (See, e.g., Schena, M. et al.
(1995) Science 270:467-470; Shalom D. et al. (1996) Genome Res. 6:639-b45.) Fluorescent probes are prepared and used for hybridization to the elements on the substrate. The substrate is analyzed by procedures described above.
VIII. Complementary Polynucieotides Sequences complementary to the GTPAP-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring GTPAP.
Although use of oligonucleotides comprising from about 15 to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments. Appropriate oligonucleotides are designed using OLIGO 4.06 software (National Biosciences) and the coding sequence of GTPAP. To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5' sequence and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding to the GTPAP-encoding transcript.
IX. Expression of GTPAP
Expression and purification of GTPAP is achieved using bacterial or virus-based expression WO 00131263 PCT/lJS99J28013 systems. For expression of GTPAP in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA
transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the TS or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21 (DE3).
Antibiotic resistant bacteria express GTPAP upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of GTPAP in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Auto~raphica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding GTPAP by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Snodoptera fru iperda (Sf~9) insect cells in most cases, or human hepatocytes, in some cases.
Infection of the latter requires additional genetic modifications to baculovirus. (See Engelhard, E.K.
et al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al.
(1996} Hum. Gene Ther.
7:1937-1945.) In most expression systems, GTPAP is synthesized as a fusion protein with, e.g., giutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysates. GST, a 26-kilodalton enzyme from Schistosoma japonicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Pharmacia Biotech). Following purification, the GST moiety can be proteolytically cleaved from GTPAP at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG
antibodies (Eastman Kodak). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN). Methods for protein expression and purification are discussed in Ausubel (1995, supra, ch. 10 and 16). Purified GTPAP obtained by these methods can be used directly in the following activity assay.
X. Demonstration of GTPAP Activity The role of GTPAP can be assayed in vitro by monitoring the mobilization of Ca++ as part of the signal transduction pathway. (See, e.g., Grynkievicz, G. et al. (1985) J.
Biol. Chem. 260:3440;
McColl, S. et al. (1993) J. Immunol. 150:4550-4555; and Aussel, C. et al.
(1988) J. Immunol. 140-215.) The assay requires preloading neutrophils or T cells with a fluorescent dye such as FURA-2.

Upon binding Ca++, FURA-2 exhibits an absorption shift that can be observed by scanning the excitation spectrum between 300 and 400 nm, while monitoring the emission at 510 nm. When the cells are exposed to one or more activating stimuli artificially (i.e., anti-CD3 antibody ligation of the T cell receptor) or physiologically (i.e., by allogeneic stimulation), Ca+t flux takes place. Ca~ flux results from the release of Ca'Tfrom intracellular organelles or from Ca++
entry into the cell through activated Ca'~ channels. This flux can be observed and quantified by assaying the cells in a fluorometer or fluorescence activated cell sorter. Measurements of Ca++ flux are compared between cells in their normal state and those preloaded with GTPAP. Increased mobilization attributable to increased GTPAP availability results in increased emission.
Alternatively, GTPAP activity is measured by quantifying the amount of a non-hydrolyzable GTP analogue, GTPyS, bound over a 10 minute incubation period. Varying amounts of GTPAP are incubated at 30°C in 50mM Tris buffer, pH 7.5, containing 1mM
dithiothreitol, 1mM EDTA and IuM
['SS]GTPyS. Samples are passed through nitrocellulose filters and washed twice with a buffer consisting of 50mM Tris-HCI, pH 7.8, 1mM NaN3, IOmM MgCI,, 1mM EDTA, 0.5mM
dithiothreitol, O.OImM PMSF, and 200mM NaCI. The filter-bound counts are measured by liquid scintillation to quantify the amount of bound ['SS]GTP~yS. GTPAP activity may also be measured as the amount of GTP hydrolysed over a 10 minute incubation period at 37°C. GTPAP is incubated in 50mM Tris-HCI buffer, pH 7.8, containing 1mM dithiothreitol, 2mM EDTA, lO,uM
[a-32P]GTP, and l,uM H-rab protein. GTPase activity is initiated by adding MgCI, to a finaE
concentration of 10 mM.
Samples are removed at various time points, mixed with an equal volume of ice-cold 0.5mM EDTA, and frozen. Aliquots are spotted onto polyethyleneimine-cellulose thin layer chromatography plates, which are developed in 1 M LiCI, dried, and autoradiographed. The signal detected is proportional to GTPAP activity.
Alternatively, GTPAP activity may be demonstrated as the ability to interact with its associated Ga or LMW GTPase in an in vitro binding assay. The candidate GTPases are expressed as fusion proteins with glutathione S-transferase (GST), and purified by affinity chromatography on glutathione-Sepharose. The GTPases are loaded with GDP by incubating 20 mM
Tris buffer, pH 8.0, containing 100 mM NaCI, 2 mM EDTA, 5 mM MgCl2, 0.2 mM DTT, 100 pM AMP-PNP and 10 ~tM
GDP at 30°C for 20 minutes. GTPAP is expressed as a FLAG fusion proteins in a baculovirus system:
Extracts of these baculovirus cells containing GTPAP-FLAG fusion proteins are precleared with GST
beads, then incubated with GST-GTPase fusion proteins. The complexes formed are precipitated by glutathione-Sepharose and separated by SDS-polyacrylamide gel electrophoresis.
The separated proteins are blotted onto nitrocellulose membranes and probed with commercially available anti- -FLAG antibodies. GTPAP activity is proportional to the amount of GTPAP-FLAG
fusion protein detected in the complex.
XI. Functional Assays GTPAP function is assessed by expressing the sequences encoding GTPAP at S physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA
expression. Vectors of choice include pCMV SPORT (Life Technologies) and pCR3.l (Invitrogen, Carlsbad CA), both of which contain the cytomegalovirus promoter. 5-10 ~g of recombinant vector are transiently transfected into a human cell line, for example, an endothelial or hematopoietic cell line, using either liposome formulations or electroporation. 1-2 ~g of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector: Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP; Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties. FCM detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA
with propidium iodide; changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake; alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M.G. ( 1994) Flow C ometry, Oxford, New York NY.
2S The influence of GTPAP on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding GTPAP and either CD64 or CD64-GFP.
CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human imrnunoglobulin G {IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 {DYNAL, Lake Success NY). mRNA can be purified from the cells using methods well known by those of skill in the art. Expression of mRNA encoding GTPAP and other genes of interest can be analyzed by northern analysis or microarray techniques.

XII. Production of GTPAP Specific Antibodies GTPAP substantially purified using polyacrylamide gel electrophoresis (PAGE;
see, e.g., Harrington, M.G. (1990) Methods Enzymol. 182:488-495), or other purification techniques, is used to immunize rabbits and to produce antibodies using standard protocols.
Alternatively, the GTPAP amino acid sequence is analyzed using LASERGENE
software (DNASTAR) to determine regions of high immunogenicity, and a corresponding oligopeptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art. (See, e.g., Ausubel, 1995, su ra, ch. 11.) Typically, oligopeptides of about 1 S residues in length are synthesized using an ABI 431A
peptide synthesizer (Perkin-Elmer) using fmoc-chemistry and coupled to KLH
(Sigma-Aldrich, St.
Louis MO) by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity. (See, e.g., Ausubel, 1995, s_ u~~ra.) Rabbits are immunized with the oligopeptide-KLH complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-GTPAP activity by, for example, binding the peptide or GTPAP to a substrate, blocking with 1%
BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XIII. Purification of Naturally Occurring GTPAP Using Specific Antibodies Naturally occurring or recombinant GTPAP is substantially purified by immunoaffinity chromatography using antibodies specific for GTPAP. An immunoaffinity column is constructed by covalently coupling anti-GTPAP antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.
Media containing GTPAP are passed over the immunoaff nity column, and the column is washed under conditions that allow the preferential absorbance of GTPAP (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/GTPAP binding (e.g., a buffer of pH 2 to pH 3, or a high concentration of a chaotrope, such as urea or thiocyanate ion), and GTPAP is collected.
XIV. Identification of Molecules Which Interact with GTPAP
GTPAP, or biologically active fragments thereof, are labeled with ''-SI Bolton-Hunter reagent. (See, e.g., Bolton A.E. and W.M. Hunter (1973) Biochem. J. 133:529-539.) Candidate molecules previously arrayed in the wells of a mufti-well plate are incubated with the labeled GTPAP, washed, and any wells with labeled GTPAP complex are assayed. Data obtained using different concentrations of GTPAP are used to calculate values for the number, affinity, and association of GTPAP with the candidate molecules.
Various modifications and variations of the described methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention.
Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments.
Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims.

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WO 00I31Z63 PCT/US991Z$013 SEQUENCE LISTING
<110> INCYTE PHARMACEUTICALS, INC.
HILLMAN, Jennifer L.
TANG, Y. Tom SANDMAN, Olga LAL, Preeti YUE, Henry LU, Dyung Aina M.
BAUGHN, Mariah R.
YANG, Junming AZIMZAI, Yalda <120> GTPASE ASSOCIATED PROTEINS
<130> PF-0629 PCT
<140> To Be Assigned <141> Herewith <150> 60/109,592; 60/11x,610; 60/127,990 <151> 1998-11-23; 1999-02-04; 1999-04-06 <160> 58 <170> PERL Program <210> 1 <211> 1002 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 708398CD1 <400> 1 Met Pra Ser Lys Phe Ser Cys Arg Gln Leu Arg Glu Ala Gly Gln Cys Phe Glu Ser Phe Leu Val Val Arg Gly Leu Asp Met Glu Thr Asp Arg Glu Arg Leu Arg Thr Ile Tyr Asn Arg Asp Phe Lys Ile Ser Phe GIy Thr Pro Ala Pro Gly Phe Ser Ser Met Leu Tyr Gly Met Lys Ile Ala Asn Leu Ala Tyr Val Thr Lys Thr Arg Val Arg Phe Phe Arg Leu Asp Arg Trp Ala Asp Val Arg Phe Pro Glu Lys Arg Arg Met Lys Leu Gly Ser Asp IIe Ser Lys His His Lys Ser Leu Leu Ala Lys Ile Phe Tyr Asp Arg Ala Glu Tyr Leu His Gly Lys His Gly Va1 Asp Val Glu Val Gln Gly Pro His Glu Ala Arg WO 00!31263 PCT/US99/28013 Asp Gly Gln Leu Leu Ile Arg Leu Asp Leu Asn Arg Lys Glu Val Leu Thr Leu Arg Leu Arg Asn Gly Gly Thr Gln Ser Val Thr Leu Thr His Leu Phe Pro Leu Cys Arg Thr Pro Gln Phe Ala Phe Tyr Asn Glu Asp Gln Glu Leu Pro Cys Pro Leu Gly Pro Gly Glu Cys Tyr Glu Leu His Val His Cys Lys Thr Ser Phe Val Gly Tyr Phe Pro Ala Thr Val Leu Trp Glu Leu Leu Gly Pro Gly Glu Ser Gly Ser Glu Gly Ala Gly Thr Phe Tyr Ile Ala Arg Phe Leu Ala Ala Val Ala His Ser Pro Leu Ala Ala Gln Leu Lys Pro Met Thr Pro Phe Lys Arg Thr Arg Ile Thr Gly Asn Pro Val VaI Thr Asn Arg Ile Glu Glu Gly Glu Arg Pro Asp Arg Ala Lys Gly Tyr Asp Leu Glu Leu Ser Met Ala Leu Gly Thr Tyr Tyr Pro Pro Pro Arg Leu Arg Gln Leu Leu Pro Met Leu Leu Gln Gly Thr Ser Ile Phe Thr Ala Pro Lys Glu Ile Ala Glu Ile Lys Ala Gln Leu Glu Thr Ala Leu Lys Trp Arg Asn Tyr Glu Va1 Lys Leu Arg Leu Leu Leu His Leu Glu Glu Leu Gln Met Glu His Asp Ile Arg His Tyr Asp Leu Glu Ser Vai Pro Met Thr Trp Asp Pro Val Asp Gln Asn Pro Arg Leu Leu Thr Leu Glu Val Pro Gly Val Thr Glu Ser Arg Pro Ser Val Leu Arg Gly Asp His Leu Phe Ala Leu Leu Ser Ser Glu Thr His Gln Glu Asp Pro Ile Thr Tyr Lys Gly Phe Val His Lys Val Glu Leu Asp Arg Val Lys Leu Ser Phe Ser Met Ser Leu Leu Ser Arg Phe Val Asp Gly Leu Thr Phe Lys Val Asn Phe Thr Phe Asn Arg Gln Pro Leu Arg Val Gln His Arg A1a Leu Glu Leu Thr Gly Arg Trp Leu Leu Trp Pro Met Leu Phe Pro Val Ala Pro Arg Asp Val Pro Leu Leu Pro Ser Asp Val Lys Leu Lys Leu Tyr Asp Arg Ser Leu Glu Ser Asn Pro G1u Gln Leu Gln Ala Met Arg His I1e Val Thr Gly Thr Thr Arg Pro Ala Pro Tyr Ile Ile Phe Gly Pro Pro Gly Thr Gly Lys Thr Val Thr Leu Val Glu Ala Ile Lys Gln Val Val Lys His Leu Pro Lys Ala His Ile Leu Ala Cys Ala Pro Ser Asn Ser Gly Ala Asp Leu Leu Cys Gln Arg Leu Arg Val His Leu Pro Ser 'Sex Tle Tyr Arg Leu Leu Ala Pro Ser Arg Asp Ile Arg Met Val Pro Glu Asp Ile Lys Pro Cys Cys Asn Trp Asp Ala Lys Lys Gly Glu Tyr Val Phe Pro Ala Lys Lys Lys Leu Gln Glu Tyr Arg Val Leu Ile Thr Thr Leu Ile Thr Ala Gly Arg Leu VaI

Ser Ala Gln Phe Pro Ile Asp His Phe Thr His Ile Phe Ile Asp Glu Ala Gly His Cys Met Glu Pro Glu 5er Leu Val Ala Ile Ala Gly Leu Met Glu Val Lys Glu Thr Gly Asp Pro Gly Gly Gln Leu Val Leu Ala Gly Asp Pro Arg Gln Leu Gly Pro Val Leu Arg Sex Pro Leu Thr Gln Lys His Gly Leu Gly Tyr Ser Leu Leu Glu Arg Leu Leu ile Tyr Asn Ser Leu Tyr Lys Lys Gly Pra Asp Gly Tyr Asp Pro Gln Phe Ile Thr Lys Leu Leu Arg Asn Tyr Arg Sex His Pro Thr Ile Leu Asp Ile Pro Asn Gln Leu Tyr Tyr Glu Gly Glu Leu Gln Ala Cys Ala Asp Val Val Asp Arg Glu Arg Phe Cys Arg Trp Ala G1y Leu Pro Arg Gln Gly Phe Pro Ile Tle Phe His Gly Val Met Gly Lys Asp Glu Arg G1u Gly Asn Ser Pro Ser Phe Phe Asn Pro Glu Glu Ala Ala Thr Val Thr Ser Tyr Leu Lys Leu Leu Leu Ala Pro Ser Ser Lys Lys Gly Lys Ala Arg Leu Ser Pro Arg Ser Val Gly Val Ile Ser Pro Tyr Arg Lys Gln Val Glu Lys Ile Arg Tyr Cys Ile Thr Lys Leu Asp Arg Glu Leu Arg Gly Leu Asp Asp Ile Lys Asp Leu Lys Val Gly Ser Val Glu Glu Phe Gln Gly Gln Glu Arg Ser Val Ile Leu Ile Ser Thr Val Arg Ser Ser Gln Ser Phe Val Gln Leu Asp Leu Asp Phe Asn Leu Gly Phe Leu Lys Asn Pro Lys Arg Phe Asn Val Ala Val Thr Arg Ala Lys Ala Leu Leu Ile Ile Val Gly Asn Pro Leu Leu Leu Gly His Asp Pro Asp Trp Lys Val Phe Leu Glu Phe Cys Lys Glu Asn G1y Gly Tyr Thr Gly Cys Pro Phe Pro Ala Lys Leu Asp Leu Gln Gln Gly Gln Asn Leu Leu Gln Gly Leu Ser Lys Leu Ser Pro Ser Thr Sex Gly Pro His Ser His Asp Tyr Leu Pro Gln Glu Arg GIu GIy Glu Gly Gly Leu Ser Leu Gln Val Glu Pro Glu Trp Arg Asn Glu <210> 2 <2I1> 338 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1259937GD1 <400> 2 Met Ala Ala Leu Ala Gln Glu Asp Gly Trp Thr Lys Gly Gln Val Leu Va1 Lys Val Asn Ser Ala Gly Asp Ala 21e Gly Leu G1n Pro Asp Ala Arg G1y Val Ala Thr Ser Leu Gly Leu Asn GIu Arg Leu Phe Va1 Val Asn Pro Gln Glu Val His Glu Leu Ile Pro His Pro Asp Gln Leu Gly Pro Thr Val Gly Ser Ala Glu Gly Leu Asp Leu Val Ser Ala Lys Asp Leu Ala Gly Gln Leu Thr Asp His Asp Trp Ser Leu Phe Asn Ser Ile His G1n Val Glu Leu Ile His Tyr Val Leu Gly Pro Gln His Leu Arg Asp Val Thr Thr Ala Asn Leu Glu Arg Phe Met Arg Arg Phe Asn Glu Leu Gln Tyr Trp Val Ala Thr Glu Leu Cys Leu Cys Pro Val Pro Gly Pro Arg Ala G1n Leu Leu 7.40 145 I50 Arg Lys Phe Ile Lys Leu A1a Ala His Leu Lys Glu Gln Lys Asn Leu Asn Ser Phe Phe Ala Val Met Phe Gly Leu Ser Asn Ser Ala Ile Ser Arg Leu Ala His Thr Trp Glu Arg Leu Pro His Lys Val Arg Lys Leu Tyr Ser Ala Leu Glu Arg Leu Leu Asp Pro Ser Trp Asn His Arg Val Tyr Arg Leu Ala Leu Ala Lys Leu Ser Pro Pro Val Ile Pro Phe Met Pro Leu Leu Leu Lys Asp Met Thr Phe Ile His Glu Gly Asn His Thr Leu Val Glu Asn Leu Tle Asn Phe Glu Lys Met Arg Met Met Ala Arg Ala Ala Arg Met Leu His His Cys Arg Ser His Asn Pro Val Pro Leu Ser Pro Leu Arg Sex Arg Val 275 2$0 285 Ser His Leu His Glu Asp Ser Gln Val Ala Arg Ile Ser Thr Cys Ser Glu Gln Ser Leu Ser Thr Arg Ser Pro Ala Ser Thr Trp Ala Tyr Val Gln Gln Leu Lys Val Ile Asp Asn Gln Arg Glu Leu Ser Arg Leu Ser Arg Glu Leu Glu Pro <210> 3 <211> 211 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1452285CD1 <400> 3 Met Gln Ala Pro His Lys Glu His Leu Tyr Lys Leu Leu Val Ile Gly Asp Leu Gly Val Gly Lys Thr Ser Ile Ile Lys Arg Tyr Val His Gln Asn Phe Ser Ser His Tyr Arg Ala Thr Ile Gly Val Asp Phe Ala Leu Lys Val Leu His Trp Asp Pro Glu Thr Val Val Arg Leu Gln Leu Trp Asp Ile Ala Gly Gln Glu Arg Phe Gly Asn Met Thr Arg Val Tyr Tyr Arg Glu Ala Met Gly Ala Phe Ile Val Phe Asp Val Thr Arg Pro Ala Thr Phe Glu Ala Val Ala Lys Trp Lys Asn Asp Leu Asp Ser Lys Leu Ser Leu Pro Asn Gly Lys Pro Val Ser Val Val Leu Leu Ala Asn Lys Cys Asp Gln Gly Lys Asp Val Leu Met Asn Asn Gly Leu Lys Met Asp Gln Phe Cys Lys Glu His Gly Phe Val Gly Trp Phe Glu Thr Ser Ala Lys Glu Asn Ile Asn Ile Asp Glu Ala Ser Arg Cys Leu Val Lys His Ile Leu Ala Asn Glu Cys Asp Leu Met Glu Ser Ile Glu Pro Asp Val Val Lys Pro His Leu Thr Ser Thr Lys Val Ala Ser Cys Ser Gly Cys Ala Lys Sex <210> 4 <211> 516 <222> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1812894CD1 <400> 4 Met Glu Thr Met Lys Ala Val Ala G1u Val Ser Glu Ser Thr Lys Ala Glu Ala Val Ala Ala Val Gln Arg Gln Cys Gln Glu Glu Val Ala Ser Leu Gln Ala Ile Leu Lys Asp Ser Ile Ser Ser Tyr Glu Aia Gln Ile Thr Ala Leu Lys Gln Glu Arg Gln Gln Gln Gln Gln Asp Cys Glu Glu Lys Glu Arg Glu Leu Gly Arg Leu Lys Gln Leu Leu Ser Arg Ala Tyr Pro Leu Asp Ser Leu Glu Lys Gln Met Glu Lys Ala His Glu Asp Ser Glu Lys Leu Arg Glu Ile Val Leu Pro Met Glu Lys Glu Ile Glu Glu Leu Lys Ala Lys Leu Leu Arg Ala Glu Glu Leu Ile Gln Glu Ile Gln Arg Arg Pro Arg His Ala Pro Ser Leu His Gly Ser Thr Glu Leu Leu Pro Leu Ser Arg Asp Pro Ser Pro Pro Leu Glu Pro Leu Glu Glu Leu Ser Gly Asp Gly Gly Pro Ala Ala Glu Ala Phe Ala His Asn Cys Asp Asp Ser Ala Ser Ile Ser Ser Phe Ser Leu Gly Gly Gly Val Gly Ser Ser Sex Ser Leu Pro Gln Ser Arg Gln Gly Leu Ser Pro Glu Gln Glu Glu Thr Ala Ser Leu Val Ser Thr Gly Thr Leu Val Pro Glu Gly Ile Tyr Leu Pro Pro Pro Gly Tyr Gln Leu Val Pro Asp Thr Gln Trp Glu Gln Leu Gln Thr Glu Gly Arg Gln Leu Gln Lys Asp Leu Glu Ser Val Ser Arg Glu Arg Asp Glu Leu Gln Glu Gly Leu Arg Arg Ser Asn Glu Asp Cys Ala Lys Gln Met Gln Val Leu Leu Ala Gln Val Gln Asn Ser Glu Gln Leu Leu Arg Thr Leu Gln Gly Thr Val Ser Gln Ala Gln Glu Arg Val Gln Leu Gln Met Ala Glu Leu Val Thr Thr His Lys Cys Leu His His Glu Val Lys Arg Leu Asn Glu Glu Asn Gln Gly Leu Arg Ala Glu Gln Leu Pro Ser Ser Ala Pro Gln Gly Ser Gln Gln Glu Gln Gly Glu Glu Glu Ser Leu Pro Ser Ser WO OOI3I263 PCT/US99/2$013 Val Pro Glu Leu Gln Gln Leu Leu Cys Cys Thr Arg Gln Glu Ala Arg Ala Arg Leu Gln Ala Gln Glu His Gly Ala Glu Arg Leu Arg Ile Glu Ile Val Thr Leu Arg Glu Ala Leu Glu Glu Glu Thr Val Ala Arg Ala Ser Leu Glu Gly Gln Leu Arg Val Gln Arg Glu Glu Thr Glu Val Leu Glu A1a Ser Leu Cys Ser Leu Arg Thr Glu Met Glu Arg Val Gln Gln Glu Gln Ser Lys Ala Gln Leu Pro Asp Leu Leu Ser Glu Gln Arg Ala Lys Val Leu Arg Leu Gln Ala Glu Leu Glu Thr Ser Glu Gln Val Gln Arg Asp Phe Val Arg Leu Ser Gln 470 475 4$0 Ala Leu Gln Val Arg Leu Glu Arg Ile Arg Gln Ala Glu Thr Leu Glu Gln Val Arg Ser Ile Met Asp Glu Ala Pro Leu Thr Asp Val Arg Asp Ile Lys Asp Thr <210> 5 <211> 445 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3074884CD1 <400> 5 Met Pro Glu Asp Ala Asp Glu Asn Ala Glu Glu Glu Leu Leu Arg Gly Glu Pro Leu Leu Pro Ala Gly Thr Gln Arg Val Cys Leu Val His Pro Asp Val Lys Trp Gly Pro Gly Lys Ser Gln Met Thr Arg Ala Glu Trp Gln Val Ala Glu Ala Thr Ala Leu Val His Thr Leu Asp Gly Trp Ser Val Val G1n Thr Met Val Val Ser Thr Lys Thr Pro Asp Arg Lys Leu Ile Phe Gly Lys Gly Asn Phe Glu His Leu Thr Glu Lys Ile Arg Gly Ser Pro Asp Val Thr Cys Val Phe Leu Asn Val Glu Arg Met Ala Ala Pro Thr Lys Lys Glu Leu Glu Ala Ala Trp Gly Val Glu Val Phe Asp Arg Phe Thr Val Val Leu His Ile Phe Arg Cys Asn Ala Arg Thr Lys Glu Ala Arg Leu Gln Val WO 00131263 PCTlUS99/28013 Ala Leu Ala Glu Met Pro Leu His Arg Ser Asn Leu Lys Arg Asp Val Ala His Leu Tyr Arg Gly Val Gly Ssr Arg Tyr Ile Met Gly Ser Gly Glu Ser Phe Met Gln Leu Gln Gln Arg Leu Leu Arg Giu Lys Glu Ala Lys Ile Arg Lys Ala Leu Asp Arg Leu Arg Lys Lys Arg His Leu Leu Arg Arg Gln Arg Thr Arg Arg Glu Phe Pro Val Ile Sex Val Val Gly Tyr Thr Asn Cys Gly Lys Thr Thr Leu Ile Lys Ala Leu Thr Gly Asp Ala Ala Ile Gln Pro Arg Asp Gln Leu Phe Ala Thr Leu Asp Val Thr Ala His Ala Gly Thr Leu Pro Ser Arg Met Thr Val Leu Tyr Val Asp Thr Ile Gly Phe Leu Ser Gln Leu Pro His Gly Leu Ile Glu Ser Phe Ser Ala Thr Leu G1-u Asp Val Ala His Ser Asp Leu ,Ile Leu His Val Arg Asp Val Ser His Pro Glu Ala Glu Leu Gln Lys Cys Ser Val Leu Ser Thr Leu Arg Gly Leu Gln Leu Pro Ala Pro Leu Leu Asp Sex Met Val Glu Va1 His Asn Lys Val Asp Leu Val Pro Gly Tyr Ser Pro Thr G1u Pro Asn Val Val Pro Val Ser Ala Leu Arg Gly His Gly Leu Gln Glu Leu Lys Ala Glu Leu Asp Ala Ala Val Leu Lys Ala Thr Gly Arg Gln Ile Leu Thr Leu Arg Val Arg Leu Ala Gly Ala Gln Leu Ser Trp Leu Tyr Lys Glu Ala Thr Val Gln Glu Val Asp Val ile Pro Glu Asp Gly Ala Ala Asp Val Arg Val Ile Ile Ser Asn Ser Ala Tyr Gly Lys Phe Arg Lys Leu Phe Pro Gly <210> 6 <211> 445 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3452277CD1 <400> 6 Met Tyr Tyr Gln Gln Ala Leu Met Arg Ser Thr Val Lys Ser Ser Val Ser Leu Gly Gly Ile Val Lys Tyr Ser Glu Gln Phe Ser Ser Asn Asp Ala Ile Met Ser Gly Cys Leu Pro Ser Asn Pro Trp Ile Thr Asp Asp Thr Gln Phe Trp Asp Leu Asn Ala Lys Leu Val Glu Ile Pro Thr Lys Met Arg Val Glu Arg Trp Ala Phe Asn Phe Ser Glu Leu Ile Arg Asp Pro Lys Gly Arg Gln Ser Phe Gln Tyr Phe Leu Lys Lys Glu Phe Ser Gly Glu Asn Leu Gly Phe Trp Glu Ala Cys Glu Asp Leu Lys Tyr Gly Asp Gln Ser Lys Val Lys Glu Lys Ala Glu Glu Ile Tyr Lys Leu Phe Leu Ala Pro Gly Ala Arg Arg Trp Ile Asn Ile Asp Gly Lys Thr Met Asp Ile Thr Val Lys Gly Leu Lys His Pro His Arg Tyr Val Leu Asp Ala Ala Gln Thr His Ile Tyr Met Leu Met Lys Lys Asp Ser Tyr Ala Arg Tyr Leu Lys 170 17s lso Ser Pro Ile Tyr Lys Asp Met Leu Ala Lys Ala Ile Glu Pro Gln Glu Thr Thr Lys Lys Ser Ser Thr Leu Pro Phe Met Arg Arg His Leu Arg Ser Ser Pro Ser Pro Val Ile Leu Arg Gln Leu Glu Glu Glu Ala Lys Ala Arg Glu Ala Ala Asn Thr Val Asp Ile Thr Gln Pro Gly Gln His Met Ala Pro Ser Pro His Leu Thr Val Tyr Thr Gly Thr Cys Met Pro Pro Ser Pro Ser Ser Pro Phe Sex Ser Sex Cys Arg Ser Pro Arg Lys Pro Phe A1a Ser Pro Ser Arg Phe Ile Arg Arg Pro Ser Thr Thr Ile Cys Pro Ser Pro Ile Arg Val Ala Leu Glu Ser Ser Ser Gly Leu Glu Gln Lys Gly Glu Cys Ser Gly Ser Met Ala Pro Arg Gly Pro Ser Val Thr Glu Ser Ser Glu Ala Ser Leu Asp Thr Ser Trp Pro Arg Ser Arg Pro Arg Ala Pro Pro Lys Ala Arg Met Ala Leu Ser Phe Ser Arg Phe Leu Arg Arg Gly Cys Leu Ala Ser Pro Val Phe Ala Arg Leu Ser Pro Lys Cys Pro Ala Val Ser His Gly Arg Val Gln Pro Leu Gly Asp Val Gly Gln Gln Leu Pro Arg Leu Lys Ser Lys Arg Val Ala Asn Phe Phe Gln Ile Lys Met Asp Val Pro Thr Gly Ser Gly Thr Cys Leu Met Asp Ser Glu Asp Ala Gly Thr Gly Glu Ser Gly Asp Arg Ala Thr Glu WO 00!31263 PCTNS99/28013 Lys Glu Val Ile Cys Pro Trp Glu Ser Leu c210> 7 <211> 281 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4203832CD1 <400> 7 Met Lys Leu Ala Ala Met Ile Lys Lys Met Cys Pro Ser Asp Ser Glu Leu Ser Ile Pro Ala Lys Asn Cys Tyr Arg Met Val Ile Leu Gly Ser Ser Lys Val Gly Lys Thr Ala Ile Val Ser Arg Phe Leu Thr Gly Arg Phe Glu Asp Ala Tyr Thr Pro Thr Ile Glu Asp Phe His Arg Lys Phe Tyr Ser Ile Arg Gly Glu Val Tyr Gln Leu Asp Ile Leu Asp Thr Ser Gly Asn His Pro Phe Pro Ala Met Arg Cys Leu Ser Ile Leu Thr Gly Asp Val Phe Ile Leu Val Phe Ser Leu Asp Asn Arg Asp Ser Phe Glu Glu Val Gln Arg Leu Arg Gln Gln Ile Leu Asp Thr Lys Ser Cys Leu Lys Asn Lys Thr Lys Glu Asn Val Asp Val Pro Leu Val Ile Cys G1y Asn Lys Gly Asp Arg Asp Phe Tyr Arg Glu Val Asp Gln Arg Glu ile Glu Gln Leu Val Gly Asp Asp Pro Gln Arg Cys Ala Tyr Phe Glu Ile Ser Ala Lys Lys Asn Ser Ser Leu Asp Gln Met Phe Arg Ala Leu Phe Ala Met Ala Lys Leu Pro Ser Glu Met Ser Pro Asp Leu His Arg Lys Val Ser Val Gln Tyr Cys Asp Val Leu His Lys Lys A1a Leu Arg Asn Lys Lys Leu Leu Arg Ala G1y Ser Gly Gly Gly Gly Gly Asp Pro Gly Asp Ala Phe Gly Ile Val Ala Pro Phe Ala Arg Arg Pro Ser Val His Ser Asp Leu Met Tyr Ile Arg Glu Lys Ala Ser Ala Gly Ser Gln Ala Lys Asp Lys Glu Arg Cys Val Ile Ser <220> 8 <211> 301 c212> PRT

<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 104368CD1 <400> 8 Met Thr Thr Leu Asp Asp Lys Leu Leu Gll Glu Lys Leu Gln Tyr Tyr Tyr Ser Ser Ser Glu Asp Glu Asp Ser Asp His Glu Asp Lys Asp Arg Gly Arg Cys Ala Pro Ala Ser Ser Ser Val Pro Ala Glu Ala Glu Leu Ala Gly Glu Gly Ile Ser Val Asn Thr Gly Pro Lys Gly Val Ile Asn Asp Trp Arg Arg Phe Lys Gln Leu Glu Thr Glu Gln Arg Glu Glu Gln Cys Arg Glu Met Glu Arg Leu Ile Lys Lys g0 85 90 Leu Ser Met Thr Cys Arg Ser His Leu Asp Glu Glu Glu Glu Gln g5 100 105 Gln Lys Gln Lys Asp Leu Gln G1u Lys Ile Ser Gly Lys Met Thr Leu Lys Glu Phe Ala Ile Met Asn Glu Asp Gln Asp Asp Glu Glu Phe Leu Gln Gln Tyr Arg Lys Gln Arg Met Glu Glu Met Arg Gln Gln Leu His Lys Gly Pro Gln Phe Lys G1n Val Phe Glu Ile Ser Ser Gly Glu Gly Phe Leu Asp Met Ile Asp Lys Glu Gln Lys Ser Ile Val Ile Met Val His Ile Tyr Glu Asp Gly Ile Pro Gly Thr Glu Ala Met Asn Gly Cys Met Ile Cys Leu Ala Ala Glu Tyr Pro Ala Val Lys Phe Cys Lys Val Lys Ser Ser Val Ile Gly Ala Ser Ser Gln Phe Thr Arg Asn Ala Leu Pro Ala Leu Leu Ile Tyr Lys Gly Gly Glu Leu Ile Gly Asn Phe Val Arg Val Thr Asp Gln Leu Gly Asp Asp Phe Phe Ala Val Asp Leu Glu Ala Phe Leu Gln Glu Phe Gly Leu Leu Pro Glu Lys Glu Val Leu Val Leu Thr Ser Val Arg Asn Ser Ala Thr Cys His Ser Glu Asp Ser Asp Leu Glu Ile Asp <210> 9 <211> 485 <212> PRT

WO 00/31263 PCT/US99/2$OI3 c213> Homo Sapiens c220>
<221> misc_feature c223> Incyte ID No: 1441680CD1 <400> 9 Met Arg Ala Val Leu Thr Trp Arg Asp Lys Ala Glu His Cys Ile Asn Asp Ile Ala Phe Lys Pro Asp Gly Thr Gln Leu Ile Leu Ala Ala Gly Ser Arg Leu Leu Val Tyr Asp Thr Ser Asp Gly Thr Leu Leu Gln Pro Leu Lys Gly His Lys Asp Thr Val Tyr Cys Val Ala 5p 55 60 Tyr Ala Lys Asp Gly Lys Arg Phe Ala Ser Gly Ser Ala Asp Lys Ser Val Ile Ile Trp Thr Ser Lys Leu Glu Gly Ile Leu Lys Tyr Thr His Asn Asp Ala Ile Gln Cys Val Ser Tyr Asn Pro Ile Thr His Gln Leu Ala Ser Cys Ser Ser Ser Asp Phe Gly Leu Trp Ser Pro Glu Gln Lys Ser Val Ser Lys His Lys Ser Ser Ser Lys Ile Ile Cys Cys Ser Trp Thr Asn Asp Gly Gln Tyr Leu Ala Leu Gly Met Phe Asn Gly Ile Ile Ser Ile Arg Asn Lys Asn Gly Glu Glu Lys Val Lys Ile Glu Arg Pro Gly Gly Ser Leu Ser Pro Ile Trp Ser Ile Cys Trp Asn Pro Ser Arg Glu Glu Arg Asn Asp Ile Leu Ala Val Ala Asp Trp Gly Gln Lys Val Ser Phe Tyr Gln Leu Ser Gly Lys Gln Ile Gly Lys Asp Arg Ala Leu Asn Phe Asp Pro Cys Cys Ile Ser Tyr Phe Thr Lys Gly Glu Tyr Ile Leu Leu Gly Gly Ser Asp Lys Gln Val Ser Leu Phe Thr Lys Asp Gly Val Arg Leu Gly Thr Val Gly Glu Gln Asn Ser Trp Val Trp Thr Cys Gln Ala Lys Pro Asp Ser Asn Tyr val Val Val Gly Cys Gln Asp Gly Thr Ile Ser Phe Tyr Gln Leu ile Phe Ser Thr Val His Gly Val Tyr Lys Asp Arg Tyr Ala Tyr Arg Asp Ser Met Thr Asp val Ile Val Gln His Leu Ile Thr Glu Gln Lys Val Arg Ile Lys Cys Lys Glu Leu Val Lys Lys Ile Ala Ile Tyr Arg Asn Arg Leu Ala Ile Gln Leu Pro Glu Lys Ile Leu Ile Tyr Glu Leu Tyr Ser Glu Asp Leu WO 00131263 PC'f/US99/Z8013 Ser Asp Met His Tyr Arg Val Lys Glu Lys Ile Ile Lys Lys Phe Glu Cys Asn Leu Leu Val Val Cys Ala Asn His Ile Ile Leu Cys Gln Glu Lys Arg Leu Gln Cys Leu Ser Phe Ser Gly Val Lys Glu Arg Glu Trp Gln Met Glu Ser Leu Ile Arg Tyr Ile Lys Val Ile Gly Gly Pro Pro Gly Arg Glu Gly Leu Leu Val Gly Leu Lys Lys Met Tyr Leu Leu Val Tyr Ser Phe Ile Leu Ile Val Lys Asp Tyr Phe Ser Leu Ser Thr Asp Val Leu Gly Asn Leu Thr Trp Lys His Val Cys Lys Lys His Tyr Trp Val Phe His Leu Phe Ser Trp Tyr Tyr Ile Phe Val Gln <210> 10 <211> 447 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1494955CD1 <400> 10 Met Glu Leu Ser Gln Met Ser Glu Leu Met Gly Leu Ser Val Leu Leu Gly Leu Leu Ala Leu Met Ala Thr Ala Ala Val Ala Arg Gly Trp Leu Arg Ala Gly Glu Glu Arg Ser Gly Arg Pro Ala Cys Gln Lys Ala Asn Gly Phe Pro Pro Asp Lys Ser Ser Gly Ser Lys Lys Gln Lys Gln Tyr Gln Arg Ile Arg Lys Glu Lys Pro Gln Gln His Asn Phe Thr His Arg Leu Leu Ala Ala Ala Leu Lys Ser His Ser Gly Asn ile Ser Cys Met Asp Phe Ser Ser Asn Gly Lys Tyr Leu Ala Thr Cys Ala Asp Asp Arg Thr Ile Arg Ile Trp Ser Thr Lys Asp Phe Leu Gln Arg Glu His Arg Ser Met Arg Ala Asn Val Glu Leu Asp His Ala Thr Leu Val Arg Phe Ser Pro Asp Cys Arg Ala Phe Ile Val Trp Leu Ala Asn Gly Asp Thr Leu Arg Val Phe Lys Met Thr Lys Arg Glu Asp Gly Gly Tyr Thr Phe Thr Ala Thr Pro Glu Asp Phe Pro Lys Lys His Lys Ala Pro Val Ile Asp Ile Gly Ile Ala Asn Thr Gly Lys Phe Ile Met Thr Ala Ser Ser Asp Thr Thr Val Leu Ile Trp Sex Leu Lys Gly Gln Val Leu Ser Thr Ile Asn Thr Asn Gln Met Asn Asn Thr His Ala Ala Val Ser Pro Cys Gly Arg Phe Val Ala Sex Cys Gly Phe Thr Pro Asp Val Lys Val Trp Glu Val Cys Phe Gly Lys Lys Gly Glu Phe Gln Glu Val VaI

Arg Ala Phe Glu Leu Lys Gly His Ser Ala Ala Val His Ser Phe Ala Phe Ser Asn Asp Ser Arg Arg Met Ala Ser Val Ser Lys Asp Gly Thr Trp Lys Leu Trp Asp Thr Asp Val Glu Tyr Lys Lys Lys Gln Asp Pro Tyr Leu Leu Lys Thr Gly Arg Phe Glu Glu Ala Ala Gly Ala Ala Pro Cys Arg Leu Ala Leu Ser Pro Asn Ala Gln Val Leu Ala Leu Ala Ser Gly Ser Ser Ile His Leu Tyr Asn Thr Arg Arg Gly Glu Lys 31u Glu Cys Phe Glu Arg Val His Gly Glu Cys Ile Ala Asn Leu Ser Phe Asp Ile Thr Gly Arg Phe Leu Ala Ser Cys Gly Asp Arg Ala Val Arg Leu Phe His Asn Thr Pro Gly His Arg Ala Met Val Glu Glu Met Gln Gly His Leu Lys Arg Ala Ser Asn Glu Ser Thr Arg Gln Arg Leu Gln Gln Gln Leu Thr Gln Ala Gln Glu Thr Leu Lys Ser Leu Gly Ala Leu Lys Lys <210> 11 <211> 199 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1508161CD1 <400> 11 Met Pro Val Lys Lys Lys His Arg Ala Arg Mat Ile Glu Tyr Phe Iie Asp Val Ala Arg Glu Cys Phe Asn Ile Gly Asn Phe Asn Ser Leu Met Ala I1e Ile Ser Gly Met Asn Met Ser P~:~o Val Ser Arg Leu Lys Lys Thr Trp Ala Lys Val Lys Thr Ala Lys Phe Asp Ile Leu Glu His Gln Met Asp Pro Ser Ser Asn Phe Tyr Asn Tyr Arg Thr Ala Leu Arg Gly Ala Ala Gln Arg Ser Leu Thr Ala His Ser Ser Arg Glu Lys Ile Val Ile Pro Phe Phe Ser Leu Leu Ile Lys Asp Ile Tyr Phe Leu Asn Glu Gly Cys A1a Asn Arg Leu Pro Asn Gly His Val Asn Phe Glu Lys Phe Trp Glu Leu Ala Lys Gln Val Ser Glu Phe Met Thr Trp Lys Gln Val Glu Cys Pro Phe Glu Arg Asp Arg Lys 21e Leu Gln Tyr Leu Leu Thr VaI Pro Val Phe Ser Glu Asp Ala Leu Tyr Leu Ala Ser Tyr Glu Sex Glu Gly Pro Glu Asn His Ile Glu Lys Asp Arg Trp Lys Ser Leu Arg Ser Ser Leu Leu Gly Arg Val <210> 12 <211> 694 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1811877CD1 <400> 12 Met Ala Phe Asp Pro Thr Ser Thr Leu Leu Ala Thr Gly Gly Cys Asp Gly Ala Val Arg Val Trp Asp Ile Val Arg His Tyr Gly Thr His His Phe Arg Gly Ser Pro Gly Val Val His Leu Val Ala Phe His Pro Asp Pro Thr Arg Leu Leu Leu Phe Ser Ser Ala Thr Asp Ala Ala Ile Arg Val Trp Ser Leu Gln Asp Arg Ser Cys Leu Ala Val Leu Thr Ala His Tyr Ser Ala Val Thr Ser Leu Ala Phe Ser Aia Asp Gly His Thr Met Leu Ser Ser Gly Arg Asp Lys Ile Cys Ile Ile Trp Asp Leu Gln Ser Cys Gln Ala Thr Arg Thr Val Pro Val Phe Glu Ser Val Glu Ala Ala Val Leu Leu Pro Glu Glu Pro Val Ser Gln Leu Gly Val Lys Ser Pro Gly Leu Tyr Phe Leu Thr Ala Gly Asp Gln Gly Thr Leu Arg Val Trp Glu Ala Ala Ser Gly 155 160 165 .
Gln Cys Va1 Tyr Thr Gln Ala Gln Pro Pro Gly Pro Gly Gln Glu WO 00!31263 PCT/US99I28013 Leu Thr His Cys Thr Leu Ala His Thr Ala Gly Val Val Leu Thr Ala Thr Ala Asp His Asn Leu Leu Leu Tyr Glu Ala Arg Ser Leu Arg Leu Gln Lys Gln Phe Ala Gly Tyr Ser Glu Glu Val Leu Asp Val Arg Phe Leu Gly Pro Glu Asp Ser His Val Val Val Ala Ser Asn Ser Pro Cys Leu Lys Val Phe Glu Leu Gln Thr Ser Ala Cys Gln Ile Leu His Gly His Thr Asp Ile Val Leu Ala Leu Asp Val Phe Arg Lys Gly Trp Leu Phe Ala Sex Cys Ala Lys Asp Gln Ser Val Arg Ile Trp Arg Met Asn Lys Ala Gly Gln Val Met Cys Val Ala Gln Gly Ser Gly His Thr His Ser Val Gly Thr Val Cys Cys Ser Arg Leu Lys Glu Ser Phe Leu Val Thr Gly Ser Gln Asp Cys Thr Val Lys Leu Trp Pro Leu Pro Lys Ala Leu Leu Ser Lys Asn Thr Ala Pro Asp Asn Gly Pro Ile Leu Leu Gln Ala Gln Thr Thr Gln Arg Cys His Asp Lys Asp Ile Asn Ser Val Ala Ile Ala Pro Asn Asp Lys Leu Leu Ala Thr Gly Sex Gln Asp Arg Thr Ala Lys Leu Trp Ala Leu Pro Gln Cys Gln Leu Leu GIy Val Phe Ser Gly His Arg Arg Gly Leu Trp Cys Val Gln Phe Ser Pro Met Asp Gln Val Leu Ala Thr A1a Ser Ala Asp Gly Thr Ile Lys Leu Trp Ala Leu Gln Asp Phe Ser Cys Leu Lys Thr Phe Glu Gly His Asp Ala Ser Val Leu Lys Val Ala Phe Val Ser Arg Gly Thr Gln Leu Leu Ser Ser Gly Ser Asp Gly Leu Val Lys Leu Trp Thr Ile Lys Asn Asn Glu Cys Val Arg Thr Leu Asp Ala His Glu Asp Lys Val Trp Gly Leu His Cys Ser Arg Leu Asp Asp His Ala Leu Thr Gly Ala Sex Asp Ser Arg Val Ile Leu Trp Lys Asp Val Thr Glu Ala GIu Gln Ala Glu Glu Gln Ala Arg Gln Glu Glu Gln Val Val Arg Gln Gln Glu Leu Asp Asn Leu Leu His Glu Lys Arg Tyr Leu Arg Ala Leu Gly Leu Ala Ile Ser Leu Asp Arg Pro His Thr Val Leu Thr Val Ile Gln Ala Ile Arg Arg Asp Pro Glu Ala Cys Glu Lys Leu Giu Ala Thr Met Leu Arg Leu Arg Arg Asp Gln Lys Glu Ala Leu Leu Arg Phe Cys Val Thr Trp Asn Thr Asn Ser Arg His Cys His Glu Ala Gln Ala Val Leu Gly Val Leu Leu Arg Arg Glu Ala Pro Glu Glu Leu Leu Ala Tyr Glu Gly Va1 Arg Ala Ala Leu Glu Ala Leu Leu Pro Tyr Thr Glu Arg His Phe Gln Arg Leu Ser Arg Thr Leu Gln Ala Ala Ala Phe Leu Asp Phe Leu Trp His Asn Met Lys Leu Pro Val Pro Ala Ala Ala Pro Thr Pro Trp Glu Thr His Lys Gly Ala Leu Pro <210> 13 <211> 654 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Tncyte ID No: 1848674CD1 <400> 13 Met Glu Arg Ser Gly Pro Ser Glu Val Thr Gly Ser Asp Ala Ser Gly Pro Asp Pro Gln Leu Ala Val Thr Met Gly Phe Thr Gly Phe Gly Lys Lys Ala Arg Thr Phe Asp Leu Glu Ala Met Phe Glu Gln Thr Arg Arg Thr Ala Va1 Glu Arg Ser Arg Lys Thr Leu Glu Ala Arg Glu Lys Glu Glu Glu Met Asn Arg Glu Lys Glu Leu Arg Arg Gln Asn Glu Asp Ile Glu Pro Thr Sex Ser Arg Ser Asn Val Val Arg Asp Cys Ser Lys Ser Ser Ser Arg Asp Thr Ser Ser Ser Glu Ser Glu Gln Ser Ser Asp Ser Ser Asp Asp Glu Leu Ile Gly Pro Pro Leu Pro Pro Lys Met Val Gly Lys Pro Val Asn Phe Met Glu Glu Asp IIe Leu Gly Pro Leu Pro Pro Pro Leu Asn Glu Glu Glu Glu Glu Ala Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Asn Pro Val His Lys Ile Pro Asp Ser His Glu Ile Thr Leu Lys His 170 175 1$0 Gly Thr Lys Thr Val Ser Ala Leu Gly Leu Asp Pro Ser Gly Ala Arg Leu Val Thr Gly Gly Tyr Asp Tyr Asp Val Lys Phe Trp Asp Phe Ala Gly Met Asp Ala Ser Phe Lys Ala Phe Arg Ser Leu Gln WO 00!31263 PCT/US99/28013 Pro Cys G1u Cys His Gln Ile Lys Ser Leu Gln Tyr Ser Asn Thr Gly Asp Met Ile Leu Val Val Ser Gly Ser Ser Gln Ala Lys Val Ile Asp Arg Asp Gly Phe Glu Val Met Glu Cys Ile Lys Gly Asp Gln Tyr Ile Val Asp Met Ala Asn Thr Lys Gly His Thr Ala Met Leu His Thr Gly Ser Trp His Pro Lys Ile Lys Gly Glu Phe Met Thr Cys Ser Asn Asp Ala Thr Val Arg Thr Trp Glu Val Glu Asn Pro Lys Lys Gln Lys Ser Val Phe Lys Pro Arg Thr Met Gln Gly Lys Lys Val Ile Pro Thr Thr Cys Thr Tyr Ser Arg Asp Gly Asn Leu Ile Ala Ala Ala Cys Gln Asn Gly Ser IIe Gln Ile Trp Asp Arg Asn Leu Thr Val His Pro Lys Phe His Tyr Lys Gln Ala His Asp Ser Gly Thr Asp Thr Ser Cys Val Thr Phe Ser Tyr Asp Gly Asn Val Leu Ala Ser Arg Gly Gly Asp Asp Ser Leu Lys Leu Trp Asp Tle Arg Gln Phe Asn Lys Pro Leu Phe Ser Ala Ser Gly Leu Pro Thr Met Phe Pro Met Thr Asp Cys Cys Phe Ser Pro Asp Asp Lys Leu Ile Val Thr Gly Thr Ser Ile Gln Arg Gly Cys Gly Ser Gly Lys Leu Val Phe Phe Glu Arg Arg Thr Phe Gln Arg Val Tyr Glu Ile Asp Ile Thr Asp Ala Ser Val Val Arg Cys Leu Trp His Pro Lys Leu Asn Gln Ile Met Val Gly Thr Gly Asn Gly Leu Ala Lys Val Tyr Tyr Asp Pro Asn Lys Ser Gln Arg Gly Ala Lys Leu Cys Val Val Lys Thr Gln Arg Lys Ala Lys Gln Ala Glu Thr Leu Thr Gln Asp Tyr Ile Ile Thr Pro His Ala Leu Pro Met Phe Arg Glu Pro Arg Gln Arg Ser Thr Arg Lys Gln Leu Glu Lys Asp Arg Leu Asp Pro Leu Lys Ser His Lys Pro Glu Pro Pro Val Ala Gly Pro Gly Arg Gly Gly Arg Val Gly Thr His Gly Gly Thr Leu Ser Ser Tyr Ile Val Lys Asn Ile Ala Leu Asp Lys Thr Asp Asp Ser Asn Pro Arg Glu Ala Ile Leu Arg His Ala Lys Ala Ala Glu Asp Ser Pro Tyr Trp Val Ser Pro Ala Tyr Ser Lys Thr Gln Pro Lys ~ $/~5 Thr Met Phe Ala Gln Va1 Glu Ser Asp Asp Glu Glu Ala Lys Asn Glu Pro Glu Trp Lys Lys Arg Lys Ile <230> 14 <211> i80 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 20129?OCDI
<400> 14 Met Glu Ala Asn Met Pro Lys Arg Lys Glu Pro Gly Arg Ser Leu Arg Ile Lys Val Ile Ser Met Gly Asn Ala Glu Val Gly Lys Ser Cys Ile Ile Lys Arg Tyr Cys Glu Lys Arg Phe Val Sex Lys Tyr Leu AIa Thr Ile Gly Ile Asp Tyr Gly Val Thr Lys Val His Val Arg Asp Arg Glu Ile Lys Val Asn Ile Phe Asp Met Ala Gly His Pro Phe Phe Tyr Glu Val Arg Asn Glu Phe Tyr Lys Asp Thr Gln g0 85 90 Gly Val Ile Leu Val Tyr Asp Val Gly Gln Lys Asp Ser Phe Asp 95 1d0 105 Ala Leu Asp Ala Trp Leu Ala Glu Met Lys Gln Glu Leu Gly Pro His Gly Asn Met Glu Asn Ile Ile Phe Val Val Cys Ala Asn Lys Ile Asp Cys Thr Lys His Arg Cys Val Asp Glu Ser Glu Gly Arg Leu Trp Ala Glu Ser Lys Gly Phe Leu Tyr Phe Glu Thr Ser Ala Gln Thr Gly Glu Gly Ile Asn Glu Met Phe Gln Ile His Leu Gly <210> 15 <211> 374 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 22543i5CDl <400> I5 Met Ala Ala Ser Ala Ala Ala Ala Glu Leu Gln Ala Ser Gly Gly Pro Arg His Pro Val Cys Leu Leu Val Leu G1y Met Ala Gly Ser Gly Lys Thr Thr Phe Val Gln Arg Leu Thr Gly His Leu His Ala Gln Gly Thr Pro Pro Tyr Val Ile Asn Leu Asp Pro Ala Val His Glu Val Pro Phe Pro Ala Asn Ile Asp Ile Arg Asp Thr Val Lys Tyr Lys Glu Val Met Lys Gln Tyr Gly Leu Gly Pro Asn Gly Gly gQ 85 90 Ile Val Thr Ser Leu Asn Leu Phe Ala Thr Arg Phe Asp Gln Val Met Lys Phe Ile Glu Lys Ala Gln Asn Met Ser Lys Tyr Val Leu Ile Asp Thr Pro Gly Gln IIe Glu Val Phe Thr Trp Ser Ala Ser Gly Thr Ile Ile Thr Giu Ala Leu Ala Ser Ser Phe Pro Thr Vai Val Ile Tyr Val Met Asp Thr Ser Arg Ser Thr Asn Pro Val Thr Phe Met Ser Asn Met Leu Tyr Ala Cys Ser Ile Leu Tyr Lys Thr 170 175 7.80 Lys Leu Pro Phe Ile Val Val Met Asn Lys Thr Asp Ile Ile Asp His Ser Phe Ala Val Glu Trp Met Gln Asp Phe Glu Ala Phe Gln Asp Ala Leu Asn Gln Glu Thr Thr Tyr Val Sex Asn Leu Thr Arg Ser Met Ser Leu Val Leu Asp Glu Phe Tyr Sex Ser Leu Arg Val Val Gly Val Ser Ala Val Leu Gly Thr Gly Leu Asp Glu Leu Phe Val Gln Val Thr Ser Ala Ala Glu Glu Tyr Glu Arg Glu Tyr Arg Pro Glu Tyr Glu Arg Leu Lys Lys Ser Leu Ala Asn Ala Glu Ser Gln Gln Gln Arg Glu Gln Leu Glu Arg Leu Arg Lys Asp Met Gly Ser Val Ala Leu Asp Ala G1y Thr Ala Lys Asp Ser Leu Ser Pro Val Leu His Pro Ser Asp Leu Ile Leu Thr Arg Gly Thr Leu Asp Glu Glu Asp Glu Glu Ala Asp Ser Asp Thr Asp Asp Ile Asp His Arg Val.Thr Glu Glu Ser His Glu Glu Pro Ala Phe Gln Asn Phe Met Gln Glu Ser Met Ala Gln Tyr Trp Lys Arg Asn Asn Lys <210> 16 <211> 649 <212> PRT
<213> Homo Sapiens <220>

<221> misc_feature:
<223> Incyte ID No: 24I5545CD1 <400> 16 Met Glu Gly Ala Gly Tar Arg Val Val Phe Glu Lys Gly Gly Val Tyr Leu His Thr Ser Ala Lys Lys Tyr Gln Asp Arg Asp Ser Leu Ile Ala Gly Val Ile Arg Val Val Glu Lys Asp Asn Asp Val Leu Leu His Trp Ala Pro Val Glu ..~lu Ala Gly Asp Ser Thr Gln Ile Leu Phe Ser Lys Lys Asp Ser SEA- Gly Gly Asp Ser Cys Ala Ser Glu Glu Glu Pro Thr Phe Asp Pro Gly .Tyr Glu Pro Asp Trp Ala Val Ile Ser Thr Val Arg Pro Gln Pro Cys His Ser Glu Pro Thr 95 100 lOS
Arg Gly Ala Glu Pro Ser Cys Pro Gln :~Iy Ser Trp Ala Phe Ser Val Ser Leu Gly Glu Leu Lys Ser Ile Ar;I Arg Ser Lys Pro Gly Leu Ser Trp Ala Tyr Leu Val Leu Val Thr :~ln Ala Gly Gly Ser Leu Pro Ala Leu His Phe His Arg Gly Gly Tr~r Arg Ala Leu Leu Arg Val Leu Ser Arg Tyr Leu Leu Leu Ala Ser Ser Pro Gln Asp Ser Arg Leu Tyr Leu Val Phe Pro His Asp Ser Ser Ala Leu Ser Asn Ser Phe His His Leu Gln Leu Phe Asp Gln Asp Ser Ser Asn Val Val Ser Arg Phe Leu Gln Asp Pro Tyr Ser Thr Thr Phe Ser Ser Phe Ser Arg Val Thr Asn Phe Phe Arg Gly Ala Leu Gln Pro Gln Pro Glu Gly Ala Ala Ser Asp Leu Pro Pro Pro Pro Asp Asp Glu Pro Glu Pro Gly Phe Glu Val Ile Sex Cys Val Glu Leu :;Iy Pro Arg Pro Thr Val Glu Arg Gly Pro Pro Val Thr Glu Glu Glu Trp Ala Arg His Val Gly Pro Glu Gly Arg Leu Gln Gln Val Pro Glu Leu Lys Asn Arg Ile Phe Ser Gly Gly Leu Ser Pro Ser Leu Arg Arg Glu Ala Trp Lys Phe Leu Leu Gly Tyr Leu Ser Trp Glu Gly Thr AIa Glu Glu His Lys Ala His Ile Arg Lys Lys Thr Asp Glu Tyr Phe Arg Met Lys Leu Gln Trp Lys Ser Val Ser Pro Glu Gln Glu Arg Arg Asn Ser Leu Leu His Gly Tyr Arg Ser Leu Ile Glu Arg Asp Val Ser Arg Thr Asp Arg Thr Asn Lys Phe Tyr Glu WO OOI31263 PCTlUS99128013 Gly Pro Glu Asn Pro Gly Leu Gly Leu Leu Asn Asp Ile Leu Leu Thr Tyr Cys Met Tyr His Phe Asp Leu G1I Tyr Val Gln Gly Met Ser Asp Leu Leu Ser Pro Ile Leu Tyr Val Ile Gln Asn Glu Val Asp Ala Phe Trp Cys Phe Cys Gly Phe Met Glu Leu Val Gln Gly Asn Phe Glu Glu Ser Gln Glu Thr Met Lys Arg Gln Leu Gly Arg Leu Leu Leu Leu Leu Arg Val Leu Asp Pro Leu Leu Cys Asp Phe Leu Asp Ser Gln Asp Ser Gly Ser Leu Cys Phe Cys Phe Arg Trp Leu Leu Ile Trp Phe Lys Arg Glu Phe Pro Phe Pro Asp Val Leu Arg Leu Trp Glu Val Leu Trp Thr GIy Leu Pro Gly Pro Asn Leu His Leu Leu Val Ala Cys Ala Ile Leu Asp Met Glu Arg Asp Thr Leu Met Leu Ser Gly Phe Gly Ser Asn Glu IIe Leu Lys His Ile Asn Glu Leu Thr Met Lys Leu Ser Val Glu Asp Val Leu Thr Arg Ala GIu Ala Leu His Arg Gln Leu Thr Ala Cys Thr Arg Ala Ala Pro Gln Arg Ala Gly Asp Pro Gly Ala Gly Pro Ala Thr Gln Ser Pro Thr Ala Pro Arg Pro Pro Pro Pro Arg Cys Leu Cys Thr Pro Thr Arg Ala Pro Pro Thr Pro Pro Pro Ser Thr Asp Thr Ala Pro Gln Pro Asp Ser Ser Leu Glu Ile Leu Pro Glu Glu Glu Asp Glu Gly Ala Asp Ser <210> 17 <211> 698 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2707969CD1 <400> 17 Met Cys His Asp Asp Asp Asp Lys Asp Pro Val Leu Arg Val Phe Asp Ser Arg Val Asp Lys Ile Arg Leu Leu Asn Val Arg Thr Pro Thr Leu Arg Thr Ser Met Tyr Gln Lys Cys Thr Thr Val Asp Glu Ala GIu Lys Ala Ile Glu Leu Arg Leu Ala Lys Ile Asp His Thr zzi6s Ala Ile His Pro His Leu Leu Asp Met Lys Ile Gly Gln Gly Lys Tyr Glu Pro Gly Phe Phe Pro Lys Leu Gln Ser Asp Val Leu Ser Thr Gly Pro Ala Ser Asn Lys Trp Thr Lys Arg Asn Ala Pro A1a Gln Trp Arg Arg Lys Asp Arg Gln Lys Gln His Thr Glu His Leu Arg Leu Asp Asn Asp Gln Arg Glu Lys Tyr Ile Gln Glu Ala Arg Thr Met Gly Ser Thr Ile Arg Gln Pro Lys Leu Ser Asn Leu Ser Pro Ser Val Ile Ala Gln Thr Asn Trp Lys Phe Val Glu Gly Leu Leu Lys Glu Cys Arg Asn Lys Thr Lys Arg Met Leu Val Glu Lys 170 17s lso Met Gly Arg Glu Ala Val Glu Leu Gly His Gly Glu Val Asn Ile Thr Gly Val Glu Glu Asn Thr Leu Ile Ala Ser Leu Cys Asp Leu Leu Glu Arg Ile Trp Ser His Gly Leu G1n Val Lys Gln Gly Lys Sex Ala Leu Trp Ser His Leu Leu His Tyr Gln Asp Asn Arg Gln Arg Lys Leu Thr Ser Gly Ser Leu Ser Thr Ser Gly Ile Leu Leu Asp Ser Glu Arg Arg Lys Ser Asp Ala Ser Ser Leu Met Pro Pro Leu Arg Ile Ser Leu Ile Gln Asp Met Arg His Ile Gln Asn Ile Gly Glu Ile Lys Thr Asp Val Gly Lys Ala Arg Ala Trp Val Arg Leu Ser Met Glu Lys Lys Leu Leu Ser Arg His Leu Lys Gln Leu Leu Ser Asp His Glu Leu Thr Lys Lys Leu Tyr Lys Arg Tyr Ala Phe Leu Arg Cys Asp Asp Glu Lys Glu Gln Phe Leu Tyr His Leu Leu Ser Phe Asn Ala Val Asp Tyr Phe Cys Phe Thr Asn Val Phe Thr Thr Ile Leu Ile Pro Tyr His Ile Leu Ile Val Pro Ser Lys Lys Leu Gly Gly Ser Met Phe Thr Ala Asn Pro Trp Ile Cys Ile Ser Gly Glu Leu Gly Glu Thr Gln Ile Met Gln Ile Pro Arg Asn Val Leu Glu Met Thr Phe Glu Cys Gln Asn Leu Gly Lys Leu Thr Thr Val Gln Ile Gly His Asp Asn 5er Gly Leu Tyr Ala Lys Trp Leu Val Glu Tyr Val Met Val Arg Asn Glu Ile Thr Gly His Thr Tyr Lys Phe Pro Cys Gly Arg Trp Leu Gly Lys Gly Met Asp Asp Gly Ser Leu Glu Arg Ile Leu Val Gly Glu Leu Leu Thr Ser Gln Pro Glu Val Asp Giu Arg Pro Cys Arg Thr Pro Pro Leu Gln Gln Ser Pro Ser Val Ile Arg Arg Leu Val Thr Ile Ser Pro Asn Asn Lys Pro Lys Leu Asn Thr Gly Gln Iie Gln Glu Ser Ile Gly Glu Ala Val Asn Gly Ile Val Lys His Phe His Lys Pro Glu Lys Glu Arg Gly Ser Leu Thr Leu Leu Leu Cys Gly Glu Cys Gly Leu Val Ser Ala Leu Glu Gln Ala Phe Gln His Gly Phe Lys Ser Pro Arg Leu Phe Lys Asn Val Phe Ile Trp Asp Phe Leu Glu Lys Ala Gln Thr Tyr Tyr Glu Thr Leu Glu Lys Asn Glu Val Val Pro Glu Glu Asn Trp His Thr Arg Ala Arg Asn Phe Cys Arg Phe Val Thr Ala Ile Asn Asn Thr Pro Arg Asn Ile Gly Lys Asp Gly Lys Phe Gln Met Leu Val Cys Leu Gly Ala Arg Asp His Leu Leu His His Trp Ile Ala Leu Leu Ala Asp Cys Pro Ile Thr Ala His Met Tyr Glu Asp Val Aia Leu Ile Lys Asp His Thr Leu Val Asn Ser Leu Ile Arg Val Leu Gln Thr Leu Gln Glu Phe Asn Ile Thr Leu Glu Thr Ser Leu Val Lys Gly Ile Asp Ile <210> 18 <211> 396 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2817769CD1 <400> 18 Met Pro Pro Lys Lys Gly GIy Asp Gly Ile Lys Pro Pro Pro Ile Ile Gly Arg Phe Gly Thr Ser Leu Lys Ile Gly Ile Val Gly Leu Pro Asn Val Gly Lys Ser Thr Phe Phe Asn Val Leu Thr Asn Ser Gln Ala Ser Ala Glu Asn Phe Pro Phe Cys Thr Ile Asp Pro Asn Glu Ser Arg Vai Pro Val Pro Asp Glu Arg Phe Asp Phe Leu Cys Gln Tyr His Lys Pro Ala Ser Lys Ile Pro Ala Phe Leu Asn Val WO 00/312b3 PCT/US99128013 Val Asp Ile Ala Gly Leu Val Lys Gly Ala His Asn Gly Gln Gly Leu Gly Asn Ala Phe Leu Ser His Ile Ser Ala Cys Asp Gly Ile Phe His Leu Thr Arg Ala Phe Glu Asp Asp Asp Ile Thr His Val Glu Gly Ser Val Asp Pro Ile Arg Asp Ile Glu Ile Ile His Glu Glu Leu Gln Leu Lys Asp Glu Glu Met Ile Gly Pro Ile Ile Asp Lys Leu Glu Lys Val Ala Val Arg Gly Gly Asp Lys Lys Leu Lys Pro Glu Tyr Asp Ile Met Cys Lys Val Lys Ser Trp Val Ile Asp Gln Lys Lys Pro Val Arg Phe Tyr His Asp Trp Asn Asp Lys Glu Ile Glu Val Leu Asn Lys His Leu Phe Leu Thr Ser Lys Pro Met Val Tyr Leu Val Asn Leu Ser Glu Lys Asp Tyr Ile Arg Lys Lys Asn Lys Trp Leu Ile Lys Ile Lys Glu Trp Val Asp Lys Tyr Asp Pro Gly Ala Leu Val Ile Pro Phe Ser Gly Ala Leu Glu Leu Lys Leu Gln Glu Leu Ser Ala Glu Glu Arg Gln Lys Tyr Leu Glu Ala Asn Met Thr Gln Ser Ala Leu Pro Lys Ile Ile Lys Ala Gly Phe Ala Ala Leu Gln Leu Glu Tyr Phe Phe Thr Ala Gly Pro Asp Glu Val Arg Ala Trp Thr Ile Arg Lys Gly Thr Lys Ala Pro Gln Ala Ala Gly Lys Ile His Thr Asp Phe Glu Lys Gly Phe Ile Met Ala Glu Val Met Lys Tyr Glu Asp Phe Lys Glu Glu Gly Ser Glu Asn Ala Val Lys Ala Ala Gly Lys Tyr Arg Gln Gln Gly Arg Asn Tyr Ile Val Glu Asp Gly Asp Ile Ile Phe Phe Lys Phe Asn Thr Pro Gln Gln Pro Lys Lys Lys <210> 19 <211> 634 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2917557CD1 <400> 19 Met Ser Ser Asp Ser Glu Tyr Asp Ser Asp Asp Asp Arg Thr Lys zsi6s Glu Glu Arg Ala Tyr Asp Lys Ala Lys Arg Arg Ile G1~~ Lys Arg Arg Leu Glu His Ser Lys Asn Val Asn Thr Glu Lys Leu Arg Ala Pro Ile I1e Cys Val Leu Gly His Val Asp Thr Gly Lys Thr Lys Ile Leu Asp Lys Leu Arg His Thr His Val Gln Asp Gly Glu Ala Gly Gly Ile Thr Gln Gln Ile Gly Ala Thr Asn Val Pro Leu Glu Ala Ile Asn Glu Gln Thr Lys Met Ile Lys Asn Phe Asp Arg Glu Asn Val Arg Ile Pro Gly Met Leu Ile Ile Asp Thr Pro Gly His 110 .115 120 Glu Ser Phe Ser Asn Leu Arg Asn Arg Gly Ser Ser Leu Cys Asp Ile Ala Ile Leu Val Val Asp Ile Met His Gly Leu G1u Pro Gln Thr Ile Glu Ser Ile Asn Leu Leu Lys Ser Lys Lys Cys Pro Phe Ile Val Ala Leu Asn Lys Ile Asp Arg Leu Tyr Asp Trp Lys Lys Ser Pro Asp Ser Asp Val Ala Ala Thr Leu Lys Lys Gln Lys Lys Asn Thr Lys Asp Glu Phe Glu Glu Arg Ala Lys Ala Ile Ile Val Glu Phe Ala Gln Gln Gly Leu Asn Ala Ala Leu Phe Tyr Glu Asn Lys Asp Pro Arg Thr Phe Val Ser Leu Val Pro Thr Ser Ala His Thr Gly Asp Gly Met Gly Ser Leu Ile Tyr Leu Leu Val Glu Leu Thr Gln Thr Met Leu Ser Lys Arg Leu Ala His Cys Glu Glu Leu Arg Ala Gln Val Met Glu Val Lys Ala Leu Pro Gly Met Gly Thr Thr Ile Asp Val Ile Leu Ile Asn Gly Arg Leu Lys Glu Gly Asp Thr Ile Ile Val Pro Gly Val Glu Gly Pro Ile Val Thr Gin Ile Arg Gly Leu Leu Leu Pro Pro Pro Met Lys Glu Leu Arg Val Lys Asn Gln Tyr Glu Lys His Lys Glu Val Glu Ala Ala Gln Gly Val Lys Ile Leu Gly Lys Asp Leu Glu Lys Thr Leu Ala Gly Leu Pro Leu Leu Val Ala Tyr Lys Glu Asp Glu Ile Pro Val Leu Lys Asp Glu Leu Ile His Glu Leu Lys Gln Thr Leu Asn Ala I1e Lys Leu Glu Glu Lys Gly Val Tyr Val Gln Ala Ser Thr Leu Gly Ser Leu Glu Ala Leu Leu Glu Phe Leu Lys Thr Sex Glu Val Pro Tyr Ala Gly Ile Asn Ile Gly Pro Val His Lys Ljs Asp Val Met Lys Ala Ser Val Met Leu Glu His Asp Pro G1n Tjr Ala Val Ile Leu Ala Phe Asp Val Arg Ile Glu Arg Asp Ala Gln Glu Met Ala Asp Ser Leu Gly Val Arg Tle Phe Ser Ala Glu Ile Ile Tyr His Leu Phe Asp Ala Phe Thr Lys Tyr Arg Gln Asp Tyr Lys Lys Gln Lys Gln Glu Glu Phe Lys His Ile Ala Val Phe Pro Cys Lys Ile Lys Ile Leu Pro Gln Tyr Ile Phe Asn Ser Arg Asp Pro Ile Val Met Gly Val Thr Val Glu Ala Gly Gln Val Lys Gln Gly Thr Pro Met Cys Val Pro Ser Lys Asn Phe Val Asp Ile Gly Ile Val Thr Ser Ile Glu Ile Asn His Lys Gln Val Asp Val Ala Lys Lys Gly Gln Glu Val Cys Val Lys Ile Glu Pro Ile Pro Gly Glu Ser Pro Lys Met Phe Gly Arg His Phe Glu Ala Thr Asp Ile Leu Val Ser Lys Ile Ser Arg Gln Ser Ile Asp Ala Leu Lys Asp Trp Phe Arg Asp Glu Met Gln Lys Ser Asp Trp Gln Leu Ile Val Glu Leu Lys Lys Val Phe Glu Ile Ile <210> 20 <211> 196 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3421335CD1 <400> 20 Met Gly Ser Val Asn Ser Arg Gly His Lys Ala Glu Ala Gln Val Val Met Met Gly Leu Asp Ser Ala Gly Lys Thr Thr Leu Leu Tyr Lys Leu Lys Gly His Gln Leu Val Glu Thr Leu Pro Thr Val Gly Phe Asn Val Glu Pro Leu Lys Ala Pro Gly His Val Ser Leu Thr Leu Trp Asp Val Gly Gly Gln Ala Pro Leu Arg Ala Ser Trp Lys Asp Tyr Leu Glu Gly Thr Asp Ile Leu Val Tyr Val Leu Asp Ser Thr Asp Glu Ala Arg Leu Pro Glu Ser Ala Ala Glu Leu Thr Glu Val Leu Asn Asp Pro_Asn Met Aia Gly Val Pro Phe Leu Val Leu Ala Asn Lys Gln Glu Ala Pro Asp Ala Leu Pra Leu Leu Lys Ile Arg Asn Arg Leu Ser Leu Glu Arg Phe Gln Asp His Cys Trp Glu Leu Arg Gly Cys Ser Ala Leu Thr Gly Glu Gly Leu Pro Glu Ala Leu Gln Ser Leu Trp Ser Leu Leu Lys Ser Arg Ser Cys Met Cys Leu Gln Ala Arg Ala His Gly Ala Glu Arg Gly Asp Ser Lys Arg Ser <210> 21 <211> 446 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 605761CD1 <400> 21 Met Ala Ala Arg Lys Gly Arg Arg Arg Thr Cys Glu Thr Gly Glu Pro Met Glu Ala Glu Ser Gly Asp Thr Ser Ser Glu Gly Pro Ala Gln Val Tyr Leu Pro Gly Arg Gly Pro Pro Leu Arg Glu Gly Glu Glu Leu Val Met Asp Glu Glu Ala Tyr Val Leu Tyr His Arg Ala Gln Thr Gly Ala Pro Cys Leu Ser Phe Asp Ile Val Arg Asp His Leu Gly Asp Asn Arg Thr Glu Leu Pro Leu Thr Leu Tyr Leu Cys Ala Gly Thr Gln Ala Glu Ser Ala G1n Ser Asn Arg Leu Met Met Leu Arg Met His Asn Leu His Gly Thr Lys Pro Pro Pro Ser GIu Gly Ser Asp Glu Glu Glu Glu Glu Glu Asp Glu Glu Asp Glu Glu Glu Arg Lys Pro Gln Leu Glu Leu Ala Met Val Pro His Tyr Gly Gly Ile Asn Arg Val Arg Val Ser Trp Leu Gly Glu Glu Pro Val Ala Gly Val Trp Ser Glu Lys Gly Gln Val Glu Val Phe Ala Leu Arg Arg Leu Leu Gln Val Val Glu Glu Pro G1n Ala Leu Ala Ala Phe Leu Arg Asp Glu Gln Ala Gln Met Lys Pro Ile Phe Ser Phe Ala Gly His Met Gly Glu Gly Phe Ala Leu Asp Trp Ser Pro Arg Val Thr Gly Arg Leu-Leu Thr Gly Asp Cys Gln Lys Asn Ile His Leu Trp Thr Pro Thr Asp Gly Gly Ser T=p His Val Asp Gln Arg Pro Phe Val Gly His Thr Arg Ser Val Glu Asp Leu Gln Trp Ser Pro Thr Glu Asn Thr Val Phe Ala Ser Cys Ser Ala Asp Ala Ser Ile Arg Ile Trp Asp Tle Arg Ala Ala Pro Ser Lys Ala Cys Met Leu Thr Thr Ala Thr Ala His Asp Gly Asp Val Asn Val Ile Ser Trp Ser Arg Arg Glu Pro Phe Leu Leu Ser Gly Gly Asp Asp Gly Ala Leu Lys Ile Trp Asp Leu Arg Gln Phe Lys Ser Gly Ser Pro Val Ala Thr Phe Lys Gln His Val Ala Pro Val Thr Ser Val Glu Trp His Pro Gln Asp Ser Gly Val Phe Ala Ala Ser.Gly Ala Asp His GIn Ile Thr Gln Trp Asp Leu Ala Val Glu Arg Asp Pro Glu Ala Gly Asp Val Glu Ala Asp Pro Gly Leu Ala Asp Leu Pro Gln Gln Leu Leu Phe Val His Gln Gly Glu Thr Glu Leu Lys Glu Leu His Trp His Pro Gln Cys Pro Gly Leu Leu Val Ser Thr Ala Leu Ser Gly Phe Thr Ile Phe Arg Thr Ile Ser Val <210> 22 <211> 265 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 483862CD1 <400> 22 Met Ser Ser Gly Leu Arg Ala Ala Asp Phe Pro Arg Trp Lys Arg His Ile Ser Glu Gln Leu Arg Arg Arg Asp Arg Leu Gln Arg Gln Ala Phe Glu Glu Ile Ile Leu Gln Tyr Asn Lys Leu Leu Glu Lys Ser Asp Leu His Ser Val Leu Ala Gln Lys Leu Gln Ala Glu Lys His Asp Val Pro Asn Arg His Glu Ile Ser Pro Gly His Asp Gly Thr Trp Asn Asp Asn Gln Leu Gln Glu Met Ala Gln Leu Arg Ile Lys His Gln Glu Glu Leu Thr Glu Leu His Lys Lys Arg Gly Glu Leu Ala Gln Leu Val Ile Asp Leu Asn Asn Gln Met Gln Arg Lys Asp Arg Glu Met Gln Met Asn Glu Ala Lys Ile A1a Glu Cys Leu Gln Thr Ile Ser Asp Leu Glu Thr Glu Cjs Leu Asp Leu Arg Thr Lys Leu Cys Asp Leu Glu Arg A1a Asn Gln Thr Leu Lys Asp Glu Tyr Asp Ala Leu G1n Ile Thr Phe Thr Ala Leu Glu Gly Lys Leu Arg Lys Thr Thr Glu Glu Asn Gln Glu Leu Val Thr Arg Trp Met Ala Glu Lys Ala Gln Glu Ala Asn Arg Leu Asn Ala GIu Asn Glu 200 .205 210 Lys Asp Ser Arg Arg Arg Gln Ala Arg Leu Gln Lys Glu Leu Ala Glu Ala Ala Lys Glu Pro Leu Pro Val Glu Gln Asp Asp Asp Ile Glu Val Ile Val Asp Glu Thr Ser Asp His Thr Glu Glu Thr Ser Pro Val Arg Ala Ile Ser Arg Ala Ala Thr <210> 23 <211> 185 <212> PRT
<213> Homo sapiens <220> _ <221> misc_feature c223> Incyte ID No: 1256777CD1 <400> 23 Met Leu Lys Ala Lys Ile Leu Phe Val Gly Pro Cys Glu Ser Gly Lys Thr Val Leu Ala Asn Phe Leu Thr Glu Ser Ser Asp Ile Thr Glu Tyr Ser Pro Thr Gln Gly Va1 Arg Ile Leu Glu Phe Glu Asn Pro His Val Thr Ser Asn Asn Lys Gly Thr Gly Cys Glu Phe Glu Leu Trp Asp Cys Gly Gly Asp Ala Lys Phe Glu Ser Cys Trp Pro AIa Leu Met Lys Asp Ala His Gly Val Val Ile VaI Phe Asn Ala Asp Ile Pro Ser His Arg Lys Glu Met Glu Met Trp Tyr Ser Cys Phe Val Gln Gln Pro Ser Leu Gln Asp Thr Gln Cys Met Leu Ile Ala His His Lys Pro Gly Ser Gly Asp Asp Lys Gly Ser Leu Ser 125 130 i35 Leu Ser Pro Pro Leu Asn Lys Leu Lys Leu Val His Ser Asn Leu Glu Asp Asp Pro Glu Glu Ile Arg Met Glu Phe Ile Lys Tyr Leu Lys Ser Ile Ile Asn Sex Met Ser Glu Ser Arg Asp Arg Glu Glu Met Ser Ile Met Thr <210> 24 <211> 554 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2198779CD1 <400> 24 Met Gly Ser Arg Asn Ser Ser Ser Ala Gly Ser Gly Ser Gly Asp Pro Ser Glu Gly Leu Pro Arg Arg Gly Ala Gly Leu Arg Arg Ser Glu Glu Glu Glu Glu Glu Asp Glu Asp Val Asp Leu Ala Gln Val Leu Ala Tyr Leu Leu Arg Arg Gly Gln Val Arg Leu Val Gln Gly Gly Gly Ala Ala Asn Leu Gln Phe Ile Gln Ala Leu Leu Asp Ser Glu Glu Glu Asn Asp Arg Ala Trp Asp Gly Arg Leu Gly Asp Arg Tyr Asn Pro Pro Val Asp Ala Thr Pro Asp Thr Arg Glu Leu Glu Phe Asn Glu Ile Lys Thr Gln Val Glu Leu Ala Thr Gly Gln Leu Gly Leu Arg Arg Ala Ala Gln Lys His Ser Phe Pro Arg Met Leu His Gln Arg Glu Arg Gly Leu Cys His Arg Gly Ser Phe Ser Leu Gly Glu Gln Ser Arg Val IIe Ser His Phe Leu Pro Asn Asp Leu Gly Phe Thr Asp Ser Tyr Ser Gln Lys Ala Phe Cys Gly Ile Tyr Ser Lys Asp Gly Gln Ile Phe Met Ser Ala Cys Gln Asp Gln Thr Ile Arg Leu Tyr Asp Cys Arg Tyr Gly Arg Phe Arg Lys Phe Lys Ser Ile Lys Ala Arg Asp Val Gly Trp Ser Val Leu Asp Val Ala Phe Thr Pro Asp Gly Asn His Phe Leu Tyr 5er Ser Trp Ser Asp Tyr Ile His Ile Cys Asn Ile Tyr Gly Glu Gly Asp Thr His Thr Ala Leu Asp Leu Arg Pro Asp Glu Arg Arg Phe Ala VaI Phe Ser Ile Ala Val Ser Ser Asp Gly Arg Glu Val Leu Gly Gly Ala Asn Asp Gly Cys Leu Tyr Val Phe Asp Arg Glu Gln Asn Arg Arg Thr Leu Gln IIe Glu Sex His Glu Asp Asp Val Asn Ala Val Ala Phe Ala Asp Ile Ser Ser Gln IIe Leu Phe Ser Gly Gly Asp Asp Ala Ile Cys Lys Val Trp Asp Arg Arg Thr Met Arg Glu Asp Asp Pro Lys Pro Val Gly Ala Leu Ala Gly His Gln Asp Gly Ile Thr Phe Ile Asp Ser Lys Gly Asp Ala Arg Tyr Leu Ile Ser Asn Ser Lys Asp Gln Thr Ile Lys Leu Trp Asp Ile Arg Arg Phe Ser Ser Arg Glu Gly Met Glu Ala Ser Arg Gln Ala Ala Thr Gln Gln Asn Trp Asp Tyr Arg Trp Gln Gln Val Pro Lys Lys Gly Phe Thr Leu His Pro Tyr Pro Ala Trp Arg Lys Leu Lys Leu Pro Gly Asp Ser Ser Leu Met Thr Tyr Arg Gly His Gly Val Leu His Thr Leu Ile Arg Cys Arg Phe Ser Pro Ile His Ser Thr Gly Gln Gln Phe Ile Tyr Ser Gly Cys Ser Thr Gly Lys Val Val Val Tyr Asp Leu Leu Ser Gly His Ile Val Lys Lys Leu Thr Asn His Lys Ala Cys Val Arg Asp Val Ser Trp His Pro Phe Glu Glu Lys Ile Val Ser Ser Ser Trp Asp Gly Asn Leu Arg Leu Trp Gln Tyr Arg Gln Ala Glu Tyr Phe Gln Asp Asp Met Pro Glu Ser Glu Glu Cys Ala Ser Ala Pro Ala Pro Val Pro Gln Ser Ser Thr Pro Phe Ser Ser Pro Gln <210> 25 <211> 434 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2226116CD1 <400> 25 Met Arg Pro Ser Ser Ser Val Ser Val Sex Cys Pro Ala Leu Asn Gln Val Ser His Phe Ala Asn Leu Thr Ser Val Gly Ala Met Ala Pro Ala Arg Cys Phe Ser Ala Arg Leu Arg Thr Val Phe Gln Gly Val Gly His Trp Ala Leu Ser Thr Trp Ala Gly Leu Lys Pro Ser Arg Leu Leu Pro Gln Arg Ala Ser Pro Arg Leu Leu Ser Val Gly Arg Ala Asp Leu Ala Lys His Gln Glu Leu Pro Gly Lys Lys Leu Leu Ser Glu Lys Lys Leu Lys Arg Tyr Phe Val Asp Tyr Arg Arg Val Leu Val Cys G1y Gly Asn Gly Gly Ala Gly Ala Ser Cys Phe His Sex Glu Pro Arg Lys Glu Phe Gly Gly Pro Asp Gly Gly Asp Gly Gly Asn Gly Gly His Val Ile Leu Arg Val Asp Gln Gln Val Lys Ser Leu Ser Ser Val Leu Ser Arg Tyr Gln Gly Phe Ser G1y Glu Asp G1y Gly Ser Lys Asn Cys Phe Gly Arg Ser Gly Ala Val Leu Tyr Ile Arg Val Pro Val Gly Thr Leu Val Lys Giu Gly Gly Arg Val Val Ala Asp Leu Ser Cys Val G1y Asp Glu Tyr Ile Ala Ala Leu Gly Gly Ala Gly Gly Lys Gly Asn Arg Phe Phe Leu Ala Asn Asn Asn Arg Ala Pro Val Thr Cys Thr Pro Gly Gln Pro Gly Gln Gln Arg Val Leu His Leu Glu Leu Lys Thr Val Ala His Ala Gly Met Val Gly Phe Pro Asn Ala G1y Lys Ser Sex Leu Leu Arg Ala Ile Ser Asn Ala Arg Pro Ala Val Ala Ser Tyr Pro Phe Thr Thr Leu Lys Pro His Val Gly Ile Val His Tyr Glu Gly His Leu Gln Ile Ala Val Ala Asp Ile Pro Gly Ile Ile Arg Gly Ala His Gln Asn Arg Gly Leu Gly Ser Ala Phe Leu Arg His Ile Glu Arg Cys Arg Phe Leu Leu Phe Val Val Asp Leu Ser Gln Pro Glu Pro Trp Thr Gln Va2 Asp Asp Leu Lys Tyr Glu Leu Glu Met Tyr Glu Lys Gly Leu Ser Ala Arg Pro His Ala Ile Val Ala Asn Lys Ile Asp Leu Pro Glu Ala Gln Ala Asn Leu Ser Gln Leu Arg Asp His Leu Gly Gln Glu Val Ile Val Leu Ser A1a Leu Thr Gly Glu Asn Leu Glu G1n Leu Leu Leu His Leu Lys Val Leu Tyr Asp Ala Tyr Ala Glu Ala Glu Leu Gly Gln Gly Arg Gln Pro Leu Arg Trp <210> 26 <211> 826 WO 00/31263 PCT/US99l28013 <212> P~2T
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2504472CD1 <400> 26 Met Val Ala Pro Val Leu Glu Thr Ser His Val Phe Cys Cys Pro Asn Arg Val Arg Gly Val Leu Asn Trp Ser Ser Gly Pro Arg Gly Leu Leu Ala Phe GIy Thr Ser Cys Ser Val VaI Leu Tyr Asp Pro Leu Lys Arg Val Val Val Thr Asn Leu Asn Gly His Thr Ala Arg Val Asn Cys Ile GIn Trp Ile Cys Lys Gln Asp Gly Ser Pro Ser Thr Glu Leu Val Sex Gly Gly Ser Asp Asn Gln Val Ile His Trp Glu Ile Glu Asp Asn Gln Leu Leu Lys Ala Val His Leu Gln Gly His Glu Gly Pro Val Tyr Ala Val His Ala Val Tyr Gln Arg Arg Thr Ser Asp Pro Ala Leu Cys Thr Leu IIe Val Ser Ala Ala Ala Asp Ser Ala Val Arg Leu Trp Ser Lys Lys Gly Pro Glu Val Met Cys Leu Gln Thr Leu Asn Phe Gly Asn Gly Phe Ala Leu Ala Leu Cys Leu Ser Phe Leu Pro Asn Thr Asp Val Pro I1e Leu Ala Cys Gly Asn Asp Asp Cys Arg Ile His Ile Phe Ala Gln Gln Asn Asp Gln Phe Gln Lys Val Leu Ser Leu Cys Gly His Glu Asp Trp Ile Arg Gly Val Glu Trp Ala Ala Phe Gly Arg Asp Leu Phe Leu Ala Ser Cys Ser Gln Asp Cys Leu Ile Arg Ile Trp Lys Leu Tyr IIe Lys Ser Thr Ser Leu Glu Thr Gln Asp Asp Asp Asn Ile Arg Leu Lys Glu Asn Thr Phe Thr Ile Glu Asn Glu Ser Val Lys Ile Ala Phe Ala Val Thr Leu GIu Thr Val Leu Ala Gly His Glu Asn Trp Val Asn Ala Val His Trp Gln Pro Val Phe Tyr Lys Asp Gly Val Leu Gln Gln Pro Val Arg Leu Leu Ser AIa Ser Met Asp Lys Thr Met Ile Leu Trp Ala Pro Asp Glu Glu Ser Gly Val Trp Leu Glu Gln Val Arg Val Gly Glu Val Gly Gly Asn Thr Leu G1y Phe Tyr Asp Cys Gln Phe Asn Glu Asp Gly Ser Met Ile Ile Ala His Ala WO 00!31263 PCT/US99/2$013 Phe His Gly A1a Leu His Leu Trp Lys Gln Asn Thr Val Asn Pro Arg Glu Trp Thr Pro Glu Ile Val Ile Ser Gly His Phe Asp Gly Val Gln Asp Leu Va1 Trp Asp Pro Glu Gly Glu Phe Ile Ile Thr Val Gly Thr Asp Gln Thr Thr Arg Leu Phe Ala Pro Trp Lys Arg Lys Asp Gln Ser Gln Val Thr Trp His Glu Ile Ala Arg Pro Gln Ile His Gly Tyr Asp Leu Lys Cys Leu Ala Met Ile Asn Arg Phe GIn Phe Val Ser Gly Ala Asp Glu Lys Val Leu Arg Val Phe Ser Ala Pro Arg Asn Phe Val Glu Asn Phe Cys Ala Ile Thr Gly Gln Ser Leu Asn His Val Leu Cys Asn Gln Asp Ser Asp Leu Pro Glu Gly Ala Thr Val Pro Ala Leu Gly Leu Ser Asn Lys Ala Val Phe Gln Gly Asp Ile Ala Ser Gln Pro Ser Asp GIu Glu Glu Leu Leu Thr Ser Thr Gly Phe Glu Tyr Gln Gln Val Ala Phe Gln Pro Ser Tle Leu Thr Glu Pro Pro Thr Glu Asp His Leu Leu Gln Asn Thr Leu Trp Pro Glu Val Gln Lys Leu Tyr Gly His Gly Tyr Glu Ile Phe Cys Val Thr Cys Asn Ser Ser Lys Thr Leu Leu Ala Ser AIa Cys Lys Ala Ala Lys Lys Glu His Ala Ala Ile Ile Leu Trp Asn Thr Thr Ser Trp Lys Gln Val Gln Asn Leu Val Phe His Ser Leu Thr Val Thr Gln Met Ala Phe Ser Pro Asn Glu Lys Phe Leu Leu Ala Val Ser Arg Asp Arg Thr Trp Ser Leu Trp Lys Lys Gln Asp Thr Ile Ser Pro Glu Phe Glu Pro Val Phe Ser Leu Phe Ala Phe Thr Asn Lys Ile Thr Ser Val His Ser Arg Ile Ile Trp Ser Cys Asp Trp Sex Pro Asp Ser Lys Tyr Phe Phe Thr Gly Ser Arg Asp Lys Lys Val Val Val Trp Gly Glu Cys Asp Ser Thr Asp Asp Cys Ile Glu His Asn Ile Gly Pro Cys Ser Ser Val Leu Asp Val Gly Gly Ala Val Thr Ala Val Ser Val Cys Pro Val Leu His Pro Ser Gln Arg Tyr Val Val Ala Val Gly Leu Glu Cys Gly Lys I1e Cys Leu Tyr Thr Trp Lys Lys Thr Asp Gln Val Pro Glu Tle Asn Asp Trp Thr His Cys Val Glu Thr Ser Gln Ser Gln Ser His Thr Leu Ala Ile Arg Lys Leu Cys Trp Lys Asn Cys Ser Gly Lys Thr Glu Gln Lys Glu Ala Glu Gly Ala Glu Trp Leu His Phe Ala Ser Cys Gly Glu Asp His Thr Val Lys Ile His Arg Val Asn Lys Cys Ala Leu <210> 27 <211> 618 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3029920CD1 <400> 27 Met Lys Lys Asp Val Arg Ile Leu Leu Val Gly Glu Pro Arg Val Gly Lys Thr Ser Leu Ile Met Ser Leu Val Ser Glu Glu Phe Pro Glu Glu Val Pro Pro Arg Ala Glu Glu Ile Thr Ile Pro Ala Asp Val Thr Pro Glu Arg Val Pro Thr His Ile Val Asp Tyr Ser Glu Ala Glu Gln Ser Asp Glu Gln Leu His Gln Glu Ile Ser Gln Ala Asn Val Ile Cys IIe Val Tyr Ala Val Asn Asn Lys His Ser Ile Asp Lys Val Thr Ser Arg Trp Ile Pro Leu Ile Asn Glu Arg Thr Asp Lys Asp Ser Arg Leu Pro Leu Ile Leu Val Gly Asn Lys Ser Asp Leu Val Glu Tyr Ser Ser Met Glu Thr I1e Leu Pro Ile Met Asn Gln Tyr Thr Glu Ile Glu Thr Cys Val Glu Cys Ser Ala Lys Asn Leu Lys Asn Ile Ser Glu Leu Phe Tyr Tyr Ala Gln Lys Ala Val Leu His Pro Thr Gly Pro Leu Tyr Cys Pro Glu Glu Lys Glu Met Lys Pro Ala Cys Ile Lys Ala Leu Thr Arg Ile Phe Lys Ile Ser Asp Gln Asp Asn Asp Gly Thr Leu Asn Asp Ala Glu Leu Asn Phe Phe Gln Arg Ile Cys Phe Asn Thr Pro Leu Ala Pro Gln Ala Leu Glu Asp Val Lys Asn Val Val Arg Lys His Ile Ser Asp G1y Val Ala Asp Ser Gly Leu Thr Leu Lys Gly Phe Leu Phe Leu His Thr Leu Phe Ile Gln.Arg Gly Arg His Glu Thr Thr Trp Thr Val Leu Arg Arg Phe Gly Tyr Asp Asp Asp Leu Asp Leu Thr Pro Glu Tyr Leu Phe Pro Leu Leu Lys Ile Pro Pro Asp Cys Thr Thr Glu Leu Asn His His Ala Tyr Leu Phe Leu Gln Ser Thr Phe Asp Lys His Asp Leu Asp Arg Asp Cys Ala Leu Ser Pro Asp Glu Leu Lys Asp Leu Phe Lys Val Phe Pro Tyr Ile Pro Trp Gly Pro Asp Val Asn Asn Thr Val Cys Thr Asn Glu Arg Gly Trp Ile Thr Tyr Gln Gly Phe Leu Ser Gln Trp Thr Leu Thr Thr Tyr Leu Asp Val Gln Arg Cys Leu Glu Tyr Leu Gly Tyr Leu Gly Tyr Ser Ile Leu Thr G1u Gln Glu Ser Gln Ala Ser Ala Val Thr Val Thr Arg Asp Lys Lys Ile Asp Leu Gln Lys Lys Gln Thr Gln Arg Asn Val Phe Arg Cys Asn Val Ile Gly Val Lys Asn Cys Gly Lys Ser Gly Val Leu Gln Ala Leu Leu Gly Arg Asn Leu Met Arg Gln Lys Lys Ile Arg Glu Asp His Lys Ser Tyr Tyr Ala Ile Asn Thr Val Tyr Val Tyr GIy Gln Glu Lys Tyr Leu Leu Leu His Asp Ile Ser Glu Ser Glu Phe Leu Thr Glu Ala Glu Ile Ile Cys Asp Val Val Cys Leu Val Tyr Asp Val Ser Asn Pro Lys Ser Phe Glu Tyr Cys Ala Arg Ile Phe Lys Gln His Phe Met Asp Ser Arg Ile Pro Cys Leu IIe Val Ala Ala Lys Ser Asp Leu His Glu Val Lys Gln Glu Tyr Ser Ile Ser Pro Thr Asp Phe Cys Arg Lys His Lys Met Pro Pro Pro Gln Ala Phe Thr Cys Asn Thr Ala Asp Ala Pro Ser Lys Asp Ile Phe Val Lys Leu Thr Thr Met A1a Met Tyr Pro His Val Thr Gln Ala Asp Leu Lys Ser Ser Thr Phe Trp Leu Arg Ala Ser Phe Gly Ala Thr Val Phe Ala Val Leu Gly Phe Ala Met Tyr Lys Ala Leu Leu Lys Gln Arg <220> 28 <211> S96 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3332415CD1 <400> 28 Met Glu Pro Glu Leu Asp Ala Gln Lys Gln Pro Arg Pro Arg Arg l 5 10 15 Arg Ser Arg Arg Ala Ser Gly Leu Ser Thr Glu Gly Ala Thr Gly Pro Ser Ala Asp Thr Sex Gly Ser Glu Leu Asp Gly Arg Cys Ser Leu Arg Arg Gly Ser Ser Phe Thr Phe Leu Thr Pro Gly Pro Asn Trp Asp Phe Thr Leu Lys Arg Lys Arg Arg Glu Lys Asp Asp Asp Val Val Ser Leu Ser Ser Leu Asp Leu Lys Glu Pro Ser Asn Lys Arg Val Arg.Pro Leu Ala Arg Val Thr Ser Leu Ala Asn Leu Ile Ser Pro Val Arg Asn Gly Ala Val Arg Arg Phe Gly Gln Thr Ile Gln Ser Phe Thr Leu Arg Gly Asp His Arg Ser Pro Ala Ser Ala Gln Lys Phe Ser Ser Arg Ser Thr Val Pro Thr Pro Ala Lys Arg Arg Ser Ser Ala Leu Trp Ser Glu Met Leu Asp Ile Thr Met Lys Glu Ser Leu Thr Thr Arg Glu Ile Arg Arg Gln Glu Ala Ile Tyr Glu Met Ser Arg Giy Glu Gln Asp Leu Ile Glu Asp Leu Lys Leu Ala Arg Lys Ala Tyr His Asp Pro Met Leu Lys Leu Ser Ile Met Ser Glu Glu Glu Leu Thr His Ile Phe Gly Asp Leu Asp Ser Tyr Ile Pro Leu His Glu Asp Leu Leu Thr Arg Ile Gly Glu Ala Thr Lys Pro Asp Gly Thr Val Glu Gln Ile Gly His IIe Leu Val Ser Trp Leu Pro Arg Leu Asn Ala Tyr Arg Gly Tyr Cys Ser Asn Gln Leu Ala Ala Lys Ala Leu Leu Asp Gln Lys Lys Gln Asp Pro Arg Val Gln Asp Phe Leu Gln Arg Cys Leu Glu Ser Pro Phe Ser Arg Lys Leu Asp Leu Trp Ser Phe Leu Asp Ile Pro Arg Ser Arg Leu Val Lys Tyr Pro Leu Leu Leu Lys Glu Ile Leu Lys His Thr Pro Lys Glu His Pro Asp Val Gln Leu Leu Glu Asp Ala Ile Leu Ile Ile Gln Gly Val Leu Ser Asp Ile Asn Leu Lys Lys Gly Glu Ser Glu Cys Gln Tyr Tyr Ile Asp Lys Leu Glu Tyr Leu Asp Glu Lys WO 00!3/263 PCT/US99/2$013 Gln Arg Asp Pro Arg Ile Glu Ala Ser Lys Val Leu Leu Cys His Gly Glu Leu Arg Ser Lys Ser Gly His Lys Leu Tyr Ile Phe Leu Phe Gln Asp Ile Leu Val Leu Thr Arg Pro Val Thr Arg Asn Glu Arg His Ser Tyr Gln Val Tyr Arg Gln Pro Ile Pro Val Gln Glu Leu Val Leu Glu Asp Leu Gln Asp G1y Asp Val Arg Met Gly Gly Sex Phe Arg Gly Ala Phe Ser Asn Ser Glu Lys Ala Lys Asn Ile Phe Arg Ile Arg Phe His Asp Pro Ser Pro Ala Gln Ser His Thr Leu Gln Ala Asn Asp Val Phe His Lys Gln Gln Trp Phe Asn Cys Ile Arg Ala Ala Ile Ala Pro Phe Gln Ser Ala Gly Ser Pro Pro Glu Leu Gln Gly Leu Pro Glu Leu His Glu Glu Cys Glu GIy Asn His Pro Ser Ala Arg Lys Leu Thr Ala Gln Arg Arg Ala Ser Thr Val Ser Ser Val Thr Gln Val Glu Val Asp Glu Asn Ala Tyr Arg Cys Gly Ser Gly Met Gln Met Ala GIu Asp Ser Lys Ser Leu Lys Thr His Gln Thr Gln Pro Giy Ile Arg Arg Ala Arg Asp Lys Ala Leu Ser Gly Gly Lys Arg Lys Glu Thr Leu Val <210> 29 <211> 589 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4031536CD1 <400> 29 Met Ser Lys Pro Gly Lys Pro Thr Leu Asn His Gly Leu Val Pro Val Asp Leu Lys Ser Ala Lys Glu Pro Leu Pro His Gln Thr Val Met Arg Ile Phe Ser Ile Ser Ile Ile Ala Gln Gly Leu Pro Phe Cys Arg Arg Arg Met Lys Arg Lys Leu Asp His Gly Ser Glu Val Arg Ser Phe Ser Leu Gly Lys Lys Pro Cys Lys Val Ser Glu Tyr Thr Ser Thr Thr Gly Leu Val Pro Cys Ser Ala Thr Pro Thr Thr 8p 85 90 Phe Gly Asp Leu Arg Ala Ala Asn Gly Gln Gly Gln Gln Arg Arg Arg Ile Thr Ser Val Gln Pro Pro Thr Gly Leu Gln Glu Trp Leu Lys Met Phe Gln Ser Trp Ser Gly Pro Glu Lys Leu Leu Ala Leu Asp Glu Leu Ile Asp Ser Cys Glu Pro Thr Gln Val Lys His Met Met Gln Val Ile Glu Pro Gln Phe Gln Arg Asp Phe Ile Ser Leu Leu Pro Lys Glu Leu Ala Leu Tyr Val Leu Ser Phe Leu Glu Pro 17p 175 180 Lys Asp Leu Leu Gln Ala Ala Gln Thr Cys Arg Tyr Trp Arg Ile Leu Ala Glu Asp Asn Leu Leu Trp Arg Glu Lys Cys Lys Glu Glu Gly Lle Asp Glu Pro Leu His Ile Lys Arg Arg Lys Val Ile Lys Pro Gly Phe Ile His Ser Pro Trp Lys Ser Ala Tyr ile Arg Gln His Arg Ile Asp Thr Asn Trp Arg Arg Gly Glu Leu Lys Ser Pro Lys Val Leu Lys Gly His Asp Asp His Val Ile Thr Cys Leu Gln Phe Cys Gly Asn Arg Ile Val Ser Gly Ser Asp Asp Asn Thr Leu Lys Val Trp Ser Ala Val Thr Gly Lys Cys Leu Arg Thr Leu Val Gly His Thr Gly Gly Val Trp Ser Ser Gln Met Arg Asp Asn Ile Ile Ile Ber Gly Ser Thr Asp Arg Thr Leu Lys Val Trp Asn Ala Glu Thr Gly Glu Cys Ile His Thr Leu Tyr Gly His Thr Ser Thr Val Arg Cys Met His Leu His Glu Lys Arg Val Va1 Ser Gly Ser Arg Asp Ala Thr Leu Arg Val Trp Asp Ile Glu Thr Gly Gln Cys Leu His Val Leu Met Gly His Val Ala Ala Val Arg Cys Val Gln Tyr Asp Gly Arg Arg Val Val Ser Gly Ala Tyr Asp Phe Met Val Lys Val Trp Asp Pro Glu Thr Glu Thr Cys Leu His Thr Leu Gln Gly His Thr Asn Arg Val Tyr Ser Leu Gln Phe Asp Gly I1e His 425 430 , 435 Val Val Ser Gly Ser Leu Asp Thr Ser Ile Arg Val Trp Asp Val Glu Thr Gly Asn Cys Ile His Thr Leu Thr Gly His Gln Ser Leu Thr Ser Gly Met Glu Leu Lys Asp Asn Ile Leu Val Ser G1y Asn Ala Asp Ser Thr Val Lys Ile Trp Asp Ile Lys Thr Gly Gln Cys Leu Gln Thr Leu Gln GIy Pro Asn Lys His Gln Ser Ala Val Thr Cys Leu Gln Phe Asn Lys Asn Phe Val Ile Thr Ser Ser Asp Asp Gly Thr Val Lys Leu Trp Asp Leu Lys Thr Gly Glu Phe Ile Arg Asn Leu Val Thr Leu Glu Ser G1y GIy Ser Gly Gly Val Val Trp Arg Ile Arg Ala Ser Asn Thr Lys Leu Val Cys Ala Val Gly Ser Arg Asn Gly Thr Glu Glu Thr Lys Leu Leu VaI Leu Asp Phe Asp Val Asp Met Lys <210> 30 <211> 3375 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 708398CBI
<400> 30 ggggagaagg gagcccgcag gatcaggggt cagagttagg gggcttccct cctgctgcac 60 cctcatctca gggccgccaa cttccagctg cagcggcgac tttcagtttc atttccacgg 120 accctcctgc ctgggcccgc agccgccgcc gcgatgccca gtaagttcag ctgccggcag 180 ctccgggagg cgggccagtg tttcgagagt ttcctggtcg ttcggggact ggacatggag 240 acagatcgcg agcggctgcg gaccatttat aaccgcgact tcaagatcag ctttgggacc 300 cccgcccctg gcttctcctc catgctgtat ggaatgaaga ttgcaaatct ggcctacgtc 360 accaagactc gggtcaggtt cttcagactc gaccgctggg ccgacgtgcg gttcccagaa 420 aagaggagaa tgaagctggg gtcagatatc agcaaacacc acaagtcact gctagccaag 480 atcttttatg acagggctga gtatcttcat gggaaacatg gtgtggatgt ggaagtccag 540 gggccccatg aagcccgaga tgggcagctc cttatccgcc tggatttgaa ccgcaaagag 600 gtgctgaccc tgaggcttcg gaatggcgga acccagtctg ttaccctcac tcacctcttc 660 ccactctgcc ggacacccca gtttgctttc tacaatgaag accaggagtt gccctgtcca 720 ctgggccccg gtgaatgcta tgaactccat gtccattgta agaccagctt tgtgggctac 780 ttcccagcca cagtgctctg ggagctgctg ggacctgggg agtcgggttc agaaggagcc 840 ggcacattct acattgcccg cttcttggct gccgtcgccc acagccccct ggctgcacag 900 ctgaagccca tgactccctt caagcggacc cggatcaccg gaaaccctgt ggtgaccaat 960 cggatagagg aaggagagag acctgaccgc gctaagggct atgacctgga gttaagtatg 1020 gcgctgggga catactaccc acctccccgc ctcaggcagc tgctccccat gcttcttcag 1080 ggaacaagta tcttcactgc ccctaaggag atcgcagaga tcaaggccca gctggagaca 1140 gccctgaagt ggaggaacta tgaggtgaag ctgcggctgc tgctgcacct ggaggaactg 1200 cagatggagc atgatatccg gcactatgac ctggagtcgg tgcccatgac ctgggaccct 1260 gtggaccaga accccaggct gctcacgctg gaggttcctg gagtgactga gagccgcccc 1320 tcagtgctac ggggcgacca cctgtttgcc cttttgtcct cggagacaca ccaggaggac 1380 cccatcacat ataagggctt tgtgcacaag gtggaattgg accgtgtcaa gctgagcttt 1440 tccatgagcc tcctgagccg ctttgtggat gggctgacct tcaaggtgaa ctttaccttc 1500 aaccgccagc cgctgcgagt ccagcaccgt gccctggagc tgacagggcg ctggctgctg 1560 tggcccatgc tctttcctgt ggcacctcgg gacgtcccgc tgctgccctc agatgtgaaa 1620 ctcaagctgt acgaccggag tctggagtca aacccagagc agctgcaggc catgaggcac 1680 attgttacgg gcaccacccg tccagccccc tacatcatct ttgggcctcc aggcaccggc 1740 aagactgtca cgttagtgga ggcaattaag caggtggtga agcacttgcc caaagcccac 1800 atcttggcct gcgctccatc caactcaggg gctgacctac tctgtcaaag gctccgggtc 1860 caccttccta gctccatcta ccgcctcctg gcccccagca gggacatccg catggtacct 1920 4l /b~

gaggacatca agccctgctg caactgggac gcaaagaagg gggagtatgt atttcccgcc 1980 aagaagaagc tgcaggaata ccgggtctta attaccaccc tcatcactgc cggcaggttg 20.40 gtctcggccc agtttcccat tgatcacttc acacacatct tcatcgatga ggctggccac 2100 tgcatggagc ctgagagtct ggtagctata gcagggctga tggaagtaaa ggaaacaggt 2160 gatccaggag ggcagctggt gctggcagga gaccctcggc agctggggcc tgtgctgcgt 2220 tccccactga cccagaagca tggactggga tactcactgc tggagcggct gctcatctac 2280 aactccctgt acaagaaggg ccctgatggc tatgaccccc agttcataac caagctgctc 2340 cgcaactaca ggtctcatcc caccatcctg gacattccta accagctcta ttatgaaggg 2400 gagctgcagg cctgtgctga tgtcgtggat cgagaacgct tctgccgctg ggcgggccta 2960 cctcgacagg gctttcccat catctttcac ggcgtaatgg gcaaagatga gcgtgaaggc 2520 aacagcccat ccttcttcaa ccctgaagag gctgccacag tgacttccta cctgaagctg 2580 ctcctggccc cctcctccaa gaagggcaaa gctcgcctga gccctcgaag tgtgggcgtc 2640 atctccccgt accggaaaca ggtggagaaa atccgttact gcatcaccaa acttgacagg 2700 gagcttcgag gactggatga catcaaggac ttgaaggtgg gttcagtaga agaattccaa 2760 ggccaagaac gaagcgtcat cctcatctcc accgtgcgaa gcagccagag ctttgtgcag 2820 ctggatctgg actttaatct gggtttcctt aagaacccca agaggttcaa tgtagctgtg 2880 acccgggcca aggccctgct catcatcgtg gggaaccccc ttctcctggg ccatgaccct 2940 gactggaaag tattcctgga gttctgtaaa gaaaacggag ggtataccgg gtgtcccttc 3000 cctgccaaac tggacctgca acagggacag aatttactgc aaggtctgag caagctcagc 3060 ccctctacct cagggcccca cagccatgac tacctccccc aggagcggga gggtgaaggg 3120 ggcctgtctc tgcaagtgga gccagagtgg aggaatgagc tctgaagaca cagcacccag 3180 ccttctcgca ccagccaagc cttaactgcc tgcctgaccc tgaaccagaa cccagctgaa 3240 ctgcccctcc aagggacagg aaggctgggg gagggagttt acaacccaag ccattccacc 3300 ccctcccctg ctggggagaa tgacacatca agctgctaac aattggggga aggggaagga 3360 agaaaactct gaaac 3375 <210> 31 <211> 2434 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ZD No: 1259937CB1 <400> 31 caaggatccg atgggtatat ggagtgtgag gtaatggatc attcatgtgg aaggatgcag 60 ggggtttttg agaccagggt ttggaagaga gttcagcact gctggtagtt ttgggaatca 120 cccatgtgca ggcgacacat gaggcagtaa ggaactctgc aggggtccct gagatttgga 180 aatgtaggga agagcaatgg attgaggtcc gaacctggag gatctgctat acgcagagct 240 gggaggaggg acagagtcag taccagagtc ggaaaaaagc agggtgggaa ggggaacctg 300 agtcaggaga cttgcctggc aggcgctgcc ctgccagcag aggcctgaca gtggtttcca 360 tgaactgcat ccctgctgtg ggctgggaca gggccactga cacagtatcg gagcacagaa 420 ggggaaagga gcaggaggga ttccaactct gccagttagc agctgtgtgg ctttgggcat 480 gttacttaac ctctctgagc ctcatttatt tcatccataa aatggaaata aaaataatac 540 ttttgtcaaa ggcgcattgt gaatatttag atcctcagaa taatgcctgg cttgtagcaa 600 atggtagctg gaggaaaagg aagagaaaac caaagtcagc agctgaagga ttttcatatt 660 agaactgctc tggacctatc tggcagatgc agaagcacac acacacggag gggcatggat 720 ttgccccgcc cttagacatg ttgtgtcttc tcctggatcc ttggtcccag gtgccttacc 780 tgagctcagg tgaatgtggc aagcagagcc ctctggtggt gtgaatgctg tgtggcgccc 840 gtgctcctgg tgacacaggg acctcacaat ccctccctcc acggtctcct ctcatgtcct 900 cccagcctta ttttctcgtt cctcttcctc ccaggcccgg aacttgcctg tttggctccc 960 caaccaggac gagccccttc ctggcagcag ctgtgccatc caagttgggg ataaagtccc 1020:
ctatgacatc tgccggccag accactcagt gttgaccctg cagctgcctg tgacagcctc 1080 cgtgagagag gtgatggcag cgttggccca ggaggatggc tggaccaagg ggcaggtgct 1140 ggtgaaggtc aattctgcag gtgatgccat tggcctgcag ccagatgccc gtggtgtggc 1200 cacatctctg gggctcaatg agcgtctctt tgttgtcaac ccacaggaag tgcatgagct 1260 gatcccacac cctgaccagc tggggcccac tgtgggctct gctgaggggc tggacctggt 1320 gagtgccaag gacctggcag gccagctgac ggaccacgac tggagcctct tcaacagtat 1380 ccaccaggtg gagctgatcc actatgtgct gggcccccag catctgcggg atgtcaccac 1440 cgccaacctg gagcgcttca tgcgccgctt caatgagctg cagtactggg tggccaccga 1500 gctgtgtctc tgccccgtgc ccggcccccg ggcccagctg ctcaggaagt tcattaagct 1560 ggcggcccac ctcaaggagc agaagaatct caattccttc tttgccgtca tgtttggcct 1620 cagcaactcg gccatcagcc gcctagccca cacctgggag cggctgcctc acaaagtccg 1680 gaagctgtac tccgccctcg agaggctgct ggatccctca tggaaccacc gggtataccg 1740 actggccctc gccaagctct cccctcctgt catccccttc atgccccttc ttctcaaaga 1800 catgaccttc attcatgagg gaaaccacac actagtggag aatctcatca actttgagaa 1860 gatgagaatg atggccagag ccgcgcggat gctgcaccac tgccgaagcc acaaccctgt 1920 gcctctctca ccactcagaa gccgagtttc ccacctccac gaggacagcc aggtggcgag 1980 gatttccaca tgctcggagc agtccctgag cacccggagt ccagccagca cctgggctta 2040 tgtccagcag ctgaaggtca ttgacaacca gcgggaactc tcccgcctct cccgagagct 2100 ggagccatga ggaggggctg ggactggagc tggagcaggc acttgcagcc gggaaagcca 2160 gggtgtgccg ggccaagata ctcacaggct ggccacagct gggcaaggct ctccgtggag 2220 tggactcgag tccctggagc aggcagtgtg gaggcagcca tcccctgtga tgactggcag 2280 ctaaggagga cctcggagtg gacccgagcc aggaataacg aatgacccaa ggccaaggaa 2340 gggaggacag agaggcccca ggagtgggtg gagagtggag tgcgctggga cgttgtgtgc 2400 aatagagagg tctccacacc agaaaaaaaa aaaa 2434 <210> 32 <211> 892 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1452285CB1 <400> 32 cacgcctctc tctgcaccta cacttgcgct ccccaagtct ctctcgtgcg cagagcccag 50 gctgcgcttc cctggtcagg cacggcacgt ctggccggcc gccaggatgc aggccccgca 120 caaggagcac ctgtacaagt tgctggtgat tggcgacctg ggcgtgggga agaccagtat 18D
catcaagcgc tacgtgcacc agaacttctc ctcgcactac cgggccacaa tcggcgtgga 240 cttcgcgctc aaggtgctcc actgggaccc ggagactgtg gtgcgcctgc agctctggga 300 tatcgcaggt caagaaagat ttggaaacat gacgagggtc tattaccgag aagctatggg 360 tgcatttatt gtcttcgatg tcaccaggcc agccacattt gaagcagtgg caaagtggaa 420 aaatgatttg gactccaagt taagtctccc taatggcaaa ccggtttcag tggttttgtt 480 ggccaacaaa tgtgaccagg ggaaggatgt gctcatgaac aatggcctca agatggacca 540 gttctgcaag gagcacggtt tcgtaggatg gtttgaaaca tcagcaaagg aaaatataaa 600 cattgatgaa gcctccagat gcctggtgaa acacatactt gcaaatgagt gtgacctaat 660 ggagtctatt gagccggacg tcgtgaagcc ccatctcaca tcaaccaagg ttgccagctg 720 ctctggctgt gccaaatcct agtaggcacc tttgctggtg tctggtagga atgacctcat 780 tgttccacaa attgtgcctc tatttttacc attttgggta aacgtcagga tagagatacc 840 acatgtggca agccaaagat ctatgcctcc atatgtgcct ttctgttagc tt 892 <2I0> 33 <211> 2288 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1812894CB1 <400> 33 cggctcgagc ccagatggag gcaacagtac taggttgcag gacttgctaa gccggtaggt 60 ggcctggggt aagagatggg aagagaggct gatccctgtc ccccacagca ctggaggact 120 cccggtccca ggaaggggca aatggtgagg ccgagtcagg tgagctcagc cggcttcggg 180 ctgagctggc aggcgccctg gcagaaatgg aaaccatgaa ggctgtggca gaggtgagcg 240 agagcacgaa ggccgaggct gtggctgcgg tgcagcggca gtgccaagag gaggtggcct 300 cgctgcaggc catcctgaaa gactccatca gcagctatga agcccagatc accgccctga 360 agcaggagcg acagcagcag cagcaggact gtgaggagaa ggagcgggag ctgggccgcc 420 tgaagcagct gctgtcccgg gcctaccccc tggactccct ggagaagcag atggaaaagg 480 cccacgagga ctcggagaag ctgcgggaga tcgtactgcc catggaaaag gagatcgagg 540 agctgaaggc gaagctgctg agggccgagg agctgattca ggagatccag agacgtcccc 600 ggcatgcccc ttccctgcac ggctccacgg agttgctgcc cctgtcccgg gatccatcgc 660 ccccgctgga gcctctggag gagctgagcg gagatggggg tccagccgct gaggccttcg 720 ctcacaactg cgatgacagc gcctccatct cctccttctc ccttggcggt ggggtcggca 780 gcagctcctc cctgccccaa agccgccagg gcctgagccc tgaacaggaa gagacggcct 840 cgctggtgtc tacgggcacc ctggttcccg agggcatcta cctgccccct cctggctacc 900 agctcgtccc agacactcag tgggagcagc tgcagacaga gggccgacag ctgcagaagg 960 acctggagag cgtcagtcgc gagcgggacg agctccaaga gggcctgaga cggagcaatg 1020 aggactgtgc caagcagatg caggtgctcc tggcccaggt ccagaactca gagcagctgc 1080 tgcggaccct gcaagggacc gtgagccagg cccaggagcg ggtgcagctg cagatggcgg 1140 agctggtcac cacccacaag tgcctgcacc atgaggtaaa gcggttgaat gaggaaaacc 1200 aagggctccg ggccgagcag ctgccatcct cagcccccca gggctcgcag caggagcagg 1260 gcgaggagga atcactgccc agctctgtgc cagagctgca gcagctgctg tgctgcacgc 1320 ggcaagaggc gagggcccgg ctgcaggccc aggagcacgg ggccgagcgc ctgcggatcg 1380 agatcgtgac gctgcgggag gctctggagg aggagacagt ggccagggcc agcctggagg 1440 ggcagctgag ggtgcagcgg gaggagacag aggtgctgga ggcctccctg tgcagcctga 1500 ggacagagat ggagcgggtg cagcaggaac agagcaaggc ccagctccca gacctcctct 1560 cagaacagag ggccaaggtg ctgcggctgc aggcagagct ggagaccagt gagcaggtgc 1620 agagggattt cgtgcgactg tcccaggccc tgcaggtgcg cctagagcgg atccgccagg 1680 ctgagaccct ggagcaagtg cgcagcatca tggatgaggc gccactcacg gacgtcaggg 1740 acatcaagga cacctgaggg gtcaggatat ccccaccccc accctgggaa agacgccttt 1800 ccccactcct gaaccatgag gcctcgctct ggggtcttgg atggcttttc caccgtccct 1860 gagactgggg ttgaggggac tgacgggggc caccaccgcc ccgccctcca gcgcctcctc 1920 ccagggtggc tgggcctcct gttctcaggg atcacacctg ggtgaggggc ccaagcccct 1980 cccggaacca aaggtgcagg ctcaggcctg cggctttctg gctgctgtgc tgcctcctgg 2040 gctccagccc tcccctgccc ccagcccgtc ccctgcccag ggcacagcgg agccatgggg 2100 gctgggagtc cccatcagag gcagtgaggt gggccccggc cctgggacag gcagctgcct 2160 tctggtctgc atgacactaa gacgcttgtc cacagcggcg acccaggcct ccaagcttgc 2220 acagaggcaa ggccagactt ttccgtcgtt tattttcaat aaataagcag ctcagcgcaa 2280 aaaaaaaa <210> 34 <211> 1813 <212> DNA
<213> Homo sapiens <220>
<221> unsure <222> 1708, 1711, 1713, 1715 <223> Incyte ID No: a or g or c or t, unknown, or other <220>
<221> misc_feature <223> Incyte ID No: 3074884081 <400> 34 gcacgaagga ggcccggctt caggtggccc tggcggagat gccggaagat gcggacgaga 60 acgccgagga ggagctgctg cggggagagc ctctgctgcc ggcggggacc cagcgcgtgt 120 gtctggttca ccctgacgtc aagtggggcc cggggaagtc gcagatgact cgagccgagt 180 ggcaggtggc ggaggccaca gcgctggtgc acacgctgga cggctggtcc gtggtgcaga 240 caatggtcgt gtccaccaaa acgccggaca ggaagctcat ctttggcaaa gggaactttg 300 agcacctgac agaaaagatc cgagggtctc cagacgtcac gtgcgtcttc ctgaacgtgg 360 agaggatggc tgccccgacc aagaaagaac tggaagccgc ctggggcgtg gaggtgtttg 420 accgcttcac ggtcgtcctg cacatcttcc gctgtaacgc ccgcacgaag gaggcccggc 480 ttcaggtggc cctggcggag atgccgctgc acaggtcgaa cttgaaaagg gacgtcgccc 540 acctgtaccg aggagtcggc tcgcgctaca tcatggggtc aggagaatcc ttcatgcagc 600 tgcagcagcg tctcctgaga gagaaggagg ccaagatcag gaaggccttg gacaggcttc 660 gcaagaagag gcacctgctc cgccggcagc ggacgaggcg ggagttcccc gtgatctccg 720 tggtggggta caccaactgc ggaaagacca cgctgatcaa ggcactgacg ggcgatgccg 780 ccatccagcc acgggaccag ctgtttgcca cgctggacgt cacggcccac gcgggcacgc 840 tgccctcacg catgaccgtc ctgtacgtgg acaccatcgg cttcctctcc cagctgccgc 900 acggcctcat cgagtccttc tccgccaccc tggaagacgt ggcccactcg gatctcatct 960 tgcacgtgag ggacgtcagc caccccgagg cggagctcca gaaatgcagc gttctgtcca 1020 cgctgcgtgg cctgcagctg cccgccccgc tcctggactc catggtggag gttcacaaca 1080 aggtggacct cgtgcccggg tacagcccca cggaaccgaa cgtcgtgccc gtgtctgccc 1140 tgcggggcca cgggctccag gagctgaaag ctgagctcga tgcggcggtt ttgaaggcga 1200 cggggagaca gatcctcact ctccgtgtga ggctcgcagg ggcgcagctc agctggctgt 1260 ataaggaggc cacagttcag gaggtggacg tgatccctga ggacggggcg gccgacgtga 1320 gggtcatcat cagcaactca gcctacggca aattccggaa gctctttcca ggatgaacgg 1380 acgcccacag aggcctgcgg ggtgggggca tcgctgcctg gggagctgag gcgttaccgc 1440 tgtgttgggg gcagcttggt gtcaggtgca gcagggtcct ccttgtctgg ttctgcaccc 1500 gtctcgctcc cagccatttg ctgggatgac cgtgcaggcc ggtgacacgg ccgcacctgc 1560 cccaaagcgg gccgeccgag cgtccactcc aagcctgagc atccacacaa ttccagtggg 1620 ccctcggtgc ctgctgtgaa ctgctttccc tcggaatgtt tccgtaacag gacattaaac 1680 ctttgttttt acttccgtga aaaaaaanac ngngnaaaaa aaaaaggggc ggcccgctcc 1740 tagaggattc caagccttac cgtaacgcgt tgcattggcg agcggtcata agcttcttct 1800 aatagggggt cac <210> 35 <211> 1733 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3452277081 <400> 35 ctacggcctg gaccgagtga ccaatccgaa tgaagtcaag gtaaaccaga aacaaacagt 60 cgttgctgtc aaaaaagaga tcatgtatta ccaacaggcc ttgatgaggt ccacagtgaa 120 gtcttctgtg tccctgggag ggattgtgaa atacagtgag cagttctcat ccaacgatgc 180 catcatgtca ggctgcctcc ccagcaaccc ctggatcacc gatgacaccc agttctggga 240 cttaaatgcc aaattggtgg aaatcccaac caagacgcga gtggaacgat gggccttcaa 300 cttcagcgaa ttgatccgag accccaaagg tcgacagagc ttccagtact tcctcaagaa 360 agaattcagt ggagagaatc tgggattctg ggaagcctgc gaggatctga agtatggaga 420 tcagtccaaa gtcaaggaga aagcagagga gatttacaag ctgttcctgg ccccgggggc 480 gaggcgctgg atcaacatag atggcaaaac catggacatc acagtgaagg ggctgaagca 540 cccccaccgc tatgtgctgg acgccgcaca aacccacatt tacatgctca tgaagaagga 600 ttcttatgct cgctatttaa aatctccgat ctataaggac atgctggcca aagctattga 660 acctcaggaa accaccaaga aaagctccac cctccctttt atgcggcgtc acctgcgctc 720 cagcccaagc cctgtcatcc tgagacagct ggaagaggaa gccaaggccc gagaagcagc 780 caacactgtg gacatcaccc agccgggcca gcacatggct cccagccccc atctgaccgt 840 gtacaccggg acctgcatgc ccccgtctcc ttctagcccc ttctcctcct cctgccgctc 900 ccccagg.aag cctttcgcct cacccagccg cttcatccgg cgacccagca ccaccatctg 960 cccctcaccc atcagagtgg ccttggagag ctcatcgggc ttggagcaga aaggggagtg 1020 cagcgggtcc atggcccccc gtgggccctc tgtcaccgag agcagcgagg cctccctcga 1080 cacctcctgg cctcgcagcc ggcccagggc ccctcctaag gcccgcatgg ctctgtcctt 1140 cagcaggttt ctgagacgag gctgtctggc ctcacctgtc tttgccaggc tctcacccaa 1200 gtgccctgct gtgtcccacg ggagggtgca gcccctgggg gacgtgggcc agcagctgcc 1260 acgaCtgaaa tccaagagag tagcaaactt tttccagatc aaaatggatg tgcccacggg 1320 gagcgggacc tgcttgatgg actcggagga tgctggaaca ggagagtcgg gtgaccgggc 1380 cacagaaaag gaggtcatct gcccctggga gagcctgtaa ggaaagaggc aggctgagct 1440 gggggctctg gaccaggaag atgctctgac agatgccatg gtatgggcca caggacacac 1500 ttgctcgaga accaaagtgc atttgggtga catttgaaga ttggggagac aagatggggt 1560 agattgtggc aaagaatgct ctggctggtt accaggggcc aactccttct cctcttcctg 1620 accctccctc ccctgggcag aagaaacgca tgtggaccag aagactttcc ctgctgcctt 1680 aaaaccaata aaaggttaac tttaagtttc ttggaaaaaa aaaaaaaaag ggg 1733 <210> 36 <211> 1776 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte TD No: 4203832CE1 <400> 36 cccagccgag cccagcctag cccgagccca gcccgagcga accgcgagcc ccaagcccga 60 gccgcgccca gcccgagcag agccctccag CCgCtCaCCC CgCgtgCCaC CCCdgCgaCC 120 ctcagccgct ctctgccctt ctctcggccc cgcgcccgcc ctcgcggccc ctctgcccaa 180 tgaaactggc cgcgatgatc aagaagatgt gcccgagcga ctcggagctg agtatcccgg 240 ccaagaactg ctatcgcatg gtcatcctcg gctcgtccaa ggtgggcaag acggccatcg 300 tgtcgcgctt cctcaccggc cgcttcgagg acgcctacac gcctaccatc gaggacttcc 360 accgcaagtt ctactccatc cgcggcgagg tctaccagct cgacatcctc gacacgtccg 420 gcaaccaccc gttccccgcc atgcggtgcc tctccatcct cacaggagac gttttcatcc 480 tggtgttcag tctggacaac cgcgactcct tcgaggaggt gcagcggctc aggcagcaga 540 tcctcgacac caagtcttgc ctcaagaaca aaaccaagga gaacgtggac gtgcccctgg 600 tcatctgcgg caacaagggt gaccgcgact tctaccgcga ggtggaccag cgcgagatcg 660 agcagctggt gggcgacgac ccccagcgct gcgcctactt cgagatctcg gccaagaaga 720 acagcagcct ggaccagatg ttccgcgcgc tcttcgccat ggccaagctg cccagcgaga 780 tgagcccaga cctgcaccgc aaggtctcgg tgcagtactg cgacgtgctg cacaagaagg 840 cgctgcggaa caagaagctg ctgcgggccg gcagcggcgg cgrcggcggc gacccgggcg 900 acgcctttgg catcgtggca cccttcgcgc gccggcccag cgtacacagc gacctcatgt 960 WO 00/31263 PCT/US99/2$013 acatccgcga gaaggccagc gccggcagcc aggccaagga caaggagcgc tgcgtcatca 120 gctaggagcc ccgccgcgct ggcgacacaa cctaaggagg acctttttgt taagtcaaat 1080 ccaacggccc ggtgcgcccc aggccgggag cgcgcgcgga ctggcgtctc ccctcccggc 1140 gatccgcccc cagcactggg gaggcgccac tgaaccgaga agggacggtc atctgctccg 1200 gaaggaaaga gaacgggcca agactgggac tattccccac ccccggtccc ccattgaggc 1260 ccgccacccc cataactttg ggagcgaggg cccagccgag ggtggattta tcttctcaaa 1320 gacctaagag tgagcgcggg gtgggggagg gatgtgaagt tatccagcct ctgctaggct 1380 tcaagaaacc gtcatgcccg cttgagggtc aggacccacg gggcattatc ttgtctgtga 1440 ttccgggttg ctgtgacagc cggtagagcc tctgccctcc cgaaactaag cgggggggcg 1500 tgggtcaaat catagccaag tgacttgttt acatgtgagt gaaactgcac aaaggaacac 1560 aaaacaaaac ttgcacttta acggtagttc cggtgtcaac atggacacga acaaaacctt 1620 acccaggtgt ttatactgtg tgtgtgtgag gtctttaaag ttattgcttt atttggtttt 1680 ttaatataca ataaaataat ttaaaatgga aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1740 aaaaaaaaaa aaaaaaaaaa gaaaaaaaaa aaaaaa 1776 <210> 37 <211> 1316 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 104368CB1 <400> 37 cggacgcgtg gggcggcttt tctctttagc gctcagggcg ctgacccact gctcttcctc 60 ttaagaaagt gctccattcc ttccggcgcc cggagctgct ggcccaaagg gatccggagc 120 gagctagggc agacaccatg accacccttg atgataagtt gctgggggag aaactgcagt 180 actactatag cagcagtgag gatgaggaca gtgaccacga ggacaaggac cgaggcagat 240 gtgccccagc cagcagttct gtgcctgcag aggctgagct ggcaggcgaa ggcatctcag 300 ttaacacagg cccaaaaggt gtgatcaatg actggcgccg cttcaagcag ttggagacag 360 agcagaggga ggagcagtgc cgggagatgg aaaggctgat caagaagctg tcaatgactt 420 gcaggtccca tctggatgaa gaggaggagc aacagaaaca gaaagacctc caggagaaga 480 tcagtgggaa gatgactctg aaggagtttg ccataatgaa tgaggaccaa gatgatgaag 540 agtttctgca gcagtaccgg aagcagcgaa tggaagagat gcggcagcag cttcacaagg 600 ggccccaatt caagcaggtt tttgagatct ccagtggaga agggttttta gacatgattg 660 ataaagaaca gaaaagcatt gtcatcatgg ttcatattta tgaggatggc attccaggga 720 ccgaagccat gaatggttgc atgatctgcc ttgccgcaga gtacccagct gtcaagttct 780 gcaaggtgaa gagctcagtt attggcgcca gcagtcagtt caccaggaat gcccttcctg 840 ccctgctgat ctataagggg ggtgaattga tcggcaattt tgttcgtgtt actgaccagc 900 tgggggatga tttctttgct gtggaccttg aagcttttct ccaggaattt ggattactcc 960 cagaaaagga agtcttggtg ctgacatctg tgcgtaactc tgccacgtgt cacagtgagg 1020 atagcgacct ggaaatagat tgaactgata gtctagttgc atagatttct cattgtttgg 1080 gttggaatac acgtcattgt ttatttttgt tcctttgtct tctggctttt cagctgttct 1140 ttgtagtccc ttttattatg cataaaataa agaaattctt agattaaatc agaatgctga 1200 ataaccttgt agctagcaat aaggtgactt acagttgtat aaacaggaag ccaggctttt 1260 gaactgttta cttaagattc tgtggtgtga catctctgtt attgtttcca gtcaat 1316 <210> 38 <211> 1554 <212> DNA
<213> Homo Sapiens 4~iss <220>
<221> misc_feature <223> Incyte ID No: 1441680CB1 <400> 38 gtggcttgtg gagtggcgac cgttagtgag gcggttgctg agacagacgc tgaggcgggt 60 aggaggagcc cgagccgtaa gggaagccgt gatgagggcc gtgttgacgt ggagagataa 120 agccgagcac tgtataaatg acatcgcatt taagcctgat ggaactcaac tgattttggc 180 tgccggaagc agattactgg tttatgacac ctctgatggc accttact~c agcccctcaa 240 gggacacaaa gacactgtgt actgtgtggc atatgcgaag gatggcaagc gctttgcttc 300 tggatcagct gacaaaagcg ttattatctg gacatcaaaa ctggaaggca ttctgaagta 360 cacgcacaat gatgctatac aatgtgtctc ctacaatcct attactcatc aactggcatc 420 ttgttcctcc agtgactttg ggttgtggtc tcctgaacag aagtctgtct ccaaacacaa 480 atcaagcagc aagatcatct gctgcagctg gacaaatgat ggtcagtacc tggcgctggg 540 gatgttcaat gggatcatca gcatacggaa caaaaatggc gaggagaaag taaagatcga 600 gcggccgggg ggctccctct cgccaatatg gtccatctgc tggaaccctt caagagagga 660 acgtaatgac atcctggctg tggctgactg gggacagaaa gtttccttct accagctgag 720 tggaaaacag attggaaagg atcgggcact gaactttgac ccctgctgca tcagctactt 780 tactaaaggc gagtacattt tgctgggggg ttcagacaag caagtatctc ttttcaccaa 840 ggatggagtg cggcttggga ctgttgggga gcagaactcc tgggtgtgga cgtgtcaagc 900 gaaaccggat tccaactatg tggtggtcgg ctgccaggac ggcaccattt ccttctacca 960 gcttattttc agcacagtcc atggagttta caaggaccgc tatgcctaca gggatagcat 1020 gactgacgtc attgtgcagc acctgatcac tgagcagaaa gttcggatta aatgcaaaga 1080 gcttgtcaag aagattgcca tctacagaaa tcgattggct atccaactgc cagagaaaat 1140 cctcatctat gagttgtatt cagaggactt atcagacatg cattaccggg taaaggagaa 1200 gattatcaag aagtttgagt gcaacctcct ggtggtgtgt gccaatcaca tcatcctgtg 1260 ccaggagaaa cggctgcagt gcctgtcctt cagcggagtg aaggagcggg agtggcagat 1320 ggagtctctc attcgttaca tcaaggtgat cggtggccct cctggaagag aaggcctctt 1380 agtggggctg aagaagatgt acttgttagt gtattcattc atattgattg taaaggatta 1440 tttttcactc agtactgatg tccttggaaa tcttacctgg aaacatgttt gcaaaaaaca 1500 ttattgggtc tttcatcttt tttcttggta ttacatattt gttcaataaa aata 1554 <210> 39 <211> 232 0 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1494955CB1 <400> 39 gggcgcccgc gtactcacta gctgaggtgg cagtggttcc accaacatgg agctctcgca 60 gatgtcggag ctcatggggc tgtcggtgtt gcttgggctg ctggccctga tggcgacggc 120 ggcggtagcg cgggggtggc tgcgcgcggg ggaggagagg agcggccggc ccgcctgcca 180 aaaagcaaat ggatttccac ctgacaaatc ttcgggatcc aagaagcaga aacaatatca 240 gcggattcgg aaggagaagc ctcaacaaca caacttcacc caccgcctcc tggctgcagc 300 tctgaagagc cacagcggga acatatcttg catggacttt agcagcaatg gcaaatacct 360 ggctacctgt gcagatgatc gcaccatccg catctggagc accaaggact tcctgcagcg 420 agagcaccgc agcatgagag ccaacgtgga gctggaccac gccaccctgg tgcgcttcag 480 ccctgactgc agagccttca tcgtctggct ggccaacggg gacaccctcc gtgtcttcaa 540 gatgaccaag cgggaggatg ggggctacac cttcacagcc accccagagg acttccctaa 600 aaagcacaag gcgcctgtca tcgacattgg cattgctaac acagggaagt ttatcatgac 660 tgcctccagt gacaccactg tcctcatctg gagcctgaag ggtcaagtgc tgtctaccat 720 WO 00/31263 PCT/US99/2$013 caacaccaac cagatgaaca acacacacgc tgctgtatct ccctgtggca gatttgtagc 780 ctcgtgtggc _ttcaccccag atgtgaaggt ttgggaagtc tgctttggaa agaaggggga 840 gttccaggag gtggtgcgag ccttcgaact aaagggccac tccgcggctg tgcactcgtt 900 tgctttctcc aacgactcac ggaggatggc ttctgtctcc aaggatggta catggaaact 960 gtgggacaca gatgtggaat acaagaagaa gcaggacccc tacttgctga agacaggccg 1020 ctttgaagag gcggcgggtg ccgcgccgtg ccgcctggcc ctctccccca acgcccaggt 1080 cttggccttg gccagtggca gtagtattca tctctacaat acccggcggg gcgagaagga 11.40 ggagtgcttt gagcgggtcc atggcgagtg tatcgccaac ttgtcctttg acatcactgg 1200 ccgctttctg gcctcctgtg gggaccgggc ggtgcggctg tttcacaaca ctcctggcca 1260 ccgagccatg gtggaggaga tgcagggcca cctgaagcgg gcctccaacg agagcacccg 1320 ccagaggctg cagcagcagc tgacccaggc ccaagagacc ctgaagagcc tgggtgccct 1380 gaagaagtga ctctgggagg gcccggcgca gaggattgag gaggagggat ctggcctcct 1440 catggcgctg ctgccatctt tcctcccagg tggaagcctt tcagaaggag tctcctggtt 1500 ttcttactgg tggccctgct tcttcccatt gaaactactc ttgtctactt aggtctctct 1560 cttcttgctg gctgtgactc ctccctgact agtggccaag gtgcttttct tcctcccagg 1620 cccagtgggt ggaatctgtc cccacctggc actgaggaga atggtagaga ggagaggaga 1680 gagagagaga atgtgatttt tggccttgtg gcagcacatc ctcacaccca aagaagtttg 1740 taaatgttcc _agaacaacct agagaacacc tgagtactaa gcagcagttt tgcaaggatg 1800 ggagactggg atagcttccc atcacagaac tgtgttccat caaaaagaca ctaagggatt 1860 tccttctggg cctcagttct atttgtaaga tggagaataa tcctctctgt gaactccttg 1920 caaagatgat atgaggctaa gagaatatca agtccccagg tctggaagaa aagtagaaaa 1980 gagtagtact attgtccaat gtcatgaaag tggtaaaagt gggaaccagt gtgctttgaa 2040 accaaattag aaacacattc cttgggaagg caaagttttc tgggacttga tcatacattt 2100 tatatggttg ggacttctct cttcgggaga tgatatcttg tttaaggaga cctcttttca 2160 gttcatcaag ttcatcagat atttgagtgc ccactctgtg cccaaataaa tatgagctgg 2220 ggattaaata cgaataagac atggtttctg ccatcaaaga tggctggtgg gagagagaga 2280 tacaccctta ttaagtgctt tgtgttagtt tattcatagc 2320 <210> 40 <211> 879 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1508161CB1 <400> 40 gaagaatttg ttcaggcgtt cgtgcagaag gaccctttgg ataatgacaa gagttgctac 60 agtgaacgga agaaaacacg aaacttagaa gcttacgtgg aatggtttaa tcgcctcagc 120 tacttggttg ctacagaaat ctgtatgcct gttaagaaaa aacaccgagc aagaatgatt 180 gagtatttca ttgacgtagc tcgggagtgt tttaacattg gcaacttcaa ctccttgatg 240 gcgataatct ctggtatgaa tatgagccca gtctctcgac taaaaaaaac ttgggccaaa 300 gtgaagactg caaaatttga cattcttgag catcagatgg acccttcaag caatttctat 360 aattatcgaa cagctcttcg tggggcagca caaaggtctt taactgctca tagtagtaga 420 gaaaagattg tgataccatt cttcagtctc ttaatcaaag atatttattt cctcaatgag 480 ggttgtgcca accgccttcc caatggccat gtcaattttg agaaattttg ggaactggcc 540 aaacaagtga gtgaatttat gacatggaaa caagtggagt gtccatttga gagggaccgg 600 aagatcttgc agtatctgct cacagtacca gtcttcagtg aagatgctct ctacttggct 660 tcttatgaga gtgaaggacc tgaaaatcat atagagaaag acagatggaa gtctttaagg 720 tcgagcctct taggcagagt ttaacacatg ggagctgcct gcctgctgct gctgctgctt 780 cctgcagatc atggaggggc tggcctttgt tttctggcat ctcgtaccac gaacactcat 840 gaagaccctg cagtcattgg agcacccggg tcagcaaag 879 <210> 41 <211> 2248 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte iD No: 1811877CB1 <400> 41 ggaggaccag gaggacatca ctgcctttga cctcagccct gacaacgagg tgctggtgac 60 agccagtcgg gcattgctgc tggctcagtg ggcctggcaa gagggcagcg ttacccgcct 120 gtggaaggcg atacacacgg cccccgtggc caccatggcc ttcgacccca cctccactct 180 gctagccaca ggtggctgtg atggggccgt gcgcgtctgg gacatcgtgc ggcactacgg 240 gacacaccac ttccgaggct cgcccggtgt cgtgcaccta gtggccttcc acccggaccc 300 tacacgcctg ctgctcttct cctcggccac ggatgccgcc atccgcgtgt ggtcactgca 360 ggaccggtca tgcctggctg tgctgactgc ccactacagc gccgtcacct cactggcctt 420 cagcgccgac ggccacacca tgctcagctc cggccgtgac aagatatgta tcatctggga 480 ccttcagagc tgccaggcca cgaggaccgt gcctgtgttt gagagcgtgg aggctgctgt 540 gctgttgcca gaggagccag tgtcccagct gggtgtgaag tccccagggc tgtactttct 600 gacagctggc gaccaaggca ctctgcgcgt gtgggaggca gcttctgggc agtgtgtgta 660 cacgcaggcc cagccgccgg gccctgggca ggagctgacc cactgcaccc tggcacacac 720 cgccggcgtg gtcctcaccg ccaccgccga ccacaacctg ttgctctacg aggctcgctc 780 cctgcggctg cagaaacagt tcgctggcta cagtgaggag gttttggatg tccggtttct 840 tgggcccgag gactcccacg ttgtcgtggc ctccaatagc ccctgcctaa aagtgtttga 900 gctgcagacg tcagcctgcc agatcctcca cggccacacg gatatcgtcc tggccctgga 960 tgtgttccgg aaggggtggc tctttgccag ctgtgccaag gatcagagcg tccgtatctg 1020 gagaatgaac aaggctggcc aggtgatgtg cgtggctcag ggttccggtc acacacacag 1080 tgtgggcacc gtctgctgct ctaggctgaa ggagtccttc ctggtgacag gcagccagga 1140 ctgcactgtg aagctgtggc ctcttcccaa agccttgctg tccaagaaca cagccccaga 1200 caacggccct atcctcctgc aggcccagac cactcagcgc tgccatgata aggacatcaa 1260 cagcgtggct attgccccca acgacaagct gctggccaca ggctcacagg accgcacggc 1320 caagctctgg gccctgccac agtgccagct gctgggtgtc ttctcaggcc accggcgtgg 1380 cctctggtgc gtccagttct ctcccatgga ccaggtgctg gccacggcct cagctgatgg 1440 caccatcaag ctctgggcac tccaggactt cagctgtctc aagacatttg aggggcacga 1500 tgcttctgtg ctgaaggtgg cctttgtgag ccgtggcacg cagctgctgt ccagcggttc 1560 ggatggcctc gtgaagctct ggaccatcaa gaacaacgag tgtgtgcgga cgctggatgc 1620 ccacgaggac aaggtctggg ggctgcactg cagccggctg gacgaccacg ccctcactgg 1680 ggccagtgac tcccgagtca tcctctggaa ggatgtgacc gaggcggagc aggcagagga 1740 gcaggccagg caagaggagc aggtggtcag gcagcaagag ctggacaacc tgctgcatga 1800 gaagcggtac ctgcgggcgc tgggcctggc catctccctg gatcggcccc acaccgtgct 1860 gactgtcatc caggccatcc ggagggacac tgaggcctgc gagaagctgg aagccaccat 1920 gctccgactg cggcgcgacc agaaagaggc cctgctgcgc ttctgcgtca cgtggaacac 1980 caactcgcgg cactgccacg aggcccaggc cgtgctgggt gtgctcttga ggcgagaggc 2040 ccccgaggag ctgctggcct acgaaggcgt gcgggcagcg cttgaggccc tgctgcccta 2100 cactgagcgg cactttcagc ggctcagcag gaccctccag gccgccgctt tcttggactt 2160 cctgtggcac aacatgaagc tccctgtgcc ggccgccgcc cccaccccct gggaaaccca 2220 taaaggcgca ctgccctaaa aaaaaaaa 2248 <210> 42 <211> 2146 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1848674CB1 <400> 42 gttattggca agttcccctg cagttgtttg ggctgtccct gtggctggtt ctggggtgtg 60 cggccagcca tggagcgctc tgggcccagc gaagtgacag gctcagacgc gtcgggaccg 120 gacccgcagc ttgcggtcac catgggcttc acggggttcg gtaaaaaagc tcgcacattt 180 gacttggaag caatgtttga acaaactcga aggacagctg tggaaagaag tcgcaaaaca 240 ctggaagcaa gagaaaaaga ggaagaaatg aacagagaga aagaattaag aagacaaaat 300 gaagatattg agccaacatc ctcaagatca aatgtggtca gagattgctc caaatcatct 360 tccagggata cgagcagcag tgaaagtgaa cagagttctg actcttctga tgatgagtta 420 attggccctc ctttaccccc taaaatggta ggaaaaccag ttaattttat ggaggaagat 480 atcctcggtc ctttacctcc acctcttaat gaagaagaag aagaagcaga ggaagaagaa 540 gaggaagagg aggaagagga aaatcctgtb cacaagattc ctgactcgca tgagataacg 600 ctgaagcatg gcactaaaac agtgtctgct ttgggtctgg atccctcagg tgcccgtttg 660 gtgacaggag gatatgacta tgatgttaag ttttgggatt ttgctggaat ggatgcttct 720 tttaaggcat ttcgatccct tcagccctgt gagtgccatc agatcaagtc attacagtat 780 agtaacacag gagacatgat tcttgttgta tctggaagct ctcaggccaa ggtgattgac 840 agagatggtt ttgaagtaat ggaatgtata aaaggagacc agtatattgt ggacatggcc 900 aacaccaagg gtcatacagc aatgcttcat actggctcat ggcatcccaa aataaaggga 960 gaatttatga cttgctcaaa tgatgcgact gtgaggacgt gggaagttga aaatccaaag 1020 aagcaaaaaa gtgtgtttaa accacggacg atgcaaggca aaaaagtcat tcccactacg 1080 tgcacatata gtagagatgg aaacctcata gcagctgcct gccagaatgg aagcatacag 1140 atctgggacc gaaatttgac tgttcatcct aagttccact ataaacaggc tcatgactcg 1200 ggcacagaca cttcttgcgt gactttttcc tatgatggta atgtccttgc ctctcgtgga 1260 ggtgacgatt cattaaaatt atgggacatc cgacaattta ataaaccact tttttcagcc 1320 tcgggtcttc ccaccatgtt cccaatgact gactgctgtt tcagtccaga tgataagctc 1380 atagtcactg gtacatctat tcaaagagga tgtggcagcg gcaaacttgt tttctttgag 1440 cgtaggactt tccaaagggt gtatgaaata gacatcacag atgcgagtgt tgttcgctgc 1500 ctgtggcatc caaagctgaa ccagatcatg gttggaactg gaaatggatt ggctaaagtc 1560 tattacgacc ccaacaagag tcagagggga gcaaaattat gtgtggttaa aacccagcgg 1620 aaggcaaaac aagctgagac tctaactcag gactacatca tcacccctca tgccttgcct 1680 atgttccgtg agccccgcca acggagtaca aggaaacagc tggagaagga cagactggat 1740 cccctgaagt cgcataaacc tgaacctcct gtagcaggcc caggtcgtgg tggccgagtt 1800 ggaacccacg ggggcactct ctcttcctat attgtgaaga acattgcttt ggacaagacc 1860 gatgacagta atcctcggga agccattttg cgtcatgcca aagcagcaga agacagccca 1920 tattgggttt ctccagcata ttccaagact cagcccaaaa ccatgtttgc ccaagttgaa 1980 tctgatgatg aggaagcaaa gaatgagcca gaatggaaaa aacgtaaaat ttgaagaatc 2040 tcatttgaga gctgtttgca tgagtgggag gggtatggga caggtttggg tttttttttt 2100 atgctcatga aattaaaaat tcatttttat gaaaaaaaaa aaaaaa 2146 <210> 43 <211> 714 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2012970CB1 <400> 43 ggatggcgag cagcggaggc gaggcggtga cgagagcagc ggctccgcca ttggacgagg 60 WO 00/3t263 PCT/US99/28013 aggcctgagg gacgggccag cggtgcacaa gaagagaccg aggcgggtgg ccccgagaga 120 gccagggcca tggaggccaa catgccgaag cggaaggagc ctggcaggtc tctccgtatc 180 aaagtcatct ccatgggcaa cgccgaagtg gggaaaagct gtattataaa gcgatactgt 240 gagaaaagat tcgtgtctaa atacctggca acaattggaa ttgactatgg agtcacaaag 300 gtacacgtca gagacagaga aatcaaagtt aacatctttg atatggctgg acatcccttc 360 ttctatgagg ttcgaaatga gttttacaag gacacacagg gtgtgatact ggtctatgat 420 gttgggcaga aagactcctt tgacgccctt gatgcgtggc tggcagaaat gaagcaagag 480 cttggacctc atggaaacat ggaaaatatt atatttgtag tttgtgccaa caagattgat 540 tgtaccaaac atcgctgtgt agatgaaagt gaaggacgtc tttgggctga aagcaaaggg 600 ttcctgtact ttgaaacttc agcacaaact ggagaaggca ttaatgagat gttccagata 660 catcttggat agaactaatg gataaattag tctgtttaaa aaagaaaaaa aaaa 714 <210> 44 <2I1> 1779 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2254315CB1 <400> 44 caggaggaag atggcggcgt ccgcagctgc cgctgagctc caggcttctg ggggtccgcg 60 gcacccagtg tgtctgttgg tgttgggaat ggcgggatcc gggaaaacca cttttgtaca 120 gaggctcaca ggacacctgc atgcccaagg cactccaccg tatgtgatca acctggatcc 180 agcagtacat gaagttccct ttcctgccaa tattgatatt cgtgatactg taaagtataa 240 agaagtaatg aaacaatatg gacttggacc caatggcggc atagtgacct cactcaatct 300 ctttgctacc agatttgatc aggtgatgaa atttattgag aaggcccaga acatgtccaa 360 atatgtgttg attgacacac ctggacagat tgaggtattc acctggtcag cttctgggac 420 aattatcact gaagcccttg catcctcatt tccaacagtt gtcatctatg taatggacac 480 atcgagaagt accaacccag tgaccttcat gtccaacatg ctctatgcct gcagcatctt 540 atacaaaacc aagctgcctt tcattgtggt catgaataaa actgacatca ttgaccacag 600 ctttgcagtg gaatggatgc aggattttga ggctttccaa gatgccttga atcaagagac 660 tacatacgtc agtaacctga ctcgttcaat gagcctggtg ttagatgagt tttacagctc 720 actcagggtg gtgggtgtct ctgctgttct gggtactgga ttagatgaac tctttgtgca 780 agttaccagt gctgccgaag aatatgaaag ggagtatcgt cctgaatatg aacgtctgaa 840 aaaatcactg gccaacgcag agagccaaca gcagagagaa caactggaac gccttcgaaa 900 agatatgggt tctgtagcct tggatgcagg gactgccaaa gacagcttat ctcctgtgct 960 gcacccttct gatttgatcc tgactcgagg aaccttggat gaagaggatg aggaagcaga 1020 cagcgatact gatgacattg accacagagt tacagaggaa agccatgaag agccagcatt 1080 ccagaatttt atgcaagaat cgatggcaca atactggaag agaaacaata aataggagac 1140 tttagcacac ttcacttgtt tctagaagtc cagaattttg gacctccacg tgaaagaact 1200 gttcttacct ctgaactggg ggctcccata agggataatt ttcctcagag tagcaaagtt 1260 tctcttatta gagaaatctt gtgactcaga tgaagtcagg gatagaagac ccttggacct 1320 ggcaggttaa tgctgattat tccttggcct ttcccttgta tttatgcaag gaaggatata 1380 ctgagctgat actcttccaa gcctacaact tcaagtttta tcatttgaac tcaagtactt 1440 ttgctgctga ggaatggaat caaaagaacg tagtctcctg gtgaccacct cagatctcta 1500 ttattaggct agatgtatag cctctactcc cccagcttct tgctcttgac cctgcactgt 1560 aagttgccct tctattagca gccaaggaaa agggaaacat gagcttatcc agaacggtgg 1620 cagagtctcc ttggcaatca accaacgttg ctatgaaata tgcctcacac tgtatagctc 1680 attataggac gtcaggtttg ttgaaaaaag tgggcaagac atgattaatg aatcagaatc 1740 ctgtttcatt ggtgacttgg ataaagactt tttaatttt 1779 <210> 45 <211> 2234 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2415545CB1 <400> 45 ccccttctga aaaatggttt cacccgctcc ttctctagaa cgggtcgggc cgctaccact 60 gtccggcccg gaggggaact gttttctccg gaagtgacaa cacgctgact aggaaaagga 120 ggaggcgggg cagtggggcc ttcggcggcg actatggaag gagccggcta cagggtggtg 180 tttgagaagg gcggagtgta cctgcacacc agcgctaaga agtatcagga ccgagactct 240 ctcatcgctg gtgtcatccg tgtcgtggaa aaggacaatg acgtcctcct gcactgggct 300 cctgtagagg aggctggaga ttccacccaa atcctcttct ccaagaagga ctccagtggg 360 ggtgactcat gtgcttctga ggaggaacca acctttgacc ccggctatga acctgactgg 420 gctgtcatca gcactgtgcg gccacagccc tgccactcag agcccacgag aggtgcagag 480 cccagctgcc cccagggctc ctgggccttc tcagtgagtc tgggggagct aaagtccatc 540 cgccgctcca agccaggcct cagctgggcc tacctggttc tggtgaccca ggctggaggt 600 tccctgcccg cactgcactt ccaccgcggg ggcacccgcg ccctgctccg cgtcctcagc 660 cgctacctgc tgttggccag ctccccgcag gactcccgcc tctaccttgt cttcccccac 720 gactcctctg ctctctccaa ctccttccac cacctgcagc tctttgacca ggacagctcc 780 aatgtggtgt cacgcttcct ccaggatccc tactccacca ccttcagcag cttctcccga 840 gtgaccaact tcttccgggg tgccctgcag ccacagcctg agggagccgc ctccgacctt 900 cccccgccac ccgacgatga gcccgagcct ggattcgagg tcatttcctg tgtggagctg 960 gggcctcggc caaccgtgga gcggggccct ccagttacag aggaggagtg ggcacgccac 1020 gtgggccctg aaggtcgcct gcagcaggtc cctgagctga agaaccggat cttctcgggg 1080 ggtctgagcc ccagcctgcg gcgcgaggcc tggaagttcc tcctagggta cctcagctgg 1140 gaaggcacag ctgaggagca caaggcccac atacgcaaga aaacggatga gtatttccgc 1200 atgaagctgc agtggaaatc tgtgagccct gagcaggagc ggagaaactc acttctgcat 1260 ggataccgca gcctcatcga aagggatgtg agccgcactg acaggaccaa caagttctac 1320 gagggtcccg agaacccggg gctgggcctg ctgaacgata tcctcctcac ctactgcatg 1380 tatcacttcg acctcggcta cgtccagggc atgagtgatc ttctctcccc gatcctctac 1440 gtcattcaga acgaggtgga tgctttctgg tgtttctgtg gcttcatgga gctcgtgcaa 1500 gggaactttg aagagagcca ggagaccatg aagcggcaac tcgggcgact gctgctgctc 1560 ctgagggtgc tggaccccct gctctgcgac ttcctggatt cccaggactc cggctctctc 1620 tgcttctgtt tccggtggct gctcatctgg ttcaagaggg aattcccctt cccggatgtc 1680 cttcggctgt gggaggtgct gtggacaggg ctccctggcc ccaatctgca cctgctggtg 1740 gcctgcgcca tcctggacat ggagagggac accctcatgc tgtccggctt cggctccaat 1800 gagatcctca agcacatcaa cgagctgact atgaagctga gcgtggagga cgtgctgacc 1860 cgcgccgagg ccctgcaccg ccagctaacc gcctgcaccc gagctgcccc acaacgtgca 1920 ggagatcctg gggctggccc cgccacgcag agccccacag cccctcgccc accgcctccc 1980 cgctgcctct gtacgcccac ccgggccccg cccaccccgc cgccctccac ggacacagcc 2040 ccgcagcccg acagcagcct ggagatcctg cccgaggagg aggacgaggg cgccgactcc 2100 taaccccgcc aggcagcctc gttctgcaca ggcactttag cccgagccag gcacacctgc 2160 gagggggcag gtgtgctccg ccgccctgct gataagctgg cttcattaaa ctgacacttc 2220 tcaaaaaaaa aaaa 2234 <210> 46 <211> 3150 <212> DNA
<213> Homo sapiens WO 00/31263 PCTNS99I2$013 <220>
<221> unsure <222> 96, 97, 99, 3070-3072, 3074, 3078, 3080-3082, 3085-3087, 3091, <222> 3099, 3100, 3103, 3107, 3110-3112, 3114, 3115, 3121, 3123, 3125, <222> 3128, 3136, 3138, 3140, 3141, 3143, 3145, 3147, 3149 <223> Incyte ID No: a or g or c or t, unknown, or other <220>
<221> misc_feature <223> Incyte ID No: 2707969CB1 <400> 46 acacaggagc aatgcaaaat ttgataaagc atttttctgt cagatcagct gagccctact 60 gcccttcctc tcaagattcc tggagaccca gatgtnngna tctttcattg acaacaaaat 120 aatgtgtcat gatgatgatg ataaagaccc tgtactccgg gtatttgatt cccgagttga 180 caagatcagg ctgttgaatg ttcggacacc tactctccgt acatccatgt accagaagtg 240 taccactgtg gatgaagcag agaaagcaat tgagctgcgt ctggcaaaaa ttgaccatac 300 tgcaattcac ccacatttac ttgacatgaa gattggacaa gggaaatatg agccgggctt 360 cttccctaag ctgcagtctg atgtactttc cactgggcca gccagcaaca agtggacgaa 420 aaggaatgcc cctgcccagt ggaggcggaa agatcggcag aagcagcaca cagaacacct 480 gcgtttagat aatgaccaga gggagaagta catccaggaa gccaggacta tgggcagcac 540 tatccgccag cccaaactgt ccaacctctc tccatcagtg attgcccaga ccaattggaa 600 gtttgtagag ggcctgctga aggaatgccg caataagacc aagaggatgc tggtggaaaa 660 gatgggccga gaagctgtgg agctagggca tggggaggtg aacatcacag gggtggaaga 720 gaacaccctg attgccagcc tttgtgatct cctggaaagg atctggagtc atggactaca 780 agtgaaacag gggaaatcag ccttatggtc ccacctgtta cattatcagg acaaccggca 840 gagaaaactc acatcaggaa gcctcagtac ctcaggaata cttcttgatt cagaacgtag 900 gaagtctgat gccagctcac tcatgcctcc cctgaggatc tccctgattc aggatatgag 960 gcacatccag aacatcgggg aaatcaagac tgatgtggga aaggccagag catgggtgcg 1020 actgtccatg gaaaaaaagt tactttccag acacctgaag cagctcctct cagaccatga 1080 gctcaccaaa aagttatata agcgctatgc cttcetgcgc tgtgatgacg agaaggagca 1140 gttcctctat cacctcctgt ctttcaatgc cgtcgattac ttttgcttca ccaatgtctt 1200 cacaactatc ctgatcccgt accacattct gatcgtacca agcaagaagc tggggggctc 1260 catgttcact gccaacccat ggatctgtat atcaggagaa ttgggtgaga cacagatcat 1320 gcagattccc aggaatgtgc tagagatgac cttcgagtgc cagaacttgg ggaagcttac 1380 tactgtccag attggccatg ataactctgg gctgtatgcc aaatggctgg tggagtatgt 1440 gatggtcagg aatgagatca caggacatac ctacaagttc ccgtgtggcc ggtggttagg 1500 gaagggcatg gatgatggaa gcctggagcg gatcctagtt ggggagctgc tcacatccca 1560 gcctgaggtg gatgagaggc catgccggac cccgccgctg cagcagtccc ccagtgtcat 1620 ccggaggctt gttaccatct cacccaacaa caagcccaag ctgaacactg ggcagatcca 1680 ggagtccatc ggggaggcag tcaatggcat tgtgaagcac ttccataagc ctgagaaaga 1740 gcgaggcagt ctgacgctgt tgctctgtgg agagtgtggc cttgtctcgg ccttggaaca 1800 ggctttccag catggattta aatcgccccg gctcttcaaa aatgtcttca tttgggattt 1860 cctggaaaaa gcacaaacct attatgagac attagagaag aatgaagtag tccctgagga 1920 aaactggcat acaagagccc ggaacttctg ccgatttgtc actgcaatca acaatactcc 1980 ccggaacatc ggcaaggatg gcaagtttca gatgctggtg tgcttgggag ccagagatca 2040 cctcctacac cactggattg ccctgctggc tgactgcccc atcactgcac acatgtatga 2100 ggatgtggca ctgatcaaag accatacact tgtcaattcc ttgattcgtg tgctgcagac 2160 attgcaggag ttcaacatca cgctggagac gtcccttgtc aagggcatcg acatctgacc 2220 tcccagcacc agccagcagc aggactgaga aagactcacc ctgcagctct gacctttttt 2280 cccaaaggga cttaagcgat tgtgcaggag taggagacaa aatgtacact cactgtaaaa 2340 agagaactag aggatttttg gaataaataa tctattttag agtttatttg ctgatttgct 2400 ttttacacac tttcatgtga aagagtgata gggagaggga gcgaggctgg tgccgcttat 2460 tttgaagctg gtgccctccc tcgccgtggc cacatgctgg aagcctgagg cctccctgga 2520 ctgagcctgt ggcactgcgt gcgggacagt tatgtttcct tgccccgtcg cattaatgag 2580 WO 00/31263 PCT/IlS99I28013 gcccttccac atcattttta aactaatgtt tttctatatt aacattatta tggatatttg 2640 gctttcatag gccacacaca ggtgtgctgc gcgggaagcc ccatgctcca atcaaaggga 2700 tttttagtag tgcctctaag caagcaccga tgagtcagtc ccacgtattt tcttttttgt 2750 cagtattgtt tgggaaggag acatgccggg atgtgtcatc gtgccaaata ccacatttcc 2820 tgttggcaca gtttcacaga agtaaacata agcatgtttt aacaggtttt tcttttcttt 2880 tttctttttt aaaatgtttt atttatttaa cccgccattg tgtgttttta agtattttct 2940 ttttttaagg aaaggaaaag cttgtcacaa tctaactggc tatgttatta ttattaaatt 3000 tatgttttgc aacttagaaa ccagctacag tatggcccac ttaataaaac acctgaaaca 3050 aaaaaaaagn nngngggngn nngtnnngag naggagggnn ggngggnggn nngnngggag 3120 ntnanttntg gggtgngngn ngngnangnt 3150 <210> 47 <211> 1806 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2817769CB1 <400> 47 gtctgcgcgc aggtgccgct cggcgcccgg gccgcccgtt ccgcggctgt cgccgccgtc 60 gtgcgtgccg ctcggcggag gggacgggcc tgcgttctct cctccttcct ccccgcctcc 120 agctgccggc aggacctttc tctcgctgcc gctgggaccc cgtgtcatcg cccaggccga 180 gcacgatgcc ccctaaaaag ggaggtgatg gaattaaacc acccccaatc attggaagat 240 ttggaacctc actgaaaatt ggtattgttg gattgccaaa tgttgggaaa tctactttct 300 tcaatgtgtt aaccaatagt caggcttcag cagaaaactt cccgttctgc actattgatc 360 ctaatgagag cagagtacct gtgccagatg aaaggtttga ctttctttgt caataccaca 420 aaccagcaag caaaattcct gcctttctaa atgtggtgga tattgctggc cttgtgaaag 480 gagctcacaa tgggcagggc ctggggaatg cttttttatc tcatattagt gcctgtgatg 540 gcatctttca tctaacacgt gcttttgaag atgatgatat cacgcacgtt gaaggaagtg 600 tagatcctat tcgagatata gaaataatac atgaagagct tcagcttaaa gatgaggaaa 660 tgattgggcc cattatagat aaactagaaa aggtggctgt gagaggagga gataaaaaac 720 taaaacctga atatgatata atgtgcaaag taaaatcctg ggttatagat caaaagaaac 780 ctgttcgctt ctatcatgat tggaatgaca aagagattga agtgttgaat aaacacttat 840 ttttgacttc aaaaccaatg gtctacttgg ttaatctttc tgaaaaagac tacattagaa 900 agaaaaacaa atggttgata aaaattaaag agtgggtgga caagtatgac ccaggtgctt 960 tggtcattcc ttttagtggg gccttggaac tcaagttgca agaattgagt gctgaggaga 1020 gacagaagta tctggaagcg aacatgacac aaagtgcttt gccaaagatc attaaggctg 1080 ggtttgcagc actccaacta gaatactttt tcactgcagg cccagatgaa gtgcgtgcat 1140 ggaccatcag gaaagggact aaggctcctc aggctgcagg aaagattcac acagattttg 2200 aaaagggatt cattatggct gaagtaatga aatacgaaga ttttaaagag gaaggttctg 1260 aaaatgcagt caaggctgct ggaaagtaca gacaacaagg cagaaattat attgttgaag 1320 atggagatat tatcttcttc aaatttaaca cacctcaaca accgaagaag aaataaaatt 1380 tagttattgc tcagataaac atacaacttc caaaaggcat ctgattttta aaaaattaaa 1440 atttctgaaa accaatgcga caaataaagt tggggagatg ggaatctttg acaaacaaat 1500 tatttttatt tgttttaaaa ttaaaatact gtgtaccccc ccccactcca tgaaatgcag 1550 gttcactaaa tgtgaacagc tttgcttttc acgtgattaa gaccctactc caaattgtag 1620 aagcttttca ggaaccatat tactctcatg atacttcatt aatctccatc atgtatgcca 1680 agcctgacac atttgacagt gaggacaatg tggcttgctc ctttttgaat ctacagataa 1740 tgcatgtttt acagtactcc agatgtctac actcaataaa acatttgaca aaaccaaaaa 1800 aaaaaa 1806 <210> 48 <211> 2880 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2917557CB1 <400> 48 gaggaggagg aggaggaaga agaggaagaa gaagatgaag aaagtgaaga agaggaggaa 60 gaggagggag aaagtgaagg cagtgaaggt gatgaggaag atgaaaaggt gtcagatgag 120 aaggattcag ggaagacatt agataaaaag ccaagtaaag aaatgagctc agattctgaa 180 tatgactctg atgatgatcg gactaaagaa gaaagggctt atgacaaagc aaaacggagg 240 attgagaaac ggcgacttga acatagtaaa aatgtaaaca ccgaaaagct aagagcccct 300 attatctgcg tacttgggca tgtggacaca gggaagacaa aaattctaga taagctccgt 360 cacacacatg tacaagatgg tgaagcaggt ggtatcacac aacaaattgg ggccaccaat 420 gttcctcttg aagctattaa tgaacagact aagatgatta aaaattttga tagagagaat 480 gtacggattc caggaatgct aattattgat actcctgggc atgaatcttt cagtaatctg 540 agaaatagag gaagctctct ttgtgacatt gccattttag ttgttgatat tatgcatggt 600 ttggagcccc agacaattga gtctatcaac cttctcaaat ctaaaaaatg tcccttcatt 660 gttgcactca ataagattga taggttatat gattggaaaa agagtcctga ctctgatgtg 720 gctgctactt taaagaagca gaaaaagaat acaaaagatg aatttgagga gcgagcaaag 780 gctattattg tagaatttgc acagcagggt ttgaatgctg ctttgtttta tgagaataaa 840 gatccccgca cttttgtgtc tttggtacct acctctgcac atactggtga tggcatggga 900 agtctgatct accttcttgt agagttaact cagaccatgt tgagcaagag acttgcacac 960 tgtgaagagc tgagagcaca ggtgatggag gttaaagctc tcccggggat gggcaccact 1020 atagatgtca tcttgatcaa tgggcgtttg aaggaaggag atacaatcat tgttcctgga 1080 gtagaagggc ccattgtaac tcagattcga ggcctcctgt tacctcctcc tatgaaggaa 1140 ttacgagtga agaaccagta tgaaaagcat aaagaagtag aagcagctca gggggtaaag 1200 attcttggaa aagacctgga gaaaacattg gctggtttac ccctccttgt ggcttataaa 126 0 gaagatgaaa tccctgttct taaagatgaa ttgatccatg agttaaagca gacactaaat 1320 gctatcaaat tagaagaaaa aggagtctat gtccaggcat ctacactggg ttctttggaa 1380 gctctactgg aatttctgaa aacatcagaa gtgccctatg caggaattaa cattggccca 1440 gtgcataaaa aagatgttat gaaggcttca gtgatgttgg aacatgaccc tcagtatgca 1500 gtaattttgg ccttcgatgt gagaattgaa cgagatgcac aagaaatggc tgatagttta 1560 ggagttagaa tttttagtgc agaaattatt tatcatttat ttgatgcctt tacaaaatat 1620 agacaagact acaagaaaca gaaacaagaa gaatttaagc acatagcagt atttccctgc 1680 aagataaaaa tcctccctca gtacattttt aattctcgag atccgatagt gatgggggtg 1740 acggtggaag caggtcaggt gaaacagggg acacccatgt gtgtcacaag caaaaatttt 1800 gttgacatcg gaatagtaac aagtattgaa ataaaccata aacaagtgga tgttgcaaaa 1860 aaaggacaag aagtttgtgt aaaaatagaa cctatccctg gtgagtcacc caaaatgttt 1920 ggaagacatt ttgaagctac agatattctt gttagtaaga tcagccggca gtccattgat 1980 gcactcaaag actggttcag agatgaaatg cagaagagtg actggcagct tattgtggag 2040 ctgaagaaag tatttgaaat catctaattt tttcacatgg agcaggaact ggagtaaatg 2100 caatactgtg ttgtaatatc ccaacaaaaa tcagacaaaa aatggaacag acgtatttgg 2160 acactgatgg acttaagtat ggaaggaaga aaaataggtg tataaaatgt tttccatgag 2220 aaaccaagaa acttacactg gtttgacagt ggtcagttac atgtccccac agttccaatg 2280 tgcctgttca ctcacctctc ccttccccaa cccttctcta cttggctgct gttttaaagt 2340 ttgcccttcc ccaaatttgg atttttatta cagatctaaa gctctttcga ttttatactg 2400 attaaatcag tactgcagta tttgattaac caagcttctg cagattttgt gattcttggg 2460 acttttttga cgtaagaaat acttctttat ttatgcatat tcttcccaca gtgatttttc 2520 cagcattctt ctgccatatg cctttagggc ttttataaaa tagaaaatta ggcattctga 2580 tatttcttta gctgctttgt gtgaaaccat ggtgtaaaag cacagctggc tgctttttac 2640 tgcttgtgta gtcacgagtc cattgtaatc atcacaattc taaaccaaac taccaataaa 2700 WO 00131263 PCT/US99/280i3 gaaaacagac atccaccagt aagcaagctc tgttaggctt ccatgttagt gtagcttctc 2760 tcccacaagt tgtcctccta ggacaagaat tatcttacaa actaaactat catcacacta 2820 ccttgtatgc cagcacctgg taacagtaga gatttttata cattaatctt gatctgtttt 2880 <210> 49 <211> 1109 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3421335CB1 <400> 49 cccacgcgtc cgctcgctct tgggtcatgc ctggccagca gaaagcagct ccatagggga 60 ggagagccac gcaggatctc acagctgcag tctaatagta acacagagga ttcagcagtg 120 gccaccatgg gttctgtgaa ttccagaggt cacaaggcgg aagcccaggt ggtgatgatg 180 ggcctggact cggcgggcaa gaccacgctc ctttacaagc tgaagggcca ccagctggtg 240 gagaccctgc ccactgttgg tttcaacgtg gagcctctga aagctcctgg gcacgtgtca 300 ctgactctct gggacgttgg ggggcaggcc ccgctcagag ccagctggaa ggactatctg 360 gaaggcacag atatcctcgt gtacgtgctg gacagcacag atgaagcccg cttacccgag 420 tcggcggctg agctcacaga agtcctgaac gaccccaaca tggctggcgt ccccttcttg 480 gtgctggcca acaagcagga ggcacctgat gcacttccgc tgcttaagat cagaaacagg 540 ctgagtctag agagattcca ggaccactgc tgggagctcc ggggctgcag tgccctcact 600 ggggaggggc tgcccgaggc cctgcagagc ctgtggagcc tcctgaaatc tcgcagctgc 660 atgtgtctgc aggcgagagc ccatggggct gagcgcggag acagcaagag atcttgatcc 720 agacagagca gcatatcttt gctcatacaa actagaagaa ccagctgatc cttgagaaat 780 ttacgcttag tctatcaaac aagaaatgct ggcttggccc ggtggctcat gcctgtaatc 840 ccagcactgt gggagaccac ggtgggggaa tcccttgagc ccaggagttg gagagcaaca 900 tcacaacacc ccatttctac taataatcaa aaaattggcc gggcatggtg gcatgtgcct 960 gtagtcccag ctacttggga ggctgaggca ggagaatcgc ttgagcccaa gaggtagagg 1020 ttgcagtgag ccaagatcgc gccactgcac tccagtctgg gcaacagagt gagaccctgt 1080 tctagtggtg ataataataa tgatgtagt 1109 <210> 50 <211> 2407 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 605761CB1 <400> 50 ctttcgctgg cgccattacc tgagttctcc tccagcgttt ccgcaccctc tccgattagc 60 ggtcccagga gtttccaagg taaccgcgca gtagggcgga tctcattagg cggaaagcga 120 aacccggaag tgacgctctt accgggtgtc agcagcgaga gggttcgaag atggcggcgc 180 gcaagggtcg gcgtcgcacg tgtgaaaccg gggaacccat ggaagccgag tccggcgaca 240 caagttccga gggcccggcc caggtctacc tgcccggccg ggggccgccg ctacgcgaag 300 gggaggagct ggtcatggac gaggaggcct atgtgctcta ccaccgagcg cagactggcg 360 ccccctgtct cagctttgac atagtccggg atcacctggg agacaaccgg acagagcttc 420 ctcttacact ttacttgtgt gctgggaccc aggctgagag cgcccagagc aacagactga 480 tgatgcttcg gatgcacaat ctgcatggga caaagccccc accctcagag ggcagtgatg 540 s~iss aagaagaaga ggaggaagat gaagaggatg aagaagagcg gaaacctcag ctggagctgg 600 ccatggtgcc ccactatggt ggcatcaacc gagttcgggt gtcatggctg ggtgaagagc 660 ctgtggctgg ggtgtggtca gagaagggcc aggtggaggt gtttgcgctg cggcggcttc 720 tgcaggtggt ggaggagccc caggccctgg cagccttcct ccgggatgag caggcccaaa 780 tgaagcccat cttctccttc gctggacaca tgggcgaggg ctttgccctt gactggtccc 840 cccgggtgac cggtcgcctg ctgaccggtg actgtcaaaa gaacatccac ctctggacac 900 ctacggacgg cggctcctgg cacgtggacc agcggccatt cgtgggccac acacgctctg 960 tggaggacct gcagtggtca ccgactgaga acacggtgtt tgcctcctgc tcagctgacg 1020 cctccatccg catctgggac atccgggcag cccccagcaa ggcctgcatg ctcaccacag 1080 ccaccgccca tgatggggac gtcaatgtca tcagctggag ccgccgggag cccttcctgc 1140 tcagtggcgg ggatgatggg gccctcaaga tctgggacct tcggcagttc aagtctggtt 1200 ccccagtggc caccttcaag cagcacgtgg cccccgtgac ctccgtcgag tggcaccccc 1260 aggacagcgg ggtctttgca gcctcgggtg cagaccacca gatcacacag tgggacctgg 1320 cagtggagcg ggaccctgag gcgggcgacg tggaggccga ccccggactg gccgacctcc 1380 cgcagcagct gctgttcgtg caccagggcg agaccgagct gaaggagctg cactggcacc 1440 cgcagtgccc agggctcctg gtcagcacgg cgctgtcagg cttcaccatc ttccgcacca 1500 tcagcgtctg aggcgtccca ctggctctga tcttgcttcc tgcttggaaa ctgaagtcga 1560 attgggctcc cctggaaggg gttcattcag gtctgttgac tgagactggc cggcctgtgg 1620 gctgccgtga tggattctgt ttgacgtatt gttctctaga aggcctggct ctgatccagt 1680 gacccctctc accaaagaac tcggtttaac cagggctctg taagaccact cccacccaga 1740 gacttgtgtg gcctggtgtg gcctgtgtgt cggattcctt cctgtcagct gtgacccatt 1800 tgacctgtgt ccccagaacc cagttttttg tttgtttgtt tgagacggag tcttggtctg 1860 tcgcccaggc tggagtgcag tagcacgatc ttggctcact gcaacctccg cctcctgggt 1920 taaagtgatt ctctcagctc agtctcccag gtagctggga ttacaggcat gtgccaccac 1980 accccgttaa tttttgtatt tttagtagag acggggtttc accatgttgg ccaggctggt 2040 ctcaaattct tgatctcaag tgatctgtcc gccccggcct cccagagtgc tgggttggga 2100 ttacaggcgt gagccaccgc gtccggctca ggacccagtt ttggctgctg gttcccagca 2160 ggggactcgg gggatataca gtggctgcac caaattggag gtgtgggttc ctccaacaca 2220 atttgcttct gcccgttgtc ttcctgccag ctgggtttgg ccaggatttc tccgtgtggg 2280 ggctacatgc gaccctctcc cctcctccct gactttagag gctggtgctg tgtcgggagg 2340 aaggtcaggg ctcctgagca gcaataaagg accaggaaga ggcctgaggt gtaaaaaaaa 2400 aaaaaaa 2407 <210> 51 <211> 1158 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 483862CB1 <400> 51 ggaagaccgt cccggatggc ctcggggact gccagtgtgt ggaggtgagc tccgggattg 60 ccggcattcc cgcttctgct ggttgcttca tgctgcaggc tgcggccgtc agccctcgct 120 cgcattggtg gcgctgaggt gccggggcag caagtgacat gtcgtcgggc ctccgcgccg 180 ctgacttccc ccgctggaag cgccacatct cggagcaact gaggcgccgg gaccggctgc 240 agagacaggc gttcgaggag atcatcctgc agtataacaa attgctggaa aagtcagatc 300 ttcattcagt gttggcccag aaactacagg ctgaaaagca tgacgtacca aacaggcacg 360 agataagtcc cggacatgat ggcacatgga atgacaatca gctacaagaa atggcccaac 420 tgaggattaa gcaccaagag gaactgactg aattacacaa gaaacgtggg gagttagctc 480 aactggtgat tgacctgaat aaccaaatgc agcggaagga cagggagatg cagatgaatg 540 aagcaaaaat tgcagaatgt ttgcagacta tctctgacct ggagacggag tgcctagacc 600 tgcgcactaa gctttgtgac cttgaaagag ccaaccagac cctgaaggat gaatatgatg 660 ccctgcagat cacttttact gccttggagg gaaaactgag gaaaactacg gaagagaacc 720 aggagctggt caccagatgg atggctgaga aagcccagga agccaatcgg cttaatgcag 780 agaatgaaaa agactccagg aggcggcaag cccggctgca gaaagagctt gcagaagcag 840 caaaggaacc tctaccagtc gaacaggatg atgacattga ggtcattgtg gatgaaactt 900 ctgatcacac agaagagacc tctcctgtgc gagccatcag cagagcagcc acgtaagtag 960 gcaggtttgg gccagggaaa agacagcttg aggagcaata tgaaggcaca tctgtggaca 1020 tgacaaagaa tgcagtcaga tgcacccaac cccttactcc ttttctggga cacccagcgt 1080 cgaacacacc acagaggtgt ctagtctttc tcagttcacc tctgcttaat gggagggaag 1140 cagaacacgg gtggcttc 1158 <210> 52 <211> 1026 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1256777CB1 <400> 52 ctgcgggcct ctctccgtcg'ccatggaaac gaaagcggcc aagtagagct ccgtcctgac 60 gcgccgcctc ccgtgggctc cggccggcta agccgcggcg gacaactatg ctgaaagcca 120 agatcctctt cgtggggcct tgcgagagtg gaaaaactgt tttggccaac tttctgacag 180 aatcttctga catcactgaa tacagcccaa cccaaggagt gaggatccta gaatttgaga 240 acccgcatgt taccagcaac aacaaaggca cgggctgtga attcgagcta tgggactgtg 300 gtggcgatgc taagtttgag tcctgctggc cggccctgat gaaggatgct catggagtgg 360 tgatcgtctt caatgctgac atcccaagcc accggaagga aatggagatg tggtattcct 420 gctttgtcca acagccgtcc ttacaggaca cacagtgtat gctaattgca caccacaaac 480 caggctctgg agatgataaa ggaagcctgt ctttgtcgcc acccttgaac aagctgaagc 540 tggtgcactc aaacctggaa gatgaccctg aggagatccg gatggaattc ataaagtatt 600 taaaaagcat aatcaactcc atgtctgaga gcagagacag ggaggagatg tcaattatga 660 cctagccagc cttcacctgg gactgccaca tccccagtga aatcagcatg tttctcggtg 720 cagatctgaa atcacatcca gctcctgatg ttttcttctc cctctgactg cagaggaagt 780 gttcctacct gcaggaaggc acctgtcaca cagggcgttc actcagacca tctgtgctct 840 gccctgagtt cagttgagaa aatcctatta tcaaatttgg atttcctggc cccagaactt 900 cccaaagacc tgtaaaatgg agggatttac cacctcacat atgtccagtt aaacagtttg 960 tggacttgta accgtcgcag cccaatgata caacagtagt ttaatcacgt gaaaaaaaaa 1020 aaaaaa 1026 <210> 53 <211> 2456 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte TD No: 2198779081 <400> 53 gacgagcgac gagatgacgg aggagcggtt ggccaacgca tgccggcagt cggtgtaaac 60 aaggcctcgc gccgctgcgg gtcctgcgac cgctcctggc tgggatttcg attggtcggt 120 cagagaggtt acctggaaat ccaacaccgc ccaacacccc tcccgctccc cagtccgggg 180 acttcgatag gattggagaa ggagttgaca ggaggagccc ccgcacagga cctaagaatg 240 591b5 ctgtgaccag aagatgggat cgcggaacag cagcagtgca ggatccgggt ccggagaccc 300 ctccgagggc ttgccccgaa gaggggctgg cctgcgtcgg agtgaggaag aggaagaaga 360 ggatgaagat gtggatctgg cccaggtact ggcctatctc ctccgcagag gccaagtgag 424 gttggtgcag ggaggaggtg cagcaaattt acaattcatt caggccctct tggactcaga 480 ggaagagaat gacagagctt gggatggtcg tcttggggat cgatacaacc cacctgtgga 540 tgctacccct gacacccggg agctggaatt caatgagatc aagacacaag tggaactggc 600 cacagggcag ctggggctta ggcgggccgc ccagaagcac agctttcctc gaatgttgca 660 ccagagagaa cggggcctct gccatcgggg aagcttctcc cttggagaac agtctcgagt 'i20 gatatctcac ttcttgccca atgatctggg cttcactgat agctactctc agaaggcttt 780 ctgtggcatc tacagcaaag atggtcaaat attcatgtct gcttgccaag accagacaat 840 ccgactctat gactgccgat atggccgttt ccgtaaattc aagagcatca aggcccgcga 900 tgtaggctgg agcgtcttgg atgtggcctt cacccctgat gggaaccact tcctctactc 960 tagctggtct gattacattc atatctgcaa tatctatggt gagggagata cacacactgc 1020 cctggatctc aggccagatg agcgtcgctt tgctgtcttc tccattgctg tctcctcaga 1080 tggacgagaa gtactaggag gggccaatga tggctgcctg tatgtctttg accgagaaca 1140 gaaccggcgc acccttcaga ttgagtccca tgaggatgat gtgaatgcag tggcctttgc 1200 tgatataagc tcccaaatcc tgttctctgg gggagatgat gccatctgca aagtgtggga 1260 tcgacgcacc atgcgggagg atgaccccaa gcctgtgggt gcactggctg gacaccagga 1320 tggcatcacc ttcattgaca gcaagggtga tgcccggtat ctgatctcca actctaaaga 1380 ccagaccatc aaactctggg atatccgacg cttttccagc cgggaaggca tggaagcttc 1440 acgccaggct gccacacagc aaaactggga ctatcggtgg cagcaagtgc ccaaaaaagg 1500 gtttactctg catccctacc cagcctggcg gaagctgaag ctcccagggg acagctcctt 1560 gatgacctac cggggccacg gagtgctgca caccctcatc cgctgccggt tctcccccat 1620 tcatagcact ggccagcagt tcatctacag tggctgctcc actggcaaag tggttgtgta 1680 cgaccttcta agtggccaca ttgtgaagaa gctgaccaac cacaaggcct gtgtgcgtga 1740 cgtcagttgg cacccctttg aagagaagat tgtcagcagt tcgtgggacg ggaacctgcg 1800 tctgtggcag taccgccagg ctgagtactt ccaggatgac atgccagaat ctgaggaatg 1860 tgccagcgcc cctgccccag tgccccaatc ctctacaccc ttttcctcac cccagtagat 1920 ccaacctcca gccccatata gggtgaacct cttgataagc tctctgcctc ctcctccctt 1980 tctcccttgt ggggaatgtt tggaggaatc actggcattt gatggggaat aacataagcc 2040 tgggctctga gcctcagctg agccctggaa gattctcccc atggggcaga gtggtctcct 2100 tacgtgctca cacccagtca gcttgggtcc ctatctctgg ccagagtttg gcaggactgc 2160 cattatctgg ggtgtggcct ctgccagcaa gagaagtgtc ctgggtgttt ttaatcatgt 2220 ttgaatgtta ggggttggat cctagagtag atgcctgagg ccacatctga acagacctgt 2280 cagccaggcc tgccaggtct tcacgttgag gattcaactg gccaatcaca ggacaggtgt 2340 cctggccttt cttcctgagg tctctagggg aggggcatgg gtaagggtgt ttcctcagca 2400 ccctcctggg gtggggatta tgtctgctgt catgtctggg tctttaaggt aggaca 2456 <210> 54 <211> 1771 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2226I16CB1 <400> 54 cggctcgagt taatattttc gttgagcgga accttgctat tccataagag gatgtgtcca 60 gtgttgtgga agatttcatg ttttaaatcc tttgtacaga aatcctgctc ccaagtcaca I20 gataggctga cgggtcagag ggcaagacgt gacccagggc cgagagggtg agtgaccagg 180 aaaatcggat tcatcagttc acttgtttgt ttcagaaacg tgcacaaaga cctgctgcat 240 gaggccctcg tcttcagttt ctgtttcatg cccagcatta aaccaagtat ctcattttgc 300 caatttgact tctgtagggg ccatggcacc tgcaaggtgt ttctcagcaa gattgaggac 360 WO 00/31263 PCTIUS99/2$013 cgtgtttcag ggcgtggggc attgggcttt gtccacatgg gctggcctga agcccagccg 420 gctactgcca cagcgggctt ctcccaggct gctctcggtc ggccgtgcgg acctcgccaa 480 gcatcaggaa ctcccgggga agaagctgct ctctgagaaa aagctgaaaa ggtactttgt 540 ggactatcgg agagtgcttg tctgtggagg aaacggaggc gctggggcaa gctgcttcca 600 cagtgagccc cgcaaggagt ttggaggccc tgatggaggg gacggaggca acggtggaca 660 cgtcattctg agagttgacc agcaag.tcaa gtccctgtcg tcggtcctgt cgcggtacca 720 gggtttcagt ggagaagatg gagggagtaa aaactgcttc gggcgcagtg gcgccgtcct 780 ctacatccgg gtccccgtgg gcacgctggt gaaggaggga ggcagagttg tggccgacct 840 gtcttgcgtg ggagatgagt acattgccgc gctgggcggg gcaggaggga aaggcaaccg 900 cttcttcctg gccaacaaca accgtgcccc tgtgacctgt acccctggac agccaggaca 960 gcagcgagtt ctccacctgg agctcaagac ggtggcccac gccggaatgg tgggattccc 1020 caacgccggg aagtcctcac tgctccgggc catttcaaac gccagacccg ccgtggcttc 1080 ctacccgttc accaccctga agccccacgt cgggatcgtc cactacgaag gccacctaca 1140 aatagcagtg gccgacatcc ccggcatcat acgaggcgcc caccagaaca ggggtctggg 1200 gtccgccttc ctcaggcaca tcgagcgctg ccgctttctc ttgttcgtgg tggatctttc 1260 tcagcctgag ccgtggactc aagttgacga tttaaaatat gaactggaga tgtatgaaaa 1320 gggcctgtct gcgaggcccc acgcaatcgt cgcaaacaag attgacctcc ctgaagccca 1380 agccaatctg tcccagctcc gggatcactt gggacaggag gtcatcgtgc tgtcggcgtt 1440 gaccggcgag aacctggagc agctgctgtt gcacctgaag gtgctgtatg acgcctacgc 1500 ggaggccgag ctgggccagg gccgccagcc gctcaggtgg tagccacgcc agagcggggt 1560 cgcctctggg cctctgtctg agcaaacctg ggtgtgaatt cggtggtttt gaatgcataa 1620 agtgccttgt ggacacgggg gagttgtggt gcttctgggt ctctgggccc cgcctgctgg 1680 cctgagatgc cctcatgttg ggaagcattc cgtgcccccc accccgcctg ccctccgtat 1740 ttcctgcacc tgtcagcctg cgctgactga t 1771 <210> 55 <211> 2724 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2504472CB1 <400> 55 gctgaccagt tggcgacatg gtggcacccg tgctggagac ttctcacgtg ttttgctgcc 60 caaaccgggt gcggggagtc ctgaactgga gctctgggcc cagaggactt ctggcctttg 120 gcacgtcctg ctccgtggtg ctctatgacc ccctgaaaag ggttgttgtt accaacttga 180 atggtcacac cgcccgagtc aattgcatac agtggatttg taaacaggat ggctcccctt 240 ctactgaatt agtttctgga ggatctgata atcaagtgat tcactgggaa atagaggata 300 atcagctttt aaaagcagtg catcttcaag gccatgaagg acctgtttat gcggtgcatg 360 ctgtttacca gaggaggaca tcagatcctg cattatgtac actgatcgtt tctgcagctg 420 cagattctgc tgttcgactc tggtctaaaa agggtccaga agtaatgtgc cttcagactt 480 taaactttgg aaatggattt gctttggctc tctgcttatc ttttttgcca aatactgatg 540 taccaatatt agcatgtggc aatgatgatt gcagaattca catatttgct caacaaaatg 600 atcagtttca gaaagtgctt tctctctgtg gacatgagga ttggattaga ggagtggaat 660 gggcagcctt tggtagagat cttttcctag caagctgttc acaagattgc ctgataagaa 720 tatggaagct gtatataaag tcaacatctt tagaaactca ggatgacgat aacataagac 780 tgaaagaaaa tacttttacc atagaaaatg aaagtgttaa aatagcattt gctgttactc 840 tggagacagt gctagccggt catgaaaact gggtaaatgc agttcactgg caacctgtgt 900 tttacaaaga tggtgtccta cagcagccag tgagattatt atctgcttcc atggataaaa 960 ccatgattct ctgggctcca gatgaagagt caggagtttg gctagaacag gttcgagtag 1020 gtgaagtagg tgggaatact ttgggatttt atgattgcca gttcaatgaa gatggctcca 1080 tgatcattgc tcatgctttc cacggagcgt tgcacctttg gaaacagaat acagttaacc 1140 6i/65 WO 00/3/263 PCTlUS99/28013 caagagagtg gactccagag attgtcattt caggacactt tgatggtgtc caagacctag 1200 tctgggatcc agaaggagaa tttattatca ctgttggtac tgatcagaca actagacttt 1260 ttgctccatg gaagagaaaa gaccaatcac aggtgacttg gcatgaaatt gcaaggcctc 1320 agatacatgg gtatgacctg aaatgtttgg caatgattaa tcggtttcag tttgtatctg 1380 gagcagatga aaaagttctt cgggtttttt ctgcacctcg gaattttgtg gaaaattttt 1440 gtgccattac aggacaatca ctgaatcatg tgctctgtaa tcaagatagt gatcttccag 1500 aaggagccac tgtccctgca ttgggattat caaataaagc tgtctttcag ggagatatag 1560 cttctcagcc ttctgatgaa gaggagctgt taactagtac tggttttgag tatcagcagg 1620 tggcctttca gccctccata cttactgagc ctcccactga ggatcatctt ctgcagaata 1680 ctttgtggcc tgaagttcaa aaactatatg ggcacggtta tgaaatattt tgtgttactt 1740 gtaacagttc aaagactctg cttgcctcag cttgtaaggc agctaagaaa gagcatgcag 1800 ctatcattct ttggaacact acatcttgga aacaggtgca gaatttagtt ttccacagtt 1860 tgacagtcac gcagatggcc ttctcaccta atgagaagtt cttactagct gtttccagag 1920 atcgaacctg gtcattgtgg aaaaagcagg atacaatctc acctgagttc gagccagttt 1980 ttagtctttt tgccttcacc aacaaaatta cttctgtgca cagtagaatt atttggtctt 2040 gtgattggag tcctgacagc aagtatttct tcactgggag tcgagacaaa aaggtggttg 2100 tctggggtga gtgcgactcc actgatgact gtattgagca caacattggc ccctgctcct 2160 cagtcctgga cgtgggtggg gctgtgacag ctgtcagcgt ctgcccagtg ctccaccctt 2220 ctcaacgata cgtggttgca gtaggattgg agtgtggaaa gatttgctta tatacctgga 2280 aaaagactga tcaagttcca gaaataaatg actggaccca ctgtgtagaa acaagtcaaa 2340 gccaaagtca tacactggct atcagaaaat tatgctggaa gaattgcagt ggaaaaactg 2400 aacagaagga agcagaaggt gctgagtggt tacactttgc aagctgtggt gaagatcaca 2460 ctgtgaagat acacagagtc aataaatgtg cactgtaatg gacttaataa ctacatgctt 2520 gcagtcactg gtatcttaaa atattatcat gtaaacaggt catctttacc ttcataactg 2580 aattgagttt ctgggttttt tttttttttg agatggagtc ttgctttgtc acaacctcca 2640 cctcccaggt tcaagcgatt ctctttcttc agcctcctga gtagctggga ctagaggcac 2700 accaccatgc ccggctaatt tttg 2724 <210> 56 <211> 2963 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3029920CB1 <400> 56 ggccgaagag gctggcaggt ggcgccgtgg ggtgggtgct cctggtgaga ggagtccact 60 ccgtgcgtgc gggcggaggc cggcccccga gagccgccga catgaagaaa gacgtgcgga 120 tcctgctggt gggagaacct agagttggga agacatcact gattatgtct ctggtcagtg 180 aagaatttcc agaagaggtt cctccccggg cagaagaaat caccattcca gctgatgtca 240 ccccagagag agttccaaca cacattgtag attactcaga agcagaacag agtgatgaac 300 aacttcatca agaaatatct caggctaatg tcatctgtat agtgtatgcc gttaacaaca 360 agcattctat tgataaggta acaagtcgat ggattcctct cataaatgaa agaacagaca 420 aagacagcag gctgccttta atattggttg ggaacaaatc tgatctggtg gaatatagta 480 gtatggagac catccttcct attatgaacc agtatacaga aatagaaacc tgtgtggagt 540 gttcagcgaa aaacctgaag aacatatcag agctctttta ttacgcacag aaagctgttc 600 ttcatcctac agggcccctg tactgcccag aggagaagga gatgaaacca gcttgtataa 660 aagcccttac tcgtatattt aaaatatctg atcaagataa tgatggtact ctcaatgatg 720 ctgaactcaa cttctttcag aggatttgtt tcaacactcc attagctcct caagctctgg 780 aggatgtcaa gaatgtagtc agaaaacata taagtgatgg tgtggctgac agtgggttga 840 ccctgaaagg ttttctcttt ttacacacac tttttatcca gagagggaga cacgaaacta 900 cttggactgt gcttcgacga tttggttatg atgatgacct ggatttgaca cctgaatatt 960 tgttccccct gctgaaaata cctcctgatt gcactactga attaaatcat catgcatatt 1020 tatttctcca aagcaccttt gacaagcatg atttggatag agactgtgct ttgtcacctg 1080 atgagcttaa agatttattt aaagttttcc cttacatacc ttgggggcca gatgtgaata 1140 acacagtttg taccaatgaa agaggctgga taacctacca gggattcctt tcccagtgga 1200 cgctcacgac ttatttagat gtacagcggt gcctggaata tttgggctat ctaggctatt 1260 caatattgac tgagcaagag tctcaagctt cagctgttac agtgacaaga gataaaaaga 1320 tagacctgca gaaaaaacaa actcaaagaa atgtgttcag atgtaatgta attggagtga 1380 aaaactgtgg gaaaagtgga gttcttcagg ctcttcttgg aagaaactta atgaggcaga 1440 agaaaattcg tgaagatcat aaatcctact atgcgattaa cactgtttat gtatatggac 1500 aagagaaata cttgttgttg catgatatct cagaatcgga atttctaact gaagctgaaa 1560 tcatttgtga tgttgtatgc ctggtatatg atgtcagcaa tcccaaatcc tttgaatact 1620 gtgccaggat ttttaagcaa cactttatgg acagcagaat accttgctta atcgtagctg 1680 caaagtcaga cctgcatgaa gttaaacaag aatacagtat ttcacctact gatttctgca 1740 ggaaacacaa aatgcctcca ccacaagcct tcacttgcaa tactgctgat gcccccagta 1800 aggatatctt tgttaaattg acaacaatgg ccatgtatcc gcacgtgaca caagctgacc 1860 tcaagagctc cacgttttgg cttcgagcaa gttttggtgc tactgttttt gcagttttgg 1920 gctttgctat gtacaaagca ttattgaaac agcgatgata taaaaagaaa tactgtccct 1980 accaaaaaca aatactttta tgtacattct gaatgcttta agttctgcta gaattattga 2040 gatatttata catgcagagt tactttatta atatttgtaa ttcatgcata agagtatttt 2100 aatgatagtt ataactgcag tattggctag catatggaaa gaaaacagct aacagccaaa 2160 ctaaaatggc taaattccag aggccaaaag ggaatatttt gtaaatatat gtacatattc 2220 aggcaagata tggtctccca agctgagttc tagaaatgat gtttctagac atttctaagt 2280 ggtattgtta gtgctcactt ggctcactct tctaggttta agttagccca gagattgtat 2340 ttactcatgg atcactttat ttatttcaca tttactcaga atgatccttt gggttctata 2400 aggacataag gtacaatttg ccattgtctc tccattttta aaaacataca agtcagtgtc 2460 agcttaccaa catgacattt tttcagtcag ttgtggtagg ccagccttga agccatcgca 2520 cagtctagaa acttgtgtag ctgagtgtgc agctcacctt taagggtgaa gttaggtaaa 2580 agcaattagc agaggcgtta tctatgtgat tatgttgctt ccttgtcagt atgttgaatt 2640 ttatagccct ttcaatgaaa taaaaaaaaa atttgtatat taccaatgtt tttagtttaa 2700 ataaagagtc acccttacta ctgttgaatt tcatcccaag tgtaaatcat tctataatgg 2760 ctgtgtctgt tatagtatat tacagtaact gcatgtgtca ccaagtgttc tatatcaggc 2820 taggataacc tagaggcagt aattttttaa atgataaaat aaatctaatg aatataaact 2880 ctcatgataa acctattttt tccatcatca gccttttcaa gtatttaaat aaataactgc 2940 tgtgtactgt gaaaaaaaaa aaa 2963 <210> 57 <211> 3332 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte TD No: 3332415CB1 <400> 57 gcctggcaga ggctggcggg catcgtgccc gtccctgccg gtctcccggg cacccggcca 60 ccgccccacc ccctcctccc tgccatggag cccgagctgg acgctcagaa gcagcctcga 120 ccgcggaggc gaagccgccg ggcctctggg ctcagcacgg agggagcgac ggggccttcg 180 gccgacacct ccgggtcgga.gctggacggg agatgttccc ttcggagagg cagctccttc 240 acattcttaa cacctggccc caactgggac ttcactttga aaagaaaacg cagagagaaa 300 gatgatgatg ttgtaagcct tagcagcctt gatctgaagg agccaagcaa taaaagagtt 360 cgacctctgg ctcgtgtcac gtccttggca aatttaatct ctcctgtaag aaatggagct 420 gtcagacgtt ttggtcaaac aatacagtca tttacccttc gtggtgacca cagatcccca 480 gcctctgccc agaagttttc tagcaggtca acagtcccaa cacccgccaa gagaaggagc 540 WO 00/3t263 PCT/US99/28013 agtgcactgt ggtcagagat gctggacatc accatgaagg agtctctcac caccagggag 600 atcagacggc aggaggcaat atatgaaatg tcccgaggtg aacaggattt aattgaggat 660 ctcaaacttg caagaaaggc ctaccatgac cccatgttaa agttgtccat catgtcagaa 720 gaggaactca cacatatatt tggtgatctg gactcttaca tacctctgca tgaagatttg 780 ttgacaagaa taggagaagc aaccaagcct gatggaacag tggagcagat tggtcacatt 840 ctcgtgagct ggttaccgcg cttgaatgcc tacagaggtt actgtagtaa ccagctggca 900 gccaaagctc ttcttgatca aaagaaacag gatccaagag tccaagactt cctccagcga 960 tgtctcgagt ctcccttcag tcgaaaacta gatctttgga gtttcctaga tatccctcga 1020 agtcgcctag tcaaataccc tttactgtta aaagaaattc ttaaacacac tccaaaagag 1080 caccctgatg ttcagcttct ggaggatgct atattgataa tacagggagt cctctctgat 1140 atcaacttga agaaaggtga atccgagtgc cagtattaca tcgacaagct ggagtacctg 1200 gatgaaaagc agagggaccc cagaatcgaa gcgagcaaag tgctgctgtg ccatggggag 1260 ctgcggagca agagtggaca taaactttac attttcctgt ttcaagacat cttggttctg 1320 actcggcccg tcacacggaa cgaacggcac tcttaccagg tttaccggca gccaatccca 1380 gtccaagagc tagtcctaga agacctgcag gatggagatg tgagaatggg aggctccttt 1440 cgaggagctt tcagtaactc agagaaagct aaaaatatct ttagaattcg cttccatgac 1500 ccctctccag cccagtctca cactctgcaa gccaatgacg tgttccacaa gcagcagtgg 1560 ttcaactgta ttcgagcggc cattgccccc ttccagtcgg caggcagtcc acctgagctg 1620 cagggcctgc cggagctgca cgaagagtgt gaggggaacc acccctctgc gaggaaactc 1680 acagcccaga ggagggcatc cacagtttcc agtgttactc aggtagaagt tgatgaaaac 1740 gcttacagat gtggctctgg catgcagatg gcagaggaca gcaagagctt aaagacacac 1800 cagacacagc ccggcatccg aagagcgagg gacaaagccc tttctggtgg caaacggaaa 1860 gagactttgg tgtagagaag gctctgtgtg ttaactgatg ggagagactg tttgtttata 1920 aatgtgtaca gttttgtttt ctcgtaaggg gagcatcata gggttacttt ataccagttg 1980 taacattttc attgtttttg gttgttcttt tttctttttt taatggcagc taaagatata 2040 cagattactg ttaaattgca gtcctttttt ttttaaagat attttcttga gttatttaga 2100 acatggtaag cctggtattt .tttaatcaaa caaaatattt atgaaatggg ttttctctta 2360 attctggatt catcatggct ttctaatacc aattgtaata tttacaatat tcaccaaaac 2220 ttagaatttt gcaaatgctg gaattctgcc agtgtttctt tgctaagcct tgcatgcaaa 2280 atttgaaatt ttaacattgg cacccaaaac ctacatggaa tgtatgtctg gagtatttca 2340 aactttacat tgaaacataa tttccttgga aaacaaacca taagcctgag gaggttttta 2400 tcaactggaa tgctttatat tagtttgttt ttcactgtac attcctcatt ttacattcat 2460 ttaacctgcc gattatttaa tttttttatt gtaaagtagt ttttagcatt tgcttttatt 2520 tttttacttt gatgcctttt caaattggca tgtctttaaa gtatttttct tcctgattaa 2580 aaatgtgtgt gtatgtgtgt gtgtgtgtgt atatatatat atttttttaa atcacattaa 2640 ttttaccaag tgaaaccaag ccatactgtt tttgagccaa ttaagaaaat tgccattttt 2700 aaagtgtagc atttcagggt aaagacccat gaaatggctt gatgtattct agactactga 2760 aagaaaacca cttcaaagat tttgttgaaa gttttagtgt tgtctgaaat gcaagaggga 2820 aggtgattgg tagtgagtta aaagaaaaag agaggaaaag agagtagttt tgtcttcaag 2880 taaaatgtct ggttgtgcca gacatttcac aagtgtgaaa ggagatagga gaagctcaac 2940 ttgagggcgt gtagtaagtt gtagaaggct cgaggggacg tggacttatt tgccttggtt 3000 tgcaatacct gcaaataatg agtttgaaaa gaaacaatga aatgtgttaa aaatttgacc 3060 atattagata aattttggtg gatttagtca taagatggaa aaagactggt gaatctttta 3120 ttacaaaatg tttctgttaa aatgggatca tcatctttga aaggggggag gaggagtaaa 3180 agcccgatta taatggtgat caattcaagt cagtgttgac tattctgtga aatatatttg 3240 gccagtggaa atgataatca gaaaagactg taaatagatc catccaaatg atttctctgt 3300 acaaatgaat gatactatta aaaaaaaaaa as 3332 <210> 58 <211> 2617 <212> DNA
<213> Homo Sapiens <220>

WO 00/31263 PCT/US99/2$013 <223> Incyte ID No: 4031536CB1 <400> 58 tttagtaatg tgcctgtatt acatgtagag agtattcgtc aaccaagagg agttttaaaa 60 tgtcaaaacc gggaaaacct actctaaacc atggcttggt tcctgttgat cttaaaagtg 120 caaaagagcc tctaccacat caaactgtga tgaggatatt tagcattagc atcattgccc 180 aaggcctccc tttttgtcga agacggatga aaagaaagtt ggaccatggt tctgaggtcc 240 gctctttttc tttgggaaag aaaccatgca aagtctcaga atatacaagt accactgggc 300 ttgtaccatg ttcagcaaca ccaacaactt ttggggacct cagagcagcc aatggccaag 360 ggcaacaacg acgccgaatt acatctgtcc agccacctac aggcctccag gaatggctaa 420 aaatgtttca gagctggagt ggaccagaga aattgcttgc tttagatgaa ctcattgata 480 gttgtgaacc aacacaagta aaacatatga tgcaagtgat agaaccccag tttcaacgag 540 acttcatttc attgctccct aaagagttgg cactctatgt gctttcattc ctggaaccca 600 aagacctgct acaagcagct cagacatgtc gctactggag aattttggct gaagacaacc 660 ttctctggag agagaaatgc aaagaagagg ggattgatga accattgcac atcaagagaa 720 gaaaagtaat aaaaccaggt ttcatacaca gtccatggaa aagtgcatac atcagacagc 780 acagaattga tactaactgg aggcgaggag aactcaaatc tcctaaggtg ctgaaaggac 840 atgatgatca tgtgatcaca tgcttacagt tttgtggtaa ccgaatagtt agtggttctg 900 atgacaacac tttaaaagtt tggtcagcag tcacaggcaa atgtctgaga acattagtgg 960 gacatacagg tggagtatgg tcatcacaaa tgagagacaa catcatcatt agtggatcta 1020 cagatcggac actcaaagtg tggaatgcag agactggaga atgtatacac accttatatg 1080 ggcatacttc cactgtgcgt tgtatgcatc ttcatgaaaa aagagttgtt agcggttctc 1140 gagatgccac tcttagggtt tgggatattg agacaggcca gtgtttacat gttttgatgg 1200 gtcatgttgc agcagtccgc tgtgttcaat atgatggcag gagggttgtt agtggagcat 1260 atgattttat ggtaaaggtg tgggatccag agactgaaac ctgtctacac acgttgcagg 1320 ggcatactaa tagagtctat tcattacagt ttgatggtat ccatgtggtg agtggatctc 1380 ttgatacatc aatccgtgtt tgggatgtgg agacagggaa ttgcattcac acgttaacag 1440 ggcaccagtc gttaacaagt ggaatggaac tcaaagacaa tattcttgtc tctgggaatg 1500 cagattctac agttaaaatc tgggatatca aaacaggaca gtgtttacaa acattgcaag 1560 gtcccaacaa gcatcagagt gctgtgacct gtttacagtt caacaagaac tttgtaatta 1620 ccagctcaga tgatggaact gtaaaactat gggacttgaa aacgggtgaa tttattcgaa 1680 acctagtcac attggagagt ggggggagtg ggggagttgt gtggcggatc agagcctcaa 1740 acacaaagct ggtgtgtgca gttgggagtc ggaatgggac tgaagaaacc aagctgctgg 1800 tgctggactt tgatgtggac atgaagtgaa gagcagaaaa gatgaatttg tccaattgtg 1860 tagacgatat actccctgcc cttccccctg caaaaagaaa aaaagaaaag aaaaagaaaa 1920 aaatcccttg ttctcagtgg tgcaggatgt tggcttgggg caacagattg aaaagacnta 1980 cagactaaga aggaaaagaa gaagagatga caaaccataa ctgacaagag aggcgtctgc 2040 tgtctcatca cataaaaggc ttcacttttg actgagggca gctttgcaaa atgagacttt 2100 ctaaatcaaa ccaggtgcaa ttatttcttt attttcttct ccagtggtca ttgggcagtg 2160 ttaatgctga aacatcatta cagattctgc tagcctgttc ttttaccact gacagctaga 2220 cacctagaaa ggaactgcaa taatatcaaa acaagtactg gttgactttc taattagaga 2280 gcatctgcaa caaaaagtca tttttctgga gtggaaaagc ttaaaaaaat tactgtgaat 2340 tgtttttgta cagttatcat gaaaagcttt tttttttttt tttgccaacc attgccaatg 2400 tcaatcaatc acagtattag cctctgttaa tctatttact gttgcttcca tatacattct 2460 tcaatgcata tgttgctcaa aggtggcaag ttgtcctggg ttctgtgagt cctgagatgg 2520 atttaattct tgatgctggt gctagaagta ggtcttcaaa tatgggattg ttgtcccaac 2580 cctgtactgt actcccagtg gccaaactta tttatgc 2617

Claims (20)

What is claimed is:

1. A substantially purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-29 and fragments thereof.

2. A substantially purified variant having at least 90% amino acid sequence identity to the amino acid sequence of claim 1.

3. An isolated and purified polynucleotide encoding the polypeptide of claim 1.

4. An isolated and purified polynucleotide variant having at least 90%
polynucleotide sequence identity to the polynucleotide of claim 3.

5. An isolated and purified polynucleotide which hybridizes under stringent conditions to the polynucleotide of claim 3.

6. An isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide of claim 3.

7. A method for detecting a polynucleotide, the method comprising the steps of:
(a) hybridizing the polynucleotide of claim 6 to at least one nucleic acid in a sample, thereby forming a hybridization complex; and (b) detecting the hybridization complex, wherein the presence of the hybridization complex correlates with the presence of the polynucleotide in the sample.

8. The method of claim 7 further comprising amplifying the polynucleotide prior to hybridization.

9. An isolated and purified polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:30-58 and fragments thereof.

10. An isolated and purified polynucleotide variant having at least 90%
polynucleotide sequence identity to the polynucleotide of claim 9.

11. An isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide of claim 9.

12. An expression vector comprising at least a fragment of the polynucleotide of claim 3.

13. A host cell comprising the expression vector of claim 12.

14. A method for producing a polypeptide, the method comprising the steps of a) culturing the host cell of claim 13 under conditions suitable for the expression of the polypeptide; and b) recovering the polypeptide from the host cell culture.

15. A pharmaceutical composition comprising the polypeptide of claim 1 in conjunction with a suitable pharmaceutical carrier.

16. A purified antibody which specifically binds to the polypeptide of claim 1.

17. A purified agonist of the polypeptide of claim 1.

18. A purified antagonist of the polypeptide of claim 1.

19. A method for treating or preventing a disorder associated with decreased expression or activity of GTPAP, the method comprising administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 15.

20. A method for treating or preventing a disorder associated with increased expression or activity of GTPAP, the method comprising administering to a subject in need of such treatment an effective amount of the antagonist of claim 18.