CA2407435A1 - Rna metabolism proteins - Google Patents

Abstract

The invention provides human RNA metabolism proteins (RMEP) and polynucleotides which identify and encode RMEP. The invention also provides expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of RMEP.

Description

RNA METABOLISM PROTEINS
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of RNA
metabolism proteins and to the use of these sequences in the diagnosis, treatment, and prevention of nervous system, autoimmune/inflammatory, cell proliferative, and developmental disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of RNA
metabolism proteins.
BACKGROUND OF THE INVENTION
Ribonucleic acid (RNA) is a linear single-stranded polymer of four nucleotides, ATP, CTP, UTP, and GTP. In most organisms, RNA is transcribed as a copy of deoxyribonucleic acid (DNA), the genetic material of the organism. In retroviruses RNA rather than DNA
serves as the genetic material. RNA copies of the genetic material encode proteins or serve various structural, catalytic, or regulatory roles in organisms. RNA is classified according to its cellular localization and function.
Messenger RNAs (mRNAs) encode polypeptides. Ribosomal RNAs (rRNAs) are assembled, along with ribosomal proteins, into ribosomes, which are cytoplasmic particles that translate mRNA into polypeptides. Transfer RNAs (tRNAs) are cytosolic adaptor molecules that function in mRNA
translation by recognizing both an mRNA colon and the amino acid that matches that colon.
Heterogeneous nuclear RNAs (hnRNAs) include mRNA precursors and other nuclear RNAs of various sizes. Small nuclear RNAs (snRNAs) are a part of the nuclear spliceosome complex that removes intervening, non-coding sequences (introns) and rejoins exons in pre-mRNAs.
Proteins are associated with RNA during its transcription from DNA, RNA
processing, and translation of mRNA into protein. Proteins are also associated with RNA as it is used for structural, catalytic, and regulatory purposes.
RNA Processing Various proteins are necessary for processing of transcribed RNAs in the nucleus. Pre-mRNA
processing steps include capping at the 5' end with methylguanosine, polyadenylating the 3' end, and splicing to remove introns. The spliceosomal complex is comprised of five small nuclear ribonucleoprotein particles (snRNPs) designated U1, U2, U4, U5, and U6. Each snRNP contains a single species of snRNA and about ten proteins. The RNA components of some snRNPs recognize and base-pair with intron consensus sequences. The protein components mediate spliceosome assembly and the splicing reaction.
An early step in pre-mRNA cleavage involves the cleavage factor Im (CF Im).
The human CF

Im protein aids in the recruitment and assembly of processing factors that make up the 3' end processing complex (Ruegsegger, U. et aI (1998) MoI. Cell. 1:243-253). The marine formin binding proteins (FBP's) FBP11 and FBP12 are components of pxe-mRNA splicing complexes that facilitate the bridging of 5' and 3' ends of the intron. These proteins function through bridging interactions invloving U1 and U2 snRNPs. Autoantibodies to snRNP proteins are found in the blood of patients with systemic lupus erythematosus (Stryer, L. (1995) Biochemistry W.H. Freeman and Company, New York NY, p. 863).
Heterogeneous nuclear ribonucleoproteins (hnRNPs) have been identified that have roles in splicing, exporting of the mature RNAs to the cytoplasm, and mRNA translation (Biamonti, G. et al.
(1998) Clin. Exp. Rheumatol. 16:317-326). Some examples of hnRNPs include the yeast proteins Hrplp, involved in cleavage and polyadenylation at the 3' end of the RNA;
Cbp80p, involved in capping the 5' end of the RNA; and Npl3p, a homolog of mammalian hnRNP A1, involved in export of mRNA from the nucleus (Shen, E.C. et al. (1998) Genes Dev. 12:679-691).
HnRNPs have been shown to be important targets of the autoimmune response in rheumatic diseases (Biamonti, supra).
Many snRNP and hnRNP proteins are characterized by an RNA recognition motif (RRM).
(Reviewed in Birney, E. et al. (1993) Nucleic Acids Res. 21:5803-5816.) The RRM is about 80 amino acids in length and forms four j3-strands and two a-helices arranged in an a/~3 sandwich. The RRM
contains a core RNP-1 octapeptide motif along with surrounding conserved sequences. In addition to snRNP proteins, examples of RNA-binding proteins which contain the above motifs include heteronuclear ribonucleoproteins which stabilize nascent RNA and factors which regulate alternative splicing. Alternative splicing factors include developmentally regulated proteins, specific examples of which have been identified in lower eukaryotes such as Drosophila melanoaaster and Caenorhabditis e1_ e~ans. These proteins play key roles in developmental processes such as pattern formation and sex determination, respectively. (See, for example, Hodgkin, J. et al. (1994) Development 120:3681-3689.) RNA Stability and Degradation RNA helicases alter and regulate RNA conformation and secondary structure by using energy derived from ATP hydrolysis to destabilize and unwind RNA duplexes. The most well-characterized and ubiquitous family of RNA helicases is the DEAD-box family, so named for the conserved B-type ATP-binding motif which is diagnostic of proteins in this family. Over 40 DEAD-box helicases have been identified in organisms as diverse as bacteria, insects, yeast, amphibians, mammals, and plants.
DEAD-box helicases function in diverse processes such as translation initiation, splicing, ribosome assembly, and RNA editing, transport, and stability. Some DEAD-box helicases play tissue- and stage-specific roles in spermatogenesis and embxyogenesis. All DEAD-box helicases contain several conserved sequence motifs spread out over about 420 amino acids. These motifs include an A-type ATP binding motif, the DEAD-box/B-type ATP-binding motif, a serinelarginine/threonine tripeptide of unknown function, and a C-terminal glycine-rich motif with a possible role in substrate binding and unwinding. In addition, alignment of divergent DEAD-box helicase sequences has shown that 37 amino acid residues are identical among these sequences, suggesting that conservation of these residues is important for helicase function. (Reviewed in Linder, P. et al. (1989) Nature 337:121-122.) Overexpression of the DEAD-box 1 protein (DDXl) may play a role in the progression of neuroblastoma (Nb) and retinoblastoma (Rb) tumors. These observations suggest that DDX1 may promote or enhance tumor progression by altering the normal secondary structure and expression levels of RNA in cancer cells. Other DEAD-box helicases have been implicated either directly or indirectly in ultraviolet light-induced tumors, B-cell lymphoma, and myeloid malignancies.
(Reviewed in Godbout, R. et al. (1998) J. Biol. Chem. 273:21161-21168.) Ribonucleases (RNases) catalyze the hydrolysis of phosphodiester bonds in RNA
chains, thus cleaving the RNA. For example, RNase P is a ribonucleoprotein enzyme which cleaves the 5' end of pre-tRNAs as part of their maturation process. RNase H digests the RNA strand of an RNA/DNA
hybrid. Such hybrids occur in cells invaded by retroviruses, and RNase H is an important enzyme in the retroviral replication cycle. RNase H domains are often found as a domain associated with reverse transcriptases. RNase activity in serum and cell extracts is elevated in a variety of cancers and infectious diseases (Schein, C.H. (1997) Nat. Biotechnol. 15:529-536).
Regulation of RNase activity is being investigated as a means to control tumor angiogenesis, allergic reactions, viral infection and replication, and fungal infections.
Degradation of mRNAs having premature termination or nonsense codons is accomplished through a surveillance mechanism that has been termed nonsense-mediated mRNA
decay (NMD).
This mechanism helps eliminate flawed mRNAs that might code for nonfunctional or deleterious polypeptides. Various NMD components are linked to both yeast and human RNA
metabolism disorders (Hentze, M. and Kulozik, A. (1999) Cell 96:307-310).
TRANSLATION
Ribosomal RNAs (rRNAs) are assembled, along with ribosomal proteins, into ribosomes, which are cytoplasmic particles that translate messenger RNA (mRNA) into polypeptides. The eukaryotic ribosome is composed of a 60S (large) subunit and a 40S (small) subunit, which together form the 80S ribosome. In addition to the 18S, 28S, SS, and 5.85 rRNAs, ribosomes contain from 50 to over 80 different ribosomal proteins, depending on the organism. Ribosomal proteins are classified according to which subunit they belong (i.e., L, if associated with the large 60S large subunit or S if associated with the small 40S subunit). E. coli ribosomes have been the most thoroughly studied and contain 50 proteins, many of which are conserved in all life foams. The structures of nine ribosomal proteins have been solved to less than 3.0/~ resolution (i.e., S5, S6, 517, L1, L6, L9, L12, L14, L30), revealing common motifs, such as (3-a-~i protein folds in addition to acidic and basic RNA-binding motifs positioned between (3-strands. Most ribosomal proteins are believed to contact rRNA directly (reviewed in Liljas, A. and Garber, M. (1995) Curr. Opin. Struct. Biol. 5:721-727, see also Woodson, S.A. and Leontis, N.B. (1998) Curr. Opin. Struct. Biol. 8:294-300;
Ramakrishnan, V. and White, S.W. (1998) Trends Biochem. Sci. 23:208-212.) Ribosomal proteins may undergo post-translational modifications or interact with other ribosome-associated proteins to regulate translation. For example, the highly homologous 40S
ribosomal protein S6 kinases (S6K1 and S6K2) play a key role in the regulation of cell growth by controlling the biosynthesis of translational components which make up the protein synthetic apparatus (including the ribosomal proteins). In the case of S6K1, at least eight phosphorylation sites are believed to mediate kinase activation in a hierarchical fashion (Dufner and Thomas (1999) Exp.
Cell. Res. 253:100-109). Some of the ribosomal proteins, including L1, also function as translational repressors by binding to polycistronic mRNAs encoding ribosomal proteins (reviewed in Liljas, A.
supra and Garber, M. supra).
Recent evidence suggests that a number of ribosomal proteins have secondary functions independent of their involvement in protein biosynthesis. These proteins function as regulators of cell proliferation and, in some instances, as inducers of cell death. For example, the expression of human ribosomal protein Ll3a has been shown to induce apoptosis by arresting cell growth in the G2/M
phase of the cell cycle. Inhibition of expression of Ll3a induces apoptosis in target cells, which suggests that this protein is necessary, in the appropriate amount, for cell survival. Similar results have been obtained in yeast where inactivation of yeast homologues of Ll3a, rp22 aiid rp23, results in severe growth retardation and death. A closely related ribosomal protein, L7, arrests cells in G1 and also induces apoptosis. Thus, it appears that a subset of ribosomal proteins may function as cell cycle checkpoints and compose a new family of cell proliferation regulators.
Mapping of individual ribosomal proteins on the surface of intact ribosomes is accomplished using 3D immunocryoelectronmicroscopy, whereby antibodies raised against specific ribosomal proteins are visualized. Progress has been made toward the mapping of L1, L7, and L12 while the structure of the intact ribosome has been solved to only 20-2S A resolution and inconsistencies exist among different crude structures (Frank, J. (1997) Curr. Opin. Struct. Biol.
7:266-272).
Three distinct sites have been identified on the ribosome. The aminoacyl-tRNA
acceptor site (A site) receives charged tRNAs (with the exception of the initiator-tRNA).
The peptidyl-tRNA site (P site) binds the nascent polypeptide as the amino acid from the A site is added to the elongating chain. Deacylated tRNAs bind in the exit site (E site) prior to their release from the ribosome. The structure of the ribosome is reviewed in Stryer, L. (1995) Biochemistry W.H.
Freeman and Company, New York NY pp. 888-9081; Lodish, H. et al. (1995) Molecular Cell Biolo~y Scientific American Books, New York NY pp. 119-138; and Lewin, B (1997) Genes VI Oxford University Press, Inc. New York, NY).
tRNA Char~in~
Correct translation of the genetic code depends upon each amino acid forming a linkage with the appropriate transfer RNA (tRNA). The aminoacyl-tRNA synthetases (aaRSs) are essential proteins found in all living organisms. The aaRSs are responsible for the activation and correct attachment of an amino acid with its cognate tRNA, as the first step in protein biosynthesis.
Prokaryotic organisms have at least twenty different types of aaRSs, one for each different amino acid, while eukaryotes usually have two aaRSs, a cytosolic form and a mitochondrial form, for each different amino acid. The 20 aaRS enzymes can be divided into two structural classes. Class I enzymes add amino acids to the 2' hydroxyl at the 3' end of tRNAs while Class II enzymes add amino acids to the 3' hydroxyl at the 3' end of tRNAs. Each class is characterized by a distinctive topology of the catalytic domain. Class I
enzymes contain a catalytic domain based on the nucleotide-binding 'Rossman fold'. In particular, a consensus tetrapeptide motif is highly conserved (Prosite Document PDOC00161, Aminoacyl-transfer RNA synthetases class-I signature). Class II enzymes contain a central catalytic domain, which consists of a seven-stranded antiparallel 13-sheet domain, as well as N- and C-terminal regulatory domains.
Class II enzymes are separated into two groups based on the heterodimeric or homodimeric structure of the enzyme; the latter group is further subdivided by the structure of the N-and C-terminal regulatory domains (Hartlein, M. and Cusack, S. (1995) J. Mol. Evol. 40:519-530). The different aaRSs are believed to be the result of divergent evolution, likely following gene duplication events. Notably, amino acids such as Gln, were among the last to appear in nature and evolutionary studies suggest that Gln-RSs appeared first in eukaryotes and were later horizontally transferred to prokaryotes (Lamour, V. et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91:8670-74 and Siatecka, M. et al.
(1998) Eur. J. Biochem.
256:80-7). The importance of Gln RS and Gln-tRNAG'" are discussed below.
In addition to their function in protein synthesis, specific aminoacyl tRNA
synthetases also play roles in cellular fidelity, RNA splicing, RNA trafficking, apoptosis, and transcriptional and translational regulation. For example, human tyrosyl-tRNA synthetase can be proteolytically cleaved into two fragments with distinct cytokine activities. The carboxy-terminal domain exhibits monocyte and leukocyte chemotaxis activity as well as stimulating production of myeloperoxidase, tumor necrosis factor-a, and tissue factor. The N-terminal domain binds to the interleukin-8 type A receptor and functions as an interleukin-8-like cytokine. Human tyrosyl-tRNA synthetase is secreted from apoptotic tumor cells and may accelerate apoptosis (Wakasugi, K. and Schimmel, P. (1999) Science 284:147-151). Mitochondrial Neurospora crassaTyrRS and S. cerevisiaeLeuRS are essential factors for certain group I intron splicing activities, and human mitochondrial LeuRS
can substitute for the yeast LeuRS in a yeast null strain. Certain bacterial aaRSs are involved in regulating their own transcription or translation (Martinis, supra). Several aaRSs are able to synthesize diadenosine oligophosphates, a class of signalling molecules with roles in cell proliferation, differentiation, and apoptosis (Kisselev, L.L et al. (1998) FEBS Lett. 427:157-163; Vartanian, A.
et al. (1999) FEBS Lett.
456:175-180).
Under optimal conditions, polypeptide synthesis proceeds at a rate of approximately 40 amino acid residues per second. The rate of misincorporation during translation in on the order of 10~ and is primarily the result of aminoacyl-t-RNAs being charged with the incorrect amino acid. Incorrectly charged tRNA are tonic to cells as they result in the incorporation of incorrect amino acid residues into an elongating polypeptide. The rate of translation is presumed to be a compromise between the optimal rate of elongation and the need for translational fidelity.
Mathematical calculations predict that 10-4 is indeed the maximum acceptable error rate for protein synthesis in a biological system (reviewed in Stryer, L. supra and Watson, J. et al. (1987) The Benjamin/Cummings Publishing Co., Inc. Menlo Park, CA). A particularly error prone aminoacyl-tRNA charging event, the charging of tRNAG'n with Gln. A mechanism exist for the correction of this mischarging event which likely has its origins in evolution. Gln was among the last of the 20 naturally occurring amino acids used polypeptide synthesis to appear in nature. Gram positive eubacteria, cyanobacteria, Archeae, and eukaryotic organelles posses a noncanonical pathway for the synthesis of Gln-tRNAG'n based on the transformation of Glu-tRNA~'° (synthesized by Glu-tRNA synthetase, GluRS) using the enzyme Glu-tRNA~''1 amidotransferase (Glu-AdT). The reactions involved in the transamidation pathway are as follows (Curnow, A.W, et al. (1997) Nucleic Acids Symposium 36:2-4):
GluRS
( 1 ) tRNA~'n + GIu + ATP -~ GIu-tRNA~'~ + AMP + PPi Glu-AdT
(2) Glu-tRNAG'n + Gln + ATP --~ GIn-tRNA~'" + Glu + ADP + P
A similar enzyme, Asp-tRNA'~" amidotransferase, exists in Archaea, which transforms Asp-tRNA'~" to Asn-tRNA'~°. Formylase, the enzyme that transforms Met-tRNA~et to fMet-tRNA~e' in eubacteria, is likely to be a related enzyme. A hydrolytic activity has also been identified that destroys mischarged Val-tRNAne (Schimmel, P. et al. (1998) FASEB J. 12:1599-1609). I
likely scenario for the evolution of Glu-AdT in primitive life forms is the absence a specific glutaminyl-tRNA synthetase (GlnRS), requiring an alternative pathway for the synthesis of Gln-tRNAG'". In fact, deletion of the Glu-AdT operon in Gram positive bacteria is lethal (Curnow, A.W. et al. (1997) Proc. Natl. Acad. Sci.
U.S.A. 94:11819-11826). The existence of GluRS activity in other organisms has been inferred by the high degree of conservation in translation machinery in nature; however, GluRS
has not been identified in all organisms, including Homo sapiens. Such an enzyme would be responsible for ensuring translational fidelity and reducing the synthesis of defective polypeptides.
Autoantibodies against aminoacyl-tRNAs are generated by patients with autoimmune diseases such as rheumatic arthritis, dermatomyositis and polymyositis, and correlate strongly with complicating interstitial lung disease (1LD) (Freist, W. et aI. (1999) Biol.
Chem. 380:623-646; Freist, W. et al. (1996) Biol. Chem. Hoppe Seyler 377:343-356). These antibodies appear to be generated in response to viral infection, and coxsackie virus has been used to induce experimental viral myositis in animals.
Comparison of aaRS structures between humans and pathogens has been useful in the design IS of novel antibiotics (Schimmel, supra). Genetically engineered aaRSs have been utilized to allow site-specific incorporation of unnatural amino acids into proteins in vivo (Liu, D.R. et al. (1997) Proc.
Natl. Acad. Sci. USA 94:10092-10097).
Translation Initiation Initiation of translation can be divided into three stages, 'The first stage brings an initiator transfer RNA (Met-tRNAf) together with the 40S ribosomal subunit to form the 43S preinitiation complex. The second stage binds the 43S preinitiation complex to the mRNA, followed by migration of the complex to the correct AUG initiation codon. The third stage brings the 60S ribosomal subunit to the 40S subunit to generate an 80S ribosome at the inititation codon.
Regulation of translation primarily involves the first and second stage in the initiation process (V.M.
Pain (1996) Eur. J.
Biochem. 236:747-771).
Several initiation factors, many of which contain multiple subunits, are involved in bringing an initiator tRNA and 40S ribosomal subunit together. One eukaryotic initiation factor (EIF) EIFSA
is an 18-kD protein containing the unique amino acid residue, hypusine (N
epsilon-(4-amino-2-hydroxybutyl)lysine) (Rinaudo, M, et al. (1993) Gene 137:303-307). eIF2, a guanine nucleotide binding protein, recruits the initiator tRNA to the 40S ribosomal subunit.
Only when eIF2 is bound to GTP does it associate with the initiator tRNA. elF2B, a guanine nucleotide exchange protein, is responsible for converting eIF2 from the GDP-bound inactive form to the GTP-bound active form.
Two other factors, eIFlA and eIF3 bind and stabilize the 40S subunit by interacting with 18S
ribosomal RNA and specific ribosomal structural proteins. eIF3 is also involved in association of the 40S ribosomal subunit with mRNA. The Met-tRNA f, eIFlA, elF3, and 40S
ribosomal subunit together make up the 43S preinitiation complex (Pain, s_ upra).
Additional factors are required for binding of the 43S preinitiation complex to an mRNA
molecule, and the process is regulated at several levels. eIF4F is a complex consisting of three proteins: eIF4E, eIF4A, and elF4G. eIF4E recognizes and binds to the mRNA 5'-terminal m'GTP
cap, elF4A is a bidirectional RNA-dependent helicase, and eIF4G is a scaffolding polypeptide, elF4G
has three binding domains. The N-terminal third of eIF4G interacts with eIF4E, the central third interacts with elF4A, and the C-terminal third interacts with eIF3 bound to the 43S preinitiation complex. Thus, elF4G acts as a bridge between the 40S ribosomal subunit and the mRNA (M.W.
Hentze (1997) Science 275:500-501).
The ability of eIF4F to initiate binding of the 43S preinitiation complex is regulated by structural features of the mRNA. The mRNA molecule has an untranslated region (UTR) between the 5' cap and the AUG start codon. In some mRNAs this region forms secondary structures that impede binding of the 43S preinitiation complex. The helicase activity of eIF4A is thought to function in removing this secondary structure to facilitate binding of the 43S
preinitiation complex (Pain, s_upra).
Translation Elongation Elongation is the process whereby additional amino acids are joined to the initiator methionine to form the complete polypeptide chain. The elongation factors EF1 a, EF1 (3 y, and EF2 are involved in elongating the polypeptide chain following initiation. EFl a is a GTP-binding protein.
In EF1 a's GTP-bound form, it brings an aminoacyl-tRNA to the ribosome's A
site. The amino acid attached to the newly arrived aminoacyl-tRNA forms a peptide bond with the initiatior methionine.
The GTP on EF1 a is hydrolyzed to GDP, and EF1 a-GDP dissociates from the ribosome. EFl (3 y binds EF1 a -GDP and induces the dissociation of GDP from EF1 a, allowing EF1 a to bind GTP and a new cycle to begin.
As subsequent aminoacyl-tRNAs are brought to the ribosome, EF-G, another GTP-binding protein, catalyzes the translocation of tRNAs from the A site to the P site and finally to the E site of the ribosome. This allows the processivity of translation.
Translation Termination The release factor eRF carries out termination of translation. eRF recognizes stop codons in the mRNA, leading to the release of the polypeptide chain from the ribosome.
The discovery of new RNA metabolism 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 nervous system, autoimmune/inflammatory, cell proliferative, and developmental disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of RNA metabolism proteins.
nervous system disorders, autoimmunelinflammatory disorders, and cell proliferative disorders including cancer SUMMARY OF THE INVENTION
The invention features purified polypeptides, RNA metabolism proteins, referred to collectively as "RMEP" and individually as "RMEP-1," "RMEP-2," "RMEP-3," "RMEP-4," "RMEP-5," "RMEP-6," "RMEP-7," "RMEP-8," "RMEP-9," "RMEP-10," "RMEP-11," "RMEP-12," "RMEP-13,"
"RMEP-14," "RMEP-15," "RMEP-16," "RMEP-17," "RMEP-18," "RMEP-19," "RMEP-20,"
"RMEP-21," "RMEP-22," "RMEP-23," "RMEP-24," "RMEP-25," "RMEP-26," "RMEP-27,"
"RMEP-28," "RMEP-29," "RMEP-30," "RMEP-31," "RMEP-32," "RMEP-33," "RMEP-34,"
"RMEP-35," "RMEP-36," "RMEP-37," "RMEP-38," "RMEP-39," "RMEP-40," "RMEP-41,"
"RMEP-42," "RMEP-43," "RMEP-44," "RMEP-45," "RMEP-46," and "RMEP-47." In one aspect, the invention provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID
N0:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90%
identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47. In one alternative, the invention provides an isolated polypeptide comprising the amino acid sequence of SEQ ID NO:1-47, The invention further provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47. In one alternative, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ
ID NO:1-47. In another alternative, the polynucleotide is selected from the group consisting of SEQ ID N0:48-94:
Additionally, the invention provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID
NO:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47. In one alternative, the invention provides a cell transformed with the recombinant polynucleotide. In another alternative, the invention provides a transgenic organism comprising the recombinant polynucleotide.
The invention also provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90%
identical to an amino acid sequence selected from the group consisting of SEQ
ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47. The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed.
Additionally, the invention provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47.
The invention further provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID
N0:48-94, b) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:48-94, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). In one alternative, the polynucleotide comprises at least 60 contiguous nucleotides.
Additionally, the invention provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID
N0:48-94, b) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90%

identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:48-94, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and optionally, if present, the amount thereof. In one alternative, the probe comprises at least 60 contiguous nucleotides.
The invention further provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID
N0:48-94, b) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:48-94, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerise chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide ox fragment thereof, and, optionally, if present, the amount thereof.
The invention further provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:l-47, b) a naturally occurring polypeptide comprising an-amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, and a pharmaceutically acceptable excipient Tn one embodiment, the composition comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-47. The invention additionally provides a method of treating a disease or condition associated with decreased expression of functional RMEP, comprising administering to a patient in need of such treatment the composition.
The invention also provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
N0:1-47. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. In one alternative, the invention provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with decreased expression of functional RMEP, comprising administering to a patient in need of such treatment the composition.
Additionally, the invention provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample.
In one alternative, the invention provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with overexpression of functional RMEP, comprising administering to a patient in need of such treatment the composition.
The invention further provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, b) a naturally occurring polypeptide cmoprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:I-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
N0:1-47. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide.
The invention further provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-47. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide.
The invention further provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence selected from the group consisting of SEQ ID N0:48-94, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, and b) detecting altered expression of the target polynucleotide.
The invention further provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound; b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
ID N0:48-94, ii) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:48-94, iii) a polynucleotide having a sequence complementary to i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID
N0:48-94, ii) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:48-94, iii) a polynucleotide complementary to the polynucleotide of i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Alternatively, the target polynucleotide comprises a fragment of a polynucleotide sequence selected from the group consisting of i)-v) above;
c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.
BRIEF DESCRIPTION OF THE TABLES
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences of the present invention.
Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog for polypeptides of the invention. The probability score for the match between each polypeptide and its GenBank homolog is also shown.
Table 3 shows structural features of polypeptide sequences of the invention, including predicted motifs and domains, along with the methods, algorithms, and searchable databases used for analysis of the polypeptides.
Table 4 lists the cDNA fragments which were used to assemble polynucleotide sequences of the invention, along with selected fragments of the polynucleotide sequences.
Table 5 shows the representative cDNA library for polynucleotides of the invention.
Table 6 provides an appendix which describes the tissues and vectors used for construction of the cDNA libraries shown in Table 5.
Table 7 shows the tools, programs, and algorithms used to analyze the polynucleotides and polypeptides of the invention, 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 eonnection 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
"RMEP" refers to the amino acid sequences of substantially purified RMEP
obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, marine, 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 RMEP. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of RMEP either by directly interacting with RMEP or by acting on components of the biological pathway in which RMEP
participates.
An "allelic variant" is an alternative form of the gene encoding RMEP. 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 in a given sequence.
"Altered" nucleic acid sequences encoding RMEP include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as RMEP or a polypeptide with at least one functional characteristic of RMEP. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding RMEP, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence encoding RMEP. 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 RMEP. 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 RMEP 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, polypeptide, 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 a 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 polymerise chain reaction (PCR) technologies well known in the art.
The term "antagonist" refers to a molecule which inhibits or attenuates the biological activity of RMEP. Antagonists may include proteins such as antibodies, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of RMEP either by directly interacting with RMEP or by acting on components of the biological pathway in which RMEP
participates.
The term "antibody" refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F(ab')2, and Fv fragments, which are capable of binding an epitopic determinant.
Antibodies that bind RMEP 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 (KLH). 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 capable of base-pairing with the "sense"
(coding) strand of a specific nucleic acid sequence. Antisense compositions may include DNA; RNA;
peptide nucleic acid (PNA); oligonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides having modified sugar groups such as 2'-methoxyethyl sugars or 2'-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2'-deoxyuracil, or 7-deaza-2'-deoxyguanosine.
Antisense molecules may be produced by any method including chemical synthesis or transcription.
Once introduced into a cell, the complementary antisense molecule base-pairs with a naturally occurring nucleic acid sequence produced by the cell to form duplexes which 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 of a reference DNA molecule.
The term "biologically active" refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, "immunologically active" or "immunogenic"
refers to the capability of the natural, recombinant, or synthetic RMEP, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.
"Complementary" describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing. For example, 5'-AGT-3' pairs with its complement, 3'-TCA-5'.
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 RMEP or fragments of RMEP 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., NaCl), 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 subjected to repeated DNA sequence analysis to resolve uncalled bases, extended using the XL-PCR kit (Applied Biosystems, Foster City CA) in the 5' and/or the 3' direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genomic DNA fragments using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (GCG, Madison WI) or Phrap (University of Washington, Seattle WA). Some sequences have been both extended and assembled to produce the consensus sequence.
"Conservative amino acid substitutions" are those substitutions that are predicted to Ieast interfere with the properties of the original protein, i.e., the structure and especially the function of the 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 Ile Leu, Val Leu Tle, Val Lys Arg, Gln, Glu Met Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Val Trp Phe, Tyr Tyr His, Phe, Trp Val 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 a chemically modified polynucleotide or polypeptide. Chemical modifications of a polynucleotide 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 "detectable label" refers to a reporter molecule or enzyme that is capable of generating a measurable signal and is covalently or noncovalently joined to a polynucleotide or polypeptide.
"Differential expression" refers to increased or upregulated; or decreased, downregulated, or absent gene or protein expression, determined by comparing at least two different samples. Such comparisons may be carried out between, for example, a treated and an untreated sample, or a diseased and a normal sample.
A "fragment" is a unique portion of RMEP or the polynucleotide encoding RMEP
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, 15, 16, 20, 25, 30, 40, 50, 60, 75, 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 ID N0:48-94 comprises a region of unique polynucleotide sequence that specifically identifies SEQ ID N0:48-94, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ ID N0:48-94 is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID N0:48-94 from related polynucleotide sequences. The precise length of a fragment of SEQ
ID N0:48-94 and the region of SEQ ID N0:48-94 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 N0:1-47 is encoded by a fragment of SEQ ID N0:48-94. A
fragment of SEQ ID NO: l-47 comprises a region of unique amino acid sequence that specifically identifies SEQ ID NO:1-47. For example, a fragment of SEQ ID NO:1-47 is useful as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID N0:1-47.
The precise length of a fragment of SEQ ID N0:1-47 and the region of SEQ ID N0:1-47 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 "full length" polynucleotide sequence is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A "full length" polynucleotide sequence encodes a "full length" polypeptide sequence.
"Homology" refers to sequence similarity or, interchangeably, sequence identity, between two or more polynucleotide sequences or two or more polypeptide sequences.
The terms "percent identity" and "% identity," as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide 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 Iiiggins, 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 sequences.
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://www.ncbi.nlm.nih.gov/BLAST/. The BLAST software suite includes various sequence analysis programs including "blastn," 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 aceessed and used interactively at http://www.ncbi.nlm.nih.gov/gorf/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 2Ø12 (April-21-2000) set at default parameters. Such default parameters may be, for example:
Matrix: BLOSUM62 Reward for match: 1 Pefialty for misrraatch: -2 Opera Gap: S arid Extension Gap: 2 penalties Gap x drop-off. 50 Expect: 10 Word Size: 11 Filter: on Percent identity may be measured over the length of an entire defined 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 sequence, for instance, a fragment of at least 20, at least 30, at least 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 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 charge and hydrophobicity 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: I~tuple=1, gap penalty=3, window=5, and "diagonals saved"=S. 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 polypeptide sequences, one may use the "BLAST 2 Sequences"
tool Version 2Ø12 (April-21-2000) with blastp set at default parameters. Such default parameters may be, for example:
Matrix: BLOSUM62 Open Gap: 11 arzd Extension Gap: 1 pefaalties Gap x drop-off.' SO
Expect: 10 Word Size: 3 Filter: ofa 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 15, at least 20, at least 30, at least 40, at least S0, at least 70 or at least 150 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 artificial 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 chromosome replication, segregation and maintenance.
The term "humanized antibody" refers to an antibody molecule in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely 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 complementarity.
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 1 S annealing of nucleic acid sequences are routinely determinable by one of ordinary skill in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency, and therefore hybridization specificity. Permissive annealing conditions occur, for example, at 68°C in the presence of about 6 x SSC, about 1 % (w/v) SDS, and about 100 ~ ~ml sheared, 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. Such wash temperatures are typically selected to be about S°C
to 20°C lower than the thermal melting point (T"~ for the specific sequence at a defined ionic strength and pH. The Tm 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 for nucleic acid hybridization are well known and can be found in Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY; 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, sheared and denatured salmon sperm DNA at about 100-200 ~g/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, 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., Cot or Rot 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.
An "immunogenic fragment" is a polypeptide or oligopeptide fragment of RMEP
which is capable of eliciting an immune response when introduced into a living organism, for example, a mammal. The term "immunogenic fragment" also includes any polypeptide or oligopeptide fragment of RMEP which is useful in any of the antibody production methods disclosed herein or known in the art.
The term "microarray" refers to an arrangement of a plurality of polynucleotides, polypeptides, or other chemical compounds on a substrate.
The terms "element" and "array element" refer to a polynucleotide, polypeptide, or other chemical compound having a unique and defined position on a microarray.
The term "modulate" refers to a change in the activity of RMEP. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of RMEP.
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.
"Operably linked" refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with a 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. 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.
"Post-translational modification" of an RMEP may involve lipidation, glycosylation, phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu of RMEP.
"Probe" refers to nucleic acid sequences encoding RMEP, 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 polymerase chain reaction (PCR).
Probes and primers as used in the present invention typically comprise at least 15 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, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY; Ausubel, F.M. et al. (1987) Current Protocols in Molecular Biolo~y, Greene Publ. Assoc. & Wiley-Intersciences, New York NY; Innis, M. 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 0.5, 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 fox designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead InstituteJMIT 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 pxobes 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, supra. 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.
A "regulatory element" refers to a nucleic acid sequence usually derived from untranslated regions of a gene and includes enhancers, promoters, introns, and 5' and 3' untranslated regions (UTRs).

Regulatory elements interact with host or viral proteins which control transcription, translation, or RNA
stability.
"Reporter molecules" are chemical or biochemical moieties used for labeling a nucleic acid, amino acid, or antibody. Reporter molecules include radionuclides; enzymes;
fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors;
magnetic particles; and other moieties known in the art.
An "RNA equivalent," in reference to a DNA sequence, is composed of the same linear sequence of nucleotides as the reference DNA sequence with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The term "sample" is used in its broadest sense. A sample suspected of containing RMEP, nucleic acids encoding RMEP, or fragments thereof may comprise a bodily fluid;
an extract from a cell, chromosome, organelle, or membrane isolated from a cell; a cell; genomic DNA, 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 comprising 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 "substantially 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 60% free, preferably at least 75% free, and most preferably at least 90% free from other components with which they are naturally associated.
A "substitution" refers to the replacement of one or more amino acid residues or nucleotides by different amino acid residues or nucleotides, respectively.
"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.
A "transcript image" refers to the collective pattern of gene expression by a particular cell type or tissue under given conditions at a given time.
"Transformation" describes a process by which exogenous DNA is introduced into 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, bacteriophage or 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 paxt of the host chromosome, as well as transiently transformed cells which express the inserted DNA or RNA for limited periods of time.
A "transgenic organism," as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art.
The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation. Techniques for transferring the DNA of the present invention into such organisms are widely known and provided in references such as Sambrook et al. (1989), su ra, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% 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 have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternative 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 axe polynucleotide sequences that vary from one species to another. The resulting polypeptides will generally have significant amino acid identity relative to each other. A polymorphic variant is a variation in the polynucleotide 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 91 %, at least 92%, at least 93%, at least 94%, at least 95 %, at least 96%, at least 97%, at least 98%, or at least 99% 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 RNA metabolism proteins (RMEP), the polynucleotides encoding RMEP, and the use of these compositions for the diagnosis, treatment, or prevention of nervous system, autoimmunelinf7ammatory, cell proliferative, and developmental disorders.
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences of the invention. Each polynucleotide and its corresponding polypeptide are correlated to a single Incyte project identification number (Incyte Project ID). Each polypeptide sequence is denoted by both a polypeptide sequence identification number (Polypeptide SEQ ID NO:) and an Incyte polypeptide sequence number (Incyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) as shown.
Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database. Columns 1 and 2 show the polypeptide sequence identification number (Polypeptide SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the invention. Column 3 shows the GenBank identification number (Genbank ID NO:) of the nearest GenBank homolog. Column 4 shows the probability score for the match between each polypeptide and its GenBank homolog.
Colwnn 5 shows the annotation of the GenBank homolog along with relevant citations where applicable, all of which are expressly incorporated by reference herein.
Table 3 shows various structural features of the polypeptides of the invention. Columns l and 2 show the polypeptide sequence identification number (SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for each polypeptide of the invention. Column 3 shows the number of amino acid residues in each polypeptide. Column 4 shows potential phosphorylation sites, and column 5 shows potential glycosylation sites, as determined by the MOTIFS
program of the GCG sequence analysis software package (Genetics Computer Group, Madison Wn.
Column 6 shows amino acid residues comprising signature sequences, domains, and motifs. Column 7 shows analytical methods for protein structurelfanction analysis and in some cases, searchable databases to which the analytical methods were applied.
Together, Tables 2 and 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are RNA metabolism proteins. SEQ ID N0:46 is 29% identical to Glu-tRNAG'~ amidotransferase, subunit A, of Neisseria menin i~ t~ (GenBank ID g7226601) as determined by the Basic Local Alignment Search Tool (BLAST, see Table 2). The BLAST probability score is 1.3e-37, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:46 also contains amidase signature sequences as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains (see Table 3). Data from BLIMPS and PROFILESCAN analyses provide further corroborative evidence that SEQ ID N0:46 contains amidase signature sequences, features of polypeptides involved in transamination reactions. These data provide evidence that SEQ ID N0:46 is related to the Glu-tRNAG'n amidotransferases found in prokaryotes and some cellular organelles but, until the instant invention, not in humans.
SEQ ID N0:47 is 97%
identical to the 60S acidic ribosomal protein of Zea mays (GenBank ID g790508) as determined by the Basic Local Alignment Search Tool (BLAST, see Table 2). The BLAST probability score is 5.4e-51.
SEQ ID N0:47 also contains a 60S acidic ribosomal protein domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM
database of conserved protein family domains (see Table 3). Data from BLIMPS analyses provide further corroborative evidence that SEQ ID N0:47 is a phosphorylated (hence likely to be acidic) ribosomal protein. SEQ ID NO:1-45 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ ID NO;1-47 are described in Table 7.
As shown in Table 4, the full length polynucleotide sequences of the present invention were assembled using cDNA sequences or coding (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Columns 1 and 2 list the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and the corresponding Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) for each polynucleotide of the invention.
Column 3 shows the length of each polynucleotide sequence in basepairs. Column 4 lists fragments of the polynucleotide sequences which are useful, for example, in hybridization or amplification technologies that identify SEQ ID N0:48-94 or that distinguish between SEQ ID
N0:48-94 and related polynucleotide sequences. Column 5 shows identification numbers corresponding to cDNA
sequences, coding sequences (exons) predicted from genomic DNA, and/or sequence assemblages comprised of both cDNA and genomic DNA. These sequences were used to assemble the full length polynucleotide sequences of the invention. Columns 6 and 7 of Table 4 show the nucleotide start (5') and stop (3') positions of the cDNA sequences in column 5 relative to their respective full length sequences.
The identification numbers in Column 5 of Table 4 may refer specifically, for example, to Incyte cDNAs along with their corresponding cDNA libraries. For example, 642017H1 is the identification number of an Incyte cDNA sequence, and BRSTNOT03 is the cDNA
library from which it is derived. Incyte cDNAs for which cDNA libraries are not indicated were derived from pooled cDNA libraries (e.g., 70822015V1). Alternatively, the identification numbers in column 5 may refer to GenBank cDNAs or ESTs (e.g., g1136841) which contributed to the assembly of the full length polynucleotide sequences. Alternatively, the identification numbers in column 5 may refer to coding regions predicted by Genscan analysis of genomic DNA. The Genscan-predicted coding sequences may have been edited prior to assembly. (See Example IV.) Alternatively, the identification numbers in column 5 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an "exon stitching" algorithm. (See Example V.) Alternatively, the identification numbers in column 5 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an "exon-stretching" algorithm. (See Example V.) In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in column 5 was obtained to confirm the final consensus polynucleotide sequence, but the relevant Incyte cDNA identification numbers are not shown.
Table 5 shows the representative cDNA libraries for those full length polynucleotide sequences which were assembled using Incyte cDNA sequences. The representative cDNA
library is the Incyte cDNA library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and confirm the above polynucleotide sequences. The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.
The invention also encompasses RMEP variants. A preferred RMEP 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 RMEP amino acid sequence, and which contains at least one functional or structural characteristic of RMEP.
The invention also encompasses polynucleotides which encode RMEP. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID N0:48-94, which encodes RMEP. The polynucleotide sequences of SEQ ID N0:48-94, as presented in the Sequence Listing, embrace the equivalent RNA sequences, wherein occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The invention also encompasses a variant of a polynucleotide sequence encoding RMEP. In particular, such a variant polynucleotide sequence will have at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to the polynucleotide sequence encoding RMEP. A particular aspect of the invention encompasses a variant of a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID
N0:48-94 which has at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID N0:48-94.
Any one of the polynucleotide variants described above can encode an amino acid sequence which contains at least one functional or sti~zctural characteristic of RMEP.
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 RMEP, 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 RMEP, and all such variations are to be considered as being specifically disclosed.
Although nucleotide sequences which encode RMEP and its variants are generally capable of hybridizing to the nucleotide sequence of the naturally occurring RMEP under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding RMEP 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 eukaxyotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding RMEP 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 RMEP
and RMEP 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 RMEP 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 N0:48-94 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 (Applied Biosystems), 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 cycler (MJ Research, Watertown MA) and ABI CATALYST 800 thermal cycler (Applied Biosystems).
Sequencing is then carried out using either the ABI 373 or 377 DNA sequencing system (Applied Biosystems), 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 Biology and Biotechnolo~y, Wiley VCH, New York NY, pp. 856-853.) The nucleic acid sequences encoding RMEP 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 pximers 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.) In 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. Genomic 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 to electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), 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 RMEP may be cloned in recombinant DNA molecules that direct expression of RMEP, 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 RMEP.
The nucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter RMEP-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.
The nucleotides of the present invention may be subjected to DNA shuffling techniques such as MOLECULARBREEDING (Maxygen Inc., Santa Clara CA; described in U.S. Patent Number 5,837,458; Chang, C.-C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians, F.C. et al. (1999) Nat.
Biotechnol. 17:259-264; and Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-319) to alter or improve the biological properties of RMEP, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through "artificial" breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized, Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occurring genes in a directed and controllable manner.
In another embodiment, sequences encoding RMEP 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, RMEP itself or a fragment thereof may be synthesized using chemical methods.
For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques. (See, e.g., Creighton, T. (1984) Proteins, Structures and Molecular Properties, WH Freeman, New York NY, pp. 55-60; and Roberge, J.Y. et al. (1995) Science 269:202-204.) Automated synthesis may be achieved using the ABI
431A peptide synthesizer (Applied Biosystems). Additionally, the amino acid sequence of RMEP, or any part thereof, may be altered during direct synthesis and/or combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide or a polypeptide having a sequence of a naturally occurring 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, su ra, pp. 28-53.) In order to express a biologically active RMEP, the nucleotide sequences encoding RMEP 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 RMEP. Such elements may vary in their strength and specificity.
Specific initiation signals may also be used to achieve more efficient translation of sequences encoding RMEP. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding RMEP 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 RMEP 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 Cloning, 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 Biolo~v, 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 RMEP. 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. (See, e.g., Sambrook, supra; Ausubel, supra; Van Heeke, G. and S.M. Schuster (1989) J. Biol. Chem. 264:5503-5509; 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; Takamatsu, N. (1987) EMBO
J. 6:307-311; The McGraw Hill Yearbook of Science and Technolo~y (1992) McGraw Hill, New York NY, pp. 191-196; Logan, J, and T. Shenk (1984) Proc. Natl. Acad. Sci. USA
81:3655-3659; and Harrington, J,J. et al. (1997) Nat. Genet. 15:345-355.) 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. (See, e.g., Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5(6):350-356; Yu, M. et al. (1993) Proc.
Natl. Acad. Sci. USA
90(13):6340-6344; Buller, R.M. et al. (1985) Nature 317(6040):813-815;
McGregor, D.P. et al. (1994) Mol. Immunol. 31(3):219-226; and Verma, LM. and N. Somia (1997) Nature 389:239-242.) 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 RMEP. For example, routine cloning, subcloning, and propagation of polynucleotide sequences encoding RMEP 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 RMEP 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.
264:5503-5509.) When large quantities of RMEP are needed, e.g. for the production of antibodies, vectors which direct high level expression of RMEP may be used. For example, vectors containing the strong, inducible SP6 or T7 bacteriophage promoter may be used.
Yeast expression systems may be used for production of RMEP. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH
promoters, may be used in the yeast Saccharomvces 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, supra;
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 RMEP. Transcription of sequences encoding RMEP may be driven by viral promoters, e.g., the 35S 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 Technolo~v (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 RMEP
may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential El or E3 region of the viral genome may be used to obtain infective virus which expresses RMEP 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 anuno 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 RMEP in cell lines is preferred. For example, sequences encoding RMEP 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 11:223-232;
Lowy, I. et al. (1980) Cell 22:817-823.) Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dlafr 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., Wigler, M. et a1. (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),13 glucuronidase and its substrate 13-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 presencelabsence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be conf'Irmed. For example, if the sequence encoding RMEP is inserted within a marker gene sequence, transformed cells containing sequences encoding RMEP can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding RMEP 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 RMEP
and that express RMEP 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 RMEP 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 (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on RMEP is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art. (See, e.g., Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS Press, St. Paul MN, Sect. IV;
Coligan, J.E, et al.
(1997) Current Protocols in Immunology, Greene Pub. Associates and Wiley-Interscience, New York NY; and Pound, J.D. (1998) 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 polynucleotides encoding RMEP
include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide. Alternatively, the sequences encoding RMEP, 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 ease of detection 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 RMEP 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 polynucleotides which encode RMEP may be designed to contain signal sequences which direct secretion of RMEP 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, andlor 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 RMEP 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 RMEP protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of RMEP 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-nayc, 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 RMEP encoding sequence and the heterologous protein sequence, so that RMEP
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 RMEP 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, 35S-methionine.
RMEP of the present invention or fragments thereof may be used to screen for compounds that specifically bind to RMEP. At least one and up to a plurality of test compounds may be screened for specific binding to RMEP. Examples of test compounds include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.
In one embodiment, the compound thus identified is closely related to the natural ligand of RMEP, e. g., a ligand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner. (See, e.g., Coligan, J.E. et al. (1991) Current Protocols in Immunolo~y 1(2):
Chapter 5.) Similarly, the compound can be closely related to the natural receptor to which RMEP
binds, or to at least a fragment of the receptor, e.g., the ligand binding site. In either case, the compound can be rationally designed using known techniques. In one embodiment, screening for these compounds involves producing appropriate cells which express RMEP, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E.
coli. Cells expressing RMEP or cell membrane fractions which contain RMEP are then contacted with a test compound and binding, stimulation, or inhibition of activity of either RMEP or the compound is analyzed.
An assay may simply test binding of a test compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. For example, the assay may comprise the steps of combining at least one test compound with RMEP, either in solution or affixed to a solid support, and detecting the binding of RMEP to the compound. Alternatively, the assay may detect or measure binding of a test compound in the presence of a labeled competitor.
Additionally, the assay may be carried out using cell-free preparations, chemical libraries, or natural product mixtures, and the test compounds) may be free in solution or affixed to a solid support.
RMEP of the present invention or fragments thereof may be used to screen for compounds that modulate the activity of RMEP. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for RMEP
activity, wherein RMEP is combined with at least one test compound, and the activity of RMEP in the presence of a test compound is compared with the activity of RMEP in the absence of the test compound. A change in the activity of RMEP in the presence of the test compound is indicative of a compound that modulates the activity of RMEP. Alternatively, a test compound is combined with an in vitro or cell-free system comprising RMEP under conditions suitable for RMEP
activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of RMEP may do so indirectly and need not come in direct contact with the test compound. At least one and up to a plurality of test compounds may be screened.
In another embodiment, polynucleotides encoding RMEP or their mammalian homologs may be "knocked out" in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of human disease. (See, e.g., U.S. Patent Number 5,175,383 and U.S. Patent Number 5,767,337.) For example, mouse ES cells, such as the mouse 129/SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e.g., the neomycin phosphotransferase gene (neo;
Capecchi, M.R. (1989) Science 244:1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-loxP
S system to knockout a gene of interest in a tissue- or developmental stage-specific manner (Marth, J.D.
(1996) Clin. Invest. 97:1999-2002; Wagner, K.U. et al. (1997) Nucleic Acids Res. 25:4323-4330).
Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL16 mouse strain. The blastocysts are surgically transferred to pseudopregnant dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains.
Transgenic animals thus generated may be tested with potential therapeutic or toxic agents.
Polynucleotides encoding RMEP may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J.A. et al. (1998) Science 282:1145-1147).
Polynucleotides encoding RMEP can also be used to create "knockin" humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of a polynucleotide encoding RMEP is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease.
Alternatively, a mammal inbred to overexpress RMEP, e.g., by secreting RMEP in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol. Annu. Rev. 4:55-74).
THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of RMEP and RNA metabolism proteins. In addition, the expression of RMEP is closely associated with diseased, proliferative, tumorous, and nervous tissues, adrenal tissue, brain tumor tissue, fetal colon tissue, adult colon tissue, prostate epithelial tissue, lymph node cancer tissue, ovarian tissue, pancreatic tissue, and fetal spleen tissue, as well as with diseases of the lung, and physiological conditions that result in anoxia. Therefore, RMEP appears to play a role in nervous system, autoimmune/inflammatory, cell proliferative, and developmental disorders, as well as neoplasms involving lung-specific tissues. In the treatment of disorders associated with increased RMEP expression or activity, it is desirable to decrease the expression or activity of RMEP. In the treatment of disorders associated with decreased RMEP expression or activity, it is desirable to increase the expression or activity of RMEP.
Therefore, in one embodiment, RMEP 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 RMEP. Examples of such disorders include, but are not limited to, a nervous system disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease; prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome;
fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorder of the central nervous system, cerebral palsy, a neuroskeletal disorder, an autonomic nervous system disorder, a cranial nerve disorder, a spinal cord disease, muscular dystrophy and other neuromuscular disorder, a peripheral nervous system disorder, dermatomyositis and polymyositis; inherited, metabolic, endocrine, and toxic myopathy; myasthenia gravis, periodic paralysis; a mental disorder including mood, anxiety, and schizophrenic disorders; seasonal affective disorder (SAD); akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette's disorder; 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 polyenodocrinopathy-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; a cell proliferative disorder such as actinic keratosis, arteriosclerosis, athexosclerosis, 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, and a developmental disorder such as renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss.
In another embodiment, a vector capable of expressing RMEP 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 RMEP including, but not limited to, those described above.
In a further embodiment, a composition comprising a substantially purified RMEP 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 RMEP including, but not limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of RMEP
may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of RMEP including, but not limited to, those listed above.
In a further embodiment, an antagonist of RMEP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of RMEP.
Examples of such disorders include, but are not limited to, those nervous system, autoimmunelintlammatory, cell proliferatave, and developmental described above. In one aspect, an antibody which specitrcally binds RMEP 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 RMEP.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding RMEP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of RMEP 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 RMEP may be produced using methods which are generally known in the art.
In particular, purified RMEP may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind RMEP. Antibodies to RMEP 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 RMEP 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 Corynebacterium parvum are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to RMEP
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.
Short stretches of RMEP 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 RMEP 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. (1983) 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 314:452-454.) Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce RMEP-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.) 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 RMEP may also be generated. For example, such fragments include, but are not limited to, F(ab~2 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 246:1275-1281.) 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 RMEP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering RMEP 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 RMEP. Affinity is expressed as an association constant, I~, which is defined as the molar concentration of RMEP-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 RMEP
epitopes, represents the average affinity, or avidity, of the antibodies for RMEP. The I~ determined for a preparation of monoclonal antibodies, which are monospecific fox a particular RMEP epitope, represents a true measure of affinity. High-affinity antibody preparations with I~ ranging from about I09 to 1012 Llmole are preferred for use in immunoassays in which the RMEP-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with I~
ranging from about 106 to 10' L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of RMEP, preferably in active form, from the antibody (Catty, D. (1988) Antibodies, Volume I: A Practical Approach, IRL Press, Washington DC; Liddell, J.E. and A. Cryer (1991) A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity ofpolyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibodylml, preferably 5-10 mg specific antibodylml, is generally employed in procedures requiring precipitation of RMEP-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 Coligan et al. supra.) In another embodiment of the invention, the polynucleotides encoding RMEP, or any fragment or complement thereof, may be used for therapeutic purposes, In one aspect, modifications of gene expression can be achieved by designing complementary sequences or antisense molecules (DNA, RNA, PNA, or modified oligonucleotides) to the coding or regulatory regions of the gene encoding RMEP.
Such technology is well known in the° art, and antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding RMEP.
(See, e.g., Agrawal, S., ed. (1996) Antisense Therapeutics, Humana Press Inc., Totawa NJ.) In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the cellular sequence encoding the target protein. (See, e.g., Slater, J.E. et al. (1998) J. Allergy Cli. Immunol. 102(3):469-475; and Scanlon, K.J. et al. (1995) 9(13):1288-1296.) Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors. (See, e.g., Miller, A.D. (1990) Blood 76:271; Ausubel, supra; Uckert, W. and W. Walther (1994) Pharmacol. Ther.
63(3):323-347.) Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art. (See, e.g., Rossi, J.J. (1995) Br. Med. Bull.
51(1):217-225; Boado, R.J. et al. (1998) J. Pharm. Sci. 87(11):1308-1315; and Morns, M.C. et al. (1997) Nucleic Acids Res.
25(14):2730-2736.) In another embodiment of the invention, polynucleotides encoding RMEP may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e.g., in the cases of severe combined immunodeficiency (SCID)-X1 disease characterized by X-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R.M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995) Science 270:470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R.G. et aI. (1995) Hum. Gene Therapy 6:667-703), thalassamias, familial hypercholesterolemia, and hemophilia resulting from Factor VIII or Factor IX
deficiencies (Crystal, R.G. (1995) Science 270:404-410; Verma, LM. and N. Somia (1997) Nature 389:239-242)), (ii) express a conditionally lethal gene product (e.g., in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular parasites (e.g., against human retroviruses, such as human immunodeficiency virus (HIV) (Baltimore, D. (1988) Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci. USA. 93:11395-11399), hepatitis B or C
virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis; and protozoan parasites such as Plasmodium falciparum and Trypanosoma cruzi). In the case where a genetic deficiency in RMEP expression or regulation causes disease, the expression of RMEP from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.
In a further embodiment of the invention, diseases or disorders caused by deficiencies in RMEP
are treated by constructing mammalian expression vectors encoding RMEP and introducing these vectors by mechanical means into RMEP-deficient cells. Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA microinjection into individual cells, (ii) ballistic gold particle delivery, (iii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R.A. and W.F. Anderson (1993) Annu. Rev.
Biochem. 62:191-217;
Ivics, Z. (1997) Cell 91:501-510; Boulay, J-L. and H. Recipon (1998) Curr.
Opin. Biotechnol. 9:445-450).
Expression vectors that may be effective for the expression of RMEP include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX vectors (Invitrogen, Carlsbad CA), PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV (Stratagene, La Jolla CA), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto CA). RMEP may be expressed using (i) a constitutively active promoter, (e.g., from cytomegalovirus (CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or (3-actin genes), (ii) an inducible promoter (e.g., the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc. Natl.
Acad. Sci. USA
89:5547-5551; Gossen, M, et al. (1995) Science 268:1766-1769; Rossi, F.M.V.
and H.M. Blau (1998) Curr. Opin. Biotechnol. 9:451-456), commercially available in the T-REX
plasmid (Invitrogen)); the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND;
Invitrogen); the FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F.M.V.
and Blau, H.M. supra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding RMEP from a normal individual.

Commercially available liposome transformation kits (e.g., the PERFECT LIPID
TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters.
In the alternative, transformation is performed using the calcium phosphate method (Graham, F.L. and A.J. Eb (1973) Virology 52:456-467), or by electroporation (Neumann, E. et al.
(1982) EMBO J.
1:841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.
In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to RMEP expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding RMEP under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirus cis-acting RNA sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e.g., PFB and PFBNEO) are commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc.
Natl. Acad. Sci. USA 92:6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al.
(1987) J. Virol. 61:1647-1650; Bender, M.A. et al. (1987) J. Virol. 61:1639-1646; Adam, M.A. and A.D. Miller (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol.
72:8463-8471; Zufferey, R.
et al. (1998) J. Virol. 72:9873-9880). U.5. Patent Number 5,910,434 to Rigg ("Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant") discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference.
Propagation of retrovirus vectors, transduction of a population of cells (e.g., CD4+ T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Ranga, U. et aI. (1997) J. Virol.
71:7020-7029; Bauer, G. et al. (1997) Blood 89:2259-2267; Bonyhadi, M.L. (1997) J. Virol. 71:4707-4716;
Ranga, U, et al.
(1998) Proc. Natl. Acad. Sci. USA 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).
In the alternative, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding RMEP to cells which have one or more genetic abnormalities with respect to the expression of RMEP. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M.E. et al. (1995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Patent Number 5,707,618 to Armentano ("Adenovirus vectors for gene therapy"), hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P.A. et al. (1999) Annu.
Rev. Nutr. 19:511-544 and Verma, LM. and N. Somia (1997) Nature 18:389:239-242, both incorporated by reference herein.
In another alternative, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding RMEP to target cells which have one or more genetic abnormalities with respect to the expression of RMEP. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing RMEP to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector has been used to deliver a reporter gene to the eyes of primates (Liu, X. et al. (1999) Exp.
Eye Res. 169:385-395).
The construction of a HSV-1 virus vector has also been disclosed in detail in U.S. Patent Number 5,804,413 to DeLuca ("Herpes simplex virus strains for gene transfer"), which is hereby incorporated by reference. U.S. Patent Number 5,804,413 teaches the use of recombinant HSV
d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under the control of the appropriate promoter for purposes including human gene therapy. Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22. For HSV
vectors, see also Goins, W.F. et al. (1999) J. Virol. 73:519-532 and Xu, H. et al. (1994) Dev. Biol.
163:152-161, hereby incorporated by reference. The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.
In another alternative, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding RMEP to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and K.-J. Li (1998) Curr. Opin. Biotechnol. 9:464-469). During alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e.g., protease and polymerase). Similarly, inserting the coding sequence for RMEP
into the alphavirus genome in place of the capsid-coding region results in the production of a large number of RMEP-coding RNAs and the synthesis of high levels of RMEP in vector transduced cells. While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphaviruses can be altered to suit the needs of the gene therapy application (Dryga, S.A. et al. (1997) Virology 228:74-83). The wide host range of alphaviruses will allow the introduction of RMEP into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction. The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA and RNA
transfections, and performing alphavirus infections, are well known to those with ordinary skill in the art.
Oligonucleotides derived from the transcription initiation site, e.g., between about positions -10 and +10 from the start site, may also be employed to inhibit gene expression.
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 Immunologic 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 RMEP.
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 of the 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.
Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding RMEP. 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 not as easily recognized by endogenous endonucleases.
An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding RMEP. Compounds which may be effective in altering expression of a specific polynucleotide may include, but are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-forming oligonucleotides, transcription factors and other polypeptide transcriptional regulators, and non-macromolecular chemical entities which are capable of interacting with specific polynucleotide sequences. Effective compounds may alter polynucleotide expression by acting as either inhibitors or promoters of polynucleotide expression. Thus, in the treatment of disorders associated with increased RMEP
expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding RMEP may be therapeutically useful, and in the treament of disorders associated with decreased RMEP expression or activity, a compound which specifically promotes expression of the polynucleotide encoding RMEP may be therapeutically useful.
At least one, and up to a plurality, of test compounds may be screened for effectiveness in altering expression of a specific polynucleotide. A test compound may be obtained by any method commonly known in the art, including chemical modification of a compound known to be effective in altering polynucleotide expression; selection from an existing, commercially-available or proprietary library of naturally-occurring or non-natural chemical compounds; rational design of a compound based on chemical and/or structural properties of the target polynucleotide;
and selection from a library of chemical compounds created combinatorially or randomly. A sample comprising a polynucleotide encoding RMEP is exposed to at least one test compound thus obtained. The sample may comprise, for example, an intact or permeabilized cell, or an in vitro cell-free or reconstituted biochemical system. Alterations in the expression of a polynucleotide encoding RMEP are assayed by any method commonly known in the art. Typically, the expression of a specific nucleotide is detected by hybridization with a probe having a nucleotide sequence complementary to the sequence of the polynucleotide encoding RMEP. The amount of hybridization may be quantified, thus forming the basis for a comparison of the expression of the polynucleotide both with and without exposure to one or more test compounds. Detection of a change in the expression of a polynucleotide exposed to a test compound indicates that the test compound is effective in altering the expression of the polynucleotide. A screen for a compound effective in altering expression of a specific polynucleotide can be carried out, for example, using a Schizosaccharom~ces pombe gene expression system (Atkins, D. et al. (1999) U.S. Patent No. 5,932,435; Arndt, G.M. et al. (2000) Nucleic Acids Res. 28:E15) or a human cell line such as HeLa cell (Clarks, M.L, et al. (2000) Biochem.
Biophys. Res. Commun.
268:8-13). A particular embodiment of the present invention involves screening a combinatorial library of oligonucleotides (such as deoxyribonucleotides, ribonucleotides, peptide nucleic acids, and modified oligonucleotides) for antisense activity against a specific polynucleotide sequence (Bruise, T.W. et al. (1997) U.S. Patent No. 5,686,242; Bntice, T.W. et al. (2000) U.S.
Patent No. 6,022,691).
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 liposome injections, or by polycationic amino polymers may be achieved using methods which are well known in the art. (See, e.g., Goldman, C.K. et al.
(1997) Nat. Biotechnol.
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 composition which generally comprises an active ingredient formulated with a pharmaceutically acceptable excipient.
Excipients may include, for example, sugars, starches, ceIluloses, gums, and proteins. Various formulations are commonly known and are thoroughly discussed in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing, Easton PA). Such compositions may consist of RMEP, antibodies to RMEP, and mimetics, agonists, antagonists, or inhibitors of RMEP.
The compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, infra-arterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.
Compositions for pulmonary administration may be prepared in liquid or dry powder form.
These compositions are generally aerosolized immediately prior to inhalation by the patient. In the case of small molecules (e.g. traditional low molecular weight organic drugs), aerosol delivery of fast-acting formulations is well-known in the art. In the case of macromolecules (e.g.
larger peptides and proteins), recent developments in the field of pulmonary delivery via the alveolar region of the lung have enabled the practical delivery of drugs such as insulin to blood circulation (see, e.g., Patton, J.S. et al., U.S.
Patent No. 5,997,848). Pulmonary delivery has the advantage of administration without needle injection, and obviates the need for potentially toxic penetration enhancers.

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.
Specialized forms of compositions may be prepared for direct intracellular delivery of macromolecules comprising RMEP or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, RMEP or a fragment thereof may be joined to a short cationic N-terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated have been found to transduce into the cells of all tissues, including the brain, in a mouse model system (Schwarze, S.R. et al. (1999) Science 285:1569-1572).
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, monkeys, 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 RMEP
or fragments thereof, antibodies of RMEP, and agonists, antagonists or inhibitors of RMEP, 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 EDSO (the dose therapeutically effective in 50% of the population) or LDSO
(the dose lethal to 50%o of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LDSO/EDSO ratio. 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 EDSO 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 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 RMEP may be used for the diagnosis of disorders characterized by expression of RMEP, or in assays to monitor patients being treated with RMEP or agonists, antagonists, or inhibitors of RMEP. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for RMEP
include methods which utilize the antibody and a label to detect RMEP 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 RMEP, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of RMEP
expression. Normal or standard values for RMEP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to RMEP under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of RMEP
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 RMEP 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 RMEP may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of RMEP, and to monitor regulation of RMEP levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding RMEP or closely related molecules may be used to identify nucleic acid sequences which encode RMEP. The specificity of the probe, whether it is made from a highly 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 will determine whether the probe identifies only naturally occurring sequences encoding RMEP, 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 RMEP encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID
N0:48-94 or from genomic sequences including promoters, enhancers, and introns of the RMEP
gene.
Means for producing specific hybridization probes for DNAs encoding RMEP
include the cloning of polynucleotide sequences encoding RMEP or RMEP 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
polymerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as 32P or 355, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.
Polynucleotide sequences encoding RMEP may be used for the diagnosis of disorders associated with expression of RMEP. Examples of such disorders include, but are not limited to, a nervous system disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease; prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome; fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorder of the central nervous system, cerebral palsy, a neuroskeletal disorder, an autonomic nervous system disorder, a cranial nerve disorder, a spinal cord disease, muscular dystrophy and other neuromuscular disorder, a peripheral nervous system disorder, dermatomyositis and polymyositis; inherited, metabolic, endocrine, and toxic myopathy; myasthenia gravis, periodic paralysis; a mental disorder including mood, anxiety, and schizophrenic disorders; seasonal affective disorder (SAD); akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette's disorder; 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 polyenodocrinopathy-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; 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, and a developmental disorder such as renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss. The polynucleotide sequences encoding RMEP may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR
technologies; in dipstick, pin, and multiformat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered RMEP expression. Such qualitative or quantitative methods are well known in the art.
In a particular aspect, the nucleotide sequences encoding RMEP may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding RMEP 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 RMEP 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 monitor the treatment of an individual patient.
In order to provide a basis for the diagnosis of a disorder associated with expression of RMEP, 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 RMEP, 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 RMEP
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 RMEP, or a fragment of a polynucleotide complementary to the polynucleotide encoding RMEP, 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.
In a particular aspect, oligonucleotide primers derived from the polynucleotide sequences encoding RMEP may be used to detect single nucleotide polymorphisms (SNPs).
SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from the polynucleotide sequences encoding RMEP are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP
(isSNP), are capable of identifying polymorphisms by comparing the sequence of individual overlapping DNA fragments which assemble into a common consensus sequence. These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc., San Diego CA).
Methods which may also be used to quantify the expression of RMEP include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standaxd 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 or polynucleotide of interest is presented in various dilutions and a spectrophotometric or 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 elements on a microarray. The microarray can be used in transcript imaging techniques which monitor the relative expression levels of large numbers of genes simultaneously as described below. The microarray may also be used 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, to monitor progression/regression of disease as a function of gene expression, and to develop and monitor the activities of therapeutic agents in the treatment of disease. In particular, this information may be used to develop a pharmacogenomic profile of a patient in order to select the most appropriate and effective treatment regimen for that patient. For example, therapeutic agents which are highly effective and display the fewest side effects may be selected for a patient based on his/her pharmacogenomic profile.
In another embodiment, RMEP, fragments of RMEP, or antibodies specific for RMEP may be used as elements on a microaxray. The microarray may be used to monitor or measure protein-protein interactions, drug-target interactions, and'gene expression profiles, as described above.
A particular embodiment relates to the use of the polynucleotides of the present invention to generate a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time. (See SeiEaamer et al., "Comparative Gene Transcript Analysis,"
U.S. Patent Number 5,840,484, expressly incorporated by reference herein.) Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity.
Transcript images may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect gene expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.
Transcript images which profile the expression of the polynucleotides of the present invention may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E.F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S. and N.L. Anderson (2000) Toxicol. Lett. 112-113:467-471, expressly incorporated by reference herein). If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties. These fingerprints or signatures are most useful and refined when they contain expression information from a large number of genes and gene families. Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data. The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity. (See, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released February 29, 2000, available at http://www.niehs.nih.gov/oc/news/toxchip.htm.) Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.
In one embodiment, the toxicity of a test compound is assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the polynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biological sample. Differences in the transcript levels between the two samples are indicative of a toxic response caused by the test compound in the treated sample.
Another particular embodiment relates to the use of the polypeptide sequences of the present invention to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type. In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the prtotein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of the present invention. In some cases, further sequence data may be obtained for definitive protein identification.
A proteomic profile may also be generated using antibodies specific for RMEP
to quantify the levels of RMEP expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. (1999) Anal.
Biochem. 270:103-111;
Mendoze, L.G. et al. (1999) Biotechniques 27:778-788). Detection may be performed by a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol- or amino reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.
Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level.
There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N.L. and J.

Seilhamer (1997) Electrophoresis 18:533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the polypeptides of the present invention.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the polypeptides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared with the amount in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.
Microarrays may be prepared, used, and analyzed using methods known in the art. (See, e.g., Brennan, T.M. et al. (1995) U.S. Patent No. 5,474,796; Schena, M. et al.
(1996) Proc. Natl. Acad. Sci.
USA 93:10614-10619; Baldeschweiler et al. (1995) PCT application W095/251116;
Shalom D. et al.
(1995) PCT application W095/35505; Heller, R.A. et al. (1997) Proc. Natl.
Acad. Sci. USA 94:2150-2155; and Heller, M.J. et al. (1997) U.S. Patent No. 5,605,662.) Various types of microarrays are well known and thoroughly described in DNA Microarravs: A Practical Approach, M.
Schena, ed. (1999) Oxford University Press, London, hereby expressly incorporated by reference.
In another embodiment of the invention, nucleic acid sequences encoding RMEP
may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence. Either coding or noncoding sequences may be used, and in some instances, noncoding sequences may be preferable over coding sequences. For example, conservation of a coding sequence among members of a multi-gene family may potentially cause undesired cross hybridization during chromosomal mapping. 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 (HACs), yeast artificial chromosomes (PACs), bacterial artificial chromosomes (BACs), bacterial P1 constructions, or single chromosome cDNA libraries. (See, e.g., Harrington, J.J. et al. (1997) Nat.
Genet. 15:345-355; Price, C.M. (1993) Blood Rev. 7:127-134; and Trask, B.J.
(1991) Trends Genet.

7:149-154.) Once mapped, the nucleic acid sequences of the invention may be used to develop genetic linkage maps, for example, which correlate the inheritance of a disease state with the inheritance of a particular chromosome region or restriction fragment length polymorphism (RFLP). (See, for example, Lander, E.S. and D. Botstein (1986) Proc. Natl. Acad. Sci. USA
83:7353-7357.) Fluorescent in situ hybridization (FISH) may be correlated with other physical and genetic map data. (See, e.g., Heinz-Ulrich, et al. (1995) in Meyers, su ra, 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 location of the gene encoding RMEP on a physical map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA
associated with that disorder and thus may further positional cloning efforts.
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 exact chromosomal locus is not known.
This information is valuable to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the gene or genes responsible for a disease or syndrome have been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to 11q22-23, 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 instant 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, RMEP, its catalytic or immunogenic fragments, or oligopeptides 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 RMEP 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 RMEP, or fragments thereof, and washed. Bound RMEP is then detected by methods well known in the art. Purified RMEP 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 RMEP specifically compete with a test compound for binding RMEP. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with RMEP.
In additional embodiments, the nucleotide sequences which encode RMEP 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.
The disclosures of all patents, applications, and publications mentioned above and below, including U.S. Ser. No. 60/201,875, U.S. Ser. No. 60/200,184, U.S. Ser. No.
60/202,090, U.S. Ser.
No. 60/210,232, and U.S. Ser. No. 60/220,553, are hereby expressly incorporated by reference.
EXAMPLES
I. Construction of cDNA Libraries Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD
database (Incyte Genomics, Palo Alto CA) and shown in Table 4, column 5. 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 CsCl 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, Stratagene 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, supra, 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), PSPORT1 plasmid (Life Technologies), PCDNA2.1 plasmid (Invitrogen, Carlsbad CA), PBK-CMV plasmid (Stratagene), or pINCY (Incyte Genomics, Palo Alto CA), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XL1-BlueMRF, or SOLR from Stratagene or DHSa, DH10B, or ElectroMAX
DH10B from Life Technologies.
II. Isolation of cDNA Clones Plasmids obtained as described in Example I 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 Ultra 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 lyophilization, 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 plasmid 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 Incyte cDNA recovered in plasmids as described in Example II were sequenced as follows.
Sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Applied Biosystems) 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 (Applied Biosystems).
Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Molecular Dynamics); the ABI
PRISM 373 or 377 sequencing system (Applied Biosystems) 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, sera, unit 7.7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.
The polynucleotide sequences derived from Incyte cDNAs were validated by removing vector, linker, and poly(A) sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programming, and dinucleotide nearest neighbor analysis. The Incyte cDNA
sequences or translations thereof 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 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, for example, Eddy, S.R. (1996) Curr. Opin. Struct. Biol. 6:361-365.) The queries were performed using programs based on BLAST, FASTA, BLIMPS, and HMMER. The Incyte cDNA
sequences were assembled to produce full length polynucleotide sequences. Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched sequences, or Genscan-predicted coding sequences (see Examples IV and V) were used to extend Incyte cDNA assemblages to full length. Assembly was performed using programs based on Phred, Phrap, and Conned, and cDNA assemblages 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 polypeptide sequences. Alternatively, a polypeptide of the invention may begin at any of the methionine residues of the full length translated polypeptide. Full length polypeptide sequences were subsequently analyzed by querying against databases such as the GenBank protein databases (genpept), SwissProt, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, and hidden Markov model (HMM)-based protein family databases such as PFAM.
Full length polynucleotide sequences are also analyzed using MACDNASIS PRO
software (Hitachi Software Engineering, South San Francisco CA) and LASERGENE software (DNASTAR).
Polynucleotide and polypeptide sequence alignments are generated using 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.
Table 7 summarizes the tools, programs, and algorithms used for the analysis and assembly of Incyte cDNA and full length sequences and provides applicable descriptions, references, and threshold parameters. The first column of Table 7 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 or the lower the probability value, the greater the identity between two sequences).
The programs described above for the assembly and analysis of full length polynucleotide and polypeptide sequences were also used to identify polynucleotide sequence fragments from SEQ ID
N0:48-94. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 4.
IV. Identification and Editing of Coding Sequences from Genomic DNA
Putative RNA metabolism proteins were initially identified by running the Genscan gene identification program against public genomic sequence databases (e.g., gbpri and gbhtg). Genscan is a general-purpose gene identification program which analyzes genomic DNA
sequences from a variety of organisms (See Burge, C. and S. Karlin (1997) J. Mol. Biol. 268:78-94, and Burge, C. and S. Karlin (1998) Curr. Opin. Struct. Biol. 8:346-354). The program concatenates predicted exons to form an assembled cDNA sequence extending from a methionine to a stop codon. The output of Genscan is a FASTA database of polynucleotide and polypeptide sequences. The maximum range of sequence for Genscan to analyze at once was set to 30 kb. To determine which of these Genscan predicted cDNA
sequences encode RNA metabolism proteins, the encoded polypeptides were analyzed by querying against PFAM models for RNA metabolism proteins. Potential RNA metabolism proteins were also identified by homology to Incyte cDNA sequences that had been annotated as RNA
metabolism proteins.
These selected Genscan-predicted sequences were then compared by BLAST
analysis to the genpept and gbpri public databases. Where necessary, the Genscan-predicted sequences were then edited by comparison to the top BLAST hit from genpept to correct errors in the sequence predicted by Genscan, such as extra or omitted exons. BLAST analysis was also used to find any Incyte cDNA or public cDNA coverage of the Genscan-predicted sequences, thus providing evidence for transcription. When Incyte cDNA coverage was available, this information was used to correct or conf'~rm the Genscan predicted sequence. Full length polynucleotide sequences were obtained by assembling Genscan-predicted coding sequences with Incyte cDNA sequences and/or public cDNA
sequences using the assembly process described in Example III. Alternatively, full length polynucleotide sequences were derived entirely from edited or unedited Genscan-predicted coding sequences.
V. Assembly of Genomic Sequence Data with cDNA Sequence Data "Stitched" Seguences Partial cDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example IV. Partial cDNAs assembled as described in Example III were mapped to genomic DNA and parsed into clusters containing related cDNAs and Genscan exon predictions from one or more genomic sequences. Each cluster was analyzed using an algorithm based on graph theory and dynamic programming to integrate cDNA and genomic information, generating possible splice variants that were subsequently confirmed, edited, or extended to create a full length sequence.
Sequence intervals in which the entire length of the interval was present on more than one sequence in the cluster were identified, and intervals thus identified were considered to be equivalent by transitivity.
For example, if an interval was present on a cDNA and two genomic sequences, then all three intervals were considered to be equivalent. This process allows unrelated but consecutive genomic sequences to be brought together, bridged by cDNA sequence. Intervals thus identified were then "stitched" together by the stitching algorithm in the order that they appear along their parent sequences to generate the longest possible sequence, as well as sequence variants. Linkages between intervals which proceed along one type of parent sequence (cDNA to cDNA or genomic sequence to genomic sequence) were given preference over linkages which change parent type (cDNA to genomic sequence). The resultant stitched sequences were translated and compared by BLAST analysis to the genpept and gbpri public databases. Incorrect exons predicted by Genscan were corrected by comparison to the top BLAST hit from genpept. Sequences were further extended with additional cDNA sequences, or by inspection of genomic DNA, when necessary.
"Stretched" Seguences Partial DNA sequences were extended to full length with an algorithm based on BLAST
analysis. First, partial cDNAs assembled as described in Example III were queried against public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases using the BLAST program. The nearest GenBank protein homolog was then compared by BLAST analysis to either Incyte cDNA sequences or GenScan exon predicted sequences described in Example IV. A
chimeric protein was generated by using the resultant high-scoring segment pairs (HSPs) to map the translated sequences onto the GenBank protein homolog. Insertions or deletions may occur in the chimeric protein with respect to the original GenBank protein homolog. The GenBank protein homolog, the chimeric protein, or both were used as probes to search for homologous genomic sequences from the public human genome databases. Partial DNA sequences were therefore "stretched" or extended by the addition of homologous genomic sequences. The resultant stretched sequences were examined to determine whether it contained a complete gene.
VI. Chromosomal Mapping of RMEP Encoding Polynucleotides The sequences which were used to assemble SEQ ID N0:48-94 were compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that matched SEQ ID N0:48-94 were assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for Genome Research (WIGR), and Genethon were used to determine if any of the clustered sequences had been previously mapped. Inclusion of a mapped sequence in a cluster resulted in the assignment of all sequences of that cluster, including its particular SEQ ID NO:, to that map location.
Map locations are represented by ranges, or intervals, of human chromosomes.
The map position of an interval, in centiMorgans, is measured relative to the terminus of the chromosome's p-arm. (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination.) The cM distances are based on genetic markers mapped by Genethon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters. Human genome maps and other resources available to the public, such as the NCBI "GeneMap'99" World Wide Web site (http://www.ncbi.nlm.nih.gov/genemap~, can be employed to determine if previously identified disease genes map within or in proximity to the intervals indicated above.
In this manner, SEQ ID N0:53 was mapped to chromosome 1 within the interval from 159.6 to 164.1 centiMorgans. SEQ ID N0:61 was mapped to chromosome 8 within the interval from 30.70 to 60.00 centiMorgans. SEQ ID N0:69 was mapped to chromosome 10 within the interval from 158.30 centiMorgans to the q terminus. SEQ ID N0:70 was mapped to chromosome 1 within the interval from 63.90 to 74.80 centiMorgans. SEQ ID N0:71 was mapped to chromosome 1 within the interval from 159.60 to 164.10 centiMorgans. SEQ ID N0:73 was mapped to chromosome 11 within the interval from 34.30 to 37.00 centiMorgans. SEQ ID N0:75 was mapped to chromosome 2 within the interval from 107.10 to 118.00 centiMorgans. SEQ ID N0:76 was mapped to chromosome 7 within the interval from 7.80 to 10.60 centiMorgans. SEQ ID NO:79 was mapped to chromosome 22 within the interval from 22.20 to 40.20 centiMorgans. SEQ ID N0:81 was mapped to chromosome 4 within the interval from the p terminus to 6.70 centiMorgans. SEQ ID NO: 84 was mapped to chromosome 5 within the interval from 156.0 to 157.6 centiMorgans. SEQ ID NO:
88 was mapped to chromosome 11 within the interval from 117.9 to 123.5 centiMorgans. SEQ ID
NO:91 was mapped to chromosome 5 within the interval from 152.3 to 155.5 centiMorgans.
VII. Analysis of Polynucleotide Expression 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, supra, ch. 7; Ausubel (1995) sera, ch. 4 and 16.) Analogous computer techniques applying BLAST were used to search for identical or related molecules in cDNA databases such as GenBank or LIFESEQ (Incyte Genomics). 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 exact or similar. The basis of the search is the product score, which is defined as:
BLAST Score x Percent Identity 5 x minimum {length(Seq. 1), length(Seq. 2)}
The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows: the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 times the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and -4 for every mismatch. Two sequences may share more than one HSP (separated by gaps). If there is more than one HSP, then the pair with the highest BLAST score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST
alignment. For example, a product score of 100 is produced only for 100% identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100%
identity and 70%
overlap at one end, or by 88% identity and 100% overlap at the other. A
product score of 50 is produced either by 100% identity and 50% overlap at one end, or 79% identity and 100% overlap.
Alternatively, polynucleotide sequences encoding RMEP are analyzed with respect to the tissue sources from which they were derived. For example, some full length sequences are assembled, at least in part, with overlapping Incyte cDNA sequences (see Example III). Each cDNA
sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organ/tissue categories: cardiovascular system; connective tissue;
digestive system;
embryonic structures; endocrine system; exocrine glands; genitalia, female;
genitalia, male; germ cells;
heroic and immune system; liver; musculoskeletal system; nervous system;
pancreas; respiratory system;
sense organs; skin; stomatognathic system; unclassified/mixed; or urinary tract. The number of libraries in each category is counted and divided by the total number of libraries across all categories. Similarly, each human tissue is classified into one of the following disease/condition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category is counted and divided by the total number of libraries across all categories.
The resulting percentages reflect the tissue- and disease-specific expression of cDNA encoding RMEP.

cDNA sequences and cDNA library/tissue information are found in the LIFESEQ
GOLD database (Incyte Genomics, Palo Alto CA).
VIII. Extension of RMEP Encoding Polynucleotides Full length polynucleotide sequences were also 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 was synthesized 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 nucleotides in length, to have a GC content of about 50% 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 Mg2+, (NH4)yS 04, and 2-mercaptoethanol, Taq DNA polymerase (Amersham Pharmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerase (Stratagene), with the following parameters for primer pair PCI A andPCI 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, 5 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: 57°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 ~1 PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1X TE
and 0.5 ~l 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 5 /d to 10 /c1 aliquot of the reaction mixture was analyzed by electrophoresis on a 1 % agarose 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 relegation into pUC 18 vector (Amersham Pharmacia Biotech). For shotgun sequencing, the digested nucleotides were separated on low concentrateon (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 polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, and individual colonies were picked and cultured overnight at 37 °C in 384-well plates in LB/2x carb liquid media.
The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase (Amersham Pharmacia Biotech) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1:
94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 60°C, 1 min;
Step 4: 72°C, 2 min; Step 5: steps 2, 3, and 4 repeated 29 times; Step 6: 72°C, 5 min; Step 7: storage at 4°C.
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 (Applied Biosystems).
In like manner, full length polynucleotide sequences are verified using the above procedure or are used to obtain 5' regulatory sequences using the above procedure along with oligonucleotides designed for such extension, and an appropriate genomic library.
IX. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID N0:48-94 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.
Oligonucleotides are designed using state-of the-art software such as OLIGO
4.06 software (National Biosciences) and labeled by combining 50 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-25 superfine size exclusion dextran 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 Plus, 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 0.5% sodium dodecyl sulfate.

Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.
X. Microarrays The linkage or synthesis of array elements upon a microarray can be achieved utilizing photolithography, piezoelectric printing (ink jet printing, See, e.g., Baldeschweiler, sera.), mechanical microspotting technologies, and derivatives thereof. The substrate in each of the aforementioned technologies should be uniform and solid with a non-porous surface (Schena (1999), supra). Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers. Alternatively, a procedure 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 using available methods and machines well known to those of ordinary skill in the art and may contain any appropriate number of elements. (See, e.g., Schena, M. et al.
(1995) Science 270:467-470;
Shalom D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and J. Hodgson (1998) Nat. Biotechnol.
16:27-31.) Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers thereof may comprise the elements of the microarray. Fragments or oligomers suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). The array elements are hybridized with polynucleotides in a biological sample. The polynucleotides in the biological sample are conjugated to a fluorescent label or other molecular tag for ease of detection.
After hybridization, nonhybridized nucleotides from the biological sample are removed, and a fluorescence scanner is used to detect hybridization at each array element.
Alternatively, laser desorbtion and mass spectrometry may be used for detection of hybridization.
The degree of complementarity and the relative abundance of each polynucleotide which hybridizes to an element on the microarray may be assessed. In one embodiment, microarray preparation and usage is described in detail below.
Tissue or Cell Sample Preparation Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and poly(A)+ RNA is purified using the oligo-(dT) cellulose method. Each poly(A)+
RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/~.il oligo-(dT) primer (2lmer), 1X first strand buffer, 0.03 units/iil RNase inhibitor, 500 ~M dATP, 500 ~M dGTP, 500 ~M dTTP, 40 ~M
dCTP, 40 ~M dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Pharmacia Biotech). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly(A)+ RNA with GEMBRIGHT kits (Incyte). Specific control poly(A)+ RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA. After incubation at 37° C for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of O.SM sodium hydroxide and incubated for 20 minutes at 85 ° C to the stop the reaction and degrade the RNA. Samples are purified using two successive CHROMA SPIN 30 gel filtration spin columns (CLONTECH
Laboratories, Inc.
(CLONTECH), Palo Alto CA) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100%
ethanol. The sample is then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook NY) and resuspended in 14 iil SX SSC/0.2% SDS.
Microarray Preparation Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts.
PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert. Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 fig. Amplified array elements are then purified using SEPHACRYL-400 (Amersham Pharmacia Biotech).
Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0.1 % SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4%
hydrofluoric acid (VWR
Scientific Products Corporation (VWR), West Chester PA), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are cured in a 110°C
oven.
Array elements are applied to the coated glass substrate using a procedure described in US
Patent No. 5,807,522, incorporated herein by reference. 1 irl of the array element DNA, at an average concentration of 100 ng/iil, is loaded into the open capillary printing element by a high-speed robotic apparatus. The apparatus then deposits about 5 n1 of array element sample per slide.
Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene).
Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water.
Non-specific binding sites are blocked by incubation of microarrays in 0.2%
casein in phosphate buffered saline (PBS) (Tropix, Inc., Bedford MA) for 30 minutes at 60°
C followed by washes in 0.2%
SDS and distilled water as before.
Hybridization Hybridization reactions contain 9 ~~1 of sample mixture consisting of 0.2 ~g each of Cy3 and Cy5 labeled cDNA synthesis products in SX SSC, 0.2% SDS hybridization buffer.
The sample mixture is heated to 65 ° C for 5 minutes and is aliquoted onto the microarray surface and covered with an 1.8 cm2 coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 ~~1 of SX SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60° C. The arrays are washed for 10 min at 45 ° C in a first wash buffer (1X SSC, 0.1 % SDS), three times for 10 minutes each at 45 ° C in a second wash buffer (0.1X SSC), and dried.
Detection Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara CA) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of CyS. The excitation laser light is focused on the array using a 20X microscope objective (Nikon, Inc., Melville NY). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster-scanned past the objective. The 1.8 cm x 1.8 cm array used in the present example is scanned with a resolution of 20 micrometers.
In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially.
Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT 81477, Hamamatsu Photonics Systems, Bridgewater NJ) corresponding to the two fluorophores. Appropriate filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for CyS. Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.
The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the sample mixture at a known concentration. A
specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1:100,000. When two samples from different sources (e.g., representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.
The output of the photomultiplier tube is digitized using a 12-bit RTI-835H
analog-to-digital (A/D) conversion board (Analog Devices, Inc., Norwood MA) installed in an IBM-compatible PC
computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simultaneously, the data are first corrected for optical crosstalk (due to overlapping emission spectra) between the fluorophores using each fluorophore's emission spectrum.
A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte).
XI. Complementary Polynucleotides Sequences complementary to the RMEP-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring RMEP. 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 RMEP. 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 RMEP-encoding transcript.
XII. Expression of RMEP
Expression and purification of RMEP is achieved using bacterial or virus-based expression systems. For expression of RMEP 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 T5 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 RMEP upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of RMEP 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 RMEP 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 Spodoptera frugiperda (Sf9) 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, RMEP is synthesized as a fusion protein with, e.g., glutathione 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 RMEP 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 RMEP obtained by these methods can be used directly in the assays shown in Examples XVI and XVII where applicable.
XIII. ~nctional Assays RMEP function is assessed by expressing the sequences encoding RMEP at 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 PCR3.1 (Invitrogen, Carlsbad CA), both of which contain the cytomegalovirus promoter. 5-10 ~cg 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 ,ug 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 Cytometry, Oxford, New York NY.
The influence of RMEP on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding RMEP 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 immunoglobulin 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 RMEP and other genes of interest can be analyzed by northern analysis or microarray techniques.
XIV. Production of RMEP Specific Antibodies RMEP 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 RMEP 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, supra, ch. 11.) Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431A
peptide synthesizer (Applied Biosystems) 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, supra.) Rabbits are immunized with the oligopeptide-I~LH
complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-RMEP
activity by, for example, binding the peptide or RMEP to a substrate, blocking with 1 % BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XV. Purification of Naturally Occurring RMEP Using Specific Antibodies Naturally occurring or recombinant RMEP is substantially purified by immunoaffinity chromatography using antibodies specific for RMEP. An immunoafhnity column is constructed by covalently coupling anti-RMEP 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 RMEP are passed over the immunoafFnity column, and the column is washed under conditions that allow the preferential absorbance of RMEP (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/RMEP 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 RMEP is collected.
XVI. Identification of Molecules Which Interact with RMEP
RMEP, or biologically active fragments thereof, are labeled with lzsl 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 multi-well plate are incubated with the labeled RMEP, washed, and any wells with labeled RMEP complex are assayed. Data obtained using different concentrations of RMEP are used to calculate values for the number, affinity, and association of RMEP with the candidate molecules.
Alternatively, molecules interacting with RMEP are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989) Nature 340:245-246, or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (Clontech).
RMEP may also be used in the PATHCALLING process (CuraGen Corp., New Haven CT) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K.
et al. (2000) U.S. Patent No. 6,057,101 ).
XVII. Demonstration of RMEP Activity RMEP activity is demonstrated by a polyacrylamide gel mobility-shift assay. In preparation for this assay, RMEP is expressed by transforming a mammalian cell line such as COS7, HeLa or CHO with a eukaryotic expression vector containing RMEP cDNA. The cells are incubated for 48-72 hours after transformation under conditions appropriate for the cell line to allow expression and accumulation of RMEP. Extracts containing solubilized proteins can be prepared from cells expressing RMEP by methods well known in the art. Portions of the extract containing RMEP are added to [32P]-labeled RNA. Radioactive RNA can be synthesized in vitro by techniques well known in the art. The mixtures are incubated at 25 °C in the presence of RNase inhibitors under buffered conditions for 5-10 minutes. After incubation, the samples are analyzed by polyacrylamide gel electrophoresis followed by autoradiography. The presence of a band on the autoradiogram indicates the formation of a complex between RMEP and the radioactive transcript. A band of similar mobility will not be present in samples prepared using control extracts prepared from untransformed cells.
In the alternative, ribosomal protein function of RMEP is assessed by expressing the sequences encoding ribosomal proteins at 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 PCR3.1 (Invitrogen Corporation), both of which contain the cytomegalovirus promoter (P~~). Between 5-10 ~g of recombinant vector are transfected into a human cell line, preferably of endothelial or hematopoietic origin, using either liposome formulations or electroporation. 1-2 ~g of an additional plasmid containing sequences encoding a marker protein are cotransfected.
Transient 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 MG (1994) Flow ~tometry, Oxford University Press, New York NY.
The influence of ribosomal proteins on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding a ribosomal protein 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 immunoglobulin G (IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 (DYNAL, Inc., 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 a ribosomal protein and other genes of interest can be analyzed by northern analysis or microarray techniques.
In the alternative, RMEP activity is measured as the aminoaeylation of a substrate tRNA in the presence of [l4C]cysteine. RMEP is incubated with tRNA~ys and [14C]cysteine (or appropriate tRNA and amino acid substrates) in a buffered solution. [14C]-labeled product is separated from free [14C]-amino acid by chromatography, and the incorporated [laC] is quantified by scintillation counter.
The amount of [14C] deteeted is proportional to the activity of RMEP in this assay.
In the alternative, RMEP activity is measured by incubating a sample containing RMEP in a solution containing 1 mM ATP, 5 mM Hepes-KOH (pH 7.0), 2.5 mM KCl, 1.5 mM
magnesium chloride, and 0.5 mM DTT along with misacylated [14C]-Glu-tRNAGln (e.g., 1 ~iM) and a similar concentration of unlabeled L-glutamine. Following the quenching of the reaction with 3 M sodium acetate (pH 5.0), the mixture is extracted with an equal volume of water-saturated phenol, and the aqueous and organic phases are separated by centrifugation at 15,000 x g at room temperature for 1 min. The aqueous phase is removed and precipitated with 3 volumes of ethanol at -70°C for 15 min.
The precipitated aminoacyl-tRNAs are recovered by centrifugation at 15,000 x g at 4°C forl5 min.
The pellet is resuspended in of 25 mM KOH, deacylated at 65°C for 10 min., neutralized with 0.1 M
HCl (to final pH 6-7), and dried under vacuum. The dried pellet is resuspended in water and spotted onto a cellulose TLC plate. The plate is developed in either isopropanol/fornuc acid/water or ammonialwater/chloroform/methanol, The image is subjected to densitometric analysis and the relative amounts of Glu and Gln are calculated based on the Rf values and relative intensities of the spots. RMEP activity is calculated based on the amount of Gln resulting from the transformation of Glu while acylated as Glu-tRNAG'" (adapted from Curnow, A.W. et al. (1997) Proc. Natt. Acad. Sci.
94:11819-26).
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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G~.~ ~ P'~. A'~., U ~ E~-~ E~-<110> INCYTE GENOMICS, INC.
LAL, Preeti YUE, Henry TANG, Y. Tom LU, Dyung Aina M.
AZIMZAI, Yalda AU-YOUNG, Janice HILLMAN, Jennifer L.
BAUGHN, Mariah R.
YAO, Monique G.
BURFORD, Neil BATRA, Sajeev POLICKY, Jennifer J.
<120> RNA METABOLISM PROTEINS
<130> PF-0771 PCT
<140> To Be Assigned <141> Herewith <150> 60/200,184; 60/201,875; 60/202,090; 60/210,232; 60/220,553 <151> 2000-04-28; 2000-05-04; 2000-05-04; 2000-06-06; 2000-07-25 <160> 94 <170> PERL Program <210> 1 <211> 245 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1622129CD1 <400> 1 Met Ala Gly Leu Glu Leu Leu Ser Asp Gln Gly Tyr Arg Val Asp Gly Arg Arg Ala Gly Glu Leu Arg Lys Ile Gln Ala Arg Met Gly Val Phe Ala Gln Ala Asp Gly Ser Ala Tyr Ile Glu Gln Gly Asn Thr Lys Ala Leu Ala Val Val Tyr Gly Pro His Glu Ile Arg Gly Ser Arg Ala Arg Ala Leu Pro Asp Arg Ala Leu Val Asn Cys Gln Tyr Ser Ser AIa Thr Phe Ser Thr Gly Glu Arg Lys Arg Arg Pro His Gly Asp Arg Lys Ser Cys Glu Met Gly Leu Gln Leu Arg Gln Thr Phe Glu Ala Ala Ile Leu Thr Gln Leu His Pro Arg Ser Gln Ile Asp Ile Tyr Val Gln Val Leu Gln Ala Asp Gly Gly Thr Tyr Ala Ala Cys Val Asn Ala Ala Thr Leu Ala Val Leu Asp Ala Gly Ile Pro Met Arg Asp Phe Val Cys Ala Cys Ser Ala Gly Phe Val Asp Gly Thr Ala Leu Ala Asp Leu Ser His Val Glu Glu Ala Ala Gly Gly Pro Gln Leu Ala Leu Ala Leu Leu Pro Ala Ser Gly G1n Ile Ala Leu Leu Glu Met Asp Ala Arg Leu His Glu Asp His Leu Glu Arg Val Leu Glu Ala Ala Ala Gln Ala Ala Arg Asp Val His Thr Leu Leu Asp Arg Val Val Arg Gln His Va1 Arg Glu Ala Ser Ile Leu Leu Gly Asp <210> 2 <211> 118 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1820078CD1 <400> 2 Met Thr Asp Thr Ala Glu Ala Val Pro Lys Phe Glu Glu Met Phe Ala Ser Arg Phe Thr Glu Asn Asp Lys Glu Tyr Gln Glu Tyr Leu Lys Arg Pro Pro Glu Ser Pro Pro Tle Val Glu Glu Trp Asn Ser Arg Ala Gly Gly Asn Gln Arg Asn Arg Gly Asn Arg Leu Gln Asp Asn Arg Gln Phe Arg Gly Arg Asp Asn Arg Trp Gly Trp Pro Ser Asp Asn Arg Ser Asn Gln Trp His Gly Arg Ser Trp Gly Asn Asn Tyr Pro Gln His Arg Gln Glu Pro Tyr Tyr Pro Gln Gln Tyr Gly His Tyr Gly Tyr Asn Gln Arg Pro Pro Tyr Gly Tyr Tyr <210> 3 <211> 179 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1527017CD1 <400> 3 Met Phe Gly Ser Ser Arg Arg Leu Ser Ser Ser Lys Leu Leu Gln Gln Gly Lys Thr Ser Ser Val Phe Glu Asp Pro Val Ile Ser Lys Phe Thr Asn Met Met Met Ile Gly Gly Asn Lys Val Leu Ala Arg Ser Leu Met Ile Gln Thr Leu Glu Ala Val Lys Arg Lys Gln Phe Glu Lys Tyr His Ala Ala Ser Ala G1u Glu Gln Ala Thr Ile Glu Arg Asn Pro Tyr Thr Ile Phe His Gln Ala Leu Lys Asn Cys Glu Pro Met Ile Gly Leu Val Pro Ile Leu Lys Gly G1y Arg Phe Tyr Gln Val Pro Val Pro Leu Pro Asp Arg Arg Arg Arg Phe Leu Ala Met Lys Trp Met Ile Thr Glu Cys Arg Asp Lys Lys His Gln Arg Thr Leu Met Pro Glu Lys Leu Ser His Lys Leu Leu Glu Ala Phe His Asn Gln Gly Pro Val Ile Lys Arg Lys His Asp Leu His Lys Met Ala Glu Ala Asn Arg Ala Leu Ala His Tyr Arg Trp Trp <210> 4 <211> 101 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1647264CD1 <400> 4 Met Glu Arg Pro Asp Lys Ala Ala Leu Asn Ala Leu Gln Pro Pro Glu Phe Arg Asn Glu Ser Ser Leu Ala Ser Thr Leu Lys Thr Leu Leu Phe Phe Thr Ala Leu Met Ile Thr Val Pro Ile Gly Leu Tyr Phe Thr Thr Lys Ser Tyr Ile Phe Glu Gly Ala Leu Gly Met Ser Asn Arg Asp Ser Tyr Phe Tyr Ala Ala Ile Val Ala Val Val Ala Val His Val Val Leu Ala Leu Phe Val Tyr Val Ala Trp Asn Glu Gly Ser Arg G1n Trp Arg Glu Gly Lys Gln Asp <210> 5 <211> 145 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1721989CD1 <400> 5 Met Ala Phe Phe Thr Gly Leu Trp Gly Pro Phe Thr Cys Val Ser Arg Val Leu Ser His His Cys Phe Ser Thr Thr Gly Ser Leu Ser Ala Ile Gln Lys Met Thr Arg Val Arg Val Val Asp Asn Ser Ala Leu Gly Asn Ser Pro Tyr His Arg Ala Pro Arg Cys Ile His Val Tyr Lys Lys Asn G1y Val Gly Lys Val Gly Asp Gln Ile Leu Leu Ala Ile Lys Gly Gln Lys Lys Lys Ala Leu Ile Val Gly His Cys Met Pro Gly Pro Arg Met Thr Pro Arg Phe Asp Ser Asn Asn Val Val Leu Ile Glu Asp Asn Gly Asn Pro Val Gly Thr Arg Ile Lys Thr Pro Ile Pro Thr Ser Leu Arg Lys Arg Glu Gly Glu Tyr Ser Lys Val Leu Ala Ile Ala Gln Asn Phe Val <210> 6 <211> 249 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1730581CD1 <400> 6 Met Ala Ala Gln Ser Ala Pro Lys Val Val Leu Lys Ser Thr Thr l 5 10 15 Lys Met Ser Leu Asn Glu Arg Phe Thr Asn Met Leu Lys Asn Lys Gln Pro Thr Pro Val Asn Ile Arg Ala Ser Met Gln Gln Gln Gln Gln Leu Ala Ser Ala Arg Asn Arg Arg Leu Ala Gln Gln Met Glu Asn Arg Pro Ser Val Gln Ala Ala Leu Lys Leu Lys Gln Lys Ser Leu Lys Gln Arg Leu Gly Lys Ser Asn Ile Gln Ala Arg Leu Gly Arg Pro Ile Gly Ala Leu Ala Arg Gly Ala Ile Gly Gly Arg Gly Leu Pro Ile Ile Gln Arg Gly Leu Pro Arg Gly Gly Leu Arg Gly Gly Arg Ala Thr Arg Thr Leu Leu Arg G1y Gly Met Ser Leu Arg Gly Gln Asn Leu Leu Arg Gly Gly Arg Ala Val Ala Pro Arg Met Gly Leu Arg Arg Gly Gly Val Arg Gly Arg Gly Gly Pro Gly Arg Gly Gly Leu Gly Arg Gly Ala Met Gly Arg Gly Gly Ile Gly Gly Arg Gly Arg Gly Met Ile Gly Arg Gly Arg Gly Gly Phe Gly Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Ala Leu Ala Arg Pro Val Leu Thr Lys Glu G1n Leu Asp Asn Gln Leu Asp Ala Tyr Met Ser Lys Thr Lys Gly His Leu Asp Ala Glu Leu Asp Ala Tyr Met 230 ' 235 240 Ala Gln Thr Asp Pro Glu Thr Asn Asp <210> 7 <211> 265 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1740714CD1 <400> 7 Met Arg Arg Ala Glu Leu Ala Gly Leu Lys Thr Met Ala Trp Val Pro Ala Glu Ser Ala Val Glu Glu Leu Met Pro Arg Leu Leu Pro Val Glu Pro Cys Asp Leu Thr Glu Gly Phe Asp Pro Ser Val Pro Pro Arg Thr Pro Gln Glu Tyr Leu Arg Arg Val Gln Ile Glu Ala Ala Gln Cys Pro Asp Val Val Val Ala Gln Ile Asp Pro Lys Lys Leu Lys Arg Lys Gln Ser Val Asn Ile Ser Leu Ser Gly Cys Gln Pro Ala Pro Glu Gly Tyr Ser Pro Thr Leu Gln Trp Gln Gln Gln Gln Val Ala Gln Phe Ser Thr Val Arg Gln Asn Val Asn Lys His Arg Ser His Trp Lys Ser Gln Gln Leu Asp Ser Asn Val Thr Met Pro Lys Ser Glu Asp Glu Glu Gly Trp Lys Lys Phe Cys Leu Gly Glu Lys Leu Cys Ala Asp Gly Ala Val Gly Pro Ala Thr Asn Glu Ser Pro Gly Ile Asp Tyr Val Gln Ala Thr Val Thr Ser Val Leu Glu Tyr Leu Ser Asn Trp Phe Gly Glu Arg Asp Phe Thr Pro Glu Leu Gly Arg Trp Leu Tyr Ala Leu Leu Ala Cys Leu Glu Lys Pro Leu Leu Pro Glu Ala His Ser Leu Ile Arg Gln Leu Ala Arg Arg Cys Ser Glu Val Arg Leu Leu Val Asp Ser Lys Asp Asp Glu Arg Val Pro Ala Leu Asn Leu Leu Ile Cys Leu Val Ser Arg Tyr Phe Asp Gln Arg Asp Leu Ala Asp Glu Pro Ser <210> 8 <211> 306 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1850596CD1 <400> 8 Met Ser Leu Lys Leu Gln Ala Ser Asn Val Thr Asn Lys Asn Asp Pro Lys Ser Ile Asn Ser Arg Val Phe Ile Gly Asn Leu Asn Thr Ala Leu Val Lys Lys Ser Asp Val Glu Thr Ile Phe Ser Lys Tyr Gly Arg Val Ala Gly Cys Ser Val His Lys Gly Tyr A1a Phe Val Gln Tyr Ser Asn Glu Arg His Ala Arg A1a A1a Val Leu Gly Glu Asn Gly Arg Val Leu Ala Gly Gln Thr Leu Asp Ile Asn Met Ala Gly Glu Pro Lys Pro Asp Arg Pro Lys Gly Leu Lys Arg Ala Ala Ser Ala Ile Tyr Ser Gly Tyr Ile Phe Asp Tyr Asp Tyr Tyr Arg Asp Asp Phe Tyr Asp Arg Leu Phe Asp Tyr Arg Gly Arg Leu Ser Pro Val Pro Val Pro Arg Ala Val Pro Val Lys Arg Pro Arg Val Thr Val Pro Leu Val Arg Arg Val Lys Thr Asn Val Pro Val Lys Leu Phe A1a Arg Ser Thr Ala Val Thr Thr Ser Ser Ala Lys Ile Lys Leu Lys Ser Ser Glu Leu Gln Ala I1e Lys Thr Glu Leu Thr Gln Ile Lys Ser Asn Ile Asp Ala Leu Leu Ser Arg Leu Glu Gln Ile Ala Ala Glu Gln Lys Ala Asn Pro Asp Gly Lys Lys Lys Gly Asp Gly Gly Gly Ala Gly Gly Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Gly Ser Ser Arg Pro Pro Ala Pro Gln Glu Asn Thr Thr Ser Glu Ala Gly Leu Pro Gln Gly Glu Ala Arg Thr Arg Asp Asp Gly Asp Glu Glu Gly Leu Leu Thr His Ser Glu Glu Glu Leu Glu His Ser Gln Asp Thr Asp Ala Asp Asp Gly Ala Leu Gln <210> 9 <211> 332 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1856109CD1 <400> 9 Met Ala Ser Gly Leu Val Arg Leu Leu Gln Gln Gly His Arg Cys Leu Leu Ala Pro Val Ala Pro Lys Leu Val Pro Pro Val Arg Gly Val Lys Lys Gly Phe Arg Ala Ala Phe Arg Phe Gln Lys Glu Leu Glu Arg Gln Arg Leu Leu Arg Cys Pro Pro Pro Pro Val Arg Arg Ser Glu Lys Pro Asn Trp Asp Tyr His Ala Glu Ile Gln Ala Phe Gly His Arg Leu Gln Glu Asn Phe Ser Leu Asp Leu Leu Lys Thr Ala Phe Val Asn Ser Cys Tyr Ile Lys Ser Glu Glu Ala Lys Arg Gln Gln Leu Gly Ile Glu Lys Glu Ala Val Leu Leu Asn Leu Lys Ser Asn Gln Glu Leu Ser Glu Gln Gly Thr Ser Phe Ser Gln Thr Cys Leu Thr Gln Phe Leu Glu Asp Glu Tyr Pro Asp Met Pro Thr Glu Gly Ile Lys Asn Leu Val Asp Phe Leu Thr Gly Glu Glu Val Val Cys His Val Ala Arg Asn Leu Ala Val Glu Gln Leu Thr Leu Ser Glu Glu Phe Pro Val Pro Pro Ala Val Leu Gln Gln Thr Phe Phe Ala Val Ile Gly Ala Leu Leu Gln Ser Ser Gly Pro Glu Arg Thr Ala Leu Phe Ile Arg Asp Phe Leu Ile Thr Gln Met Thr G1y Lys Glu Leu Phe Glu Met Trp Lys Ile Ile Asn Pro Met Gly Leu Leu Val Glu Glu Leu Lys Lys Arg Asn Val Ser Ala Pro Glu Ser Arg Leu Thr Arg Gln Ser Gly Gly Thr Thr A1a Leu Pro Leu Tyr Phe Val Gly Leu Tyr Cys Asp Lys Lys Leu Ile Ala Glu Gly Pro Gly Glu Thr Val Leu Va1 Ala Glu Glu Glu Ala Ala Arg Val Ala Leu Arg Lys Leu Tyr Gly Phe Thr Glu Asn Arg Arg Pro Trp Asn Tyr Ser Lys Pro Lys Glu Thr Leu Arg Ala Glu Lys Ser Ile Thr Ala Ser <210> 10 <211> 279 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1921719CD1 <400> 10 Met Ala Ala Pro Val Arg Arg Thr Leu Leu Gly Val Ala Gly Gly Trp Arg Arg Phe Glu Arg Leu Trp Ala Gly Ser Leu Ser Ser Arg Ser Leu Ala Leu Ala Ala Ala Pro Ser Ser Asn Gly Ser Pro Trp Arg Leu Leu Gly Ala Leu Cys Leu Gln Arg Pro Pro Val Val Ser Lys Pro Leu Thr Pro Leu Gln Glu G1u Met Ala Ser Leu Leu Gln Gln Ile Glu Ile Glu Arg Ser Leu Tyr Ser Asp His Glu Leu Arg Ala Leu Asp Glu Asn Gln Arg Leu Ala Lys Lys Lys Ala Asp Leu His Asp Glu Glu Asp Glu Gln Asp Ile Leu Leu Ala Gln Asp Leu Glu Asp Met Trp Glu Gln Lys Phe Leu Gln Phe Lys Leu Gly Ala Arg Ile Thr Glu A1a Asp Glu Lys Asn Asp Arg Thr Ser Leu Asn Arg Lys Leu Asp Arg Asn Leu Val Leu Leu Val Arg Glu Lys Phe Gly Asp Gln Asp Val Trp Ile Leu Pro Gln Ala Glu Trp Gln Pro Gly Glu Thr Leu Arg Gly Thr Ala Glu Arg Thr Leu Ala Thr Leu Ser Glu Asn Asn Met Glu Ala Lys Phe Leu Gly Asn Ala Pro Cys Gly His Tyr Thr Phe Lys Phe Pro Gln Ala Met Arg Thr Glu Ser Asn Leu Gly Ala Lys Val Phe Phe Phe Lys Ala Leu Leu Leu Thr Gly Asp Phe Ser Gln Ala Gly Asn Lys Gly His His Val Trp Val Thr Lys Asp G1u Leu Gly Asp Tyr Leu Lys Pro Lys Tyr Leu Ala Gln Val Arg Arg Phe Val Ser Asp Leu <210> 11 <211> 239 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2099829CD1 <400> 11 Met Pro Lys Ser Lys Arg Asp Lys Lys Val Ser Leu Thr Lys Thr Ala Lys Lys Gly Leu G1u Leu Lys G1n Asn Leu Ile Glu Glu Leu Arg Lys Cys Val Asp Thr Tyr Lys Tyr Leu Phe Ile Phe Ser Val Ala Asn Met Arg Asn Ser Lys Leu Lys Asp Ile Arg Asn Ala Trp Lys His Ser Arg Met Phe Phe Gly Lys Asn Lys Val Met Met Val Ala Leu Gly Arg Ser Pro Ser Asp Glu Tyr Lys Asp Asn Leu His Gln Val Ser Lys Arg Leu Arg Gly Glu Val Gly Leu Leu Phe Thr Asn Arg Thr Lys Glu Glu Val Asn Glu Trp Phe Thr Lys Tyr Thr Glu Met Asp Tyr Ala Arg Ala Gly Asn Lys Ala Ala Phe Thr Val Ser Leu Asp Pro Gly Pro Leu Glu Gln Phe Pro His Ser Met Glu Pro Gln Leu Arg Gln Leu Gly Leu Pro Thr Ala Leu Lys Arg Gly Val Val Thr Leu Leu Ser Asp Tyr Glu Val Cys Lys Glu Gly Asp Val Leu Thr Pro Glu Gln Ala Arg Val Leu Lys Leu Phe Gly Tyr Glu Met Ala Glu Phe Lys Val Thr Ile Lys Tyr Met Trp Asp Ser Gln Ser Gly Arg Phe Gln Gln Met Gly Asp Asp Leu Pro Glu Ser Ala Ser Glu Ser Thr Glu Glu Ser Asp Ser Glu Asp Asp Asp <210> 12 <211> 291 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2416915CD1 <400> 12 Met Asp Phe Glu Asn Leu Phe Ser Lys Pro Pro Asn Pro Ala Leu Gly Lys Thr Ala Thr Asp Ser Asp Glu Arg Ile Asp Asp Glu Ile Asp Thr Glu Val Glu Glu Thr Gln Glu Glu Lys I1e Lys Leu Glu Cys Glu Gln Ile Pro Lys Lys Phe Arg His Ser Ala Ile Ser Pro Lys Ser Ser Leu His Arg Lys Ser Arg Ser Lys Asp Tyr Asp Val Tyr Ser Asp Asn Asp Ile Cys Ser Gln Glu Ser Glu Asp Asn Phe Ala Lys Glu Leu Gln Gln Tyr Ile Gln Ala Arg Glu Met Ala Asn Ala Ala G1n Pro G1u Glu Ser Thr Lys Lys Glu Gly Val Lys Asp Thr Pro Gln Ala Ala Lys Gln Lys Asn Lys Asn Leu Lys Ala G1y His Lys Asn Gly Lys Gln Lys Lys Met Lys Arg Lys Trp Pro G1y Pro Gly Asn Lys Gly Ser Asn Ala Leu Leu Arg Asn Ser Gly Ser Gln Glu Glu Asp Gly Lys Pro Lys Glu Lys Gln Gln His Leu Ser Gln Ala Phe Ile Asn Gln His Thr Val Glu Arg Lys Gly Lys Gln Ile Cys Lys Tyr Phe Leu Glu Arg Lys Cys I1e Lys Gly Asp Gln Cys Lys Phe Asp His Asp Ala Glu Ile G1u Lys Lys Lys Glu Met Cys Lys Phe Tyr Val Gln Gly Tyr Cys Thr Arg Gly Glu Asn Cys Leu Tyr Leu His Asn Glu Tyr Pro Cys Lys Phe Tyr His Thr Gly Thr Lys Cys Tyr Gln Gly Glu Tyr Cys Lys Phe Ser His Ala Pro Leu Thr Pro Glu Thr Gln Glu Leu Leu Ala Lys Val Leu Asp Thr Glu Lys Lys Ser Cys Lys <210> 13 <211> 451 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2472784CD1 <400> 13 Met Ala Gly Ala Gly Pro Ala Pro Gly Leu Pro Gly Ala Gly Gly Pro Val Val Pro Gly Pro Gly Ala Gly Ile Pro Gly Lys Ser Gly Glu Glu Arg Leu Lys Glu Met Glu Ala Glu Met Ala Leu Phe Glu Gln Glu Val Leu Gly Ala Pro Val Pro Gly Ile Pro Thr Ala Val Pro Ala Val Pro Thr Val Pro Thr Val Pro Thr Val Glu Ala Met Gln Val Pro Ala Ala Pro Val Ile Arg Pro Ile Ile A1a Thr Asn Thr Tyr Gln Gln Va1 Gln Gln Thr Leu Glu A1a Arg Ala Ala Ala Ala Ala Thr Val Val Pro Pro Met Val Gly Gly Pro Pro Phe Val Gly Pro Val Gly Phe Gly Pro Gly Asp Arg Ser His Leu Asp Ser Pro Glu Ala Arg Glu Ala Met Phe Leu Arg Arg Ala A1a Ala Val Pro Arg Pro Met Ala Leu Pro Pro Pro His Gln Ala Leu Va1 Gly Pro Pro Leu Pro Gly Pro Pro Gly Pro Pro Met Met Leu Pro Pro Met Ala Arg Ala Pro Gly Pro Pro Leu G1y Ser Met Ala Ala Leu Arg Pro Pro Leu Glu Glu Pro Ala Ala Pro Arg Glu Leu Gly Leu Gly Leu Gly Leu Gly Leu Lys Glu Lys Glu Glu Ala Val Val A1a Ala A1a Ala Gly Leu Glu Glu Ala Ser A1a Ala Val Ala Val Gly Ala Gly Gly Ala Pro Ala Gly Pro Ala Val Ile Gly Pro Ser Leu Pro Leu A1a Leu Ala Met Pro Leu Pro Glu Pro Glu Pro Leu Pro Leu Pro Leu Glu Val Val Arg Gly Leu Leu Pro Pro Leu Arg Ile Pro Glu Leu Leu Ser Leu Arg Pro Arg Pro Arg Pro Pro Arg Pro Glu Pro Pro Pro Gly Leu Met Ala Leu Glu Val Pro Glu Pro Leu Gly Glu Asp Lys Lys Lys Gly Lys Pro Glu Lys Leu Lys Arg Cys Ile Arg Thr Ala Ala G1y Ser Ser Trp Glu Asp Pro Ser Leu Leu Glu Trp Asp Ala Asp Asp Phe Arg Ile Phe Cys Gly Asp Leu Gly Asn Glu Val Asn Asp Asp Ile Leu Ala Arg Ala Phe Ser Arg Phe Pro Ser Phe Leu Lys Ala Lys Val Ile Arg Asp Lys Arg Thr Gly Lys Thr Lys Gly Tyr Gly Phe Val Ser Phe Lys Asp Pro Ser Asp Tyr Val Arg Ala Met Arg Glu Met Asn Gly Lys Tyr Val Gly Ser Arg Pro Ile Lys Leu Arg Lys Ser Met Trp Lys Asp Arg Asn Leu Asp Val Val Arg Lys Lys Gln Lys Glu Lys Lys Lys Leu Gly Leu Arg <210> 14 <211> 600 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2598981CD1 <400> 14 Met Pro Glu Ile Arg Val Thr Pro Leu Gly Ala Gly Gln Asp Val Gly Arg Ser Cys Ile Leu Val Ser Ile Ala Gly Lys Asn Val Met Leu Asp Cys Gly Met His Met Gly Phe Asn Asp Asp Arg Arg Phe Pro Asp Phe Ser Tyr Ile Thr Gln Asn Gly Arg Leu Thr Asp Phe Leu Asp Cys Val Ile Ile Ser His Phe His Leu Asp His Cys Gly Ala Leu Pro Tyr Phe Ser Glu Met Val Gly Tyr Asp Gly Pro Ile Tyr Met Thr His Pro Thr Gln Ala Ile Cys Pro Ile Leu Leu Glu Asp Tyr Arg Lys Ile Ala Val Asp Lys Lys Gly Glu Ala Asn Phe Phe Thr Ser Gln Met Ile Lys Asp Cys Met Lys Lys Val Val Ala Val His Leu His Gln Thr Va1 Gln Val Asp Asp Glu Leu Glu Ile Lys Ala Tyr Tyr Ala Gly His Val Leu Gly Ala Ala Met Phe Gln Ile Lys Va1 Gly Ser Glu Ser Val Val Tyr Thr Gly Asp Tyr Asn Met Thr Pro Asp Arg His Leu Gly Ala A1a Trp Ile Asp Lys Cys Arg Pro Asn Leu Leu Ile Thr Glu Ser Thr Tyr Ala Thr Thr Ile Arg Asp Ser Lys Arg Cys Arg Glu Arg Asp Phe Leu Lys Lys Val His Glu Thr Val Glu Arg Gly Gly Lys Val Leu Ile Pro Val Phe Ala Leu Gly Arg Ala Gln Glu Leu Cys Ile Leu Leu Glu Thr Phe Trp Glu Arg Met Asn Leu Lys Val Pro Ile Tyr Phe Ser Thr G1y Leu Thr Glu Lys Ala Asn His Tyr Tyr Lys Leu Phe Ile Pro Trp Thr Asn Gln Lys Ile Arg Lys Thr Phe Val Gln Arg Asn Met Phe G1u Phe Lys His Ile Lys Ala Phe Asp Arg Ala Phe Ala Asp Asn Pro Gly Pro Met Val Val Phe Ala Thr Pro Gly Met Leu His Ala Gly Gln Ser Leu Gln Ile Phe Arg Lys Trp Ala Gly Asn Glu Lys Asn Met Val Ile Met Pro Gly Tyr Cys Val Gln Gly Thr Val Gly His Lys I1e Leu Ser Gly Gln Arg Lys Leu Glu Met Glu Gly Arg Gln Val Leu Glu Val Lys Met Gln Val Glu Tyr Met Ser Phe Ser Ala His Ala Asp Ala Lys G1y Ile Met Gln Leu Val Gly Gln Ala Glu Pro Glu Ser Val Leu Leu Val His Gly Glu Ala Lys Lys Met Glu Phe Leu Lys Gln Lys Ile Glu Gln G1u Leu Arg Val Asn Cys Tyr Met Pro Ala Asn G1y Glu Thr Val Thr Leu Pro Thr Ser Pro Ser Ile Pro Val Gly Ile Ser Leu Gly Leu Leu Lys Arg Glu Met Ala Gln Gly Leu Leu Pro Glu Ala Lys Lys Pro Arg Leu Leu His Gly Thr Leu Ile Met Lys Asp Ser Asn Phe Arg Leu Val Ser Ser Glu Gln Ala Leu Lys Glu Leu Gly Leu Ala Glu His Gln Leu Arg Phe Thr Cys Arg Val His Leu His Asp Thr Arg Lys Glu Gln Glu Thr Ala Leu Arg Val Tyr Ser His Leu Lys Ser Val Leu Lys Asp His Cys Val Gln His Leu Pro Asp Gly Ser Val Thr Val Glu Ser Val Leu Leu Gln Ala Ala Ala Pro Ser Glu Asp Pro Gly Thr Lys Val Leu Leu Val Ser Trp Thr Tyr Gln Asp Glu Glu Leu Gly Ser Phe Leu Thr Ser Leu Leu Lys Lys Gly Leu Pro Gln Ala Pro Ser <210> 15 <211> 217 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2738075CD1 <400> 15 Met Ser Gly Gly Leu A1a Pro Ser Lys Ser Thr Val Tyr Val Ser 1 5 l0 l5 Asn Leu Pro Phe Ser Leu Thr Asn Asn Asp Leu Tyr Arg Ile Phe Ser Lys Tyr Gly Lys Va1 Val Lys Val Thr Ile Met Lys Asp Lys Asp Thr Arg Lys Ser Lys Gly Val Ala Phe Ile Leu Phe Leu Asp Lys Asp Ser Ala Gln Asn Cys Thr Arg Ala Ile Asn Asn Lys Gln Leu Phe Gly Arg Val Ile Lys Ala Ser Ile Ala Ile Asp Asn Gly Arg Ala Ala Glu Phe Ile Arg Arg Arg Asn Tyr Phe Asp Lys Ser Lys Cys Tyr Glu Cys Gly Glu Ser Gly His Leu Ser Tyr Ala Cys Pro Lys Asn Met Leu Gly Glu Arg Glu Pro Pro Lys Lys Lys Glu Lys Lys Lys Lys Lys Lys Ala Pro Glu Pro Glu G1u Glu Ile Glu Glu Va1 Glu Glu Ser Glu Asp Glu Gly Glu Asp Pro Ala Leu Asp Ser Leu Ser Gln A1a Ile Ala Phe Gln Gln Ala Lys Ile Glu G1u Glu G1n Lys Lys Trp Lys Pro Ser Ser Gly Val Pro Ser Thr Ser Asp Asp Ser Arg Arg Pro Arg Ile Lys Lys Ser Thr Tyr Phe Ser Asp Glu Glu Glu Leu Ser Asp <210> 16 <211> 319 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2279049CD1 <400> 16 Met Lys Ile Glu Leu Ser Met Gln Pro Trp Asn Pro Gly Tyr Ser Ser Glu Gly Ala Thr Ala Gln Glu Thr Tyr Thr Cys Pro Lys Met Ile Glu Met Glu Gln Ala Glu Ala Gln Leu Ala Glu Leu Asp Leu Leu Ala Ser Met Phe Pro Gly Glu Asn Glu Leu Ile Val Asn Asp G1n Leu Ala Val Ala Glu Leu Lys Asp Cys Ile Glu Lys Lys Thr Met Glu Gly Arg Ser Ser Lys Val Tyr Phe Thr Ile Asn Met Asn Leu Asp Val Ser Asp G1u Lys Met Ala Met Phe Ser Leu Ala Cys Ile Leu Pro Phe Lys Tyr Pro Ala Val Leu Pro Glu Ile Thr Val Arg Ser Va1 Leu Leu Ser Arg Ser Gln Gln Thr Gln Leu Asn Thr Asp Leu Thr Ala Phe Leu Gln Lys His Cys His Gly Asp Val Cys Ile Leu Asn Ala Thr Glu Trp Val Arg G1u His Ala Ser Gly Tyr Val Ser Arg Asp Thr Ser Ser Ser Pro Thr Thr Gly Ser Thr Val Gln Ser Val Asp Leu Ile Phe Thr Arg Leu Trp Ile Tyr Ser His 185 ~ 190 195 His Ile Tyr Asn Lys Cys Lys Arg Lys Asn Ile Leu Glu Trp Ala Lys Glu Leu Ser Leu Ser Gly Phe Ser Met Pro Gly Lys Pro Gly Val Val Cys Val Glu Gly Pro Gln Ser Ala Cys Glu Glu Phe Trp Ser Arg Leu Arg Lys Leu Asn Trp Lys Arg Ile Leu Ile Arg His Arg Glu Asp Ile Pro Phe Asp Gly Thr Asn Asp Glu Thr Glu Arg Gln Arg Lys Phe Ser Ile Phe Glu Glu Lys Va1 Phe Ser Val Asn Gly Ala Arg Gly Asn His Met Asp Phe Gly Gln Leu Tyr Gln Phe Leu Asn Thr Lys Gly Cys Gly Asp Val Phe Gln Met Phe Phe Gly Val Glu Gly Gln <210> 17 <211> 108 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2660904CD1 <400> 17 Met Ser His His Ala Glu Ile Gln Arg Asp Ile Leu Glu Ser Cys Asn His Val Arg Lys Lys Val Pro Val Thr Phe Val Gly Ala Gly Gly Gln Asp Pro Glu Val Pro Glu Glu Leu Leu His Leu Leu Gln Pro Gly Gln Arg Val Pro Gln Asp Val Gln His His Leu Leu Glu Pro Arg Asp Arg Trp Ala His Leu Glu Val Leu Lys Lys Val Asp Leu Leu Leu Gln Val Met Ala Ala Thr Gly Tyr Phe His Ala Ser Leu Gln Arg Gly Glu Ile Met Arg Ser Pro Gly Pro Val Ala Arg Asn Ser Pro <210> 18 <211> 92 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3179424CD1 <400> 18 Met Ala Val Leu Ala Gly Ser Leu Leu Gly Pro Thr Ser Arg Ser Ala Ala Leu Leu Gly G1y Arg Trp Leu Gln Pro Arg Ala Trp Leu Gly Phe Pro Asp Ala Trp Gly Leu Pro Thr Pro Gln Gln Ala Arg Gly Lys Ala Arg Gly Asn G1u Tyr Gln Pro Ser Asn Ile Lys Arg Lys Asn Lys His Gly Trp Val Arg Arg Leu Ser Thr Pro A1a Gly Val Gln Val Ile Leu Arg Arg Met Leu Lys Gly Arg Lys Ser Leu Ser His <210> 19 <211> 268 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2885096CD1 <400> 19 Met Ala Gly Gly Val Pro Gly Gln Pro Ala Gly Val Gly Leu Ala Leu Ile Ala Thr Asp Ser Gln Glu Thr Arg Pro Gly Arg Ala Gly Pro Gly Ser Gly Glu Ser Leu Ser Ala Ser His Leu Phe Ile Ser Asp Phe Ala Tyr Cys Trp Glu Asn Phe Val Cys Asn Glu Gly Gln Pro Phe Met Pro Trp Tyr Lys Phe Asp Asp Asn Tyr Ala Ser Leu His Arg Thr Leu Lys Glu Ile Leu Arg Asn Pro Met Glu Ala Met Tyr Pro His Ile Phe Tyr Phe His Phe Lys Asn Leu Leu Lys Ala Cys Gly Arg Asn Glu Ser Trp Leu Cys Phe Thr Met Glu Val Thr 1'10 115 12 0 Lys His His Ser Ala Val, Phe Arg Lys Lys Gly Val Phe Arg Asn Gln Val Asp Pro Glu Thr His Cys His Ala Glu Arg Cys Phe Leu Ser Trp Phe Cys Asp Asp Ile Leu Ser Pro Asn Thr Asn Tyr Glu Val Thr Trp Tyr Thr Ser Trp Ser Pro Cys Pro Glu Cys Ala Gly Glu Val A1a Glu Phe Leu Ala Arg His Ser Asn Val Asn Leu Thr Ile Phe Thr Ala Arg Leu Cys Tyr Phe Trp Asp Thr Asp Tyr Gln Glu Gly Leu Cys Ser Leu Ser Gln Glu Gly Ala Ser Val Lys Ile Met Gly Tyr Lys Asp Phe Val Ser Cys Trp Lys Asn Phe Val Tyr Ser Asp Asp Glu Pro Phe Lys Pro Trp Lys Gly Leu Gln Thr Asn Phe Arg Leu Leu Lys Arg Arg Leu Arg Glu Ile Leu Gln <210> 20 <211> 624 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2901076CD1 <400> 20 Met Asn Ser Gly G1y Gly Phe Gly Leu Gly Leu Gly Phe Gly Leu Thr Pro Thr Ser Val Ile Gln Val Thr Asn~Leu Ser Ser Ala Val Thr Ser Glu Gln Met Arg Thr Leu Phe Ser Phe Leu Gly Glu Ile Glu Glu Leu Arg Leu Tyr Pro Pro Asp Asn Ala Pro Leu Ala Phe Ser Ser Lys Val Cys Tyr Va1 Lys Phe Arg Asp Pro Ser Ser Val Gly Val Ala Gln His Leu Thr Asn Thr Val Phe Tle Asp Arg Ala Leu Ile Val Val Pro Cys Ala Glu Gly Lys Ile Pro Glu Glu Ser Lys Ala Leu Ser Leu Leu Ala Pro A1a Pro Thr Met Thr Ser Leu Met Pro Gly Ala Gly Leu Leu Pro I1e Pro Thr Pro Asn Pro Leu Thr Thr Leu G1y Val Ser Leu Ser Ser Leu Gly Ala Ile Pro Ala Ala Ala Leu Asp Pro Asn Ile Ala Thr Leu Gly Glu Ile Pro Gln Pro Pro Leu Met Gly Asn Val Asp Pro Ser Lys Ile Asp Glu Ile Arg Arg Thr Val Tyr Val Gly Asn Leu Asn Ser Gln Thr Thr Thr Ala Asp Gln Leu Leu Glu Phe Phe Lys Gln Val Gly Glu Val Lys Phe Val Arg Met Ala Gly Asp Glu Thr Gln Pro Thr Arg Phe Ala Phe Val Glu Phe Ala Asp Gln Asn Ser VaI Pro Arg A1a Leu Ala Phe Asn Gly Val Met Phe Gly Asp Arg Pro Leu Lys Ile Asn His Ser Asn Asn Ala Ile Val Lys Pro Pro Glu Met Thr Pro Gln Ala Ala Ala Lys Glu Leu Glu Glu Val Met Lys Arg Val Arg G1u Ala Gln Ser Phe Ile Ser Ala Ala Ile Glu Pro Glu Ser Gly Lys Ser Asn Glu Arg Lys Gly Gly Arg Ser Arg Ser His Thr Arg Ser Lys Ser Arg Ser Ser Ser Lys Ser His Ser Arg Arg Lys Arg Ser Gln Ser Lys His Arg Ser Arg Ser His Asn Arg Ser Arg Ser Arg Gln Lys Asp Arg Arg Arg Ser Lys Ser Pro His Lys Lys Arg Ser Lys Ser Arg Glu Arg Arg Lys Ser Arg Ser Arg Ser His Ser Arg Asp Lys Arg Lys Asp Thr Arg Glu Lys Ile Lys Glu Lys Glu Arg Va1 Lys Glu Lys Asp Arg Glu Lys Glu Arg Glu Arg Glu Lys Glu Arg Glu Lys Glu Lys Glu Arg Gly Lys Asn Lys Asp Arg Asp Lys G1u Arg G1u Lys Asp Arg Glu Lys Asp Lys Glu Lys Asp Arg Glu Arg Glu Arg Glu Lys Glu His Glu Lys Asp Arg Asp Lys Glu Lys Glu Lys Glu Gln Asp Lys Glu Lys Glu Arg Glu Lys Asp Arg Ser Lys Glu Ile Asp Glu Lys Arg Lys Lys Asp Lys Lys Ser Arg Thr Pro Pro Arg Ser Tyr Asn Ala Ser Arg Arg Ser Arg Ser Ser Ser Arg Glu Arg Arg Arg Arg Arg Ser Arg Ser Ser Ser Arg Ser Pro Arg Thr Ser Lys Thr T1e Lys Arg Lys Ser Ser Arg Ser Pro Ser Pro Arg Ser Arg Asn Lys Lys Asp Lys Lys Arg Glu Lys Glu Arg Asp His Ile Ser Glu Arg Arg Glu Arg Glu Arg Ser Thr Ser Met Arg Lys Ser Ser Asn Asp Arg Asp Gly Lys Glu Lys Leu Glu Lys Asn Ser Thr Ser Leu Lys Glu Lys Glu His Asn Lys Glu Pro Asp Ser Ser Val Ser Lys Glu Val Asp Asp Lys Asp Ala Pro Arg Thr Glu Glu Asn Lys Ile Gln His Asn Gly Asn Cys Gln Leu Asn Glu Glu Asn Leu Ser Thr Lys Thr Glu Ala Val <210> 21 <211> 419 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3074572CD1 <400> 21 Met Ala Glu Leu Pro Ser Ala Trp Gln Tyr Cys Ala Val Arg Gly Ala Pro Gly Gln Arg Ala Val Val Gln Phe Ser Asp Ser Leu Asn Gly Lys Gln Pro Gly Asn Met Phe Thr Leu Tyr Leu Ser Arg G1u Asn Lys Asp Ser Thr Asn Pro Arg Lys Arg Asn Gln Arg Ile Leu Ala Ala Glu Thr Asp Arg Leu Ser Tyr Val Gly Asn Asn Phe Gly Thr Gly Ala Leu Lys Cys Asn Thr Leu Cys Arg His Phe Val Gly I1e Leu Asn Lys Thr Ser Gly Gln Met Glu Val Tyr Asp Ala Glu Leu Phe Asn Met Gln Pro Leu Phe Ser Asp Val Ser Val Glu Ser Glu Leu Ala Leu Glu Ser Gln Thr Lys Thr Tyr Arg G1u Lys Met Asp Ser Cys Ile Glu Ala Phe Gly Thr Thr Lys Gln Lys Arg Ala Leu Asn Thr Arg Arg Met Asn Arg Val Gly Asn Glu Ser Leu Asn Arg Ala Val Ala Lys Ala Ala Glu Thr Ile Ile Asp Thr Lys Gly Val Thr Ala Leu Val Ser Asp Ala Ile His Asn Asp Leu Gln Asp Asp Ser Leu Tyr Leu Pro Pro Cys Tyr Asp Asp Ala Ala Lys Pro Glu Asp Val Tyr Lys Phe Glu Asp Leu Leu Ser Pro Ala Glu Tyr Glu Ala Leu Gln Ser Pro Ser Glu Ala Phe Arg Asn Val Thr Ser Glu Glu Ile Leu Lys Met Ile Glu Glu Asn Ser His Cys Thr Phe Val Ile Glu Ala Leu Lys Ser Leu Pro Ser Asp Val Glu Ser Arg Asp Arg Gln Ala Arg Cys Ile Trp Phe Leu Asp Thr Leu Ile Lys Phe Arg Ala His Arg Val Val Lys Arg Lys Ser Ala Leu Gly Pro Gly Val Pro His Ile Ile Asn Thr Lys Leu Leu Lys His Phe Thr Cys Leu Thr Tyr Asn Asn Gly Arg Leu Arg Asn Leu I1e Ser Asp Ser Met Lys Ala Lys Ile Thr Ala Tyr Val Ile Ile Leu Ala Leu His Ile His Asp Phe Gln Ile Asp Leu Thr Val Leu Gln Arg Asp Leu Lys Leu Ser Glu Lys Arg Met Met Glu Ile Ala Lys Ala Met Arg Leu Lys I1e Ser Lys Arg Arg Val Ser Val Ala Ala Gly Ser Glu Glu Asp His Lys Leu Gly Thr Leu Ser Leu Pro Leu Pro Pro Ala Gln Thr Ser Asp Arg Leu Ala Lys Arg Arg Lys Ile Thr <210> 22 <211> 743 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1437895CD1 <400> 22 Met Glu Glu Glu Gly Leu Glu Cys Pro Asn Ser Ser Ser Glu Lys Arg Tyr Phe Pro Glu Ser Leu Asp Ser Ser Asp Gly Asp Glu Glu G1u Val Leu Ala Cys Glu Asp Leu Glu Leu Asn Pro Phe Asp Gly Leu Pro Tyr Ser Ser Arg Tyr Tyr Lys Leu Leu Lys Glu Arg Glu Asp Leu Pro Ile Trp Lys Glu Lys Tyr Ser Phe Met Glu Asn Leu Leu Gln Asn Gln Ile Val Ile Val Ser Gly Asp Ala Lys Cys Gly Lys Ser Ala Gln Val Pro Gln Trp Cys Ala Glu Tyr Cys Leu Ser Ile His Tyr Gln His Gly Gly Val Ile Cys Thr Gln Val His Lys Gln Thr Val Val Gln Leu Ala Leu Arg Val Ala Asp Glu Met Asp Val Asn Ile Gly His Glu Val Gly Tyr Val Ile Pro Phe Glu Asn Cys Cys Thr Asn Glu Thr Ile Leu Arg Tyr Cys Thr Asp Asp Met 155 160 l65 Leu Gln Arg Glu Met Met Ser Asn Pro Phe Leu Gly Ser Tyr Gly Val Ile Ile Leu Asp Asp Ile His Glu Arg Ser Ile Ala Thr Asp Val Leu Leu Gly Leu Leu Lys Asp Val Leu Leu Ala Arg Pro Glu Leu Lys Leu Ile Ile Asn Ser Ser Pro His Leu Ile Ser Lys Leu Asn Ser Tyr Tyr Gly Asn Val Pro Val Ile Glu Val Lys Asn Lys His Pro Val Glu Val Val Tyr Leu Ser Glu Ala Gln Lys Asp Ser Phe Glu Ser Ile Leu Arg Leu Ile Phe Glu Ile His His Ser Gly Glu Lys Gly Asp Ile Val Val Phe Leu Ala Cys Glu G1n Asp Ile Glu Lys Va1 Cys Glu Thr Val Tyr Gln Gly Ser Asn Leu Asn Pro Asp Leu Gly Glu Leu Val Val Va1 Pro Leu Tyr Pro Lys Glu Lys Cys Ser Leu Phe Lys Pro Leu Asp G1u Thr Glu Lys Arg Cys Gln Val Tyr Gln Arg Arg Val Val Leu Thr Thr Ser Ser Gly Glu Phe Leu Ile Trp Ser Asn Ser Val Arg Phe Val I1e Asp Val Gly Val Glu Arg Arg Lys Val Tyr Asn Pro Arg Ile Arg Ala Asn Ser Leu Val Met Gln Pro Ile Ser Gln Ser Gln Ala Glu Ile Arg Lys Gln Ile Leu Gly Ser Ser Ser Ser Gly Lys Phe Phe Cys Leu Tyr Thr Glu Glu Phe Ala Ser Lys Asp Met Thr Pro Leu Lys Pro Ala Glu Met Gln G1u Ala Asn Leu Thr Ser Met Val Leu Phe Met Lys Arg Ile Asp Ile Ala Gly Leu Gly His Cys Asp Phe Met Asn Arg Pro Ala Pro Glu Ser Leu Met Gln Ala Leu Glu Asp Leu Asp Tyr Leu Ala Ala Leu Asp Asn Asp Gly Asn Leu Ser Glu Phe Gly Ile Ile Met Ser Glu Phe Pro Leu Asp Pro Gln Leu Ser Lys Ser Ile Leu Ala Ser Cys Glu Phe Asp Cys Val Asp Glu Val Leu Thr Ile A1a Ala Met Val Thr Ala Pro Asn Cys Phe Ser His Val Pro His Gly Ala Glu Glu Ala Ala Leu Thr Cys Trp Lys Thr Phe Leu His Pro Glu Gly Asp His Phe Thr Leu Ile Ser Ile Tyr Lys Ala Tyr Gln Asp Thr Thr Leu Asn Ser Ser Ser Glu Tyr Cys Val Glu Lys Trp Cys Arg Asp Tyr Phe Leu Asn Cys Ser Ala Leu Arg Met Ala Asp Val Ile Arg Ala Glu Leu Leu Glu Ile Ile Lys Arg Ile Glu Leu Pro Tyr Ala Glu Pro Ala Phe Gly Ser Lys Glu Asn Thr Leu Asn Ile Lys Lys Ala Leu Leu Ser Gly Tyr Phe Met Gln Ile Ala Arg Asp Val Asp Gly Ser Gly Asn Tyr Leu Met Leu Thr His Lys Gln Val Ala Gln Leu His Pro Leu Ser Gly Tyr Ser Ile Thr Lys Lys Met Pro Glu Trp Val Leu Phe His Lys Phe Ser Ile Ser G1u Asn Asn Tyr Ile Arg Ile Thr Ser Glu Ile Ser Pro Glu Leu Phe Met Gln Leu Val Pro Gln Tyr Tyr Phe Ser Asn Leu Pro Pro Ser Glu Ser Lys Asp Ile Leu Gln Gln Val Val Asp His Leu Ser Pro Val Ser Thr Met Asn Lys Glu Gln Gln Met Cys Glu Thr Cys Pro Glu Thr Glu Gln Arg Cys Thr Leu Gln <210> 23 <211> 284 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1454656CD1 <400> 23 Met Arg Arg Pro Cys Asn Pro Val Arg Ala Ala Lys Arg Thr Ala Ala Ala Ala Arg Ala Pro Arg Gly Leu Glu Val Thr Met Leu Arg Val Ala Trp Arg Thr Leu Ser Leu Ile Arg Thr Arg Ala Val Thr Gln Val Leu Val Pro Gly Leu Pro Gly Gly Gly Ser Ala Lys Phe Pro Phe Asn Gln Trp Gly Leu Gln Pro Arg Ser Leu Leu Leu G1n Ala Ala Arg Gly Tyr Val Va1 Arg Lys Pro Ala Gln Ser Arg Leu Asp Asp Asp Pro Pro Pro Ser Thr Leu Leu Lys Asp Tyr Gln Asn Val Pro Gly Ile Glu Lys Val Asp Asp Val Val Lys Arg Leu Leu Ser Leu Glu Met Ala Asn Lys Lys Glu Met Leu Lys Ile Lys Gln Glu Gln Phe Met Lys Lys Ile Val Ala Asn Pro Glu Asp Thr Arg Ser Leu Glu Ala Arg Ile Ile Ala Leu Ser Val Lys Ile Arg Ser Tyr Glu Glu His Leu Glu Lys His Arg Lys Asp Lys Ala His Lys Arg Tyr Leu Leu Met Ser Ile Asp Gln Arg Lys Lys Met Leu Lys Asn Leu Arg Asn Thr Asn Tyr Asp Val Phe Glu Lys Ile Cys Trp Gly Leu Gly Ile Glu Tyr Thr Phe Pro Pro Leu Tyr Tyr Arg Arg 2l5 220 225 Ala His Arg Phe ValThrLys AlaLeu Cys ArgVal Arg Lys Ile Phe Gln Glu G1n LysLeuLys ArgArg Arg LeuLys Thr Lys Ala Ala Ala Ala Ala GlnLysGln LysArg Arg ProAsp Ala Ala Asn Ser Pro A1a Ala IleProLys LeuLys Asp Gln Lys Thr Ser <210> 24 <211> 248 <212> PRT

<213> Homo Sapiens <220>

<221> misc_feature <223> Incyte No: 121130CD1 ID

<400> 24 Met Ala Ala Gln Ser Ala Pro Lys Val Val Leu Lys Ser Thr Thr Lys Met Ser Leu Asn Glu Arg Phe Thr Asn Met Leu Lys Asn Lys Gln Pro Thr Pro Val Asn Ile Arg Ala Ser Met G1n Gln Gln Gln Gln Leu Ala Ser Ala Arg Asn Arg Arg Leu Ala Gln Gln Met Glu Asn Arg Pro Ser Val Gln Ala Ala Leu Lys Leu Lys Gln Ser Leu Lys Gln Arg Leu Gly Lys Ser Asn Ile Gln Ala Arg Leu Gly Arg Pro Ile Gly Ala Leu Ala Arg Gly Ala I1e Gly Gly Arg Gly Leu Pro Ile Ile Gln Arg Gly Leu Pro Arg Gly Gly Leu Arg Gly G1y 110 ll5 120 Arg Ala Thr Arg Thr Leu Leu Arg Gly Gly Met Ser Leu Arg Gly Gln Asn Leu Leu Arg Gly Gly Arg Ala Val Ala Pro Arg Met Gly Leu Arg Arg Gly G1y Val Arg Gly Arg G1y Gly Pro Gly Arg G1y Gly Leu Gly Arg Gly Ala Met Gly Arg Gly Gly Ile Gly Gly Arg Gly Arg Gly Met Ile Gly Arg Gly Arg Gly Gly Phe Gly Gly Arg Gly Arg Gly Arg Gly Arg Gly Arg Gly Ala Leu Ala Arg Pro Val Leu Thr Lys Glu Gln Leu Asp Asn Gln Leu Asp Ala Tyr Met Ser Lys Thr Lys Gly His Leu Asp Ala Glu Leu Asp Ala Tyr Met Ala Gln Thr Asp Pro Glu Thr Asn Asp <2l0> 25 <211> 214 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1257715CD1 <400> 25 Met Arg Pro Gly Gly Phe Leu Gly Ala~Gly Gln Arg Leu Ser Arg Ala Met Ser Arg Cys Val Leu Glu Pro Arg Pro Pro Gly Lys Arg Trp Met Val Ala Gly Leu Gly Asn Pro Gly Leu Pro Gly Thr Arg His Ser Val Gly Met Ala Val Leu Gly Gln Leu Ala Arg Arg Leu Gly Val Ala Glu Ser Trp Thr Arg Asp Arg His Cys Ala Ala Asp Leu Ala Leu Ala Pro Leu Gly Asp Ala Gln Leu Val Leu Leu Arg Pro Arg Arg Leu Met Asn Ala Asn Gly Arg Ser Val Ala Arg Ala Ala Glu Leu Phe Gly Leu Thr Ala Glu Glu Val Tyr Leu Val His Asp Glu Leu Asp Lys Pro Leu Gly Arg Leu Ala Leu Lys Leu Gly Gly Ser Ala Arg Gly His Asn Gly Val Arg Ser Cys Ile Ser Cys Leu Asn Ser Asn Ala Met Pro Arg Leu Arg Val Gly Ile Gly Arg Pro Ala His Pro Glu Ala Val Gln Ala His Val Leu Gly Cys Phe Ser Pro Ala Glu Gln Glu Leu Leu Pro Leu Leu Leu Asp Arg Ala Thr Asp Leu Ile Leu Asp His Ile Arg Glu Arg Ser Gln Gly Pro Ser Leu Gly Pro <210> 26 <211> 184 <2l2> PRT
<2l3> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1342022CD1 <400> 26 Met Thr Thr Arg Pro Ala Phe Ile Leu His His Ser Asp Cys Phe Ser Ser Arg Ser Ser Arg Ile Arg His Glu Gly Val Trp Arg Arg Arg Ala Glu Met Ala Pro Arg Lys Gly Lys Glu Lys Lys Glu Glu Gln Val Ile Ser Leu Gly.Pro Gln Val Ala Glu Gly Glu Asn Val Phe Gly Va1 Cys His Ile Phe Ala Ser Phe Asn Asp Thr Phe Val His Val Thr Asp Leu Ser Gly Lys Glu Thr Ile Cys Arg Val Thr Gly G1y Met Lys Val Lys Ala Asp Arg Asp Glu Ser Ser Pro Tyr Ala Ala Met Leu Ala Ala Gln Asp Val Ala Gln Arg Cys Lys Glu Leu Gly Ile Thr Ala Leu His Ile Lys Leu Arg Ala Thr Gly Gly Asn Arg Thr Lys Thr Pro Gly Pro Gly Ala Gln Ser Ala Leu Arg Ala Leu Ala Arg Ser Gly Met Lys Ile Gly Arg Ile Glu Asp Val Thr Pro Ile Pro Ser Asp Ser Thr Arg Arg Lys Gly Gly Arg Arg Gly Arg Arg Leu <210> 27 <211> 371 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 194704CD1 <400> 27 Met Ser Ala Gln Ala Gln Met Arg Ala Leu Leu Asp Gln Leu Met Gly Thr Ala Arg Asp Gly Asp Glu Thr Arg Gln Arg Val Lys Phe Thr Asp Asp Arg Val Cys Lys Ser His Leu Leu Asp Cys Cys Pro His Asp Ile Leu Ala Gly Thr Arg Met Asp Leu Gly Glu Cys Thr Lys Ile His Asp Leu Ala Leu Arg Ala Asp Tyr Glu Ile Ala Ser Lys G1u Arg Asp Leu Phe Phe Glu Leu Asp Ala Met Asp His Leu Glu Ser Phe Ile Ala Glu Cys Asp Arg Arg Thr Glu Leu Ala Lys Lys Arg Leu Ala Glu Thr Gln Glu Glu Ile Ser Ala Glu Val Ser Ala Lys Ala Glu Lys Val His Glu Leu Asn Glu Glu Ile Gly Lys Leu Leu Ala Lys Ala Glu Gln Leu Gly Ala Glu Gly Asn Val Asp Glu Ser Gln Lys Ile Leu Met Glu Val Glu Lys Val Arg A1a Lys Lys Lys Glu Ala Glu Glu Glu Tyr Arg Asn Ser Met Pro Ala Ser Ser Phe Gln Gln Gln Lys Leu Arg Val Cys Glu Val Cys Ser Ala Tyr Leu Gly Leu His Asp Asn Asp Arg Arg Leu A1a Asp His Phe Gly Gly Lys Leu His Leu Gly Phe Ile Gln Ile Arg Glu Lys Leu Asp Gln Leu Arg Lys Thr Val Ala Glu Lys Gln Glu Lys Arg Asn Gln Asp Arg Leu Arg Arg Arg Glu Glu Arg Glu Arg Glu Glu Arg Leu Ser Arg Arg Ser Gly Ser Arg Thr Arg Asp Arg Arg Arg Ser Arg Ser Arg Asp Arg Arg Arg Arg Arg Ser Arg Ser Thr Ser Arg Glu Arg Arg Lys Leu Ser Arg Ser Arg Ser Arg Asp Arg His Arg Arg His Arg Ser Arg Ser Arg Ser His Ser Arg Gly His Arg Arg Ala Ser Arg Asp Arg Ser Ala Lys Tyr Lys Phe Ser Arg Glu Arg Ala Ser Arg Glu Glu Ser Trp Glu Ser Gly Arg Ser Glu Arg Gly Pro Pro Asp Trp Arg Leu Glu Ser Ser Asn Gly Lys Met Ala Ser Arg Arg Ser Glu Glu Lys Glu Ala Gly Glu Ile <210> 28 <211> 396 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 607270CD1 <400> 28 Met Ala Ala Pro Cys Val Ser Tyr Gly Gly Ala Val Ser Tyr Arg Leu Leu Leu Trp Gly Arg Gly Ser Leu Ala Arg Lys Gln Gly Leu Trp Lys Thr Ala Ala Pro Glu Leu Gln Thr Asn Val Arg Ser Gln Ile Leu Arg Leu Arg His Thr Ala Phe Val Ile Pro Lys Lys Asn Val Pro Thr Ser Lys Arg Glu Thr Tyr Thr Glu Asp Phe Ile Lys Lys Gln Ile Glu Glu Phe Asn Ile Gly Lys Arg His Leu Ala Asn Met Met Gly Glu Asp Pro Glu Thr Phe Thr Gln Glu Asp Ile Asp Arg Ala Ile Ala Tyr Leu Phe Pro Ser Gly Leu Phe Glu Lys Arg Ala Arg Pro Val Met Lys His Pro Glu Gln Ile Phe Pro Arg Gln Arg Ala Ile Gln Trp Gly Glu Asp Gly Arg Pro Phe His Tyr Leu Phe Tyr Thr Gly Lys Gln Ser Tyr Tyr Ser Leu Met His Asp Val Tyr Gly Met Leu Leu Asn Leu Glu Lys His Gln Ser His Leu~Gln Ala Lys Ser Leu Leu Pro Glu Lys Thr Val Thr Arg Asp Val Ile Gly Ser Arg Trp Leu Ile Lys Glu Glu Leu Glu Glu Met Leu Val Glu Lys Leu Ser Asp Leu Asp Tyr Met Gln Phe Ile Arg Leu Leu Glu Lys Leu Leu Thr Ser Gln Cys Gly Ala Ala Glu Glu Glu Phe Val Gln Arg Phe Arg Arg Ser Val Thr Leu Glu Ser Lys Lys Gln Leu Ile Glu Pro Val Gln Tyr Asp G1u G1n Gly Met Ala Phe Ser Lys Ser Glu Gly Lys Arg Lys Thr Ala Lys Ala Glu Ala Ile Val Tyr Lys His Gly Ser Gly Arg Ile Lys Val Asn Gly Ile Asp Tyr Gln Leu Tyr Phe Pro Ile Thr Gln Asp Arg Glu Gln Leu Met Phe Pro Phe His Phe Val Asp Arg Leu Gly Lys His Asp Val Thr Cys Thr Val Ser Gly Gly Gly Arg Ser Ala Gln Ala G1y Ala Ile Arg Leu Ala Met Ala Lys Ala Leu Cys Ser Phe Val Thr Glu Asp Glu Val Glu Trp Met Arg Gln Ala Gly Leu Leu Thr Thr Asp Pro Arg Val Arg Glu Arg Lys Lys Pro Gly Gln Glu Gly Ala Arg Arg Lys Phe Thr Trp Lys Lys Arg <210> 29 <211> 184 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 758546CD1 <400> 29 Met Val Arg Lys Leu Lys Phe His Glu Gln Lys Leu Leu Lys Gln Val Asp Phe Leu Asn Trp Glu Val Thr Asp His Asn Leu His Glu Leu Arg Val Leu Arg Arg Tyr Arg Leu Gln Arg Arg Glu Asp Tyr Thr Arg Tyr Asn Gln Leu Ser Arg Ala Val Arg Glu Leu Ala Arg Arg Leu Arg Asp Leu Pro Glu Arg Asp Gln Phe Arg Val Arg Ala Ser Ala Ala Leu Leu Asp Lys Leu Tyr Ala Leu G1y Leu Val Pro Thr Arg Gly Ser Leu Glu Leu Cys Asp Phe Val Thr Ala Ser Ser Phe Cys Arg Arg Arg Leu Pro Thr Val Leu Leu Lys Leu Arg Met Ala Gln His Leu Gln Ala Ala Val Ala Phe Val Glu Gln Gly His Val Arg Val Gly Pro Asp Val Val Thr Asp Pro Ala Phe Leu Val Thr Arg Ser Met Glu Asp Phe Val Thr Trp Val Asp Ser Ser Lys Ile Lys Arg His Val Leu Glu Tyr Asn Glu Glu Arg Asp Asp Phe Asp Leu Glu Ala <210> 30 <211> 282 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 866043CD1 <400> 30 Met Leu Leu Ser Thr Ser Met Asp Lys Thr Phe Lys Val Trp Asn Ala Val Asp Ser Gly His Cys Leu Gln Thr Tyr Ser Leu His Thr Glu Ala Val Arg Ala Ala Arg Trp Ala Pro Cys Gly Arg Arg Ile Leu Ser Gly Gly Phe Asp Phe Ala Leu His Leu Thr Asp Leu Glu Thr Gly Thr Gln Leu Phe Ser Gly Arg Ser Asp Phe Arg Ile Thr Thr Leu Lys Phe His Pro Lys Asp His Asn Ile Phe Leu Cys Gly Gly Phe Ser Ser Glu Met Lys Ala Trp Asp Ile Arg Thr Gly Lys Val Met Arg Ser Tyr Lys Ala Thr Ile Gln G1n Thr Leu Asp Ile Leu Phe Leu Arg Glu Gly Ser Glu Phe Leu Ser Ser Thr Asp A1a Ser Thr Arg Asp Ser Ala Asp Arg Thr Ile Ile Ala Trp Asp Phe Arg Thr Ser Ala Lys Ile Ser Asn Gln Ile Phe His Glu Arg Phe Thr Cys Pro Ser Leu Ala Leu His Pro Arg Glu Pro Val Phe Leu Ala Gln Thr Asn Gly Asn Tyr Leu Ala Leu Phe Ser Thr Val Trp Pro Tyr Arg Met Ser Arg Arg Arg Arg Tyr Glu Gly His Lys Val Glu Gly Tyr Ser Val Gly Cys Glu Cys Ser Pro Gly Gly Asp Leu Leu Val Thr Gly Ser Ala Asp Gly Arg Val Leu Met Tyr Ser Phe Arg Thr Ala Ser Arg Ala Cys Thr Leu Gln Gly His Thr Gln Ala Cys Val Gly Thr Thr Tyr His Pro Val Leu Pro Ser Val Leu Ala Thr Cys Ser Trp Gly Gly Asp Met Lys Ile Trp His <210> 31 <211> 125 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 927065CD1 <400> 31 Met Pro Ala Pro Ala Ala Thr Tyr Glu Arg Val Val Tyr Lys Asn Pro Ser Glu Tyr His Tyr Met Lys Val Cys Leu Glu Phe Gln Asp Cys Gly Val Gly Leu Asn Ala Ala Gln Phe Lys Gln Leu Leu Ile Ser Ala Val Lys Asp Leu Phe Gly Glu Val Asp Ala Ala Leu Pro Leu Asp Ile Leu Thr Tyr G1u G1u Lys Thr Leu Ser Ala Ile Leu Arg Tle Cys Ser Ser Gly Leu Val Lys Leu Trp Ser Ser Leu Thr Leu Leu Arg Ile Pro Ile Lys Gly Lys Lys Cys Ala Phe Arg Val T1e Gln Val Ser Pro Phe Leu Leu Ala Leu Ser Gly Asn Ser Arg Glu Leu Val Leu Asp <210> 32 <211> 365 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 938071CD1 <400> 32 Met Ala Pro Val Ser Gly Ser Arg Ser Pro Asp Arg Glu Ala Ser Gly Ser Gly Gly Arg Arg Arg Ser Ser Ser Lys Ser Pro Lys Pro Ser Lys Ser Ala Arg Ser Pro Arg Gly Arg Arg Ser Arg Ser His Ser Cys Ser Arg Ser Gly Asp Arg Asn Gly Leu Thr His Gln Leu Gly G1y Leu Ser Gln Gly Ser Arg Asn Gln Ser Tyr Arg Ser Arg 65 70 . 75 Ser Arg Ser Arg Ser Arg Glu Arg Pro Ser Ala Pro Arg G1y Ile Pro Phe Ala Ser Ala Ser Ser Ser Val Tyr Tyr Gly Ser Tyr Ser Arg Pro Tyr Gly Ser Asp Lys Pro Trp Pro Ser Leu Leu Asp Lys Glu Arg Glu Glu Ser Leu Arg Gln Lys Arg Leu Ser Glu Arg Glu Arg I1e Gly Glu Leu Gly Ala Pro Glu Val Trp Gly Leu Ser Pro Lys Asn Pro Glu Pro Asp Ser Asp Glu His Thr Pro Val Glu Asp Glu Glu Pro Lys Lys Ser Thr Thr Ser Ala Ser Thr Ser Glu Glu Glu Lys Lys Lys Lys Ser Ser Arg Ser Lys Glu Arg Ser Lys Lys Arg Arg Lys Lys Lys Ser Ser Lys Arg Lys His Lys Lys Tyr Ser Glu Asp Ser Asp Ser Asp Ser Asp Ser Glu Thr Asp Ser Ser Asp Glu Asp Asn Lys Arg Arg A1a Lys Lys Ala Lys Lys Lys Glu Lys Lys Lys Lys His Arg Ser Lys Lys Tyr Lys Lys Lys Arg Ser Lys Lys Ser Arg Lys Glu Ser Ser Asp Ser Ser Ser Lys Glu Ser Gln Glu Glu Phe Leu Glu Asn Pro Trp Lys Asp Arg Thr Lys Ala Glu Glu Pro Ser Asp Leu Ile Gly Pro Glu Ala Pro Lys Thr Leu Thr Ser G1n Asp Asp Lys Pro Leu Lys His Arg Arg Met Glu Ala Val Arg Leu Arg Lys Glu Asn Gln Ile Tyr Ser Ala Asp Glu Lys Arg Ala Leu Ala Ser Phe Asn Gln Glu Glu Arg Arg Lys Arg Glu Asn Lys Ile Leu Ala Ser Phe Arg Glu Met Val Tyr Arg Lys Thr Lys Gly Lys Asp Asp Lys <210> 33 <211> 672 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3295984CD1 <400> 33 Met Arg Ser Ile Arg Ser Phe Ala Asn Asp Asp Arg His Val Met Val Lys His Ser Thr Ile Tyr Pro Ser Pro Glu Glu Leu Glu Ala Val Gln Asn Met Val Ser Thr Val Glu Cys Ala Leu Lys His Val Ser Asp Trp Leu Asp Glu Thr Asn Lys Gly Thr Lys Thr G1u Gly Glu Thr Glu Val Lys Lys Asp Glu Ala Gly Glu Asn Tyr Ser Lys Asp Gln Gly Gly Arg Thr Leu Cys Gly Val Met Arg Tle Gly Leu Val Ala Lys Gly Leu Leu Ile Lys Asp Asp Met Asp Leu Glu Leu Val Leu Met Cys Lys Asp Lys Pro Thr Glu Thr Leu Leu Asn Thr Val Lys Asp Asn Leu Pro Ile Gln Ile Gln Lys Leu Thr Glu Glu Lys Tyr Gln Val Glu G1n Cys Val Asn Glu Ala Ser Ile Ile Ile Arg Asn Thr Lys Glu Pro Thr Leu Thr Leu Lys Val Ile Leu Thr Ser Pro Leu Ile Arg Asp Glu Leu Glu Lys Lys Asp Gly Glu Asn Val Ser Met Lys Asp Pro Pro Asp Leu Leu Asp Arg Gln Lys Cys Leu Asn Ala Leu Ala Ser Leu Arg His Ala Lys Trp Phe Gln Ala Arg Ala Asn Gly Leu Lys Ser Cys Val Ile Val Leu Arg Ile Leu Arg Asp Leu Cys Asn Arg Val Pro Thr Trp Ala Pro Leu Lys Gly Trp Pro Leu Glu Leu Ile Cys Glu Lys Ser Ile Gly Thr Cys Asn Arg Pro Leu Gly Ala Gly Glu Ala Leu Arg Arg Val Met Glu Cys Leu Ala Ser Gly Ile Leu Leu Pro Gly Gly Pro Gly Leu His Asp Pro Cys Glu Arg Asp Pro Thr Asp Ala Leu Ser Tyr Met Thr Ile Gln Gln Lys Glu Asp Ile Thr His Ser Ala Gln His Ala Leu Arg Leu Ser Ala Phe Gly Gln Ile Tyr Lys Val Leu Glu Met Asp Pro Leu Pro Ser Ser Lys Pro Phe Gln Lys Tyr Ser Trp Ser Val Thr Asp Lys Glu Gly Ala Gly Ser Ser Ala Leu Lys Arg Pro Phe Glu Asp Gly Leu Gly Asp Asp Lys Asp Pro Asn Lys Lys Met Lys Arg Asn Leu Arg Lys Ile Leu Asp Ser Lys Ala Ile Asp Leu Met Asn Ala Leu Met Arg Leu Asn Gln Ile Arg Pro Gly Leu Gln Tyr Lys Leu Leu Ser Gln Ser Gly Pro Va1 His Ala Pro Val Phe Thr Met Ser Val Asp Val Asp Gly Thr Thr Tyr G1u Ala Ser Gly Pro Ser Lys Lys Thr Ala Lys Leu His Val Ala Val Lys Val Leu Gln Ala Met Gly Tyr Pro Thr Gly Phe Asp Ala Asp Ile Glu Cys Met Ser Ser Asp Glu Lys Ser Asp Asn Glu Ser Lys Asn Glu Thr Va1 Ser Ser Asn Ser Ser Asn Asn Thr Gly Asn Ser Thr Thr G1u Thr Ser Ser Thr Leu Glu Val Arg Thr Gln Gly Pro Ile Leu Thr Ala Ser Gly Lys Asn Pro Val Met Glu Leu Asn Glu Lys Arg Arg Gly Leu Lys Tyr Glu Leu Ile Ser Glu Thr Gly Gly Ser His Asp Lys Arg Phe Val Met Glu Val Glu Val Asp Gly Gln Lys Phe Arg Gly Ala Gly Pro Asn Lys Lys Val Ala Lys Ala Ser Ala Ala Leu Ala Ala Leu Glu Lys Leu Phe Ser Gly Pro Asn Ala Ala Asn Asn Lys Lys Lys Lys Ile Ile Pro Gln Ala Lys Gly Val Val Asn Thr Ala Val Ser Ala Ala Val Gln Ala Val Arg Gly Arg Gly Arg Gly Thr Leu Thr Arg Gly Ala Phe Val Gly Ala Thr Ala Ala Pro Gly Tyr Ile Ala Pro Gly Tyr Gly Thr Pro Tyr Gly Tyr Ser Thr Ala Ala Pro Ala Tyr Gly Leu Pro Lys Arg Met Val Leu Leu Pro Val Met Lys Phe Pro Thr Tyr Pro Val Pro His Tyr Ser Phe Phe <210> 34 <211> 430 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4545237CD1 <400> 34 Met Ala Thr Ala Val Arg Ala Val Gly Cys Leu Pro Val Leu Cys Ser Gly Thr Ala Gly His Leu Leu Gly Arg Gln Cys Ser Leu Asn Thr Leu Pro Ala Ala Ser Tle Leu Ala Trp Lys Ser Va1 Leu Gly Asn Gly His Leu Ser Ser Leu Gly Thr Arg Asp Thr His Pro Tyr Ala Ser Leu Ser Arg Ala Leu Gln Thr G1n Cys Cys Ile Ser Ser Pro Ser His Leu Met Ser Gln Gln Tyr Arg Pro Tyr Ser Phe Phe Thr Lys Leu Thr Ala Asp Glu Leu Trp Lys Gly Ala Leu Ala Glu Thr Gly Ala Gly Ala Lys Lys Gly Arg Gly Lys Arg Thr Lys Lys Lys Lys Arg Lys Asp Leu Asn Arg Gly G1n Ile Ile Gly Glu Gly Arg Tyr Gly Phe Leu Trp Pro Gly Leu Asn Va1 Pro Leu Met Lys Asn Gly Ala Val Gln Thr Ile Ala Gln Arg Ser Lys Glu Glu Gln Glu Lys Val Glu Ala Asp Met Ile Gln Gln Arg Glu Glu Trp Asp Arg Lys Lys Lys Met Lys Val Lys Arg Glu Arg Gly Trp Ser Gly Asn Ser Trp Gly Gly Ile Ser Leu Gly Pro Pro Asp Pro Gly Pro Cys G1y Glu Thr Tyr Glu Asp Phe Asp Thr Arg Ile Leu Glu Val Arg Asn Val Phe Thr Met Thr Ala Lys Glu Gly Arg Lys Lys Ser Ile Arg Val Leu Val Ala Val Gly Asn G1y Lys Gly Ala Ala Gly Phe Ser Ile Gly Lys Ala Thr Asp Arg Met Asp A1a Phe Arg Lys Ala Lys Asn Arg Ala Val His His Leu His Tyr Ile Glu Arg Tyr Glu Asp His Thr Ile Phe His Asp Ile Ser Leu Arg Phe Lys Arg Thr His Ile Lys Met Lys Lys Gln Pro Lys Gly Tyr Gly Leu Arg Cys His Arg Ala Ile I1e Thr Ile Cys Arg Leu Ile Gly Ile Lys Asp Met Tyr Ala Lys Val Ser Gly Ser Ile Asn Met Leu Ser Leu Thr Gln Gly Leu Phe Arg Gly Leu Ser Arg Gln Glu Thr His Gln Gln Leu Ala Asp Lys Lys Gly Leu His Val Val Glu Ile Arg Glu Glu Cys Gly Pro Leu Pro Ile Val Val Ala Ser Pro Arg Gly Pro Leu Arg Lys Asp Pro Glu Pro Glu Asp Glu Val Pro Asp Val Lys Leu Asp Trp Glu Asp Val Lys Thr Ala Gln Gly Met Lys Arg Ser Val Trp Ser Asn Leu Lys Arg Ala Ala Thr <210> 35 <211> 137 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4942964CD1 <400> 35 Met Ala Asp Ser Lys Ala Thr Ser Ala Val Thr Leu Arg Thr Arg Lys Phe Met Thr Asn Arg Leu Leu Ala Arg Lys Gln Phe Va1 Leu Glu Val Ile His Pro Gly Arg Ala Asn Val Ser Lys Ala Glu Leu Lys Glu Arg Leu Ala Lys Ala Tyr Glu Val Lys Asp Pro Asn Thr Ile Phe Val Phe Lys Phe Arg Thr His Phe Gly Gly Gly Lys Ser Thr Gly Phe Gly Leu Ile Tyr Asp Asn Leu Glu Ala Ala Lys Lys Phe Glu Pro Lys Tyr Arg Leu Ile Arg Asn Gly Leu Ala Thr Lys Val Glu Lys Ser Arg Lys Gln Met Lys G1u Arg Lys Asn Arg Ala Lys Lys Ile Arg Gly Val Lys Lys Thr Lys Ala Gly Asp Ala Lys Lys Lys <210> 36 <211> 380 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5702144CD1 <400> 36 Met Arg Ser Arg Val Leu Trp Gly Ala Ala Arg Trp Leu Trp Pro Arg Arg Ala Val Gly Pro Ala Arg Arg Pro Leu Ser Ser Gly Ser Pro Pro Leu Glu Glu Leu Phe Thr Arg Gly Gly Pro Leu Arg Thr Phe Leu Glu Arg Gln Ala Gly Ser Glu Ala His Leu Lys Val Arg Arg Pro Glu Leu Leu A1a Val Ile Lys Leu Leu Asn Glu Lys G1u Gln Glu Leu Arg Glu Thr Glu His Leu Leu His Asp Glu Asn Glu Asp Leu Arg Lys Leu Ala Glu Asn Glu Ile Thr Leu Cys Gln Lys Glu Ile Thr Gln Leu Lys His Gln Ile Ile Leu Leu Leu Val Pro Ser Glu Glu Thr Asp Glu Asn Asp Leu Ile Leu Glu Val Thr Ala Gly Val Gly Gly Gln Glu Ala Met Leu Phe Thr Ser Glu Ile Phe Asp Met Tyr Gln Gln Tyr Ala Ala Phe Lys Arg Trp His Phe Glu Thr Leu Glu Tyr Phe Pro Ser Glu Leu Gly Gly Leu Arg His Ala Ser Ala Ser Ile Gly Gly Ser Glu Ala Tyr Arg His Met Lys Phe Glu Gly Gly Val His Arg Val Gln Arg Val Pro Lys Thr Glu Lys 200 205 2l0 Gln Gly Arg Ile His Thr Ser Thr Met Thr Val Ala Ile Leu Pro Gln Pro Thr Glu Ile Asn Leu Val Ile Asn Pro Lys Asp Leu Arg Ile Asp Thr Lys Arg Ala Ser Gly Ala Gly Gly Gln His Val Asn Thr Thr Asp Ser Ala Val Arg Ile Val His Leu Pro Thr Gly Val Val Ser Glu Cys Gln Gln Glu Arg Ser Gln Leu Lys Asn Lys Glu Leu Ala Met Thr Lys Leu Arg Ala Lys Leu Tyr Ser Met His Leu Glu Glu Glu Ile Asn Lys Arg Gln Asn Ala Arg Lys Ile Gln Ile Gly Ser Lys Gly Arg Ser Glu Lys Ile Arg Thr Tyr Asn Phe Pro Gln Asn Arg Val Thr Asp His Arg Ile Asn Lys Thr Leu His Asp Leu Glu Thr Phe Met Gln Gly Asp Tyr Leu Leu Asp Glu Leu Val Gln Ser Leu Lys Glu Tyr Ala Asp Tyr Glu Ser Leu Val Glu Ile Ile Ser Gln Lys Val <210> 37 <2ll> 206 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5862945CD1 <400> 37 Met Ala Ala Ala Val Leu Gly G1n Leu Gly Ala Leu Trp Ile His Asn Leu Arg Ser Arg Gly Lys Leu Ala Leu Gly Val Leu Pro Gln Ser Tyr Ile His Thr Ser Ala Ser Leu Asp Ile Ser Arg Lys Trp G1u Lys Lys Asn Lys Ile Val Tyr Pro Pro Gln Leu Pro Gly Glu Pro Arg Arg Pro Ala Glu Ile Tyr His Cys Arg Arg Gln Ile Lys Tyr Ser Lys Asp Lys Met Trp Tyr Leu Ala Lys Leu Ile Arg Gly Met Ser Ile Asp Gln Ala Leu Ala Gln Leu Glu Phe Asn Asp Lys Lys Gly Ala Lys Ile Ile Lys Glu Val Leu Leu Glu Ala Gln Asp Met A1a Val Arg Asp His Asn Val Glu Phe Arg Ser Asn Leu Tyr 12 5 l3 0 13 5 Ile Ala Glu Ser Thr Ser Gly Arg Gly Gln Cys Leu Lys Arg Ile Arg Tyr His Gly Arg Gly Arg Phe Gly Ile Met Glu Lys Val Tyr Cys His Tyr Phe Val Lys Leu Val Glu Gly Pro Pro Pro Pro Pro Glu Pro Pro Lys Thr Ala Val A1a His A1a Lys Glu Tyr Ile Gln Gln Leu Arg Ser Arg Thr Ile Val His Thr Leu <210> 38 <211> 190 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6319547CD1 <400> 38 Met Glu Ala Glu Thr Lys Thr Leu Pro Leu Glu Asn Ala Ser Ile Leu Ser Glu Gly Ser Leu Gln G1u Gly His Arg Leu Trp Ile Gly Asn Leu Asp Pro Lys Ile Thr Glu Tyr His Leu Leu Lys Leu Leu Gln Lys Phe Gly Lys Val Lys Gln Phe Asp Phe Leu Phe His Lys Ser Gly A1a Leu Glu Gly Gln Pro Arg Gly Tyr Cys Phe Val Asn Phe Glu Thr Lys Gln Glu Ala G1u Gln Ala Ile Gln cys Leu Asn Gly Lys Leu Ala Leu Ser Lys Lys Leu Val Val Arg Trp Ala His Ala Gln Val Lys Arg Tyr Asp His Asn Lys Asn Asp Lys Ile Leu Pro Ile Ser Leu Glu Pro Ser Ser Ser Thr Glu Pro Thr Gln Ser Asn Leu Ser Val Thr Ala Lys Ile Lys Ala Ile Glu Ala Lys Leu Lys Met Met Ala Glu Asn Pro Asp Ala Glu Tyr Pro Ala Ala Pro Val Tyr Ser Tyr Phe Lys Pro Pro Asp Lys Lys Arg Thr Thr Pro Tyr Ser Arg Thr Ala Trp Lys Ser Arg Arg <210> 39 <211> 434 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 000124CD1 <400> 39 Met Leu Arg Cys Leu Tyr His Trp His Arg Pro Val Leu Asn Arg Arg Trp Ser Arg Leu Cys Leu Leu Lys Gln Tyr Leu Phe Thr Met Lys Leu Gln Ser Pro Glu Phe Gln Ser Leu Phe Thr Glu Gly Leu Lys Ser Leu Thr Glu Leu Phe Val Lys Glu Asn His Glu Leu Arg Ile Ala Gly Gly Ala Val Arg Asp Leu Leu Asn Gly Val Lys Pro Gln Asp Ile Asp Phe Ala Thr Thr Ala Thr Pro Thr Gln Met Lys Glu Met Phe Gln Ser Ala Gly Ile Arg Met Ile Asn Asn Arg Gly Glu Lys His Gly Thr Ile Thr Ala Arg Leu His Glu Glu Asn Phe Glu Ile Thr Thr Leu Arg Ile Asp Val Thr Thr Asp GIy Arg His Ala Glu Val Glu Phe Thr Thr Asp Trp Gln Lys Asp Ala Glu Arg Arg Asp Leu Thr Ile Asn Ser Met Phe Leu Gly Phe Asp Gly Thr Leu Phe Asp Tyr Phe Asn Gly Tyr Glu Asp Leu Lys Asn Lys Lys Val Arg Phe Val G1y His Ala Lys Gln Arg Ile Gln Glu Asp Tyr Leu Arg Ile Leu Arg Tyr Phe Arg Phe Tyr Gly Arg Ile Val Asp Lys Pro Gly Asp His Asp Pro Glu Thr Leu Glu Ala Ile Ala Glu Asn Ala Lys Gly Leu Ala Gly Ile Ser Gly Glu Arg Ile Trp Val Glu Leu Lys Lys Ile Leu Val Gly Asn His Val Asn His Leu Ile His Leu Ile Tyr Asp Leu Asp Val Ala Pro Tyr Ile Gly Leu Pro Ala Asn Ala Ser Leu Glu Glu Phe Asp Lys Val Ser Lys Asn Va1 Asp Gly Phe Ser Pro Lys Pro Val Thr Leu Leu Ala Ser Leu Phe Lys Val Gln Asp Asp Val Thr Lys Leu Asp Leu Arg Leu Lys Ile Ala Lys Glu Glu Lys Asn Leu Gly Leu Phe Ile Val Lys Asn Arg Lys Asp Leu Ile Lys Ala Thr Asp Ser Ser Asp Pro Leu Lys Pro Tyr Gln Asp Phe Ile Ile Asp Ser Arg Glu Pro Asp Ala Thr Thr Arg Val Cys Glu Leu Leu Lys Tyr Gln Gly Glu His Cys Leu Leu Lys Glu Met Gln Gln Trp Ser Ile Pro Pro Phe Pro Val Ser Gly His Asp Ile Arg Lys Val Gly Ile Ser Ser Gly Lys Glu Ile Gly Ala Leu Leu Gln Gln Leu Arg Glu Gln Trp Lys Lys Ser Gly Tyr Gln Met Glu Lys Asp Glu Leu Leu Ser Tyr Ile Lys Lys Thr <210> 40 <211> 339 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1659474CD1 <400> 40 Met Ala Ala Gly Cys Ser Glu Ala Pro Arg Pro Thr Ala Ala Ser Asp Gly Ser Leu Val Gly Gln Ala Gly Val Leu Pro Cys Leu Glu Leu Pro Thr Tyr Ala Ala Ala Cys Ala Leu Val Asn Ser Arg Tyr Ser Cys Leu Val Ala Gly Pro His Gln Arg His Ile Ala Leu Ser 50 ~ 55 60 Pro Arg Tyr Leu Asn Arg Lys Arg Thr Gly Ile Arg Glu Gln Leu Asp Ala Glu Leu Leu Arg Tyr Ser G1u Ser Leu Leu Gly Val Pro Ile Ala Tyr Asp Asn Ile Lys Val Val Gly Glu Leu Gly Asp Ile Tyr Asp Asp Gln Gly His Ile His Leu Asn Ile Glu Ala Asp Phe Val Ile Phe Cys Pro Glu Pro Gly Gln Lys Leu Met Gly Ile Val Asn Lys Val Ser Ser Ser His Ile Gly Cys Leu Val His Gly Cys Phe Asn Ala Ser Ile Pro Lys Pro Glu Gln Leu Ser Ala Glu Gln Trp Gln Thr Met Glu Ile Asn Met Gly Asp Glu Leu Glu Phe Glu Val Phe Arg Leu Asp Ser Asp Ala Ala Gly Val Phe Cys Tle Arg Gly Lys Leu Asn Ile Thr Ser Leu Gln Phe Lys Arg Ser Glu Val Ser Glu Glu Val Thr Glu Asn Gly Thr Glu Glu Ala Ala Lys Lys Pro Lys Lys Lys Lys Lys Lys Lys Asp Pro Glu Thr Tyr Glu Val Asp Ser Gly Thr Thr Lys Leu Ala Asp Asp Ala Asp Asp Thr Pro Met Glu G1u Ser Ala Leu Gln Asn Thr Asn Asn Ala Asn Gly Ile Trp Glu Glu Glu Pro Lys Lys Lys Lys Lys Lys Lys Lys His Gln Glu Val Gln Asp Gln Asp Pro Val Phe Gln Gly Ser Asp Ser Ser Gly Tyr Gln Ser Asp His Lys Lys Lys Lys Lys Glu Lys Lys Thr Asn Ser Glu Glu Ala Glu Phe Thr Pro Pro Leu Lys Cys Ser Pro Lys Arg Lys Gly Lys Ser Asn Phe Leu <210> 41 <211> 599 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2267892CD1 <400> 41 Met Asp Val His Asp Leu Phe Arg Arg Leu Gly Ala Gly Ala Lys Phe Asp Thr Arg Arg Phe Ser Ala Asp Ala Ala Arg Phe Gln Ile Gly Lys Arg Lys Tyr Asp Phe Asp Ser Ser Glu Val Leu Gln Gly Leu Asp Phe Phe Gly Asn Lys Lys Ser Val Pro Gly Val Cys Gly Ala Ser Gln Thr His Gln Lys Pro G1n Asn Gly Glu Lys Lys Glu Glu Ser Leu Thr Glu Arg Lys Arg Glu Gln Ser Lys Lys Lys Arg Lys Thr Met Thr Ser Glu Ile Ala Ser Gln Glu Glu Gly Ala Thr Ile Gln Trp Met Ser Ser Val Glu Ala Lys Ile Glu Asp Lys Lys Val Gln Arg Glu Ser Lys Leu Thr Ser Gly Lys Leu Glu Asn Leu Arg Lys Glu Lys Ile Asn Phe Leu Arg Asn Lys His Lys I1e His Val Gln Gly Thr Asp Leu Pro Asp Pro Ile Ala Thr Phe Gln Gln Leu Asp Gln Glu Tyr Lys Ile Asn Ser Arg Leu Leu G1n Asn Ile Leu Asp Ala Gly Phe Gln Met Pro Thr Pro Ile Gln Met Gln Ala Ile Pro Val Met Leu His Gly Arg Glu Leu Leu Ala Ser Ala Pro Thr Gly Ser Gly Lys Thr Leu Ala Phe Ser Ile Pro Ile Leu Met Gln Leu Lys Gln Pro Ala Asn Lys Gly Phe Arg Ala Leu Ile Ile Ser Pro Thr Arg Glu Leu Ala Ser Gln Ile His Arg Glu Leu Ile Lys Ile Ser Glu Gly Thr Gly Phe Arg Ile His Met Ile His Lys Ala A1a Val Ala Ala Lys Lys Phe Gly Pro Lys Ser Ser Lys Lys Phe Asp Ile Leu Val Thr Thr Pro Asn Arg Leu Ile Tyr Leu Leu Lys Gln Asp Pro Pro Gly Ile Asp Leu Ala Ser Val Glu Trp Leu Val Val Asp Glu Ser Asp Lys Leu Phe Glu Asp Gly Lys Thr Gly Phe Arg Asp Gln Leu Ala Ser I1e Phe Leu Ala Cys Thr Ser His Lys Val Arg Arg Ala Met Phe.Ser Ala Thr Phe Ala Tyr Asp Val Glu Gln Trp Cys Lys Leu Asn Leu Asp Asn Val Ile Ser Val Ser Ile Gly Ala Arg Asn Ser Ala Val Glu Thr Val Glu Gln Glu Leu Leu Phe Val Gly Ser G1u Thr Gly Lys Leu Leu Ala Met Arg Glu Leu Val Lys Lys Gly Phe Asn Pro Pro Val Leu Val Phe Val Gln Ser Ile Glu Arg Ala Lys Glu Leu Phe His Glu Leu Ile Tyr Glu Gly Ile Asn Val Asp Val Ile His Ala Glu Arg Thr Gln Gln Gln Arg Asp Asn Thr Val His Ser Phe Arg Ala Gly Lys Ile Trp Val Leu Ile Cys Thr Ala Leu Leu Ala Arg Gly Ile Asp Phe Lys Gly 470. 475 480 Val Asn Leu Val Ile Asn Tyr Asp Phe Pro Thr Ser Ser Val Glu Tyr Ile His Arg Ile Gly Arg Thr Gly Arg Ala Gly Asn Lys Gly Lys Ala Ile Thr Phe Phe Thr Glu Asp Asp Lys Pro Leu Leu Arg Ser Val Ala Asn Val Ile Gln Gln Ala Gly Cys Pro Val Pro Glu Tyr Ile Lys Gly Phe Gln Lys Leu Leu Ser Lys Gln Lys Lys Lys Met Ile Lys Lys Pro Leu Glu Arg Glu Ser Ile Ser Thr Thr Pro Lys Cys Phe Leu Glu Lys A1a Lys Asp Lys Gln Lys Lys Val Thr Gly Gln Asn Ser Lys Lys Lys Val Ala Leu Glu Asp Lys Ser <210> 42 <211> 334 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2670307CD1 <400> 42 Met Ala Ala Gly Ser Gly Met Ala Lys Thr Trp G1u Ser Gln Leu Ala Asn Asn Gln Glu Ala Gln Ser Asp Glu Ile Tyr Met Ile Lys Tyr Asp Lys Lys Gln Gln Gln Glu Ile Leu Ala Ala Lys Pro Gly Leu Arg Ile His His Tyr Phe Lys Tyr Cys Lys Ile Ser Ala Leu Ala Leu Leu Lys Met Val Met His Ala Arg Ser Gly Gly Asn Leu Glu Val Met Gly Leu Met Leu Gly Lys Val Asp Gly Glu Thr Met Ile Ile Met Asp Ser Phe Ala Leu Pro Val Glu Gly Thr Glu Thr Arg Val Asn Ala Gln Ala Ala Ala Tyr Glu Tyr Met Ala Ala Tyr Ile Glu Asn Ala Lys Gln Val Gly Arg Leu Glu Asn Ala Ile Gly Trp Tyr His Ser His Pro Gly Tyr Gly Cys Trp Leu Ser Gly Ile Asp Val Ser Thr Gln Met Leu Asn Gln Gln Phe G1n Glu Pro Phe Val Ala Val Val Ile Asp Pro Thr Arg Thr Ile Ser Ala Gly Lys Val Asn Leu Gly Ala Phe Arg Thr Tyr Pro Lys Gly Tyr Lys Pro Pro Asp Glu Gly.Pro Ser Glu Tyr Gln Thr Ile Pro Leu Asn Lys Ile Glu Asp Phe Gly Val His Cys Lys Gln Tyr Tyr Ala Leu Glu Val Ser Tyr Phe Lys Ser Ser Leu Asp Arg Lys Leu Leu Glu Leu Leu Trp Asn Lys Tyr Trp Val Asn Thr Leu Ser Ser Ser Ser Leu Leu Thr Asn A1a Asp Tyr Thr Thr Gly Gln Va1 Phe Asp Leu Ser Glu Lys Leu Glu Gln Ser Glu Ala Gln Leu Gly Arg Gly Ser Phe Met Leu Gly Leu Glu Thr His Asp Arg Lys Ser Glu Asp Lys Leu Ala Lys Ala Thr Arg Asp Ser Cys Lys Thr Thr Ile G1u Ala Ile His Gly Leu Met Ser Gln Val Ile Lys Asp Lys Leu Phe Asn Gln Ile Asn Ile Ser <210> 43 <211> 448 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4524210CD1 <400> 43 Met Asn Lys Glu Ile Val Thr Ala Leu Gly Lys Gln Glu Ala Glu Arg Lys Phe Glu Thr Leu Leu Lys His Leu Ser His Pro Pro Ser Phe Thr Thr Val Arg Val Asn Thr His Leu Ala Ser Val Gln His Val Lys Asn Leu Leu Leu Asp Glu Leu Gln Lys Gln Phe Asn Gly Leu Ser Val Pro Ile Leu Gln His Pro Asp Leu Gln Asp Val Leu Leu Ile Pro Val Ile Gly Pro Arg Lys Asn Ile Lys Lys Gln Gln Cys Glu Ala Ile Val Gly Ala G1n Cys Gly Asn Ala Val Leu Arg Gly Ala His Val Tyr Ala Pro Gly Ile Val Ser Ala Ser Gln Phe Met Lys Ala Gly Asp Val Ile Ser Val Tyr Ser Asp Ile Lys Gly Lys Cys Lys Lys Gly Ala Lys Glu Phe Asp Gly Thr Lys Val Phe Leu Gly Asn Gly Ile Ser Glu Leu Ser Arg Lys Glu Ile Phe Ser Gly Leu Pro Glu Leu Lys Gly Met Gly Ile Arg Met Thr Glu Pro Val Tyr Leu Ser Pro Ser Phe Asp Ser Val Leu Pro Arg Tyr Leu Phe Leu Gln Asn Leu Pro Ser Ala Leu Val Ser His Val Leu Asn Pro Gln Pro Gly Glu Lys Ile Leu Asp Leu Cys Ala Ala Pro Gly Gly Lys Thr Thr His Ile Ala Ala Leu Met His Asp Gln Gly Glu Val Ile Ala Leu Asp Lys Ile Phe Asn Lys Val Glu Lys Ile Lys Gln Asn Ala Leu Leu Leu Gly Leu Asn Ser Ile Arg Ala Phe Cys Phe Asp Gly Thr Lys A1a Val Lys Leu Asp Met Val Glu Asp Thr Glu Gly Glu Pro Pro Phe Leu Pro Glu Ser Phe Asp Arg Ile Leu Leu Asp Ala Pro Cys Ser Gly Met Gly Gln Arg Pro Asn Met Ala Cys Thr Trp Ser Val Lys Glu Val Ala Ser Tyr Gln Pro Leu Gln Arg Lys Leu Phe Thr Ala Ala_Val Gln Leu Leu Lys Pro Glu Gly Val Leu Val Tyr Ser Thr Cys Thr Ile Thr Leu Ala Glu Asn Glu Glu Gln Val Ala Trp Ala Leu Thr Lys Phe Pro Cys Leu G1n Leu Gln Pro Gln Glu Pro Gln Ile Gly Gly Glu Gly Met Arg Gly Ala Gly Leu Ser Cys Glu Gln Leu Lys Gln Leu Gln Arg Phe Asp Pro Ser Ala Val Pro Leu Pro Asp Thr Asp Met Asp Ser Leu Arg G1u Ala Arg Arg Glu Asp Met Leu Arg Leu Ala Asn Lys Asp Ser Ile Gly Phe Phe I1e A1a Lys Phe Val Lys Cys Lys Ser Thr <210> 44 <211> 420 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5584860CD1 <400> 44 Met Ala Thr Ser Leu Gly Ser Asn Thr Tyr Asn Arg Gln Asn Trp Glu Asp Ala Asp Phe Pro Ile Leu Cys Gln Thr Cys Leu Gly Glu Asn Pro Tyr Ile Arg Met Thr Lys Glu Lys Tyr Gly Lys Glu Cys Lys Ile Cys Ala Arg Pro Phe Thr Val Phe Arg Trp Cys Pro Gly Val Arg Met Arg Phe Lys Lys Thr Glu Val Cys Gln Thr Cys Ser Lys Leu Lys Asn Val Cys Gln Thr Cys Leu Leu Asp Leu Glu Tyr Gly Leu Pro Ile Gln Val Arg Asp Ala Gly Leu Ser Phe Lys Asp Asp Met Pro Lys Ser Asp Val Asn Lys Glu Tyr Tyr Thr Gln Asn Met Glu Arg Glu Ile Ser Asn Ser Asp Gly Thr Arg Pro Val Gly Met Leu Gly Lys A1a Thr Ser Thr Ser Asp Met Leu Leu Lys Leu Ala Arg Thr Thr Pro Tyr Tyr Lys Arg Asn Arg Pro His Ile Cys Ser Phe Trp Val Lys Gly Glu Cys Lys Arg Gly Glu Glu Cys Pro Tyr Arg His Glu Lys Pro Thr Asp Pro Asp Asp Pro Leu Ala Asp Gln Asn Ile Lys Asp Arg Tyr Tyr Gly I1e Asn Asp Pro Val Ala Asp Lys Leu Leu Lys Arg Ala Ser Thr Met Pro Arg Leu Asp Pro Pro Glu Asp Lys Thr Ile Thr Thr Leu Tyr Val Gly Gly Leu Gly Asp Thr Ile Thr Glu Thr Asp Leu Arg Asn His Phe Tyr Gln Phe Gly Glu I1e Arg Thr Ile Thr Val Val Gln Arg Gln Gln Cys Ala Phe Ile Gln Phe Ala Thr Arg Gln Ala Ala Glu Val Ala Ala Glu Lys Ser Phe Asn Lys Leu Ile Val Asn Gly Arg Arg Leu Asn Val Lys Trp Gly Arg Ser Gln Ala Ala Arg Gly Lys Glu Lys Glu Lys Asp Gly Thr Thr Asp Ser Gly Ile Lys Leu Glu Pro Val Pro Gly Leu Pro Gly Ala Leu Pro Pro Pro Pro Ala Ala Glu Glu Glu Ala Ser Ala Asn Tyr Phe Asn Leu Pro Pro Ser Gly Pro Pro Ala Val Val Asn Ile Ala Leu Pro Pro Pro Pro Gly I1e Ala Pro Pro Pro Pro Pro G1y Phe Gly Pro His Met Phe His Pro Met G1y Pro Pro Pro Pro Phe Met Arg Ala Pro Gly Pro Ile His Tyr Pro Ser Gln Asp Pro Gln Arg Met Gly Ala His Ala Gly Lys His Ser Ser Pro <210> 45 <211> 137 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5807892CD1 <400> 45 Met Val His Leu Thr Thr Leu Leu Cys Lys Ala Tyr Arg Gly Gly His Leu Thr Ile Arg Leu Ala Leu Gly Gly Cys Thr Asn Arg Pro Phe Tyr Arg Ile Va1 Ala Ala His Asn Lys Cys Pro Arg Asp Gly Arg Phe Val Glu Gln Leu Gly Ser Tyr Asp Pro Leu Pro Asn Ser His Gly Glu Lys Leu Val Ala Leu Asn Leu Asp Arg Ile Arg His Trp Ile Gly Cys Gly Ala His Leu Ser Lys Pro Met Glu Lys Leu Leu Gly Leu Ala Gly Phe Phe Pro Leu His Pro Met Met Ile Thr Asn Ala Glu Arg Leu Arg Arg Lys Arg Ala Arg Glu Val Leu Leu Ala Ser G1n Lys Thr Asp Ala Glu Ala Thr Asp Thr Glu Ala Thr Glu Thr <210> 46 <211> 556 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3210044CD1 <400> 46 Met Met Asn Leu Pro Phe Asn Arg Asp Ala Val Phe Tyr His Glu Asp G1u Thr Asn Cys Leu Leu Leu Ile Met Ala Pro Ser Phe Thr Ala Arg Ile Gln Leu Phe Leu Leu Arg Ala Leu Gly Phe Leu Ile Gly Leu Val Gly Arg Ala Ala Leu Val Leu Gly Gly Pro Lys Phe Ala Ser Lys Thr Pro Arg Pro Val Thr Glu Pro Leu Leu Leu Leu Ser Gly Met Gln Leu Ala Lys Leu Ile Arg Gln Arg Lys Val Lys Cys Ile Asp Val Val Gln Ala Tyr Ile Asn Arg Ile Lys Asp Val Asn Pro Met Ile Asn Gly Ile Va1 Lys Tyr Arg Phe Glu Glu Ala Met Lys Glu Ala His Ala Val Asp Gln Lys Leu Ala Glu Lys Gln Glu Asp Glu A1a Thr Leu Glu Asn Lys Trp Pro Phe Leu Gly Val Pro Leu Thr Val Lys Glu Ala Phe G1n Leu Gln Gly Met Pro Asn Ser Ser Gly Leu Met Asn Arg Arg Asp Ala Ile Ala Lys Thr Asp Ala Thr Val Val Ala Leu Leu Lys Gly Ala Gly Ala Ile Pro Leu Gly Ile Thr Asn Cys Ser Glu Leu Cys Met Trp Tyr Glu Ser Ser Asn Lys Ile Tyr Gly Arg Ser Asn Asn Pro Tyr Asp Leu Gln His Ile Val Gly Gly Ser Ser Gly G1y Glu Gly Cys Thr Leu Ala Ala Ala Cys Ser Val Ile Gly Val Gly Ser Asp Ile Gly Gly Ser Ile Arg Met Pro Ala Phe Phe Asn Gly Ile Phe Gly His Lys Pro Ser Pro Gly Val Val Pro Asn Lys Gly Gln Phe Pro Leu Ala Val Gly Ala Gln Glu Leu Phe Leu Cys Thr Gly Pro Met Cys Arg Tyr A1a Glu Asp Leu Ala Pro Met Leu Lys Val Met Ala Gly Pro Gly Ile Lys Arg Leu Lys Leu Asp Thr Lys Val His Leu Lys Asp Leu Lys Phe Tyr Trp Met Glu His Asp Gly Gly Ser Phe Leu Met Ser Lys Val Asp Gln Asp Leu Ile Met Thr Gln Lys Lys Val Val Val His Leu Glu Thr Ile Leu Gly Ala Ser Val Gln His Val Lys Leu Lys Lys Met Lys Tyr Ser Phe Gln Leu Trp Ile Ala Met Met Ser Ala Lys Gly His Asp Gly Lys Glu Pro Val Lys Phe Val Asp Leu Leu Gly Asp His Gly Lys His Val Ser Pro Leu Trp Glu Leu Ile Lys Trp Cys Leu Gly Leu Ser Val Tyr Thr Ile Pro Ser Ile Gly Leu Ala Leu Leu Glu Glu Lys Leu Arg Tyr Ser Asn Glu Lys Tyr Gln Lys Phe Lys Ala Val Glu Glu Ser Leu Arg Lys Glu Leu Val Asp Met Leu Gly Asp Asp Gly Val Phe Leu Tyr Pro Ser His Pro Thr Val Ala Pro Lys His His Val Pro Leu Thr Arg Pro Phe Asn Phe Ala Tyr Thr Gly Val Phe Ser Ala Leu G1y Leu Pro Val Thr Gln Cys Pro Leu Gly Leu Asn Ala Lys Gly Leu Pro Leu Gly Ile Gln Val Val Ala Gly Pro Phe Asn Asp His Leu Thr Leu Ala Val Ala Gln Tyr Leu Glu Lys Thr Phe Gly Gly Trp Val Cys Pro Gly Lys Phe <210> 47 <211> 111 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4942454CD1 <400> 47 Met Lys Phe Val Ala Ala Tyr Leu Leu Ala Val Leu Ala Gly Asn l 5 10 15 Ser Ser Pro Ser Ala Glu Asp Leu Thr Ala Ile Leu Glu Ser Val Gly Cys Glu Val Asp Asn Glu Lys Met Glu Leu Leu Leu Ser Gln Leu Ser Gly Lys Asp Ile Thr Glu Leu Ile Ala Ala Gly Arg Glu Lys Phe Ala Ser Val Pro Cys Gly Gly Gly Gly Val Ala Val Ala Ala Ala Ala Pro Ala Ala Gly Gly Ala Pro Ala Ala Glu Ala Lys Lys Glu Glu Lys Val Glu Glu Lys Glu Glu Ser Asp Asp Asp Met Gly Phe Ser Leu Phe Asp <210> 48 <211> 882 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1622129CB1 <400> 48 cccacgcgtc cgcggagccg ccgggagctg tagttctccc gcggctcaga gaagtaggca 60 gagagcggac ctggcggccg ggcagcatgg cggggctgga gctcttgtcg gaccagggct 120 accgggtgga cgggcggcgc gccggggagc tgcgcaagat ccaggcgcgg atgggcgtgt 180 tcgcgcaggc tgacggctcg gcctacattg agcagggcaa caccaaggca ctggctgtgg 240 tctacggccc gcacgagatc cggggctccc gggctcgagc cctgccggac agggccctag 300 tgaactgtca atatagttca gcgaccttca gcacaggtga gcgcaagcga cggccacatg 360 gggaccgtaa gtcctgtgag atgggcctgc agctccgcca gactttcgaa gcagccatcc 420 tcacacagct gcacccacgc tcccagattg atatctatgt gcaggtgcta caggcagatg 480 gtgggaccta tgcagcttgt gtgaatgcag ccacgctggc agtgctggat gccgggatac 540 ccatgagaga ctttgtgtgt gcgtgctcag ctggcttcgt ggacggcaca gccctggcgg 600 acctcagcca tgtggaggaa gcagctggtg gcccccagct ggccctggcc ctgctgccag 660 cctcaggaca gattgcgctg cttgagatgg atgcccggct gcacgaggac cacctggagc 720 gggtgttgga ggctgctgcc caggctgccc gagatgtgca caccctctta gatcgagtgg 780 tccggcagca tgtgcgtgag gcctctatct tgctggggga ctgaccaccc agccacccat 840 gtccagaata aaaccctcct ctgcccacaa aaaaaaaaaa as 882 <210> 49 <211> 1220 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1820078CB1 <400> 49 ctcaacttta gcccgccgga agcggaagtc aggtggttgt cggattttag aggaaggcgc 60 tcggttacat tggagaactg gagtggtctg gagttccacg gtgtagtgga ccagaggcca 120 cctctcctgg gcttctcagt gtctcgccgg cggggttcgg cctgagctgg attgacatag 180 cccttggcgg atttaaacaa cctaaacatt aagcagtaca gctgcctcaa acctttggga 240 ttttcagaat gactgacact gccgaagctg ttccaaagtt tgaagagatg tttgctagta 300 gattcacaga aaatgacaag gagtatcagg aatacctgaa acgccctcct gagtctcctc 360 caattgttga ggaatggaat agcagagctg gtgggaacca aagaaacaga ggcaatcggt 420 tgcaagacaa cagacagttc agaggcaggg acaacagatg ggggtggcca agtgacaatc 480 gatccaatca gtggcatgga cgatcctggg gtaacaacta cccgcaacac agacaagaac 540 cttactatcc ccagcaatat ggacattatg gttacaacca gcggcctcct tacggttact 600 actgatagaa atgttggcag cttttagtaa aagcatttac tctgttacca tgagaaaagt 660 ttgggtgtct tctgttggtc atagttttac atctgatttt acagaatgga ttattgattt 720 tttggaagtt gagactttaa aaaaaataga tcttacttgc gaaatgcgat ggttgctggg 780 aatacctgaa actgtggatt atattgcttg acttctacct cagaatcttc tttgtttcat 840 gacttaatag tgctttaagt ttggtatatt atttgacctc taggaattct ttgttttaca 900 cagaaataaa aattttaaaa tagaaaatgc ttttactttg taaggtaaga gagtatccat 960 atgcttagat gtgctcgttt ctaaaattct agaggttgat ataatcagct catgaatgca 1020 cagctatgct ttttgtgata gattgtacat aacatcagca gttgaaaggt aaaacaattg 1080 cttttttttt tttttgcatt tgttaagtga ctatggtact ttgtgattcc ttaatctata 1140 gatgagtcag ctccacactt gagtctcttt ttagagggaa atcagtaata aagctgtaaa 1200 ataaggaagg aaaaaaaaaa 1220 <210> 50 <211> 2020 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1527017CB2 <220>
<221> unsure <222> 1905, 1909, 1936, 1942, 1959, 1967, 1972, 1979, 1989, 1999, 2002 <223> a, t, c, g, or other <400> 50 gagaggagtg agtgccgtca ccgagggccg cgccagactg cgacggatac agggagggca 60 agggtttcct tttggcgctt ccctttggac cccggagtga aaaactctaa cgtccagatc 120 agtggagaga aacgcagatt taggaccctg aggagtcttt ttcacccgtt tcccgtcact 180 cgctcaggcg cgccgagggc agtccttgtg gggtcctcgt ggccagccaa gatggttgcc 240 cccgcagtga aggttgcccg aggatggtcg ggcctggcgt tgggcgtgcg gcgggctgtc 300 ttgcagcttc caggggctaa ctcaggtgag atggagccgc tatagtcctg aattcaagga 360 tcccttgatt gacaaggaat attatcgcaa gccagtggag gagctaactg aggaggagaa 420 atatgttcgg gagctcaaga agactcagct catcaaagct gctccagcag gggaaaacaa 480 gttctgtgtt tgaagaccca gtcatcagta aattcaccaa catgatgatg ataggaggaa 540 acaaagtact ggccagatcc ctcatgattc agactctgga agctgtgaaa aggaagcagt 600 ttgagaagta ccatgccgct tctgcagagg aacaggcaac catcgaacgc aacccctaca 660 ccatcttcca tcaagcactg aaaaactgtg agcctatgat tgggctggta cccatcctca 720 agggaggccg tttctaccag gtccctgtac ccctacccga ccggcgtcgc cgcttcctag 780 ccatgaagtg gatgatcact gagtgccggg ataaaaagca ccagcggaca ctgatgccgg 840 agaagctgtc acacaagctg ctggaggctt tccataacca gggccccgtg atcaagagga 900 agcatgactt gcacaagatg gcagaggcca accgtgccct ggcccactac cgctggtggt 960 agagtctcca ggaggagccc agggccctct gccgcaagaa acagtgtgag ctactgccac 1020 gctgaaaact acctgtgggt taaggatgta gttcctttgt aagggtgggc aggcctcgta 1080 agaaagatgt agcagcatat tcactatccg ttaatccttc tttctttgag gctggaactt 1140 gctctctctg cccctatttc cttgtaaaga gggagcacat tgacttggga atttcctcca 1200 ggaaactcag ggctgttttc tcttccctta ggttggggcg gacctttgga catataaagg 1260 aagcagtttt agtatcagaa aagatttatt agaaaattct cacgctgaac tggtgtagca 1320 tgtggtgcag cattcagtga aactggctgg aggaaatagg cttgtttcca gagttgtcct 1380 tatacaaaat gtataaaaag cagtttctgg tgtgacttgt gctctgcctc caccccttga 1440 catcccaaaa tatcccacca gtggctatgc ttacccattt tacagatggg taaactgagg 1500 caccaaggta gtagttgcac taatggttac acagtgcagt ggctcttggg agttgccctt 1560 ctctgcctgg ccgtggtggg ttgtggtggg gaaaggggct cagggcagga ccacggcata 1620 agtgggaaac atctcaccag gagatgggaa agtctagaag ggaagacact caaagtctgg 1680 aagggaaaag tctttgggtg aggcagagac tccactgcca gctttagagg tgggtagaag 1740 aaaggccagt gctggtgagg aaaccctgat ctggaggcta gtcggagact tcgctgtagt 1800 atacttgtgg cactggcgtt gcttccagcc gttggccgtt gttctttccc aagcccgggc 1860 ccgcccccgg gaaacttcca aatgaatttt tcccaaggca aagcnagcna accttggggg 1920 cccaagggga agcttnaaag gncccaattt ttggggaanc caagggnaaa gncccattnc 1980 ccccggggnt ttaaggccnc cnaaaaagaa ggcttccctt 2020 <210> 51 <211> 637 <212> DNA
<213> Homo .sapiens <220>
<221> misc_feature <223> Incyte ID No: 1647264CB1 <400> 51 cggccagtgc aagctaaaat taaccctcac taaagggaat aagcttgcgg ccgccgagcc 60 cagctccgcc gccgagcgcc tgtgccggca ccgtacacca tggagcgccc ggataaggcg 120 gcgctgaacg cactgcagcc tcctgagttc agaaatgaaa gctcattagc atctacactg 180 aagacgctcc tgttcttcac agctttaatg atcactgttc ctattgggtt atatttcaca 240 actaaatctt acatatttga aggcgccctt gggatgtcca atagggacag ctatttttac 300 gctgctattg ttgcagtggt cgccgtccat gtggtgctgg ccctctttgt gtatgtggcc 360 tggaatgaag gctcacgaca gtggcgtgaa ggcaaacagg attaaagtga acatcacctt 420 tttatagcat taaattcatt ttttaaaatg ataaatgctg gagggggcca tctgatttga 480 ataaagttga aagaacatgt taaagtcagt cttaaggagt cacgtttgag tatgtaaatt 540 ttgatccttc taatatgttg ggtttgatat tcagttttac tgtatgaatc gattgcaatg 600 agaattggaa aagtagtaca agaatatgta attatta 637 <210> 52 <211> 717 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1721989CB1 <400> 52 ggctgggcct ggcgcgcagg cgctaggaag aggccgcgtg gggcgaaggc ggcgcttggc 60 tggtggggcc cgcggcggga ttttcccggg cggcgagagc ggatctatct tgggatccca 120 tggctttctt tactgggctc tggggcccct tcacctgtgt aagcagagtg ctgagccatc 180 actgtttcag caccactggg agtctgagtg cgattcagaa gatgacgcgg gtacgagtgg 240 tggacaacag tgccctgggg aacagcccat accatcgggc tcctcgctgc atccatgtct 300 ataagaagaa tggagtgggc aaggtgggcg accagatact actggccatc aagggacaga 360 agaaaaaggc gctcattgtg gggcactgca tgcctggccc ccgaatgacc cccagatttg 420 actccaacaa cgtggtcctc attgaggaca acgggaaccc tgtggggaca cgaattaaga 480 cacccatccc caccagcctg cgcaagcggg aaggcgagta ttccaaggtg ctggccattg 540 ctcagaactt tgtgtgagtt gagcccaggc ctctggttgc aggactcgtg aatggagcag 600 ttctgagaac cacccttttg ctaagggagc ttgggagcca catggctgct cccttcacac 660 tgggtaacag tgtagtatcc tgtgagagaa taaatgtatt catttaaaaa aaaaaaa 717 <210> 53 <211> 2061 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1730581CB1 <400> 53 ggctcgcaca cacttcggca cgaggaaagg caggaaaggg caggccgggt gagcagacgg 60 atcggccgac tagacagcca accagcaaca acgaactgag ctcgcatact accgcttacg 120 catctaacca accgcccatc tagctaaccc gagcccctcc accgtcaact caggttcggc 180 cggtccccgg cccgcctgcc ggagccgtgg tggcagcccc gggaggagca ctggcgtctg 240 tttccttcga ttctcgggat tcgaagatgg ctgcacagtc agcgccgaaa gttgtgctaa 300 aaagcaccac caagatgtct ctaaatgagc gctttactaa tatgctgaag aacaaacagc 360 cgacgccagt gaatattcgg gcttcgatgc agcaacaaca gcagctagcc agtgccagaa 420 acagaagact ggcccagcag atggagaata gaccctctgt ccaggcagca ttaaaactta 480 agcagaagag cttaaagcag cgcctgggta agagtaacat ccaggcacgg ttaggccgac 540 ccataggggc cctggccagg ggagcaatcg gaggacgagg cctacccata atccagagag 600 gcttgcccag aggaggacta cgtgggggac gtgccaccag aaccctactt aggggcggga 660 tgtcactccg aggtcaaaac ctgctccgag gtggacgagc cgtagctccc cgaatgggct 720 taagaagagg tggtgttcga ggtcgtggag gtcctgggag agggggccta gggcgtggag 780 ctatgggtcg tggcggaatc ggtggtagag gtcggggtat gataggtcgg ggaagagggg 840 gctttggagg ccgaggccga ggccgtggac gagggagagg tgcccttgct cgccctgtat 900 tgaccaagga gcagctggac aaccaattgg atgcatatat gtcgaaaaca aaaggacacc 960 tggatgctga gttggatgcc tacatggcgc agacagatcc cgaaaccaat gattgaagcc 1020 tgcccatcct cccatgagag actcttgtta gtcaacacat ctgtaaataa ccttgagata 1080 acagatgaga agaaatctga ttgatgctgg atggacctat cacaataggc tgtggactta 1140 cttgccacca gcttgtgcat ttagtgtgtt ccttttactt tttgatactg tgttgtatga 1200 aacccttttg tcctttgatt tggttttttg tttttgtttt tttagggggg agggggggtt 1260 tcccctcctt tgcccagact tctctttgaa cacaaatgca ttagccttgt ggctagaaca 1320 ccctcttcct acctctgtct cccctcactt gtcatatgct ctgacatgct aacatttctt 1380 ttgttcatcc ctgttgcccc cacagaaaca tcccagaaaa accggtcagt gttccttcct 1440 ccctgatcct taggtttctg aaatagggtt ctgttacatc ctcttcgata gcctgtttaa 1500 aatgtttaga aggtctggag ctcaaaaatg cgttcttcca cattgataat ttagtaaact 1560 gagaacattg acatcactac agggcagcat aagaggttgc ttacatgtgg tagcagctct 1620 ggtttgattc aagttgctac catgtacatt gacagcacat ataccataac cagcgtgttg 1680 ggttgaattg cactttctac ctttgtatga gatttacaga ctttccttct gggtttgtat 1740 catgaccaga ggggtactat agggttggtt tatactgcaa tatagaggat cagaagccat 1800 ttgatttggt aggtgtgtca gaagggagaa tgatggcaga cgaactgctg gaagaggtca 1860 gaagatagcc atgctaaaat gcaattatat cctcatgttt atcccaaact aatcttggac 1920 ttttccactc attagctttg ttttgccctt gtttcccttg aaggtttaag ttcaaccata 1980 ttctgtcaac tgttcagttt cagtggaatc ttgtatttct ggttcattat aacaaactgt 2040 tcgcttaaaa aaaaaaaaaa a 2061 <210> 54 <211> 1307 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1740714CB1 <220>
<221> unsure <222> 1301 <223> a, t, c, g, or other <400> 54 gcgctgtgac ctagaatggg cgcatgcgcc gagcggaact ggctggtttg aaaaccatgg 60 cgtgggtacc agcggagtcc gcagtggaag agttgatgcc tcggctattg ccggtagagc 120 cttgcgactt gacggaaggt ttcgatccct cggtaccccc gaggacgcct caggaatacc 180 tgaggcgggt ccagatcgaa gcagctcaat gtccagatgt tgtggtagct caaattgacc 240 caaagaagtt gaaaaggaag caaagtgtga atatttctct ttcaggatgc caacccgccc 300 ctgaaggtta ttccccaaca cttcaatggc aacagcaaca agtggcacag ttttcaactg 360 ttcgacagaa tgtgaacaaa catagaagtc actggaaatc acaacagttg gatagtaatg 420 tgacaatgcc aaaatctgaa gatgaagaag gctggaagaa attttgtctg ggtgaaaagt 480 tatgtgctga cggggctgtt ggaccagcca caaatgaaag tcctggaata gattatgtac 540 aagcaacagt aactagtgtc ttggaatatc tgagtaattg gtttggagaa agagacttta 600 ctccagaatt gggaagatgg ctttatgctt tattggcttg tcttgaaaag cctttgttac 660 ctgaggctca ttcactgatt cggcagcttg caagaaggtg ctctgaagtg aggctcttag 720 tggatagcaa agatgatgag agggttcctg ctttgaattt attaatctgc ttggttagca 780 ggtattttga ccaacgtgat ttagctgatg agccatcttg atgtagctga tctctcaggg 840 atagaagata tttctcatga aggcagccta actctgagga aaacaatgcc aattcaagta 900 cagatttcaa cacatcttca acactatgtg aagggttcac atcttaacct gtgcaattca 960 gattgatact cagaatatgg gttgatttga atatctgaaa tatcaatgga aaatcccact 1020 cagtttttga tgaacagttt gaacagtttt ctgtaatcaa gcagcttgca tagaaattgt 1080 atgatgaaat tttacatagg ttcttggtgc tgttttgttc tttttttgtt ttttgttgtt 1140 ttgttattta cttatataca tataaaattt tattgaaaat atgttttggt tactaaaatt 1200 ttgtttgact cctaacaaaa gacaatggat ggccttagca tcagaattaa aataatctgg 1260 attaaatggc aatgtgttca tagtcagcaa taaaattaaa natttta 1307 <210> 55 <211> 1357 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1850596CB1 <400> 55 ggggcgcgcg acggcgccag ctcggggcag cggaacccag agaagctgaa ggggcggtag 60 cggcggcgac ggcgacgacg acgactcccg cgcgtgtgcc cagcctcttc ccgccgcagc 120 cgcccttttc ctccctccct tacgtccccg agtgcggcag taccgcctcc ttcccagccg 180 cgcggcttcc tccagacctc tcggcgcggg tgagccctat tcccagaggc aggtggtgct 240 gaccctgtaa cccaaaggag gaaacagctg gctaagctca tcattgttac tggtgggcac 300 catgtccttg aagcttcagg caagcaatgt aaccaacaag aatgacccca agtccatcaa 360 ctctcgagtc ttcattggaa acctcaacac agctctggtg aagaaatcag atgtggagac 420 catcttctct aagtatggcc gtgtggccgg ctgttctgtg cacaagggct atgcctttgt 480 tcagtactcc aatgagcgcc atgcccgggc agctgtgctg ggagagaatg ggcgggtgct 540 ggccgggcag accctggaca tcaacatggc tggagagcct aagcctgaca gacccaaggg 600 gctaaagaga gcagcatctg ccatatacag tggctacatc tttgactatg attactaccg 660 ggacgacttc tacgacaggc tcttcgacta ccggggccgt ctgtcgcccg tgccagtgcc 720 cagggcggtc cctgtgaagc gaccccgggt cacagtccct ttggtccggc gtgtcaaaac 780 taacgtacct gtcaagctct ttgcccgctc cacagctgtc accaccagct cagccaagat 840 caagttaaag agcagtgagc tgcaggccat caagacggag ctgacacaga tcaagtccaa 900 tatcgatgcc ctgctgagcc gcttggagca gatcgctgcg gagcaaaagg ccaatccaga 960 tggcaagaag aagggtgatg gaggtggcgc cggcggcggc ggcggtggtg gtggcagcgg 1020 tggcggtggc agtggtggtg gcggtggcgg tggcagcagc cggccaccag ccccccaaga 1080 gaacacaact tctgaggcag gcctgcccca gggggaagca cggacccgag acgacggcga 1140 tgaggaaggg ctcctgacac acagcgagga agagctggaa cacagccagg acacagacgc 1200 ggatgatggg gccttgcagt aagcagcctg acaggagcaa tggccaccag caggtgaagg 1260 gcatcgctgc cccaggcctc aagccgggca cccaaccctg gatgccaccc cccagcgggt 1320 accagaggaa agctggcagc aggcgcctcc tccccca 1357 <210> 56 <211> 1749 <212> DNA
<213> Homo Sapiens <220>

<221> misc_featuxe <223> Incyte ID No: 1856109CB1 <400> 56 ctggcccgac tactttcgtt ccgtcttcca tcgttttctc tcgtgcaatg gcgtccgggc 60 tggtaagatt gctgcagcag ggacatcgct gcctcctggc tccagtcgcc cccaagctgg 120 tccctccggt tcggggagtg aagaagggat tccgcgccgc cttccgcttc cagaaggagt 180 tagagcggca gcgccttctg cggtgcccgc cgccgcccgt gcgccgttca gagaagccga 240 actgggatta ccatgcagaa atacaagctt ttggacatcg gttacaggaa aacttttcct 300 tagatcttct caaaactgca tttgttaata gctgctatat taaaagtgag gaggccaaac 360 gccaacaact tgggatagag aaagaagctg ttcttctgaa tcttaaaagt aatcaagaac 420 tatccgaaca agggacatct ttttcacaga cttgccttac acagtttctt gaagacgagt 480 acccagacat gcccactgaa ggcataaaaa atcttgttga ctttctcact ggtgaggaag 540 tcgtgtgtca cgtggctaga aacttggctg tggagcagtt aacactgagt gaagaattcc 600 cagtgccccc agctgtgtta cagcagactt tctttgcagt tattggagcc ctgttacaga 660 gcagtggacc tgagaggact gcacttttca tcagggactt cttaattact caaatgactg 720 gaaaagagct ctttgagatg tggaagataa taaatcccat ggggctattg gtagaagaac 780 tgaagaaaag gaatgtttca gctcctgaat caagacttac taggcagtct ggtggcacca 840 cagctttgcc tttgtatttt gttggcttat actgtgataa aaagttgatt gcagaaggac 900 ctggggaaac agtattggtt gcagaagaag aggctgctcg agtggccctt agaaaacttt 960 atggattcac agaaaataga cggccgtgga actattccaa gcccaaagaa accttgagag 1020 cagaaaagag catcactgcc agctagccgc catggatgca gcagcctgaa acttgagagc 2080 gaaagtgaga taaatgtcaa aggtgtttca agccagacat tttcacaatt gtgaagaaat 1140 agatgttttg tttctgtttt ttactgtgtt cccaaaatta aataaatgtt aaccaagtca 1200 cagtgttttt ggttttgttt ttctgaaatc ttggtttgat caaatctttt tttttttctc 1260 ttgagatgga gtcttactct gtcgcccagg ctggactgca gtggtgcgat ctcggctcac 1320 tgcaacctcc acctcacagg ttcaagcgat tctcgtggct cagcctccct agtagctggg 1380 attacaggca cacaccacca tacctggcta atttttgtat ttttggtaga gatggggttt 1440 caccaagttg gctagactag tcttgaactc ctgacctcag gtgatccacc cgccttggcc 1500 tcccaaagtg ctgggattac aggtgtgagc cactataccc gaccagatca aatctttttt 1560 tgacattttt gcaaaaaaat tttcctaatg ttcttgattt aattgtatag aatttgtata 1620 attaggtgta ttttatttgc ctctagcttt gaggtatcat aatttatgta tcttatgtga 1680 attttttgct gtaataccaa taaagttttt tttctccaca tgttaaaaaa aaaaaaaaaa 1740 aaaaaaaaa 1749 <210> 57 <211> 991 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1921719CB1 <400> 57 cgaaagatgg cggcgcccgt aaggcggacg ctgttagggg tggcgggggg ttggcggcgg 60 ttcgagaggc tctgggccgg cagtctaagc tctcgcagcc tggctcttgc agccgcaccc 120 tcaagcaacg gatccccatg gcgcttgttg ggcgcgttgt gcctgcagcg gccacctgta 180 gtctccaagc cgttgacccc attgcaggaa gagatggcgt ctctactgca gcagattgag 240 atagagagaa gcctgtattc agaccacgag cttcgtgctc tggatgaaaa ccagcgactg 300 gcaaagaaga aagctgacct tcatgatgaa gaagatgaac aggatatatt gctggcgcaa 360 gatttggaag atatgtggga gcagaaattt ctacagttca aacttggagc tcgcataaca 420 gaagctgatg aaaagaatga ccgaacatcc ctgaacagga agctagacag gaaccttgtc 480 ctgttagtca gagagaagtt tggagaccag gatgtttgga tactgcccca ggcagagtgg 540 cagcctgggg agacccttcg aggaacagct gaacgaaccc tggccacact ctcagaaaac 600 aacatggaag ccaagttcct aggaaatgca ccctgtgggc actacacatt caagttcccc 660 caggcaatgc ggacagagag taacctcgga gccaaggtgt tcttcttcaa agcactgcta 720 ttaactggag acttttccca ggctgggaat aagggccatc atgtgtgggt cactaaggat 780 gagctgggtg actatttgaa accaaaatac ctggcccaag ttaggaggtt tgtttcagac 840 ctctgatggg ccgagctgcc tgtggacggt gctcagacaa gtctgggatt agagcctcaa 900 ggacattgtg tgattgcctc acatttgcag gtaatatcaa gcagcaaact aaattctgag 960 aaataaacga gtctattact gaaaaaaaaa a 991 <210> 58 <211> 1188 <212> DNA
<213> Homo sapiens 43!64 <220>
<221> misc_feature <223> Incyte ID No: 2099829CB1 <400> 58 ccgtcttccg ccgcacgtgg attcagcgcg atgcccaaat ccaagcgcga caagaaagtc 60 tccttaacca aaactgccaa gaaaggcttg gaattgaaac aaaacctgat agaagagctt 120 cggaaatgtg tggacaccta caagtacctt ttcatcttct ctgtggccaa catgaggaac 180 agcaagctga aggacatccg gaacgcctgg aagcacagcc ggatgttctt tggcaaaaac 240 aaggtgatga tggtggcctt gggtcggagc ccatctgatg aatacaaaga caacctgcac 300 caggtcagca aaaggttgag gggtgaggtg ggtctcctgt tcaccaaccg cacaaaggag 360 gaggtgaatg agtggttcac gaaatacaca gaaatggact acgcccgagc tggtaacaaa 420 gcagctttca ctgtgagcct ggatccaggg cccctggagc agttccccca ctccatggag 480 ccacagctca ggcagctggg cctgcccacc gccctcaaga gaggtgtggt gactctgctg 540 tctgactacg aggtgtgcaa ggagggcgat gtgctgaccc cagagcaggc tcgcgtcctg 600 aagctttttg ggtatgagat ggctgaattc aaggtgacca tcaaatacat gtgggattca 660 cagtcgggaa ggttccagca gatgggagac gacttgccag agagcgcatc tgagtccaca 720 gaagagtcag actcagaaga tgatgactga aagggactcg ggactgaagg tctcctggaa 780 gcttctgggt ctcactggac catcaggact gctgccgccc ctctggagag agcagctttt 840 tatttgtctg tagacaggga acatgatggg cactgacctc ctgtaaagaa taaaactgtg 900 ggccgggcgc ggtggctcac gcctggaatc ccagcacttt gggaagccga ggtgggcaga 960 tcataaggtc aggagattaa gaccatcctg gctaacacgg tgaaaccccg tctctactaa 1020 aaatagaaaa aaaaactagt tgggcatagt ggcatgtgcc tgtagtccca gctactcagg 1080 aggctgaggc aggagaatca cttgaacccg ggaggtggag gttgccgtga gttgagattg 1140 gaccactgct ctccagcctg ggcaacagag taaaactctg tcccaaaa 1188 <210> 59 <211> 1454 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2416915CB1 <400> 59 gttgtcactc tctcgggttg ttactctgta gcttcccggc tcgcgaaagg gaggacctgt 60 ctgggtcatg gattttgaga atcttttctc aaaacccccc aacccggccc tcggcaaaac 120 ggccacggac tctgacgaaa gaatcgatga tgaaatagat acagaagttg aagaaacaca 180 agaagagaaa attaaactgg agtgcgagca aattcccaaa aaatttagac actctgcaat 240 atcaccaaaa agttcgctgc atagaaaatc aagaagtaag gactatgatg tatatagtga 300 taatgatatc tgcagtcagg aatcagaaga taattttgcc aaagagcttc aacagtacat 360 acaagccaga gaaatggcaa atgctgctca acctgaagaa tctacaaaga aagaaggagt 420 aaaagatacc ccacaggctg ctaaacaaaa aaataaaaat cttaaagctg gtcacaagaa 480 tggcaaacag aagaaaatga agcgaaaatg gcctggccct ggaaacaaag gatcaaatgc~540 tttgctgagg aacagcggct cacaggaaga ggatggtaaa cctaaagaga agcagcagca 600 tttgagtcag gcattcatca accaacatac agtggaacgc aagggaaaac aaatttgtaa 660 atattttctt gaaaggaaat gtattaaggg agaccagtgt aaatttgatc atgatgcaga 720 gatagaaaaa aaaaaggaaa tgtgtaagtt ttatgtacaa ggatattgta ccagaggtga 780 aaactgtctg tatttgcata atgaatatcc ttgtaagttt taccatacag gaacaaaatg 840 ttatcaggga gaatactgca agttttctca tgctccactg actcctgaaa cacaagaatt 900 gttggctaaa gttttggata ctgaaaagaa gtcatgtaaa taaaatagac ataaaaaggt 960 agcaatgtac agataaagag tactttaacg cccatgcgtg ttcaagactg ttcaagactg 1020 gtgatttgga gtagtttaca agattcctca ttcagagtgc cctcttgtgt gactggggtg 1080 atgtgcagct tccataatgg atgggacaga gagctgggat ctaatgtaca agtgaagggc 1140 ttggtcttcc ctgagacatt ccagccattg gaataggaga ggagcatata tggcagaggt 1200 gatggctggt gggtaaatgt gatagtaaat tgtagaaacc tcttctgatt gattggattt 2260 ccttaataaa atcggaagca aggttaggct gagtgagggt gagtaaagag gtagaggagg 1320 tttgaggaga gagaactgct cggaagacat tggtagatgg accataaaaa cagagttagt 1380 tctctttatg acattaaata gttttacaac atatttttaa tggttcacaa tttcatttta 1440 gggcttaaaa taaa 1454 <210> 60 <211> 1588 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2472784CB1 <400> 60 cccggacgaa gggggagagt agacagcaga accagcggcg gcggctaagc agagactgta 60 gtagcggcga cagcgacgac ggcagcgatg gctggggcgg ggccagcccc gggactcccg 120 ggtgcaggag gacccgtggt cccgggtcct ggcgctggca tcccgggcaa aagcggcgag 180 gaacgcttga aggaaatgga ggcggagatg gccctgtttg agcaggaagt tctgggggct 240 ccagtacctg gaatcccaac tgctgtgcct gcggtgccca ctgtccccac ggtccccaca 300 gtagaagcga tgcaggtccc agcggctcct gtgatccgcc caattatcgc gaccaacaca 360 taccagcagg tccagcagac tctggaggcc cgagcagctg ctgcagccac agtagttcct 420 cccatggtgg gtggccctcc ttttgtaggc cctgttggct ttggccctgg tgatcggagt 480 cacctggaca gcccagaggc tcgagaagcc atgttcctgc ggcgggcagc agccgtcccc 540 cgccctatgg ccctaccgcc ccctcaccag gccctcgtgg gcccccctct gcctgggccc 600 cctggaccac ccatgatgct gccaccaatg gctcgggctc cagggccccc gctgggctcc 660 atggctgcac tgaggccccc tctggaagag ccagcagcac cccgagagct gggcctaggc 720 ctggggttgg gcctgaaaga gaaggaagag gcagtggtgg cggcggcggc tgggctggag 780 gaggctagcg cggctgtggc cgtgggggca ggaggtgccc cagctggccc tgcagtcatt 840 gggcccagcc tgccgctggc cctggccatg ccattgcccg agcctgagcc cctgcccctc 900 ccgttggagg tcgtccgcgg cctcctgccc ccgctgcgca ttcctgaact cctgtccctg 960 cgtcctcggc cccggccccc tcggccagag ccacccccag gcctcatggc tcttgaggtc 1020 ccagagcccc tgggtgaaga caagaagaag gggaagccag agaaattgaa acggtgcatt 1080 cgcacagcgg cagggagcag ctgggaggac cccagcctgc tggagtggga tgcagatgac 1140 ttccggatct tctgtgggga tctgggcaat gaggtgaacg atgacatctt ggcacgcgcc 1200 ttcagccgct tcccatcctt ccttaaggcc aaggtgatcc gtgacaagcg cacaggcaag 1260 accaagggct acggcttcgt cagcttcaag gaccccagcg actacgtgcg cgccatgcgt 1320 gagatgaatg ggaagtatgt gggctcgcgc cccatcaagc ttcgcaagag catgtggaag 1380 gaccggaatc tggacgtggt ccgcaagaag cagaaggaaa agaagaagct gggcctgaga 1440 tagggtctgt ggccaggcac ccgctcccac ctggccgggc gctggctcct ccctcagttc 1500 tctttggaaa acccccagct gtccacccat cccctgcccc aaaaccagtt tcaataaatt 1560 tacgttcatt tccaaaaaaa aaaaaaaa 1588 <210> 61 <211> 2111 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2598981CB1 <400> 61 cgcaggcggg cctcgcgggt ccgggagcgc ggcggagacg atgcctgaga tcagagtcac 60 gcccttgggg gccggccagg acgtgggccg aagctgcatc ctggtctcca ttgcgggcaa 120 gaatgtcatg ctggactgtg gaatgcacat gggcttcaat gacgaccgac gcttccctga 180 cttctcctac atcacccaga acggccgcct aacagacttc ctggactgtg tgatcattag 240 ccacttccac ctggaccact gcggggcact cccctacttc agcgagatgg tgggctacga 300 cgggcccatc tacatgactc accccaccca ggccatctgc cccatcttgc tggaggacta 360 ccgcaagatc gccgtagaca agaagggcga ggccaacttc ttcacctccc agatgatcaa 420 agactgcatg aagaaggtgg tggctgtcca cctccaccag acggtccagg tagatgatga 480 gctggagatc aaggcctact atgcaggcca cgtgctgggg gcagccatgt tccagattaa 540 agtgggctca gagtctgtgg tctacacggg tgattataac atgaccccag accgacactt 600 aggagctgcc tggattgaca agtgccgccc caacctgctc atcacagagt ccacgtacgc 660 cacgaccatc cgtgactcca agcgctgccg ggagcgagac ttcctgaaga aagtccacga 720 gaccgtggag cgtggtggga aggtgctgat acctgtgttc gcgctgggcc gcgcccagga 780 gctctgcatc ctcctggaga ccttctggga gcgcatgaac ctgaaggtgc ccatctactt 840 ctccacgggg ctgaccgaga aggccaacca ctactacaag ctgttcatcc cctggaccaa 900 ccagaagatc cgcaagactt ttgtgcagag gaacatgttt gagttcaagc acatcaaggc 960 cttcgaccgg gcttttgctg acaacccagg accgatggtt gtgtttgcca cgccaggaat 1020 gctgcacgct gggcagtccc tgcagatctt ccggaaatgg gccggaaacg aaaagaacat 1080 ggtcatcatg cccggctact gcgtgcaggg caccgtcggc cacaagatcc tcagcgggca 1140 gcggaagctc gagatggagg ggcggcaggt gctggaggtc aagatgcagg tggagtacat 1200 gtcattcagc gcacacgcgg acgccaaggg catcatgcag ctggtgggcc aggcagagcc 1260 ggagagcgtg ctgctggtgc atggcgaggc caagaagatg gagttcctga agcagaagat 1320 cgagcaggag ctccgggtca actgctacat gccggccaat ggcgagacgg tgacgctgcc 1380 cacaagcccc agcatccccg taggcatctc gctggggctg ctgaagcggg agatggcgca 1440 ggggctgctc cctgaggcca agaagcctcg gctcctgcac ggcaccctga tcatgaagga 1500 cagcaacttc cggctggtgt cctcagagca agccctcaaa gagctgggtc tggctgagca 1560 ccagctgcgc ttcacctgcc gcgtgcacct gcatgacaca cgcaaggagc aggagacggc 2620 attgcgcgtc tacagccacc tcaagagcgt cctgaaggac cactgtgtgc agcacctccc 1680 ggacggctct gtgactgtgg agtccgtcct cctccaggcc gccgcccctt ctgaggaccc 1740 aggcaccaag gtgctgctgg tctcctggac ctaccaggac gaggagctgg ggagcttcct 1800 cacatctctg ctgaagaagg gcctccccca ggcccccagc tgaggccggc aactcaccca 1860 gccgccacct ctgccctctc ccagctggac agaccctggg cctgcacttc aggactgtgg 1920 gtgccctggg tgaacagacc ctgcaggtcc catccctggg gacagaggcc ttgtgtcacc 1980 tgcctgccca ggcagctgtt tgcagctgaa gaaacaaact ggtctccagg ctgtcttgcc 2040 tttattcctg gttagggcag gtggtcctag acagcagttt ccagtaaaag ctgaacaaaa 2100 gaaaaaaaaa a 2111 <210> 62 <211> 1155 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2738075CB1 <220>
<221> unsure <222> 1150-1155 <223> a, t, c, g, or other <400> 62 cccacgcgtc cgcccacgcg tccgcccacg cgtccggccg ggaagaagca ccgtggctgc 60 tattatctgc tctccgcgcc tgacccctcc caggactcgt gatgccaagg ccgctgcgag 120 cggctacgaa gagtcggggt tgagccccag ctgagccgag ggctcgcact cttctggtct 180 cccaggccca acccacctga agaaatgagt ggtggattgg ctccaagtaa gagcacagtg 240 tatgtatcca acttgccttt ttccctgaca aacaatgact tgtaccggat attttccaag 300 tatggcaaag ttgtaaaggt taccatcatg aaagataaag ataccaggaa gagtaaaggg 360 gttgcattta ttttattttt ggataaagac tctgcacaaa actgtaccag ggcaataaac 420 aacaaacagt tatttggtag agtgataaaa gcaagcattg ctattgacaa tggaagagca 480 gctgagttca tccgaaggcg aaactacttt gataaatcta agtgttatga atgtggggaa 540 agtggacact taagttatgc ctgtccgaaa aatatgctcg gagaacgtga gcctccaaag 600 aagaaagaaa aaaagaaaaa aaagaaagct cctgaaccag aagaagaaat tgaggaagta 660 gaagaaagtg aagatgaagg ggaggatcct gctcttgaca gcctcagtca ggccatagca 720 ttccagcaag ccaaaattga agaagaacaa aaaaaatgga aacccagttc aggagtcccc 780 tcaacatcag atgattcaag acgcccaagg ataaagaaaa gcacatattt cagtgatgag 840 gaagaactta gtgattaaaa tcttgcccca gcacagtaat aaaaatcaag atttgttagt 900 aacaatcttg aagagctaat tttaataaaa ataagaaaaa ttaatactat catgttaata 960 ctattattgt catcccaaga aaaaagatat tttaaaaatt tatttgaaaa gttcattata 1020 agggctttat tcatgcctga tttgtttaca tgaggacttc tgaaattaat ccttaaaaca 1080 aacttcctga agaccgaaaa gttgaatgat ttattgttac ttatattaat aaacttttca 1140 agagaaaaan nnnnn 1155 <210> 63 <211> 1673 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2279049CB1 <400> 63 gttttgggtc gcagtatgct agaattttga ggctcccttc tgatgaaaat tgagctgtcc 60 atgcagccat ggaacccggg ttacagcagt gagggggcca cggctcaaga aacttacaca 120 tgtccaaaaa tgattgagat ggagcaggcg gaggcccagc ttgctgagtt agacctgcta 180 gccagtatgt tccctggtga gaatgagctc atagtgaatg accagctggc tgtagcagaa 240 ctgaaagatt gtattgaaaa gaagacaatg gaggggcgat cttcaaaagt ctactttact 300 atcaatatga acctggatgt atctgacgaa aaaatggcga tgttttctct ggcctgtatt 360 cttcccttta aatacccggc agttctgcct gaaattactg tcagatcagt attattgagt 420 agatcccagc agactcagct gaacacagat ctgactgcat tcctgcaaaa acattgtcat 480 ggagatgttt gtatactgaa tgccacagag tgggttagag aacacgcctc tggctatgtc 540 agcagagata cttcatcttc acccaccaca ggaagcacag tccagtcagt tgacctcatc 600 ttcacgagac tctggatcta cagccatcat atctataaca aatgcaaaag aaagaatatt 660 ctagagtggg caaaggagct ttccctgtct gggtttagca tgcctggaaa acctggtgtt 720 gtttgtgtgg aaggcccaca aagtgcctgt gaagaattct ggtcaagact cagaaaatta 780 aactggaaga gaattttaat tcgccatcga gaagacattc cttttgatgg tacaaatgat 840 gaaacggaaa gacaaaggaa attttccatt tttgaagaaa aagtgttcag tgttaatgga 900 gccaggggaa accacatgga ctttggtcag ctctatcagt tcttaaacac caaaggatgt 960 ggggatgttt tccagatgtt ctttggtgta gaaggacaat gacatcaaga gtagttgaaa 1020 gtatcttgcc actgttggcc ttttgatttt tttttcccac tttttcttga aagattaagt 1080 aattttattt tagttccatt ctagaatgtt ggggagtggg gcacaagaaa aaatagtata 1140 gctgaaatgc atctgttaaa aatgtcatga ttgaaagcag aactgagttt caaattacaa 1200 ccttaaaatt gttgttagat atttcttcac atatcagctg cccattttga aaaagaaatt 1260 atccataaag gtaatgttgg tgctccaatt tgccagccat tcccaacccc cttctccctt 1320 acctgccttc actaaagaac ccagaaaagc taattgctcc cctttcagcc tctgttgcaa 1380 ctaacaactc tcagtggcct caggacacag ctttggcctt gggaattctg ggaaaacttt 1440 tacttcctga ttaaagatac atatgcagct aggccacctc ctccccccct tactgccata 1500 aacaccaaag tgatgactgg agctggagga gttatttgaa ccacgacgaa gggccaagag 1560 aaccacgaag atgccagttg ccacattgtt gagctgctga cccaacacca gccattgcct 1620 gtctctaaac atcttatgaa ataaaaccag ttttgtttaa aaaaaaaaaa aaa 1673 <210> 64 <211> 584 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2660904CB1 <400> 64 aaaataaggc atttgggatg ccgatgttaa aaggagaagg taatcagaga agaaaaaagg 60 aagtcggtgg agagttctgc gaagattttg aagatttcta gagaagcagg gggttctgga 120 gaagggaata gacttggcca gatacccagg aagacttcct caacagatgt cccatcatgc 180 tgagattcaa cgcgacattt tagagtcatg caaccatgtg agaaaaaaag tcccagtaac 240 ctttgttggg gctggagggc aggatcccga ggtcccggag gagctgctcc acctcctcca 300 gccaggacag cgcgtgcctc aggacgtcca gcaccacctt ctggagcccc gagacaggtg 360 ggctcacctg gaggtgctga agaaggtcga cctccttctt caggtcatgg ctgcaacagg 420 atattttcat gcaagcctgc aaagaggtga gatcatgagg agcccaggcc ctgtggccag 480 aaatagcccc tgacgtgacc ttcgaggaac agcgttcttg actctgccac gaagcaggca 540 gcgccacgta ttggccgcct tgggaggact cagttttttt cttt 584 <210> 65 <211> 978 <212> DNA
<213> Homo Sapiens <220>
<222> misc_feature <223> Incyte ID No: 3179424CB1 <400> 65 ccggctacct gttggtgtgt atgcagagca tccctgtgcc ccgcggatat agactggcgc 60 gcctctgttg cgcaggcgca gaactacaac ttcagggttt tccccaacgg cctctttttt 120 gcacgttagg agaaactaca tttcccataa tcctttgttc cagggctgga gcggctctgg 180 gctccggaat cgcccgcagc cggtactgcg ggacccactg cggatatggc tgtcttggct 240 ggatccctgt tgggccccac gagtaggtcg gcagcgttgc tgggtggcag gtggctccag 300 ccccgggcct ggctggggtt cccagacgcc tggggcctcc ccaccccgca gcaggcccgg 360 ggcaaggctc gcgggaatga gtatcagccg agcaacatca aacgcaagaa caagcacggc 420 tgggtccggc gcctgagcac gccggccggc gtgcaggtca tccttcgccg aatgctcaag 480 ggccgcaagt cgctgagcca ttgaggatcg cgacgcagtc ggcgggaccc tcatggaagc 540 atcgccctcg cctcggacct tgcctggcgc tatttttgca gggagctggg gagcaggaac 600 gcctcggacc tgagtgctct ccatattgtg gggttgaagt ctggatggga gcttgccaag 660 tcccttttta ggctttttaa ttaggaagca tttcgaacct gcgcaacaga ccaaagaaca 720 gtacaaagaa catccgtgta cccagtaccc tgactaccga ctacctacaa cccgtccctg 780 ccccatcctg agttcttttg aagctgatct caggcatcgg attatttctt ctgtaaatat 840 ttcagaatgt atctctccaa gatgagagct cattaaaaga caattacaaa gcttatcaca 900 tccaaaagaa ttatcaataa ttttgaaata ttattaaacg tgtaataaat gttcaaagtt 960 ccacttgcaa aaaaaaaa 978 <210> 66 <211> 1055 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2885096CB1 <400> 66 cagcctcaga gatggatgga tctgcaatgc catggctggg ggtgttccag ggcagcctgc 60 aggggtgggg ctggcactga ttgcaactga cagccaggag accaggcctg ggagggcagg 120 cccagggtca ggggagagcc tgagtgcttc ccacctcttc atctcagact ttgcatactg 280 ctgggaaaac tttgtgtgca atgaaggtca gccattcatg ccttggtaca aattcgatga 240 caattatgca tccctgcacc gcacgctaaa ggagattctc agaaacccga tggaggcaat 300 gtacccacac atattctact tccactttaa aaacctactg aaagcctgtg gtcggaacga 360 aagctggctg tgcttcacca tggaagttac aaagcaccac tcagctgtct tccggaagaa 420 gggcgtcttc cgaaaccagg tggatcctga gacccattgt catgcagaaa ggtgcttcct 480 ctcttggttc tgtgacgaca tactgtctcc taacacaaac tacgaggtca cctggtacac 540 atcttggagc ccttgcccag agtgtgcagg ggaggtggcc gagttcctgg ccaggcacag 600 caacgtgaat ctcaccatct tcaccgcccg cctctgctac ttctgggata cagattacca 660 ggaggggctc tgcagcctga gtcaggaagg ggcctccgtg aagatcatgg gctacaaaga 720 ttttgtatct tgttggaaaa actttgtgta cagtgatgat gagccattca agccttggaa 780 gggactacaa accaactttc gacttctgaa aagaaggcta cgggagattc tccagtgagg 840 ggtctccctg ggcctcatgg tctgtctctt ctagcctcct gctcatgctg cacgggcctc 900 ccctccatcc tgcaccagct gtgcttttgc ctggtcatcc tgagcccctc ctggcctcag 960 ggccattcca tagtgccccc ctgcctcacc acctactctc cgctctccca ggttcttcct 1020 gcagaggcct ctttctgcct ccatggctat ccatc 1055 <210> 67 <211> 2220 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2901076CB1 <400> 67 cggctccgtc gctgacgcgt cgtagacgtt ggggagcggg aaggcaacgg cagcgggatc 60 gggatgaaca gcggcggcgg cttcggtttg ggcttaggct tcggcctcac ccccacgtcg 120 gtgattcagg tgacgaatct gtcgtcggcg gtgaccagcg agcagatgcg gacgcttttt 180 tccttcctag gagaaatcga ggagctgcgg ctctaccccc cggacaacgc acctcttgct 240 ttttcctcca aagtatgtta tgttaagttt cgtgatccat caagtgttgg cgtggcccag 300 catctaacta acacggtttt tattgacaga gctctgatag ttgttccttg tgcagaaggt 360 aaaatcccag aggaatccaa agccctctct ttattggctc ctgctccaac catgacaagt 420 ctgatgcctg gtgcaggatt gcttccaata ccgaccccaa atcctttgac tactcttggt 480 gtttcactta gcagtttggg agctatacca gcagcagcac tagaccccaa cattgcaaca 540 ettggagaga taccacagcc accacttatg ggaaacgtgg atccttccaa aatagatgaa 600 attaggagaa cggtttatgt tggaaatctg aattcccaga caacgacagc tgatcaacta 660 cttgaatttt ttaaacaagt tggagaagtg aagtttgtgc ggatggcagg tgatgagact 720 cagccaactc ggtttgcttt tgtggaattt gcagaccaaa attctgtacc aagggccctt 780 gcttttaatg gagttatgtt tggagacagg ccactgaaaa taaatcactc caacaatgca 840 atagtaaaac cccctgagat gacacctcag gctgcagcta aggagttaga agaagtaatg 900 aagcgagtac gagaagctca gtcatttatc tcagcagcta ttgaaccaga gtctggaaag 960 agcaatgaaa gaaaaggcgg tcgatctcgt tcccatactc gctcaaaatc caggtctagc 1020 tcaaaatccc attctagaag gaaaagatca caatcaaaac acaggagtag atcccataat 1080 agatcacgtt caagacagaa agacagacgt agatctaaga gcccacataa aaaacgctct 1140 aaatcaaggg agagacggaa gtcaaggagt cgttcgcatt cacgggacaa gagaaaagac 1200 actcgagaaa agatcaagga aaaggaaaga gtgaaagaga aagacaggga aaaggagaga 1260 gagagggaaa aggaacgtga aaaagaaaag gaacggggta aaaacaaaga ccgggacaag 1320 gaacgggaaa aggaccggga aaaagacaag gaaaaggaca gagagagaga acgggaaaaa 1380 gagcatgaga aggatcgaga caaagagaag gaaaaggaac aggacaaaga aaaggaacga 1440 gaaaaagaca gatccaaaga gatagatgaa aaaagaaaga aggataaaaa atccagaaca 1500 ccacccagga gttacaatgc atcgcgaaga tctcgtagtt ccagcaggga aaggcgtagg 1560 aggaggagca ggagttcttc cagatcgcca agaacatcaa aaaccataaa aaggaaatct 1620 tctagatctc cgtcccccag gagcagaaat aagaaggata aaaagagaga aaaagaaagg 1680 gaccacatca gtgaaagaag agagagagaa cgttcaacgt ctatgagaaa gagttctaat 1740 gatagagatg ggaaggagaa gttggagaag aacagtactt cacttaaaga gaaagagcac 1800 aataaagaac cagattcaag tgtgagcaaa gaagtagatg acaaggatgc accaaggact 1860 gaggaaaaca aaatacagca caatgggaat tgtcagctga atgaagaaaa cctctctacc 1920 aaaacagaag cagtatagga ccgacaagtg tacctctgca ctcaatgctg gaatcaaatc 1980 caaagctttt aattctctca acaagatgta aacaggaaag aaatctagtt gagcatgaag 2040 ataggatcta acagcttttc cagttgttag atgactttgt ggccatcttg ttattgagta 2100 agaaaataaa gcatggacat catgaaaata acagatgtta cccaaactca tcttctaaaa 2160 tctgtgcatt tccatggtgg ctgacacact tgtcatgtgg tctgttagtg tttgccaaga 2220 <210> 68 <211> 1890 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3074572CB1 <400> 68 ggcggtgccc ggccggggcc acgccttttc cggcccgcag cgcggcctgg gctcccgcgt 60 gtttaaaagt gcgcttgtgg ctgctgctgt cttaactcct gtgcttggcg gacagacagg 120 cgagatggcg gcggaggtgt tgccgagtgc gaggtggcag tattgtgggg cgcccgacgg 180 gagccagaga gctgtactgg tccagttctc caacgggaag ctacagagtc caggcaacat 240 gcgctttacc ttgtatgaga acaaagattc caccaacccc aggaagagga atcaacggat 300 cctggcagct gaaacagata ggctctccta tgtgggaaac aattttggga ctggagccct 360 caaatgcaac actttgtgca ggcactttgt gggaattttg aacaagacct ctggccaaat 420 ggaagtatat gatgctgaat tgttcaatat gcagccacta ttttcagatg tatcagttga 480 gagtgaactg gcgctagaga gtcagaccaa aacttacaga gaaaagatgg attcttgtat 540 tgaagccttt ggtaccacca aacagaagcg agctctgaac accaggagaa tgaacagagt 600 tggcaatgaa tctttgaatc gtgcagtggc taaagctgca gagactatca ttgatacgaa 660 gggtgtgact gctctggtca gcgatgctat ccacaatgac ttgcaagatg actccctcta 720 ccttcctccc tgctatgatg atgcagccaa gcctgaagac gtgtataaat ttgaagatct 780 tctttcccct gcggagtatg aagctcttca gagcccatct gaagctttca ggaacgtcac 840 gtcagaagaa atactgaaga tgattgagga gaacagccat tgcacctttg tcatagaagc 900 gttgaagtct ttgccatcag atgtggagag ccgagaccgc caggcccgat gcatatggtt 960 tctggatacc ctcatcaaat ttcgagctca tagggtagtt aagcggaaaa gtgctctggg 1020 acctggagtt ccccacatca tcaacaccaa actgctgaag cactttactt gcttgaccta 1080 caacaatggc agattacgga acttaatttc ggattctatg aaggcgaaga ttactgcata 2140 tgtgatcata cttgccttgc acatacatga cttccaaatt gacctgacag tgttacagag 1200 ggacttgaag ctcagtgaga aaaggatgat ggagatagcc aaagccatga ggctgaagat 2260 ctccaaaaga agggtgtctg tggccgccgg cagtgaagaa gatcacaaac tgggcaccct 1320 gtccctcccg ctgectccag cccagacctc agaccgectg gcaaagcgga ggaagattac 2380 ctagacgcat gctttccaga cagggcgttt tggctgcatc acagccactg gctggtccta 1440 ttcatttcca tttttatgta tgttttgaaa agaaaaggtc cggggatggt ggctcacacc 1500 tgaaatccca gcactttggg aggccgaggc aggaagatca ttgagctcag gagtttgaaa 1560 ccagtctgga caacataggg agaccccatc tctaccggag gaaaaaaaaa agagtcaggc 1620 ctggtggtgt gcgcctgtaa tcccagctac tcgggaggct gaggcaggac gattacttga 1680 gcttgggaaa tcaaggttgc agtgagctat gattgtgtgg ccacactcca tcctgggtca 1740 cagagtgaga ccttgtctca aaaaaagtaa cataaggaaa aaagaagcct tgctttagca 1800 caggtatgaa gccagaagcc agcatctcaa ctgtgcttgt cttatgcaga aatataaagc 1860 gatggccagg ttggacttca aaaaaaaaaa 1890 <210> 69 <211> 2893 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1437895CB1 <400> 69 aattgggctc accaggatcg tccaggataa tcttccaatc tcaagtgtgg tttattgaca 60 atcatttaca atgccgaaga gtgctgtagt gagccagcac agtgggtaac acagcaacgg 120 agaacagatg caggtttgag gaatttaact tgctaaaacc ttgaactgaa gtcttagaga 180 ttggaacata cgggtttgta taaataggct tttaagccct gtttgcaatg ggttactgat 240 aggagaaact tgcttgtgga atgtcagctg cgtgagctca ctgtcagaca agatggaaga 300 agaagggctg gagtgtccaa actcttcctc tgaaaaacgc tattttcctg aatccctgga 360 ttccagcgat ggggatgagg aagaggtttt ggcctgtgag gatttggaac ttaacccctt 420 tgatggattg ccatattcat cacgttatta taaacttctg aaagaaagag aagatcttcc 480 tatatggaaa gaaaaatact cctttatgga gaacctgctt caaaatcaaa tcgtgattgt 540 ttcaggagat gctaaatgtg gtaagagcgc tcaggttcct cagtggtgtg ctgaatattg 600 tctttccatc cactaccagc acgggggcgt gatatgcaca caggtccaca agcagactgt 660 ggtccagctc gccctgcggg tggcggatga aatggatgtt aacattggtc atgaggttgg 720 ctacgtgatc cctttcgaga actgctgtac caacgaaaca atcctgaggt attgtactga 780 tgatatgctg caaagagaaa tgatgtccaa tccttttttg ggtagctatg gggtcatcat 840 cttagatgat attcatgaaa gaagcattgc aactgatgtg ttacttggac ttcttaaaga 900 tgttttacta gcaagaccag aactgaagct cataattaac tcctcacctc acctgatcag 960 caaactcaat tcttattatg gaaacgtgcc tgtcatagaa gtgaaaaata aacaccctgt 1020 ggaggttgtg taccttagtg aggctcaaaa ggattctttt gagtctattt tacgccttat 1080 ctttgaaatt caccactcgg gtgagaaagg tgacattgta gtctttctgg cctgtgaaca 1140 agatattgag aaagtctgtg aaactgtcta tcaaggatct aacctaaacc cagatcttgg 1200 agaactggtg gttgttcctt tgtatccaaa agagaaatgt tcattgttca agccactcga 1260 tgaaacagaa aaaagatgcc aagtttatca aagaagagtg gtgttaacta ctagctctgg 1320 agagtttttg atctggagca actcagtcag atttgttatc gatgtgggtg tggaaagaag 1380 aaaggtgtac aacccgagaa taagagcaaa ctcgctcgtc atgcagccca tcagccagag 1440 ccaggcagag atacgcaagc agattcttgg ctcatcttct tcaggaaaat ttttctgcct 1500 gtacactgaa gaatttgcct ccaaagacat gacgccactg aagccagcag aaatgcagga 1560 agccaaccta acaagcatgg tgctttttat gaagaggata gacattgcgg gcctaggcca 1620 ctgtgacttc atgaacagac cagcaccaga aagtttgatg caggcattgg aagacttaga 1680 ttatctggca gcactggata atgatggaaa tctttctgaa tttggaatca tcatgtcaga 1740 gtttcctctt gatccacaac tctcgaagtc tatcttagcg tcctgtgaat ttgactgtgt 1800 agatgaagtg ctaacaatcg cagccatggt aacagctcca aattgctttt cacatgtgcc 1860 acatggagct gaagaggctg ccttgacttg ttggaagaca tttttacatc ccgaaggaga 1920 tcactttacc ctcatcagca tttacaaggc ttaccaagac acaactctga attctagcag 1980 tgagtactgt gtggaaaagt ggtgtcgtga ttacttcctc aactgttcag cactcagaat 2040 ggcagatgtt attcgagctg aactcttaga aattatcaag cgaatcgagc ttccctatgc 2200 agaacctgct tttggctcca aggaaaacac tctaaacata aagaaagctc ttctgtccgg 2160 ttactttatg cagattgctc gggatgttga tggatcaggt aactacttaa tgctgacaca 2220 taagcaggtt gctcagctgc atcccctgtc tggttactca atcaccaaga agatgccaga 2280 gtgggtcctc ttccataaat tcagcatttc tgagaacaac tacatcagga ttacctcaga 2340 aatctctcct gaactattta tgcagctggt accacaatac tatttcagta atctgcctcc 2400 tagtgaaagt aaggacattc tacagcaagt agtggatcac ctatcccctg tgtcaacaat 2460 gaataaggaa cagcaaatgt gtgagacgtg ccctgaaact gaacagagat gcactctcca 2520 gtgactcccc agcaaacaca aggtgcagca gggtcccaaa ggtagctgga tggctgaact 2580 gctggatatg ggagatacat gacgcgaaga cggatttcac atccacagga cggtcttgaa 2640 gaaaataaca ctgtgtatat tattttaaaa taaaaaatag aagtttttat tgagttcttt 2700 aaattactac tccatgcttt tcttcttctt ggaaaagttt ttaaatcaac cactcataat 2760 ttgaccaaaa ttttaaaaaa ctggtatttt gtaaatgtgt cagagacaca tgggacagaa 2820 ccctactttt tgtagaggaa cttaatctga ataaagtctg agtttttcag taaaaaaaaa 2880 aaaaaaaaaa aag 2893 <210> 70 <212> 885 <212> DNA
<213> Homo Sapiens <220>
<221> misc_teature <223> Incyte ID No: 1454656CB1 <400> 70 ccagcatgcg gcgcccatgt aacccggtcc gtgccgcaaa gcgaacggcg gccgcggcgc 60 gggccccgcg ggggttagag gtcaccatgc tgagggtcgc gtggaggacg ctgagtttga 120 ttcggacccg ggcagttacc caggtcctag tacccgggct gccgggcggt gggagcgcca 180 agtttccttt caaccagtgg ggcctgcagc ctcgaagtct cctcctccag gccgcgcgcg 240 gatatgtcgt ccggaaacca gcccagtcta ggctggatga tgacccacct ccttctacgc 300 tgctcaaaga ctaccagaat gtccctggaa ttgagaaggt tgatgatgtc gtgaaaagac 360 tcttgtcttt ggaaatggcc aacaagaagg agatgctaaa aatcaagcaa gaacagttta 420 tgaagaagat tgttgcaaac ccagaggaca ccagatccct ggaggctcga attattgcct 480 tgtctgtcaa gatccgcagt tatgaagaac acttggagaa acatcgaaag gacaaagccc 540 acaaacgcta tctgctaatg agcattgacc agaggaaaaa gatgctcaaa aacctccgta 600 acaccaacta tgatgtcttt gagaagatat gctgggggct gggaattgag tacaccttcc 660 cccctctgta ttaccgaaga gcccaccgcc gattcgtgac caagaaggct ctgtgcattc 720 gggttttcca ggagactcaa aagctgaaga agcgaagaag agccttaaag gctgcagcag 780 cagcccaaaa acaagcaaag cggaggaacc cagacagccc tgccaaagcc ataccaaaga 840 cactcaaaga cagccaataa attctgttca atcatttaaa aaaaa 885 <210> 71 <211> 1269 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 121130CB1 <400> 71 tcagacaagc actggacgtg gcggccattt tgttttggac accgagcagg agctggcggc 60 cgctgcagac gaaaggcagg aaagggcagg ccgggtgagc agacggatcg gccgactaga 120 cagccaacca gcaacaacga actgagctcg catactaccg cttacgcatc taaccaaccg 180 cccatctagc taacccgagc ccctccaccg tcaactcagg ttcggccggt ccccggcccg 240 cctgccggag ccgtggtggc agccccggga ggagcactgg cgtctgtttc cttcgattct 300 cgggattcga agatggctgc acagtcagcg ccgaaagttg tgctaaaaag caccaccaag 360 atgtctctaa atgagcgctt tactaatatg ctgaagaaca aacagccgac gccagtgaat 420 attcgggctt cgatgcagca acaacagcag ctagccagtg ccagaaacag aagactggcc 480 cagcagatgg agaatagacc ctctgtccag gcagcattaa aacttaagca gagcttaaag 540 cagcgcctgg gtaagagtaa catccaggca cggttaggcc gacccatagg ggccctggcc 600 aggggagcaa tcggaggacg aggcctaccc ataatccaga gaggcttgcc cagaggagga 660 ctacgtgggg gacgtgccac cagaacccta cttaggggcg ggatgtcact ccgaggtcaa 720 aacctgctcc gaggtggacg agccgtagct ccccgaatgg gcttaagaag aggtggtgtt 780 cgaggtcgtg gaggtcctgg gagagggggc ctagggcgtg gagctatggg tcgtggcgga 840 atcggtggta gaggtcgggg tatgataggt cggggaagag ggggctttgg aggccgaggc 900 cgaggccgtg gacgagggag aggtgccctt gctcgccctg tattgaccaa ggagcagctg 960 gacaaccaat tggatgcata tatgtcgaaa acaaaaggac acctggatgc tgagttggat 1020 gcctacatgg cgcagacaga tcccgaaacc aatgattgaa gcctgcccat cctcccatga 1080 gagactcttg ttagtcaaca catctgtaaa taaccttgag ataacagatg agaagaaatc 1140 tgattgatgc tggatggacc tatcacaata ggctgtggac ttacttgcca ccagcttgtg 1200 catttagtgt gttcctttta ctttttgata ctgtgttgta tgaaaccctt ttgtcctttg 1260 aaaaaaaaa 1269 <210> 72 <211> 1066 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1257715CB1 <400> 72 cggctcgagg tgaatggggg cagcatgagg ccgggcggct ttttgggcgc cggacagcgg 60 ctgagtagag ccatgagccg atgtgttttg gagcctcgcc ccccggggaa gcggtggatg 120 gtggctggcc tggggaatcc cggactgccc ggcacgcgac acagcgtggg catggcggtg 180 ctggggcagc tggcgcggcg gctgggtgtg gcggagagtt ggacgcgcga ccggcactgt 240 gccgccgacc tcgccctggc cccgctgggg gatgcccaac tggtcctgct ccggccacgg 300 cggcttatga acgccaacgg gcgcagcgtg gcccgggctg cggagctgtt tgggctgact 360 gccgaggaag tctacctggt gcatgatgag ctggacaagc ccctggggag actggctctg 420 aagctggggg gcagtgccag gggccacaat ggagtccgtt cctgcattag ctgcctcaac 480 tccaatgcaa tgccaaggct gcgggtgggt atcgggcgcc cggcgcaccc tgaggcggtt 540 caggcccatg tgctgggctg cttctcccct gctgagcagg agctgctgcc tctgttgctg 600 gatcgagcca ccgacctgat cttggaccac atccgtgagc gaagccaggg gccctcactg 660 gggccgtgac actagtggcc atggctgcct gcctgactgt agtgcccacc aacccagcca 720 ctgccacaga gctgccacgc cagccttggt atctactttt tatacaaatc tcctctagac 780 tgttccaggc tgcctgcgga ttaaagtggg ggtgactgtg actggaccag tccatttctg 840 gagtaggttc ttctctctgt gtcctacttg ggacgtaggg gaacttcagg aagactaaac 900 ttttcaagcc tttttagaga accaggggca cgcatctctc cttgggtggg ccatgggact 960 gtgactcctg gtggggacac gcagccttct gaggtctcgt ggccacagtg gagctgagca 1020 tgaccagcag ttgctgcagc atctccttgt gccatggctg gaacgt 1066 <210> 73 <211> 639 <212> DNA
<213> Homo Sapiens <220>
<222> misc_feature <223> Incyte ID No: 1342022CB1 <400> 73 ggggagacac gtgcccttgg tactatgacc actagaccag cattcatatt acaccacagt 60 gactgcttct cgagccgctc gagccgaatt cggcacgagg gagtctggag acgacgtgca 120 gaaatggcac ctcgaaaggg gaaggaaaag aaggaagaac aggtcatcag cctcggacct 180 caggtggctg aaggagagaa tgtatttggt gtctgccata tctttgcatc cttcaatgac 240 acttttgtcc atgtcactga tctttctggc aaagaaacca tctgccgtgt gactggtggg 300 atgaaggtaa aggcagaccg agatgaatcc tcaccatatg ctgctatgtt ggctgcccag 360 gatgtggccc agaggtgcaa ggagctgggt atcaccgccc tacacatcaa actccgggcc 420 acaggaggaa ataggaccaa gacccctgga cctggggccc agtcggccct cagagccctt 480 gcccgctcgg gtatgaagat cgggcggatt gaggatgtca cccccatccc ctctgacagc 540 actcgcagga aggggggtcg ccgtggtcgc cgtctgtgaa caagattcct caaaatattt 600 tctgttaata aattgccttc atgtaaaaaa aaaaaaaaa 639 <210> 74 <211> 1420 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 194704CB1 <400> 74 ggccgacgcg accatcgttt gtcgacgccg ctgccaccgc ctgcctgaga gaagtcgtcg 60 cggccgaccc cgtcgcctcc gccggctacc atgtccgccc aggcgcagat gcgggccctg 120 ctggaccagc tcatgggcac ggctcgggac ggagacgaaa ccagacagag ggtcaagttt 180 acagatgacc gtgtctgcaa gagtcacctt ctggactgct gcccccatga catcctggct 240 gggacgcgca tggatttagg agaatgtacc aaaatccacg acttggccct ccgagcagat 300 tatgagattg caagtaaaga aagagacctg ttttttgaat tagatgcaat ggatcacttg 360 gagtccttta ttgctgaatg tgatcggaga actgagctcg ccaagaagcg gctggcagaa 420 acacaggagg aaatcagtgc ggaagtttct gcaaaggcag aaaaagtaca tgagttaaat 480 gaagaaatag gaaaactcct tgctaaagcc gaacagctag gggctgaagg taatgtggat 540 gaatcccaga'agattcttat ggaagtggaa aaagttcgtg cgaagaaaaa agaagctgag 600 gaagaataca gaaattccat gcctgcatcc agttttcagc agcaaaagct gcgtgtctgc 660 gaggtctgtt cagcctacct tggtctccat gacaatgacc gtcgcctggc agaccacttc 720 ggtggcaagt tacacttggg gttcattcag atccgagaga agcttgatca gttgaggaaa 780 actgtcgctg aaaagcagga gaagagaaat caggatcgct tgaggaggag agaggagagg 840 gaacgggagg agcgtctgag caggaggtcg ggatcaagaa ccagagatcg caggaggtca 900 cgctcccggg atcggcgtcg gaggcggtca agatctacct cccgagagcg acggaaattg 960 tcccggtccc ggtcccgaga tagacatcgg cgccaccgca gccgttcccg gagccacagc 1020 cggggacatc gtcgggcttc ccgggaccga agtgcgaaat acaagttctc cagagagcgg 1080 gcatccagag aggagtcctg ggagagcggg cggagcgagc gagggccccc ggactggagg 1140 cttgagagct ccaacgggaa gatggcttca cggaggtcag aagagaagga ggccggcgag 1200 atctgaaccc gtctcccggg tgctgtaaat agtctgataa acgttcacac agtctaaaat 1260 taccctttat atttgctgaa tacaactcat cttttgtagt ttaaaatttc tattgttttg 1320 gagctagctg tgagtttcta gaagtgtaca gagttgctcc tgtgttcccg ggtcatgttg 1380 agtaggaata aataaatctg atgctgccaa aaaaaaaaaa 1420 <210> 75 <211> 1457 <212> DNA
<213> Homo Sapiens <220>
<221> mist feature <223> Incyte ID No: 607270CB2 <400> 75 gcgccattag cgcctgcgcc gtctctaggc cccgccccct cacccctccg gtcctggagc 60 tcccacagct aacatggcgg cgccctgtgt gtcctacggc ggagcagttt cgtaccggct 120 tcttctctgg ggtaggggta gcctcgcccg gaagcaaggc ctctggaaaa ccgcggcccc 180 tgagttgcaa acaaatgtca gatcccagat attaaggcta agacatactg catttgtaat 240 accaaagaaa aacgttceta cctcaaaacg tgaaacttac acagaggatt ttattaaaaa 300 gcagattgaa gagttcaaca taggaaagag acatttagcc aacatgatgg gagaagatcc 360 agaaactttc actcaagaag atattgacag agctattgct taccttttcc caagtggttt 420 gtttgagaaa cgagccaggc cagtaatgaa gcatcctgaa cagatttttc caagacaaag 480 agcaatccag tggggagaag atggccgtcc atttcactat ctcttctata ctggcaaaca 540 gtcatactat tcattaatgc atgatgtata tggaatgtta ctcaatttag aaaaacatca 600 aagtcacttg caagccaaaa gtctgctccc agaaaaaact gtaaccagag acgtgattgg 660 cagcagatgg ctgattaagg aggaactaga agaaatgtta gtggaaaaac tgtcagatct 720 agattatatg cagttcattc ggctgctaga aaagttattg acatcgcagt gtggtgctgc 780 tgaggaagaa tttgtgcaga ggtttcgaag aagtgtaact cttgaatcaa aaaaacagct 840 gattgaacct gtacagtatg atgagcaagg aatggccttt agcaaaagcg aaggtaaaag 900 aaagactgca aaagcagaag caattgttta taaacatgga agtggaagaa taaaagtaaa 960 tggaattgat taccagcttt acttcccgat cacacaggac agagaacagc tgatgttccc 1020 tttccacttt gttgaccggc tgggaaagca cgacgtgacc tgcacagtct cagggggcgg 1080 gaggtcagcg caggctggag caatacgact ggcaatggca aaagccttgt gcagctttgt 1140 caccgaggac gaggtcgagt ggatgagaca agctggacta cttactactg atccacgtgt 1200 gagggaacgg aagaagccag gccaagaggg agcccgcaga. aagtttacgt ggaagaaacg 1260 ctaagggttt gctcccagga aaggagagga agagctatat atatgtgccg acatgtggca 1320 gacacacagt aaataatggc tgaccagcat gagggcagta ctgtcagaaa tttctttgag 1380 ctgtgagatg gatttatttt taaatgctac tttgtaaagg tgacctttaa aaaataaaag 1440 gaaaataaag aaaaaaa 1457 <210> 76 <211> 1184 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 758546CB1 <400> 76 caggccgtcc aggtcttggg gcgccgcggc ggaaatcgcg cggatgccag aacgcgctct 60 cagcttcggg tcctgcggct gcggctgccg ccatcatggt gcggaagctt aagttccacg 120 agcagaagct gctgaagcag gtggacttcc tgaactggga ggtcaccgac cacaacctgc 180 acgagctgcg cgtgctgcgg cgttaccggc tgcagcggcg ggaggactac acgcgctaca 240 accagctgag ccgtgccgtg cgtgagctgg cgcggcgcct gcgcgacctg cccgaacgcg 300 accagttccg cgtgcgcgct tcggccgcgc tgctggacaa gctgtatgct ctcggcttgg 360 tgcccacgcg cggttcgctg gagctctgcg acttcgtcac ggcctcgtcc ttctgccgcc 420 gccgcctccc caccgtgctc ctcaagctgc gcatggcgca gcaccttcag gctgccgtgg 480 cctttgtgga gcaagggcac gtacgcgtgg gccctgacgt ggttaccgac cccgccttcc 540 ttgtcacgcg cagcatggag gactttgtca cttgggtgga ctcgtccaag atcaagcggc 600 acgtgctaga gtacaatgag gagcgcgatg acttcgatct ggaagcctag cggatctccc 660 actttgcatg gctgtctttt acagatggga aaactgaggc ctgatgctgg agattctatg 720 agggtgctct cctcaagggt atcagacggt cgtaggttct taagaatttg attcatcagt 780 ggcaggccat gcatagagcc acgggaggtg cgtccttgtt ttccaggaaa tgttcttaga 840 acttggacta ctgattatta attgactgtg ccttgggaaa cagtgggaag taacttggtg 900 cagcactggg gtattgttgg cttcttgtgt tggaaacttt gtaatgtaaa aggaaaaact 960 ggaaatcccc acgccctgtt tccctttatc gtcttgtggt tggactggtt caattcgttt 1020 aactcgaatt cttgctcctg gccgtggtta agctgtgtac agatgatgga gagtttggcc 1080 tcaagttttt ataaactgag cgagactagt gttcaggatc tcctcccttg tttaaatgtc 1140 aataaatgcc ccaactgctt tgtaagtgca aaaaaaaaaa aaaa 1184 <210> 77 <211> 1638 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte~ID No: 866043CB1 <400> 77 atcggggatc ttgccccagc cagaggetac agtggcccgg gaaggagcct caagtcacct 60 tccccatcaa agagccttct tgttcttctc tgtggacgag ccatgttcca gccagccaca 120 tgcccctggc agctgcccgc tttaagcaag taaaactctc caggaacttt cccaagtcat 180 ctttccgtgc tcaaagtgag tctgaaaccg tagtaaaaat ggcagctctt ttcagaagaa 240 aaaatgtgag gactgtgtgg taccctatac tcccagaaga ctaagacagc ggcaggcatt 300 aagcacggag acaggcaagg gtaaagacgt ggagccacag gggccccctg cagggcgtgc 360 cccagcccct ctctacgtgg gcccgggagt gtctgagttt attcagccgt atttgaatag 420 ccattataaa gaaaccacag ttccccggaa agtgcttttc cacctgagag gccacagggg 480 ccctgtcaac accattcagt ggtgtccagt cctttctaag agccacatgc ttctctccac 540 ttctatggat aaaactttca aggtatggaa cgccgtggac tccgggcact gcctgcagac 600 ctactccctg cacacagagg cagtgcgggc cgcccggtgg gctccctgtg gccggcgcat 660 cctcagtggt ggctttgact tcgcgctgca cctaacagac cttgaaacag gaacccagct 720 atttagtggt cgaagtgact ttagaatcac taccttgaaa ttccatccaa aagaccacaa 780 catcttttta tgtggaggct tcagctctga aatgaaagct tgggatataa ggactggcaa 840 ggtgatgaga agctacaagg cgaccatcca gcagaccttg gacatcctgt tcctccggga 900 aggctccgag ttcctgagca gcacagacgc ttccacccgg gactcagctg accgcaccat 960 tattgcctgg gatttccgga cctctgccaa aatctccaac cagattttcc acgagaggtt 1020 cacctgcccc agcctcgcct tgcacccgag agagcccgtg ttcctggcac agaccaatgg 1080 caactacctg gcccttttct ccactgtgtg gccctaccgg atgagcagac ggcggcgcta 1140 tgaagggcac aaggtggagg gctactcagt gggctgcgag tgctccccag gcggtgactt 1200 gctggtgacg ggcagcgccg atggccgggt cctgatgtac agcttccgca cagccagccg 1260 agcatgcaca ctgcaggggc acacacaggc ctgtgtcggc accacctatc accccgtgct 1320 gccctccgtc ctcgccacct gctcctgggg aggggacatg aagatctggc actgagcttt 1380 ttgtcactga accttcccga tgccagctgg gctcttggac tcccctcttc ctcaagggta 1440 gatgagagga acgagcacag aggttggctg tgggtcctgg gtaccacctt ctgagcctca 1500 gtttcctcat ctgtaaagtg gggagaaaag tctgtttgcc tcaggagtgt gaggactaca 1560 ctagtgaaag cgcctggcgg gcagccggcg atgcccaata aatgtgtgtt ttgctgtttg 1620 ttaagtgaaa aaaaaaaa 1638 <210> 78 <211> 701 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 927065CB1 <400> 78 tcacgcttcg tggggcggga cgaggagaag ccaaacgtaa agacaccagg agtttctcgg 60 gcccagctgt ggctgctgcc ggggagcccc aagccttggc gggtccttgc ggcgaatagg 120 agtctggtca ggcgtcaggc tagtccgacg aagagtgggt gtgatcagca ctggaaaaga 180 tgcctgcccc tgctgccaca tatgaaagag tagtttacaa aaacccttcc gagtaccact 240 acatgaaagt ctgcctagaa tttcaagatt gtggagttgg actgaatgct gcacagttca 300 aacagctgct tatttcggct gtgaaggacc tgtttgggga ggttgatgcc gccttacctt 360 tggacatcct aacctatgaa gagaagacct tgtcagccat cttgagaata tgtagcagtg 420 gtcttgtcaa attgtggagc tctttgaccc tgttaaggat ccctattaaa ggcaaaaaat 480 gtgctttccg ggtgattcag gtttctccat ttcttcttgc attatctggt aatagtaggg 540 aactagtatt ggattgaatg aatagtcttc cattttggaa acgttcatcc actctcatat 600 ttattttttg gtgccctgca tgtttgaaga ctgaaagcag gctaaaagct cttgatgaaa 660 tttgagggtg ctgaaagatg ttcccactaa tttccagcca t 701 <210> 79 <211> 1829 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 938071CB1 <400> 79 gggttttgca gaagtaccca gaactgtgtc caaggtttcc tcagatttgg gctgttccgc 60 agcggcaggt cccgggaacc aaggcaacag acatcttcct aggctcgcga gagcgccccc 120 ttgtcccacg gctgctgggg ccccccagta gccatggctc cggtgtccgg ctcacgcagc 180 ccggataggg aggcctcggg ctcgggggga agacgtcgca gttcgtcgaa gagtccgaag 240 cccagcaaat ctgcccgctc cccgcggggc cgccgctctc gctcgcactc ttgctctcgg 300 tccggggacc ggaatggact cacccatcag ctgggtggcc tcagccaagg ctcccgaaac 360 cagtcctacc gctcacgctc gcggtcgcgt tctagagagc ggccctctgc gccccggggc 420 atccccttcg cttctgcctc ctcgtcagtc tattacggca gctactcgcg cccctacggg 480 agcgacaagc cttggcctag cctcctcgac aaggagaggg aggagagcct gcggcagaag 540 agattaagtg agagagagag aattggagaa ttgggagctc ctgaagtatg gggactttct 600 ccaaagaatc ctgaaccaga ttctgatgaa catacaccag tggaggatga agagccaaag 660 aaaagcacta cttcagcttc tacttcagaa gaagaaaaaa agaagaagtc tagccgttca 720 aaagaaaggt ccaagaaaag gagaaagaaa aaatcatcga aaagaaaaca taagaagtat 780 tctgaagata gcgacagtga ctctgattct gaaacagact ccagtgatga agataacaaa 840 aggagagcaa agaaagccaa gaaaaaggaa aagaagaaga aacacagatc gaagaaatat 900 aagaaaaaga ggtctaagaa gagcagaaaa gagtccagtg attcaagctc taaagaatcc 960 caagaagagt ttctggaaaa tccctggaag gatcgaacaa aggctgaaga accatcagat 1020 ttaattggcc cagaggctcc aaaaacactt acctctcaag atgataaacc tttgaagcat 1080 cgccgaatgg aggctgtgcg actgcgaaaa gagaaccaga tctacagtgc tgatgagaag 1140 agagcccttg catcctttaa ccaagaagag agacgaaaga gagagaacaa gattctggcc 1200 agttttcgag aaatggttta cagaaagacc aaagggaagg atgacaaata aagattttct 1260 gattgtccag aagacatttt taacaacaaa aaagaaagtc tgggttccac acatacatag 1320 aaaaagatta ttatgttctg agaaagcttt acagtgctac tgtgccttct atttaattct 1380 ttcagtcctt caataaaaag ctgcttattg atataacttt agcaagttct ttgggttatt 1440 ttggattgac catagtaact ttctggttta aaaatccaaa ttatgggctg ggcacggttg 1500 ctcacgcctg tagtctcagc ctcctgaaat gctgggattg caggtgtgag caaccgtgcc 1560 tggccgtttt tgttaaggtt atttgatctg cattattatt acatgcctat gataaatttt 1620 taattacccc tgtgtataaa agggctttcc gattatccta ttgggaaaat gcccgcttgc 1680 cttatatttt taagtggttg tttttcaaaa gtgtttaaat aagggcggcc atatttcaaa 1740 gtattggaca aaaagttttt ttaattataa tttttggaga cgggggtctc ctctgttacc 1800 caggctagag ttcagttgac cgagatctt 1829 <210> 80 <211> 2541 <222> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3295984CB1 <400> 80 caagaaagag gggaaaggat cggaaaaaga agctaaaata ctatagaaaa ccatgagatc 60 tattcgatct tttgctaatg atgatcgcca tgttatggtg aaacattcaa caatctatcc 120 atctccggag gaacttgaag ctgttcagaa tatggtatct actgttgaat gtgctcttaa 180 acatgtctca gattggttgg atgaaacaaa taaaggcaca aaaacagagg gtgagacaga 240 agtgaagaaa gatgaggccg gagaaaacta ttccaaggat caaggtggtc ggacattgtg 300 tggtgtaatg aggattggcc tggttgcaaa aggcttgctg attaaagatg atatggactt 360 ggagctggtt ttaatgtgca aagacaaacc cacagagacc ctgttaaata cagtcaaaga 420 taatcttcct attcagattc agaaactcac agaagagaaa tatcaagtgg aacaatgtgt 480 aaatgaggca tctattataa ttcggaatac aaaagagccc acgctaactt tgaaggtgat 540 acttacctca cctctaatta gggacgaatt ggagaagaag gatggagaaa atgtttcgat 600 gaaagatcct ccggacttat tggacaggca gaaatgcctg aacgccttgg cgtctcttcg 660 acatgccaaa tggtttcagg caagggcaaa tggattaaaa tcatgtgtaa ttgtcctccg 720 cattctgcgt gatttgtgca acagagtccc cacatgggca ccattgaaag gatggccact 780 agaacttata tgtgaaaagt ctataggtac ttgtaataga cctttgggcg ctggggaggc 840 cttgagacga gtaatggagt gtttggcatc tggaatacta cttcctgggg gtcctggtct 900 tcatgatcct tgtgagcgag acccaacaga tgctctgagc tatatgacca tccagcaaaa 960 agaagatatt acccacagtg cacagcatgc actcagacta tcagcctttg gtcagattta 1020 caaagtgctg gagatggacc cccttccatc tagtaagcct tttcagaagt attcctggtc 1080 agttactgat aaagaaggtg ctgggtcttc agctctaaag aggccatttg aagatggatt 1140 aggggatgat aaagacccca acaagaagat gaaacgaaac ttaaggaaaa ttctggatag 1200 taaagcaata gaccttatga atgcactaat gaggctaaat cagatcaggc ctgggcttca 1260 gtataagctc ctatctcagt ctggccccgt tcatgcccca gtcttcacaa tgtctgtaga 1320 tgtggatggc acaacatatg aagcctcagg accatccaag aaaacagcaa aacttcacgt 1380 agcggtgaag gtattgcagg caatgggata tccaacaggc tttgatgcag atattgaatg 1440 tatgagttcc gatgaaaaat cagataatga aagtaaaaat gaaacagtgt cttcaaactc 1500 aagcaataat actggaaatt ctacaactga aacctccagt accttagagg taagaactca 1560 gggccctatc ctcacagcaa gtggcaaaaa ccctgtaatg gagctcaatg aaaaaagaag 1620 aggtctcaag tatgaactca tctcagagac tggtggaagc catgacaagc gctttgtaat 1680 ggaggtagaa gtagatggac agaaattcag aggcgcaggt ccaaataaga aagtggcaaa 1740 ggcgagtgca gctttagctg ccttggagaa actgttttct ggacccaatg cggcaaataa 1800 taagaaaaag aagattatcc ctcaggcaaa gggcgttgtg aatacagctg tgtctgcagc 1860 agtccaagct gttcggggca gaggaagagg aactctaaca aggggagctt ttgttggggc 1920 gacagctgct cctggctaca tagctccagg ctatggaaca ccatatggtt acagcacagc 1980 tgcccctgcc tatggtttac ccaagagaat ggttctgtta cccgttatga aatttccaac 2040 atatcctgtt ccccactact cattctttta gcaaatgaca gaagctaatt cctattgaac 2100 aacaatacag tacaacacag aatgttagag aaaaagcctt tttatcctgc tttctttgaa 2160 cacatacttg atcaaaatta tttgtaaaga acatctttcc tactttttga ttttaacaaa 2220 tgcaaattta gttctctaaa acttgaaaaa aaaaaaagaa accagttctg tgaaaacggt 2280 acctcatttc tggaaaataa cttataccag cccttctgtt ctagggaaat aaaagtctag 2340 cagttcaaag tttaagtttt aagagacgta tcagattatg taaaattaaa tttgtgaagg 2400 atgtatagag tctcaaacac tgatcacaaa taaactgctt tgttgtaaca cagagtactg 2460 cctggttcct gatgcagtca ctgattctta gttgattgat atgtatttgc cccagggcac 2520 tttaatttgg gctgtagtta t 2541 <210> 81 <211> 1647 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4545237CB1 <400> 81 gtccgcggtc ggccgggctc cgcctgcagt gtggcccgtc cggacagtcc ctcaccccgg 60 cctgcgctgc tgcgtggact cgggcctcag gaattccgct gcggcccaag gcttgccgtt 120 tgacgaggag cagtcgcggt aggcggtggg caaggctgcc ctgggcggag gccgaggcgc 180 ggctcggact ccagcatggc gaccgcggtg cgcgctgtgg gctgcctccc cgtgctgtgt 240 agcgggacgg caggtcattt attggggagg cagtgttccc taaacacctt accagcagct 300 tccattttgg catggaagag tgttctcggc aatggccatt tgtcatcact gggaaccaga 360 gacacccatc cctacgccag cttgagccgt gcactgcaga cacaatgctg tatttcttct 420 cccagtcacc tgatgagcca gcagtataga ccatatagtt tcttcactaa attgactgca 480 gatgagctgt ggaaaggcgc tttagcagag actggtgctg gagcaaaaaa aggaagaggc 540 aaaagaacta aaaagaagaa aagaaaggat ctgaacaggg gtcagatcat tggtgaaggg 600 cgttatggtt ttctatggcc cggactgaat gtccctctta tgaaaaatgg agcagtgcag 660 accattgccc aaagaagcaa ggaagagcag gagaaggtgg aggcagacat gatccagcag 720 agagaagagt gggaccgaaa gaagaagatg aaggttaaac gggagcgagg atggagtgga 780 aactcatggg gaggcatcag tcttggcccc cctgaccctg gtccctgtgg agaaacatat 840 gaggattttg ataccaggat acttgaggta agaaacgttt tcactatgac tgcgaaagag 900 ggaagaaaga aatcgatccg tgtcttggtg gctgtgggga acggaaaagg agctgcaggt 960 ttttctattg ggaaagctac tgatcggatg gatgctttca ggaaagcaaa gaacagagca 1020 gttcaccatt tgcattatat agaacgatat gaagaccata caatattcca tgatatttca 1080 ttaagattta aaaggacgca tatcaagatg aagaaacaac ccaaaggtta cggcctccgc 1140 tgccacaggg ccatcatcac catctgccgg ctcattggca tcaaagacat gtatgccaag 1200 gtctctgggt ccattaatat gctcagcctc acccagggcc tcttccgtgg gctctccaga 1260 caggaaaccc atcaacagct ggctgataag aagggcctcc atgttgtgga aatccgggag 1320 gaatgtggcc ctctgcccat tgtggttgcg tccccccggg ggcccttgag gaaggatcca 1380 gagccagaag atgaggttcc agacgtcaaa ctggactggg aagatgtgaa gactgcacag 1440 ggaatgaagc gctctgtgtg gtctaatttg aagagagccg ccacgtaacc tctctggcct 1500 tgtgcagcca gttcctgtgc tgccctgcac ctaggagaga ctcagcccct cacagcttgg 1560 gatgttacct tgccttttgt ttgttttgag ggaagtttaa tctttaaact ctttggaaat 1620 aaataattat agctttcaaa aaaaaaa 1647 <210> 82 <211> 735 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte TD No: 4942964CB1 <220>
<221> unsure <222> 721 <223> a, t, c, g, or other <400> 82 ctcgttcctg tcgcgcagca cgacctccac ttccacatct cccccggcgt cggcgcggtc 60 agttgaacca tggcggactc caaggccacc tcggcggtca ccctccgcac ccgcaagttc 120 atgaccaacc gcctcctggc ccgcaagcaa ttcgtgcttg aggtgatcca ccccggccgc 180 gccaacgtct ccaaggcgga gttgaaggag aggcttgcca aggcgtacga ggtgaaggac 240 cccaacacca tctttgtctt caagttccgc acccacttcg gaggaggaaa gtccactggt 300 ttcggcctca tctacgacaa cctcgaggct gccaagaagt tcgagccgaa ataccgcctc 360 atcaggaatg gtcttgctac taaggttgag aagtcccgca agcaaatgaa ggagcggaag 420 aacagggcca agaagatccg tggtgtcaag aagaccaaag ctggtgacgc caagaagaag 480 taaacgttcg tttacatttg tattactgtt ctgggctctg ggtggtctag ctgcaatgtc 540 ataattatgg tcgtgttagg ttttgttcca cccttggcac tgaagtgatt ttttttgtaa 600 ttcctcggca ctgaagtgaa gttttgtctg aatattgcct cgtaacataa ttgcccggtc 660 cctgttctag ttgtggcgca gtctggtttg ttttgacatt tgtaatcgtg gttaatgtgg 720 ntggatcggt tcatg <210> 83 <211> 2614 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5702144CB1 <400> 83 gtgcgctctc acccttatct ccaaattctg ggtgttgtcg cgagggctgc tgtgtccgga 60 acttccggtt ccggtcaggg tccgcgatct cggactaagg atgcggtccc gggttctgtg 120 gggcgctgcc cggtggctct ggccccgccg ggccgttggc ccagcccgcc ggcccctgag 180 ctccggtagc ccgccgctgg aggagctgtt cacccggggc gggcccttgc ggaccttcct 240 cgagcgccag gcggggtctg aagcccattt gaaggtcagg aggcccgagt tgctggcggt 300 gatcaaactg ctgaacgaga aggagcagga gctgcgggag actgagcact tgctgcacga 360 tgagaatgaa gatttaagga aacttgcaga gaatgaaatc actttgtgtc aaaaagaaat 420 aactcagctg aagcatcaga ttatcttact tttggttccc tcagaagaaa cagatgaaaa 480 tgatttgatc ctggaagtaa ctgcaggagt tggaggtcag gaggcaatgt tgtttacatc 540 agagatattt gatatgtatc agcaatatgc tgcatttaaa agatggcatt ttgaaaccct 600 ggaatatttt ccaagtgaac taggtggcct tagacatgca tctgccagca ttgggggttc 660 agaagcctat aggcacatga aatttgaagg aggtgttcac agagtacaaa gagtgccaaa 720 gacagaaaag caaggccgca tccatactag caccatgact gtagcaatat taccccagcc 780 tactgagatt aatctggtga ttaatccgaa agatttgaga attgacacta agcgagccag 840 tggagctggg gggcagcatg taaataccac ggacagtgct gtccggatag ttcatcttcc 900 aacaggtgtt gtttctgaat gtcaacaaga gagatctcag ctgaaaaata aagagctggc 960 tatgacaaag ttacgtgcaa aactgtacag catgcatcta gaagaagaaa taaataaaag 1020 acagaatgct agaaaaattc agattggaag taaaggaaga tcagagaaaa taagaacata 1080 taattttcca cagaaccggg tcacagatca cagaataaac aagacgctgc atgatcttga 1140 aacttttatg caaggagatt atctactgga tgaacttgta cagtcattga aggaatacgc 1200 cgattatgaa tctttagtag aaattatttc ccaaaaagtt taagttgatt tgttatttat 1260 agactttcgt agcttagaaa aattctacag tacatccaca tagggtgaaa gtacccttac 1320 tetcttgaaa aacgttgagt taacacagtt ggaggtaata tgcatattct gaagtcatag 1380 ataatttaca cagatctctc tcaatgcatt agcaaaaatc atacaatata cagatggtcc 1440 tcgatttaca ttgtggttaa ttcccaataa acccatcata agttaaaaat gcatataacg 1500 ttagcaacac agcagtctcc taattaatga cagcttgact taacaatttt ccaactttac 1560 catggtgtga aagaggtatg attcctaagc cctaaggagc tcctcagctt gaaatggggc 1620 tgcatcccta taaacccatc ataaagtcaa aaaatcctaa aacataagtt ggtgaccatc 1680 tgtaatcatg atgtggtggt aaatcttgga cgctacctta caataactag acaaaggaaa 1740 atcatccttt gtcctgttct gtgtaaatat ttaatgaatg atcaaaactt cagtttaaat 1800 attatgaaaa actttaaaca taaagtagta gaaataagac agtaaatact gtatcctaat 1860 atccagtcag gatacagaaa ccataccatt aacttgaaca gggataattt taatataaaa 1920 actgttaact gataatggta ttaactttta agagggatga aagagagcta tgatgtccta 1980 ggactgagag taccccagga aagaataccc ttgaaagggt ctccccttcc ccatggtgaa 2040 gtcaggccta atggagagag tggctacagc ctactcagtg attgggaaat tccctgtctt 2100 gccctgggcc agagctggtg taccgctggt ggatcaggtc ttacaagcaa agaacctcac 2160 actcccaact ggtaagccag aagcctcttg ctagggtgtg agcaaaactt ggacaggaac 2220 tctcagtaga tgtttgtgtt tgtcaagatt ctccagacaa acttccttaa aaggattggc 2280 ttgtgttgtt attattaagt ctaacaagtc caaaagctgg agtgtgaggc aggaggctgg 2340 aaacccagga aagctgatgg tgcaaggtcc agtccaaagg tatctgttgg aggattctct 2400 tgttctggga agaggacggt ctttttttct cttcagacct tcacctgact ggatcaagcc 2460 cactaacatc gaggaggaca gtctgcatta ctcagagttc actgattgat ttaaatgtca 2520 atctcatata aaacaccctc acagaaacac ctagaataat gtttgacctt ataattggaa 2580 aatcagagca aaagttaaat ctctaaaaaa aaaa 2614 <210> 84 <211> 736 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5862945CB1 <400> 84 actcggcggc ttccgtagcg ggagggcgaa agatggcggc ggcagtactg ggacagttgg 60 gtgcgttatg gatacataac ctgaggagcc gggggaagct ggccttgggt gttttacctc 120 aatcatatat ccacacaagt gcttctcttg acatttctcg aaaatgggag aagaagaata 180 aaattgttta tcctccacaa ctgcctggag aacctcggag accagcagaa atctaccact 240 gtcgaagaca aataaaatat agcaaagaca agatgtggta tttggcaaaa ttgatacgag 300 gaatgtctat tgaccaggct ttggctcagt tggaattcaa tgacaaaaaa ggggccaaaa 360 taattaaaga ggttctctta gaagcacaag atatggcagt gagagaccat aacgtggaat 420 tcaggtccaa tttatatata gctgagtcca cctcaggacg aggccagtgc ctgaaacgca 480 tccgctacca tggcagaggt cgctttggga tcatggagaa ggtttattgc cattattttg 540 tgaagttggt ggaagggccc ccacctccac ctgagccacc aaagacggca gttgcccatg 600 ccaaagagta tattcagcag cttcgcagcc ggaccatcgt tcacactcta tgatgaggag 660 attcagactc cacagtgtat atattttgcc atttattttc taaaaataaa caaaaattga 720 aggcaaaaaa aaaaaa 736 <210> 85 <211> 1046 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6319547CB1 <400> 85 ggcgtaacgc gtcacgggcg gcctggcagc tggcggcatt gaggcggacg cgtctagagg 60 tccgtctgac cgcggcgtcg ggacctggtt tccgggcatg agctgagagc accacgccga 120 ggccacgagt atttcataga cattgatgga agcagaaacc aaaactcttc ccctggagaa 180 tgcatccatc ctttcagagg gctctctgca ggaaggacac cgattatgga ttggcaacct 240 ggaccccaaa attaccgaat accacctcct caagctcctc cagaagtttg gcaaggtaaa 300 gcagtttgac ttcctcttcc acaagtcagg tgctttggag ggacagcctc gaggctactg 360 ttttgttaac tttgaaacta agcaggaagc agagcaagcc atccagtgtc tcaatggcaa 420 gttggccctg tccaagaagc tggtggtgcg atgggcacat gctcaagtaa agagatatga 480 tcataacaag aatgataaga ttcttccaat cagtctcgag ccatcctcaa gcactgagcc 540 tactcagtct aacctaagtg tcactgcaaa gataaaagcc attgaagcaa aactgaaaat 600 gatggcggaa aatcctgatg cagagtatcc agcagcgcct gtttattcct actttaagcc 660 accagataaa aaaaggacta ctccatattc tagaacagca tggaaatctc gaagatgatg 720 gttgtgaatt actgtagcag caaaagcaaa ttggtctcca cacctaaaat cgtctgcctg 780 tgtactttgt agatgtgaat ggtactattc aacggagcac aatcacatgt tagcatttgg 840 taacataatg tttttggatg ttcttatgga tgtttcttcc ctaaactatg tatggaattg 900 agcatc.atcc agaataaata gcgttgtatc ccaaattgtg atttgaaccc tgggatgctc 960 taattggctg gttggtttgg atttgtaact ccagaaacat tctatagtgt gccagagcaa 1020 aaggcaaata cacaaaatat tatttt 1046 <210> 86 <211> 2266 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 000124CB1 <400> 86 cgcgttcacc agcccggaag tgcgcgtggc ggcggtggcg gctgcggcaa cagcggggcc 60 gatgtgtagt tggtgactgc ctctccagat gctgaggtgc ctgtatcatt ggcacaggcc 120 agtgctgaac cgtaggtgga gtaggctgtg ccttctgaag cagtatctat tcacaatgaa 180 gttgcagtct cccgaattcc agtcactttt cacagaagga ctgaagagtc tgacagaatt 240 atttgtcaaa gagaatcacg aattaagaat agcaggagga gcagtgaggg atttattaaa 300 tggagtaaag cctcaggata tagattttgc caccactgct acccctactc aaatgaagga 360 gatgtttcag tcggctggga ttcggatgat aaacaacaga ggagaaaagc acggaacaat 420 tactgccagg cttcatgaag aaaattttga gattactaca ctacggattg atgtcaccac 480 tgatggaaga catgctgagg tagaatttac aactgactgg cagaaagatg cggaacgcag 540 agatctcact ataaattcta tgtttttagg ttttgatggc actttatttg actactttaa 600 tggttatgaa gatttaaaaa ataagaaagt tagatttgtt ggacatgcta aacagagaat 660 acaagaggat tatcttagaa ttttaagata cttcaggttt tatgggagaa ttgtagacaa 720 acctggtgac catgatcctg agactttgga agcaattgca gaaaatgcaa aaggcttggc 780 tggaatatca ggagaaagga tttgggtgga actgaaaaaa attcttgttg gtaaccatgt 840 aaatcatttg attcacctta tctatgatct tgatgtggct ccttatatag gtttacctgc 900 taatgcaagt ttagaagaat ttgacaaagt cagtaaaaat gttgatggtt tttcaccaaa 960 gccagtgact cttttggcct cattattcaa agtacaagat gatgtcacaa aattggattt 1020 gaggttgaag atcgcgaaag aggagaaaaa ccttggctta tttatagtta aaaataggaa 1080 agatttaatt aaagcaacag atagttcaga cccattgaaa ccctatcaag acttcattat 1140 agattctagg gaacetgatg caactactcg tgtatgtgaa ctactgaagt accaaggaga 2200 gcactgtctc ctaaaggaaa tgcagcagtg gtccattcct ccatttcctg taagtggcca 1260 tgacatcaga aaagtgggca tttcttcagg aaaagaaatt ggggctctat tacaacagtt 1320 gcgagaacag tggaaaaaaa gtggttacca aatggaaaaa gatgaacttc tgagttacat 1380 aaagaagacc taaaactgat ggctactaaa aagcagagca tttctggtaa gactaaattt 1440 tctcccctcc ctcttaatga ggttttagag actacaccag aataaaagac agtttagggg 1500 acctctgtag aacaacaagg gtcttatttt gtgaattata tatttcaaga actaaacaga 1560 gatccacctt tctggatctg atttatatca ctgaaatgta cagttctttt ggaatagttt 1620 cacctgagaa aacatagttg gctattatct atcttaacct gttcaggctt ttaaaaaaaa 1680 ctgtttttgc atagggtagt actaagatct taaaaagtgg taactgtctt gaagaaaaaa 1740 cgtttattgt ttgtttgcaa ttgaaataac agggttacct taacaatgac tgtctatgat 1800 gtgtcagttc ttatctgaat tccaaaataa acctgtgctt aaaaaagaaa taattgacca 1860 agtaagtttg cataaaatgt gaatactaaa tgtgtcccca gttgctggca ttcatatgta 1920 caggatttgt tctagcaagc tatgcttcag tatgtggttg atatttttct gtcacaatga 1980 tttctttatg catgcagagc ctgggaaagt catgggatta acttgagggt cactattgag 2040 cctattaatt aattaattat tgttttaata aaacaaacat tggtattgga agataaatat 2100 gtttatgtgg tatctgacaa tgtgtattag gtgtcatata caatggtaat atgcctgtct 2160 ttaaagtgtt attttattaa ttaaaaggat atggctatta ttatatattc tctaaagatt 2220 tattctctaa agatttgagt cctaaatgct ttcatcacgg cacgag 2266 <210> 87 <211> 1041 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1659474CB1 <400> 87 caagcagcat ggctgcaggt tgctcagagg cgccgcggcc aacggcggct tctgatgggt 60 ctctggtagg gcaggctggc gtcctgcctt gcctagagtt gccgacttat gccgctgctt 120 gtgcgctggt gaacagtcgc tactcatgcc tggtggccgg gccgcaccaa aggcacatcg 180 cgctgtcgcc ccgctacctt aacaggaaac gcaccggcat tcgagaacag cttgatgcgg 240 agctccttcg ctattctgag agccttttag gtgtccctat tgcatatgat aacatcaaag 300 ttgtgggaga gcttggagat atttatgatg atcaaggaca cattcatctt aacattgaag 360 ccgattttgt tattttctgc cctgaaccgg ggcagaagct tatgggtata gttaataaag 420 tgtcttctag ccacattggc tgtttagtac atgggtgttt caatgcctcc attcctaaac 480 ctgagcagtt gtcagctgag cagtggcaaa ccatggagat aaacatgggt gatgaactag 540 aatttgaagt atttcgttta gactcagatg ctgctggagt attctgcatt cggggaaaac 600 taaatatcac aagtttacaa ttcaagcgct ctgaagtttc tgaagaagtt acagaaaatg 660 gcactgagga agctgctaaa aaacctaaaa agaagaaaaa gaagaaagac ccagagacat 720 atgaagtgga cagtggtacc acaaagctag cagatgatgc agatgacact ccaatggaag 780 agtcagccct gcagaatact aataatgcga atggcatctg ggaggaggag ccaaagaaaa 840 agaagaagaa gaaaaagcac caggaagttc aggaccagga ccctgttttc caaggcagtg 900 actccagtgg ttaccaaagt gaccataaaa agaaaaaaaa agaaaagaaa accaacagtg 960 aagaggccga atttacccca cctttgaaat gctcaccaaa aagaaaaggg aaaagtaatt 1020 ttctttagtg tattttaaac a 1041 <210> 88 <211> 2722 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2267892CB1 <400> 88 cgctttctgg gtaaagatgg acgtccacga tctctttcgc cggctcggcg cgggggccaa 60 attcgacacg agacgcttct cggcagacgc agctcgattc cagataggaa aaaggaaata 120 tgactttgat tcttcggagg tgcttcaggg actggacttt tttggaaaca agaagtctgt 180 cccaggtgtg tgtggagcat cacaaacaca tcagaagccc caaaatggag agaaaaaaga 240 agagagccta actgaaagga agagggagca gagcaagaaa aaaaggaaga cgatgacttc 300 agaaattgct tcccaagaag aaggtgctac tatacagtgg atgtcatctg tagaagcaaa 360 gattgaagac aaaaaagttc agagagaaag taaactaact tccggaaagt tggagaatct 420 cagaaaagaa aagataaact tcttgcggaa taaacacaaa attcacgtcc aaggaaccga 480 tcttcctgac ccaattgcta catttcagca acttgaccag gaatataaaa tcaattctcg 540 actacttcag aacattctag atgcaggttt ccaaatgcct acgccaatcc aaatgcaagc 600 catcccagtt atgctgcatg gtcgggaact tctggcttct gctccaactg gatctggaaa 660 aacattagct tttagcattc ctattttaat gcagctgaaa caacccgcaa ataaaggctt 720 cagagccctg attatatcac caacacgaga acttgccagc cagattcaca gagagttaat 780 aaaaatttct gagggaacag gattcagaat acacatgatc cacaaagcag cagtggcagc 840 caagaaattt ggacctaaat catctaaaaa gtttgatatt cttgtgacta ctccaaatcg 900 actaatctat ttattaaagc aagatccccc cggaatcgac ctagcaagtg ttgagtggct 960 tgtagtagac gaatcagata aactgtttga agatggcaaa actgggttca gagaccagct 1020 ggcttccatt ttcctggcct gcacatccca caaggtccga agagctatgt tcagtgcaac 1080 ttttgcatat gatgttgaac agtggtgcaa actcaacctg gacaatgtca tcagtgtgtc 1140 cattggagca aggaattctg cagtagaaac tgtagaacaa gagcttctct ttgttggatc 1200 tgagaccgga aaacttctgg ccatgagaga acttgttaaa aagggtttca atccacctgt 1260 tcttgttttt gttcagtcca ttgaaagggc taaagaactt tttcatgagc tcatatatga 1320 aggtattaat gtggatgtta ttcatgcaga gagaacacaa caacagagag ataacacagt 1380 ccacagtttc agagcaggaa aaatctgggt tctgatttgt acagccttgc tagcaagagg 1440 gattgatttt aaaggtgtga acttggtgat caactatgac tttccaacta gctcagtgga 1500 atatatccac aggataggtc gaactggaag agcagggaat aagggaaaag caattacatt 1560 tttcactgag gatgataagc cattattaag aagcgttgct aatgttatac agcaggctgg 1620 gtgtcctgta ccagaataca taaaaggttt tcagaaacta ctaagcaaac aaaagaaaaa 1680 gatgattaag aaaccattgg aaagggagag cattagtaca actccaaaat gtttcttaga 1740.
aaaagctaag gataaacaga aaaaggtcac tggtcagaac agcaagaaga aagtagctct 180f tgaagacaaa agttaaaaac agactttaaa aatactgtcc cagaaatgta attttatgat 1860 cccagcatga atgttatttt catggaatac ttgaagtctt acagtcacct gtaccaaaca 1920 tttgaaatca actacaagta catgggactg gtgataaatg atcctaaact atcaagtcag 1980 tttcaatttg taggtgcctt ttttttttcc tgtagagatg agggtcttgc catgttgtcc 2040 aggctggtct tgaactcctg acctcacaca atcctcctgc cttagcctcc tgagtaactg 2100 agattacagg cacaagctgc tgcacccagc tctgtaggtg acttttaaat gattatacaa 2160 tggaaataac attcattgac atttctgtgg tttgaatcca gagagatact tcttatagaa 2220 aaacaaatgt ttatgctaaa aataacacca aaatgtggtg aactcttaag gacttttccc 2280 ttcaagtgtg aaggaaggtg tgatgaatgc tgtggagagg catctggaac agaaattcaa 2340 aataaagcct tgacattaaa taccccttcc actgctcact ttgtggatgg tagcatgagc 2400 tgtctaccaa gaagaaacct gctgctctct taattttaat atttcctaat ttgttgatgg 2460 ccttttgtgt tgtgaaccac aacaaagaga ggcctctttt gtggctggtt attccagttc 2520 cctgggattt taaattcttt ggtctattaa gtatccttgt attggatacg taatacctta 2580 gtgctgtcat aatgttgtac aagatcatga tcagcttctc cctttcttca ttttctgtga 2640 tttaaccatg ttctttcctg tctctttcca tttaagatat tttatttgaa tactgataaa 2700 cattttatcc cccccctttg gg 2722 <210> 89 <211> 1287 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2670307CB1 <400> 89 ccaagagtct aggtaagagt ttgttcccgt ggtgcggagg gtcaaggccc acacccggaa 60 acctagcgag gtaaagttgc gtcttggttg tagagacgac aacttctccg cttcctcggc 120 gatggcggcg tccgggagcg gtatggccca gaaaacctgg gaactggcca acaacatgca 180 ggaagctcag agtatcgatg aaatctacaa atacgacaag aaacagcagc aagaaatcct 240 ggcggcgaag cctggactaa ggattcacca ttactttaag tactgcaaaa tctcagcatt 300 ggctctgctg aagatggtga tgcatgccag atcgggaggc aacttggaag tgatgggtct 360 gatgctagga aaggtggatg gtgaaaccat gatcattatg gacagttttg ctttgcctgt 420 ggagggcact gaaacccgag taaatgctca ggctgctgca tatgaataca tggctgcata 480 catagaaaat gcaaaacagg ttggccgcct tgaaaatgca atcgggtggt atcatagcca 540 ccctggctat ggctgctggc tttctgggat tgatgttagt actcagatgc tcaatcagca 600 gttccaggaa ccatttgtag cagtggtgat tgatccaaca agaacaatat ccgcagggaa 660 agtgaatctt ggcgccttta ggacataccc aaagggctac aaacctcctg atgaaggacc 720 ttctgagtac cagactattc cacttaataa aatagaagat tttggtgtac actgcaaaca 780 atattatgcc ttagaagtct catatttcaa atcctctttg gatcgcaaat tgcttgagct 840 gttgtggaat aaatactggg tgaatacgtt gagttcttct agcttgctta ctaatgcaga 900 ctataccact ggtcaggtct ttgatttgtc tgaaaagtta gagcagtcag aagcccagct 960 gggacgaggg agtttcatgt tgggtttaga aacgcatgac cgaaaatcag aagacaaact 1020 tgccaaagct acaagagaca gctgtaaaac taccatagaa gctatccatg gattgatgtc 1080 tcaggttatt aaggataaac tgtttaatca aattaacatc tcttaaacag tctctgagaa 1140 gtactttacc tgaaagacag tatgagaaaa atattcaagt aacactttaa aaccagttac 1200 ccaaaatctg attagaagta taaggtgctc tgaagtgtcc taaatattaa tatcctgtaa 1260 taaagctctt taaaatgaaa aaaaaaa 1287 <210> 90 <211> 2226 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte TD No: 4524210CB1 <400> 90 cggctcgagc cggaagcgac tttccgccga gaaatagggg gcgcgtgttt ggaaattgat 60 agaaaagata aagggaccga gctgctgtca gcctggctta ctgatctgcg tccgtttcac 120 cacggattca gttactaagc atttttttct ttttttggtt ctttgcaacg tgagtggcat 180 tggctcagtg atttccatga gcatctctac cagaaaacat tgcctcgatg aggtgtggtg 240 gaagcccggc agccccttct aatcggctag gcttgagaaa gcgtgtacct ctgcatttcc 300 gaaattaact cagcgtgatc ggcaagattt tcctcagcat ctggtgtcaa gacactcgtc 360 actattaatt cggaaagaaa aaaaaaaaca aaacaccgtt ttccagcatt tctctttgtg 420 gagaactaaa caacaggaaa aatgtctatt ttccctaaga tatctttgag acctgaggtt 480 gaaaactatc ttaaggaagg ctttatgaat aaggagattg tgactgcttt aggtaaacaa 540 gaagcagaaa ggaagtttga aactttgtta aagcacctgt cacatcctcc atcatttaca 600 actgtcagag tgaatacaca tttagcctca gtacaacatg tgaaaaatct gttacttgat 660 gaacttcaga agcagtttaa tggattaagt gttcctattc ttcaacatcc agaccttcaa 720 gatgtgttac ttattcctgt tattggaccc agaaagaata ttaaaaaaca acagtgtgaa 780 gccattgttg gagcccagtg tggcaatgca gttttaagag gagcccatgt ctatgcccca 840 ggaattgtgt cagcatcaca atttatgaaa gctggagatg ttatttctgt atactctgat 900 attaaaggaa aatgtaagaa aggagccaaa gaatttgatg gaacaaaagt atttcttgga 960 aatgggattt ctgaactaag ccgcaaagaa atcttcagtg gattacctga actgaaaggc 1020 atgggcataa gaatgacaga accagtatat ctcagccctt catttgacag tgtactgccc 1080 cgttacttat ttttacaaaa tttgccatct gccttagtaa gtcatgtact aaatcctcaa 1140 cctggagaga agattctaga cttgtgtgca gcacctggag ggaaaacaac acacattgca 1200 gcactaatgc atgatcaggg agaagttata gcactggata aaatcttcaa caaagtagaa 1260 aaaatcaaac agaatgcctt attgttaggg ctgaattcca tcagggcatt ttgttttgat 1320 ggaacaaagg cggttaaact tgatatggtg gaggacacag aaggagaacc tccatttcta 1380 ccagaatcct ttgaccgaat tcttctggat gcaccctgta gtggaatggg acagagacca 1440 aacatggcct gtacttggtc tgtgaaggaa gtggcatcat atcagccatt acagcgaaaa 1500 ctcttcactg cagcggttca gctgctgaag ccagagggtg tgctggttta tagcacgtgc 1560 actataacac tggccgaaaa tgaagaacag gttgcctggg ccctgacaaa atttccttgc 1620 cttcagcttc agccccagga accgcagatt ggaggagaag gaatgagggg agctgggctc 1680 tcatgtgaac agttgaaaca gctgcagcga tttgatccat cggctgtgcc attaccggac 1740 actgacatgg actctcttag agaggccaga agagaagaca tgttgcgtct ggctaataag 1800 gactctatag gtttttttat tgcaaaattt gtaaaatgca aaagcacata ggagagggat 1860 ggatgctcag aaatgaaaat tccaaacatt tgctgtctgt ggtttttttt tttttttttt 1920 taaccaaagt gttgtcaggc caactgaatg atgatgtggt tgctatggaa acagaaaagg 1980 ctgccagctg ttttaccagg gatccagaga catagaggaa gtagggggtg gtatgagatt 2040 atattttctg tttttaaaag attttttttt tttatgtatt tagtagagta taaagaaaag 2100 cagatgccta tagatgtctg gagcatattt tcatttgtga tctaatgttt taatttgtaa 2160 agtgtacaag tcatttttaa tgttaaaaat tagtgaatct aacaaaagga ataaattagc 2220 aatatt 2226 <210> 91 <211> 2362 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5584860CB1 <400> 91 cccgggtcga cccacgcgtc cgaaataaga cgccgaccgg cgcggcgcta gcctcggggc 60 ttgacgggat tgtggcggtc ctctctccca attcggaagc tacagctacc tccggacgct 120 etcaagatgg cgacctctct gggttccaac acctacaaca ggcagaactg ggaggatgcg 180 gacttcccca ttctgtgcca gacatgtctt ggagaaaacc catatatccg aatgaccaaa 240 gaaaagtatg ggaaggaatg caaaatctgt gccaggccat tcacagtgtt tcgctggtgc 300 cctggagtcc gcatgcgttt caagaagact gaagtgtgcc aaacctgcag taaattgaag 360 aatgtctgtc agacctgcct cttagaccta gagtatggcc tgcecatcca ggttcgtgac 420 gcaggattgt cttttaaaga tgacatgcca aagtcagatg tcaacaaaga gtactataca 480 cagaatatgg agagagagat ttctaactct gatggaacac ggccagttgg catgctgggg 540 aaagccacat ctaccagtga catgctgctc aaactggccc ggaccacacc ctactacaaa 600 aggaatcgac cccacatttg ctccttctgg gtgaaaggag agtgtaagag aggagaggaa 660 tgtccataca gacatgagaa gcctacagat ccagatgacc cccttgctga tcagaatatt 720 aaagaccgtt attacggaat caatgatcct gtagctgaca agcttctaaa gcgggcttca 780 acaatgcctc ggctggaccc accagaggat aaaactatca ccacactata tgttggtggt 840 ctaggtgata ccattactga gacagattta agaaatcatt tctaccagtt cggagagatc 900 cggacgatca ctgttgtgca gagacagcag tgtgctttca tccagtttgc cacacggcag 960 gctgcagaag tggctgctga gaagtccttt aataagttga ttgtaaatgg ccgcagactg 1020 aatgtgaaat ggggaagatc ccaggcagcc agaggaaaag aaaaagagaa agatggaact 1080 acagactctg ggatcaaact agaacctgtt ccaggattgc caggagctct tcctcctcct 1140 cctgcagcag aagaagaagc ctctgccaac tacttcaact tgcccccaag tggtcctcca 1200 gctgtggtga acattgctct gccaccgccc cctggcattg ctccaccccc acccccaggt 1260 tttgggccac acatgttcca cccaatggga ccaccccctc ctttcatgcg ggctccagga 1320 ccaatccact atccttctca ggaccctcag aggatgggag ctcatgctgg aaaacacagc 1380 agcccctagc accttgtcac cactctgggg ctctgtggaa gaaagggcac ttaaaactcc 1440 cagtaaatct tggaataaat atatttttcc ttcccttgta gtttccatgg tagctgaatg 1500 tgctcagatg tgagcagtca gagactgaca gccatgcttt cctatacttg ttcaaaggat 1560 cgatggaccg taaataagct gccattaaca catctggtta ctgctgtaac atgactaata 1620 aaaccgaacg cctgttcccc ttacccgtgt gggggacacg cagatgagtg aattggaatg 1680 tccagcagag ttaccctccc aattatatgt tcattttgta tattttttgg tcgggggaaa 1740 aattgacctg cagtaaaaaa acctttgacc atttttatgt ccattggata ctttcctttt 1800 tatcatctta aaaaaagata actagtacta atcattgtag tggcctaagt gtgatttaac 1860 tcttgaagtc acaccctccg aaagatgagt agaaaccagc accagcacag cccagatctt 1920 ctctttcctc tccttttcct catttattcc taaaggaatc tgaccatttt acgtctctac 1980 ggcccaaaaa aagacaaaaa taaaaattcc tttttattcc tgtcaactgg atggaaacac 2040 aaatttcatg gagctgtgta ccatcgaaga aacctggtgt ctggcatgaa attactgtaa 2100 agaacttcct gtaaaacacg ttctttaaca aactgaaatg aaaagcattg gagcgtctga 2160 atgaaagacg tgacctcctg ctgggactct gatggtcttc agcattcacc ttcgtgtgtc 2220 ttcagtgtct cattgtcatc cctgcttctg tttggtctta gagtgtttgg atataactga 2280 attgtagatg gtaaaggaaa tttgatgtgt tttttgtttt taaataatta aaacgggtca 2340 atttttcaaa aaaaaaaaaa as 2362 <210> 92 <211> 731 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5807892CB1 <400> 92 tagggcggca agcggaggag gcgtggcgag cggatcatcc gcttccggag tcgaggtttt 60 cgggcttgta ccgcttggcg gtgcggcctg gtgtcggctt gcaggttctt tctgtgtttg 120 ttctctgccc tgccaaggcc gtagagctgg tgcgtgcggg tagcggggct ctccgaggag 180 ccgcacgccg gcggcaccat ggtccacctc actactctcc tctgcaaggc ctaccgtggg 240 ggccacttaa ccatccgcct tgccctgggt ggctgcacca atcggccgtt ctaccgcatt 300 gtggctgctc acaacaagtg tcccagggat ggccgtttcg tagagcagct gggctcctat 360 gatccattgc ccaacagtca tggagaaaaa ctcgttgccc tcaacctaga caggatccgt 420 cattggattg gctgcggggc ccacctctct aagcctatgg aaaagcttct gggtcttgct 480 ggctttttcc ctctgcatcc tatgatgatc acaaatgctg agagactgcg aaggaaacgg 540 gcacgtgaag tcctgttagc ttctcagaaa acagatgcag aagctacaga tacagaggct 600 acagaaacat aaatgagctg actttagtga gcatagcagt gggaacaagg tcaaggtcct 660 tttgaaacac tgcagcgatc ttaattttgt tagatttgga gttcaataaa tggagtatcc 720 tgaaaaaaaa a 731 <210> 93 <211> 2088 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3210044CB1 <400> 93 ctttccagaa aatcaaatga aagattcaga gtatattcat gaattaattt tttttcaaaa 60 ccctaaattt aatcagctgg aattacttta aaagtgtcat tctatttaac ttttgggaat 120 gatgaatttg ccttttaata gggatgctgt attttatcat gaagatgaaa caaactgtct 180 tttgttaatt atggcacctt catttaccgc ccgcattcag ttgttcctct tgcgggcgct 240 aggctttctc ataggcttag taggccgagc agctttagtc ttagggggcc caaagtttgc 300 ctcaaagacc~cctcggccgg tgactgaacc attgcttctg ctttcgggga tgcagctggc 360 caagctgatc cgacagagaa aggtgaaatg tatagatgtt gttcaggctt atatcaacag 420 aatcaaggac gtgaacccaa tgatcaatgg aattgtcaag tacaggtttg aggaagcgat 480 gaaggaggct catgctgtag atcaaaagct tgcagagaag caggaagatg aagccaccct 540 ggaaaataaa tggcccttcc ttggggttcc tttgacagtc aaggaagctt tccagctaca 600 aggaatgccc aattcttctg gactcatgaa ccgtcgtgat gccattgcca aaacagatgc 660 cactgtggtg gcattactga agggagctgg tgccattcct cttggcataa ccaactgtag 720 tgagttgtgt atgtggtatg aatccagtaa caagatctat ggccgatcaa acaacccata 780 tgatttacag catattgtag gtggaagttc tggtggtgag ggctgcacac tggcagctgc 840 ctgctcagtt attggtgtgg gctctgatat tggtggtagc attcgaatgc ctgctttctt 900 caatggtata tttggacaca agccttctcc aggtgtggtt cccaacaaag gtcagtttcc 960 cttggctgtg ggagcccagg agttgtttct gtgcactggt cctatgtgcc gctatgctga 1020 agacctggcc cccatgttga aggtcatggc aggacctggg atcaaaaggt taaaactaga 1080 cacaaaggta catttaaaag acttaaaatt ttactggatg gaacatgatg gaggctcatt 1140 tttaatgtcc aaagtggacc aagatctcat tatgactcag aaaaaggttg tggttcacct 1200 tgaaactatt ctaggagcct cagttcaaca tgttaaactg aagaaaatga agtactcttt 1260 tcagttgtgg atcgcaatga tgtcagcaaa gggacatgat gggaaggaac ctgtgaaatt 1320 tgtagatttg cttggtgacc atgggaaaca tgtcagtcct ctgtgggagt tgatcaaatg 1380 gtgcctgggt ctgtcagtgt acaccatccc ttccattgga ctggctttgt tggaagaaaa 1440 gctcagatat agcaatgaga aataccaaaa gtttaaggca gtggaagaaa gcctgcgtaa 1500 agagctggtg gatatgctag gtgatgatgg tgtgttctta tatccctcac atcccacagt 1560 ggcacctaag catcatgtcc ctctaacacg gcctttcaac tttgcttaca caggtgtctt 1620 cagtgccctg ggtttgcctg tgacccaatg cccactggga ctgaatgcca aaggactccc 1680 tttaggcatc caggttgtgg ctggaccctt taatgatcat ctgaccctgg ctgtggccca 1740 gtacttggag aaaacttttg ggggctgggt ctgtccagga aagttttagg aggaccttct 1800 gcaaggttaa tgtgtgtgtg tgtttgtgtt cgtgtggtgg tgtttctatt aattgggtga 1860 aatcaagcac cagcagacaa gcagagaaac aactggggaa tttattgact catttagtta 1920 ttctttctac ttttatttcc ttctctaact gttggtctta ctaaaatggt aatatttgct 1980 tcttgctttt atgttactgg aaaattagga catgtaaatg gataagtgca ataaagtttc 2040 ctaaatgctg aaaaaaaaaa acacaaaaaa aacaaaaaaa aaaaaaaa 2088 <210> 94 <211> 660 <212> DNA
<213> Homo sapiens <220>
<221> misc feature <223> Incyte ID No: 4942454CB1 <400> 94 ccgtcaatag cctccgcctc tccttccagt gtccgccgtc gtgcgctcgc tacccctctc 60 cctcgaggcc tttgccggcg aagagcgccc agtcgcccac caggatgaag tttgttgctg 120 cctacctgct tgctgtcctc gctgggaact ccagcccctc tgccgaggac ttgacagcca 180 ttctggagtc agttggctgt gaagttgaca atgaaaagat ggaactcctt ctgtcccaac 240 tgagcggtaa ggacattacc gagctcattg ctgctggcag ggagaagttt gcttcagtcc 300 catgtggcgg tggcggtgtg gctgttgcgg cagctgcccc tgctgctggc ggcgctcctg 360 cagctgaggc gaagaaagaa gagaaggtgg aggagaagga agaaagtgat gacgacatgg 420 gcttcagcct cttcgactaa gcctgtgcaa tagtcaagag tattgttttt gagtcgcgga 480 agcagaggga agaaaaatcg tagtcatgtt tggactttaa ctttgtttta tgttggaaag 540 tacttgaaag acttttcctg tggtaattct aggcgtaggt tgctgtgctg gttggggttt 600 actggtgaac cagagttttt ctatctccca ctatgaattt gttacetcaa gttacctgtg 660

Claims (138)

What is claimed is:

1. An isolated polypeptide selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90%
identical to an amino acid sequence selected from the group consisting of SEQ
ID NO:1-47, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47.

2. An isolated polypeptide of claim 1 selected from the group consisting of SEQ ID NO:1-47.

3. An isolated polynucleotide encoding a polypeptide of claim 1.

4. An isolated polynucleotide encoding a polypeptide of claim 2.

5. An isolated polynucleotide of claim 4 selected from the group consisting of SEQ ID
NO:48-94.

6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim 3.

7. A cell transformed with a recombinant polynucleotide of claim 6.

8. A transgenic organism comprising a recombinant polynucleotide of claim 6.

9. A method for producing a polypeptide of claim 1, the method comprising:
a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and b) recovering the polypeptide so expressed.

10. An isolated antibody which specifically binds to a polypeptide of claim 1.

11. An isolated polynucleotide selected from the group consisting of:
a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:48-94, b) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:48-94, c) a polynucleotide complementary to a polynucleotide of a), d) a polynucleotide complementary to a polynucleotide of b), and e) an RNA equivalent of a)-d).

12. An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim 11.

13. A method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, the method comprising:
a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof.

14. A method of claim 13, wherein the probe comprises at least 60 contiguous nucleotides.

15. A method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, the method comprising:
a) amplifying said target polynucleotide or fragment thereof using polymerise chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.

16. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.

17. A composition of claim 16, wherein the polypeptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1-47.

18. A method for treating a disease or condition associated with decreased expression of functional RMEP, comprising administering to a patient in need of such treatment the composition of claim 16.

19. A method for screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising:
a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample.

20. A composition comprising an agonist compound identified by a method of claim 19 and a pharmaceutically acceptable excipient.

21. A method for treating a disease or condition associated with decreased expression of functional RMEP, comprising administering to a patient in need of such treatment a composition of claim 20.

22. A method for screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising:
a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample.

23. A composition comprising an antagonist compound identified by a method of claim 22 and a pharmaceutically acceptable excipient.

24. A method for treating a disease or condition associated with overexpression of functional RMEP, comprising administering to a patient in need of such treatment a composition of claim 23.

25. A method of screening for a compound that specifically binds to the polypeptide of claim 1, said method comprising the steps of:
a) combining the polypeptide of claim 1 with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide of claim 1 to the test compound, thereby identifying a compound that specifically binds to the polypeptide of claim 1.

26. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, said method comprising:
a) combining the polypeptide of claim 1 with at least one test compound under conditions permissive for the activity of the polypeptide of claim 1, b) assessing the activity of the polypeptide of claim 1 in the presence of the test compound, and c) comparing the activity of the polypeptide of claim 1 in the presence of the test compound with the activity of the polypeptide of claim 1 in the absence of the test compound, wherein a change in the activity of the polypeptide of claim 1 in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide of claim 1.

27. A method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence of claim 5, the method comprising:
a) exposing a sample comprising the target polynucleotide to a compound, under conditions suitable for the expression of the target polynucleotide, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

28. A method for assessing toxicity of a test compound, said method comprising:
a) treating a biological sample containing nucleic acids with the test compound;
b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 11 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 11 or fragment thereof;
c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

29. A diagnostic test for a condition or disease associated with the expression of RMEP in a biological sample comprising the steps of:
a) combining the biological sample with an antibody of claim 10, under conditions suitable for the antibody to bind the polypeptide and form an antibody:polypeptide complex; and b) detecting the complex, wherein the presence of the complex correlates with the presence of the polypeptide in the biological sample.

30. The antibody of claim 10, wherein the antibody is:
a) a chimeric antibody, b) a single chain antibody, c) a Fab fragment, d) a F(ab')2 fragment, or e) a humanized antibody.

31. A composition comprising an antibody of claim 10 and an acceptable excipient.

32. A method of diagnosing a condition or disease associated with the expression of RMEP
in a subject, comprising administering to said subject an effective amount of the composition of claim 31.

33. A composition of claim 31, wherein the antibody is labeled.

34. A method of diagnosing a condition or disease associated with the expression of RMEP
in a subject, comprising administering to said subject an effective amount of the composition of claim 33.

35. A method of preparing a polyclonal antibody with the specificity of the antibody of claim comprising:
a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, or an immunogenic fragment thereof, under conditions to elicit an antibody response;
b) isolating antibodies from said animal; and c) screening the isolated antibodies with the polypeptide, thereby identifying a polyclonal antibody which binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47.

36. An antibody produced by a method of claim 35.

37. A composition comprising the antibody of claim 36 and a suitable carrier.

38. A method of making a monoclonal antibody with the specificity of the antibody of claim comprising:
a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47, or an immunogenic fragment thereof, under conditions to elicit an antibody response;
b) isolating antibody producing cells from the animal;
c) fusing the antibody producing cells with immortalized cells to form monoclonal antibody-producing hybridoma cells;
d) culturing the hybridoma cells; and e) isolating from the culture monoclonal antibody which binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-47.

39. A monoclonal antibody produced by a method of claim 38.

40. A composition comprising the antibody of claim 39 and a suitable carrier.

41. The antibody of claim 10, wherein the antibody is produced by screening a Fab expression library.

42. The antibody of claim 10, wherein the antibody is produced by screening a recombinant immunoglobulin library.

43. A method for detecting a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47 in a sample, comprising the steps of:
a) incubating the antibody of claim 10 with a sample under conditions to allow specific binding of the antibody and the polypeptide; and b) detecting specific binding, wherein specific binding indicates the presence of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-47 in the sample.

44. A method of purifying a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47 from a sample, the method comprising:
a) incubating the antibody of claim 10 with a sample under conditions to allow specific binding of the antibody and the polypeptide; and b) separating the antibody from the sample and obtaining the purified polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-47.

45. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:1.

46. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:2.

47. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:3.

48. A polypeptide of claim 1, comprising fine amino acid sequence of SEQ ID
NO:4.

49. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:5.

50. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:6.

51. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:7.

52. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:8.

53. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:9.

54. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:10.

55. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:11.

56. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:12.

57. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:13.

58. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:14.

59. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:15.

60. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:16.

61. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:17.

62. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:18.

63. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:19.

64. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:20.

65. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:21.

66. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:22.

67. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:23.

68. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:24.

69. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:25.

70. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:26.

71. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:27.

72. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:28.

73. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:29.

74. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:30.

75. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:31.

76. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:32.

77. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:33.

78. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:34.

79. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:35.

80. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:36.

81. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:37.

82. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:38.

83. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:39.

84. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:40.

85. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:41.

86. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:42.

87. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:43.

88. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:44.

89. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:45.

90. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:46.

91. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:47.

92. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:48.

93. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:49.

94. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:50.

95. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:51.

96. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:52.

97. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:53.

98. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:54.

99. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:55.

100. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:56.

101. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:57.

102. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:58.

103. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:59.

104. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:60.

105. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:61.

106. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:62.

107. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID

NO:63.

108. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:64.

109. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:65.

110. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:66.

111. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:67.

112. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:68.

113. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:69.

114. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:70.

115. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:71.

116. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:72.

117. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:73.

118. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:74.

119. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:75.

120. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:76.

121. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:77.

122. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:78.

123. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:79.

124. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:80.

125. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:81.

126. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:82.

127. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:83.

128. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:84.

129. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:85.

130. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID

NO:86.

131. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:87.

132. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:88.

133. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:89.

134. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:90.

135. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:91.

136. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:92.

137. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:93.

138. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:94.