Note: Descriptions are shown in the official language in which they were submitted.
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NUCLEIC-ACID BINDING PROTEINS
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of nucleic-
acid binding
proteins and to the use of these sequences in the diagnosis, treatment, and
prevention of reproductive,
immune, and neurological disorders, and cell proliferative disorders including
cancer.
BACKGROUND OF THE INVENTION
Multicellular organisms are comprised of diverse cell types that differ
dramatically both in
structure and function. The identity of a cell is determined by its
characteristic pattern of gene
expression, and different cell types express overlapping but distinct sets of
genes throughout
development. Spatial and temporal regulation of gene expression is critical
for the control of cell
proliferation, cell differentiation, apoptosis, and other processes that
contribute to organismal
development. Furthermore, gene expression is regulated in response to
extracellular signals that
mediate cell-cell communication and coordinate the activities of different
cell types. Appropriate
gene regulation also ensures that cells function efficiently by expressing
only those genes whose
functions are required at a given time.
Transcriptional regulatory proteins are essential for the control of gene
expression. Some of
these proteins function as transcription factors that initiate, activate,
repress, or terminate gene
transcription. Transcription factors generally bind to promoter, enhancer, or
upstream regulatory
regions of a gene in a sequence-specific manner, although some factors bind
regulatory elements
within or downstream of the coding region. Transcription factors may bind to a
specific region of
DNA singly or as a complex with other accessory factors. (Reviewed in Lewin,
B. (1990) Genes IV,
Oxford University Press, New York, NY, pp. 554-570.)
The double helix structure and repeated sequences of DNA create topological
and chemical
features which can be recognized by transcription factors. These features
include hydrogen bond
donor and acceptor groups, hydrophobic patches, major and minor grooves, and
regular repeated
stretches of sequence which induce distinct bends in the helix. Typically,
transcription factors
recognize specific DNA sequence motifs of about 20 nucleotides in length.
Multiple adjacent
transcription factor-binding motifs may be required for gene regulation.
Many transcription factors incorporate DNA-binding structural motifs which
comprise either
a helices or f3 sheets that bind to the major groove of DNA. Four well-
characterized structural motifs
are helix-turn-helix, zinc finger, leucine zipper, and helix-loop-helix.
Proteins containing these motifs
may act alone as monomers or form homo- or heterodimers that interact with
DNA.
The helix-turn-helix motif consists of two a helices connected at a fixed
angle by a short
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chain of amino acids. One of the helices binds to the major groove. Helix-turn-
helix motifs are
exemplified by the homeobox motif which is present in homeodomain proteins.
These proteins are
critical for specifying the anterior-posterior body axis during development
and are conserved
throughout the animal kingdom. The Antennapedia and Ultrabithorax proteins of
Drosophila
S melano ag~ster are prototypical homeodomain proteins. (Pabo, C.O. and R.T.
Sauer (1992) Ann. Rev.
Biochem. 61:1053-1095.)
The zinc finger motif, which binds zinc ions, generally contains tandem
repeats of about 30
amino acids consisting of periodically spaced cysteine and histidine residues.
Examples of this
sequence pattern include the C2H2-type and the C3HC4-type zinc fingers, and
the PHD domain.
(Lewin, su ra ; Aasland, R., et al. ( 1995) Trends Biochem. Sci 20:56 - 59.)
Zinc finger proteins each
contain an a helix and an antiparallel (3 sheet whose proximity and
conformation are maintained by
the zinc ion. Contact with DNA is made by the arginine preceding the a helix
and by the second,
third, and sixth residues of the a helix. Variants of the zinc finger motif
include poorly defined
cysteine-rich motifs which bind zinc or other metal ions. These motifs may not
contain histidine
residues and are generally nonrepetitive.
The leucine zipper motif comprises a stretch of amino acids rich in leucine
which can form an
amphipathic a helix. This structure provides the basis for dimerization of two
leucine zipper proteins.
The region adjacent to the leucine zipper is usually basic, and upon protein
dimerization, is optimally
positioned for binding to the major groove. Proteins containing such motifs
are generally referred to
as bZIP transcription factors.
The helix-loop-helix motif (HLH) consists of a short a helix connected by a
loop to a longer
a helix. The loop is flexible and allows the two helices to fold back against
each other and to bind to
DNA. The transcription factor Myc contains a prototypical HLH motif.
Most transcription factors contain characteristic DNA binding motifs, and
variations on the
above motifs and new motifs have been and are currently being characterized.
(Faisst, S. and S.
Meyer (1992) Nucl. Acids Res. 20:3-26.)
Mutations in transcription factors contribute to oncogenesis. This is likely
due to the role of
transcription factors in the expression of genes involved in cell
proliferation. For example, mutations
in transcription factors encoded by proto-oncogenes, such as Fos, Jun, Myc,
Rel, and Spil, may be
oncogenic due to increased stimulation of cell proliferation. Conversely,
mutations in transcription
factors encoded by tumor suppressor genes, such as p53, RBI, and WTI, may be
oncogenic due to
decreased inhibition of cell proliferation. (Latchman, D. (1995) Gene
Regulation: A Eukaryotic
Pers~,ective, Chapman and Hall, London, UK, pp 242-255.)
Gene expression is also affected by chromatin-associated proteins. In the
nucleus, DNA is
2
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packaged into chromatin, the compact organization of which limits the
accessibility of DNA to
transcription factors and plays a key role in gene regulation. (Lewin, supra,
pp. 409-410.) The
compact structure of chromatin is determined and influenced by chromatin-
associated proteins such as
histones, high mobility group (HMG) proteins, helicases, and chromodomain
proteins. There are five
classes of histones, H 1, H2A, H2B, H3, and H4, all of which are highly basic,
low molecular weight
proteins. The fundamental unit of chromatin, the nucleosome, consists of 200
base pairs of DNA
associated with two copies each of H2A, H2B, H3, and H4. H1 links adjacent
nucleosomes. HMG
proteins are low molecular weight, non-histone proteins that may play a role
in unwinding DNA and
stabilizing single-stranded DNA. Helicases, which are DNA-dependent ATPases,
unwind DNA,
allowing access for transcription factors. Chromodomain proteins play a key
role in the formation of
highly-compacted, transcriptionally silent heterochromatin.
Much of the regulation of gene expression in eucaryotic cells occurs at the
posttranscriptional
level. Messenger RNAs (mRNA), which are produced in the cell nucleus from
primary transcripts of
protein-encoding genes, are processed and transported to the cytoplasm where
the protein synthesis
machinery is located. RNA-binding proteins are a group of proteins that
participate in the processing,
editing, transport, localization, and posttranscriptional regulation of mRNAs,
and comprise the protein
component of ribosomes as well. The RNA-binding activity of many of these
proteins is mediated by
a series of RNA-binding motifs identified within them. These domains include
the RNP motif, the
arginine-rich motif, the RGG box, and the KH motif. (Reviewed in Burd, C. G.
and Dreyfuss, G.
(1994) Science 265:615 - 621.) The RNP motif is the most widely found and best
characterized of
these motifs. The RNP motif is composed of 90-100 amino acids which form an
RNA-binding
domain and is found in one or more copies in proteins that bind pre-mRNA,
mRNA, pre-ribosomal
RNA, and small nuclear RNAs. The RNP motif is composed of two short sequences
(RNP-1 and
RNP-2) and a number of other mostly hydrophobic, conserved amino acids
interspersed throughout
the motif. (Burd, supra; ExPASy PROSITE document PDOC0030.)
Many neoplastic disorders in humans can be attributed to inappropriate gene
expression.
Malignant cell growth may result from either excessive expression of tumor
promoting genes or
insufficient expression of tumor suppressor genes. (Cleary, M.L. (1992) Cancer
Surv. 15:89-104.)
Chromosomal translocations may also produce chimeric loci which fuse the
coding sequence of one
gene with the regulatory regions of a second unrelated gene. Such an
arrangement often results in
inappropriate gene transcription. The Wilms tumor suppressor gene product,
WT1, is a protein
containing a DNA-binding domain consisting of four zinc fingers and a proline-
glutamine rich region
capable of regulating transcription. (ExPASy PROSITE document PR00049.)
Deletions of the WTl
gene, or point mutations which destroy the DNA-binding activity of the protein
are associated with
development of the pediatric nephroblastoma, Wilms tumor, and Denys-Drash
syndrome. (Rauscher,
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F.J. (1993) FASEB J. 7:896-903.)
Certain proteins enriched in glutamine are associated with various
neurological disorders
including spinocerebellar ataxia, bipolar effective disorder, schizophrenia,
and autism. (Margolis,
R.L. et al. (1997) Human Genetics 100:114-122.) These proteins contain regions
with as many as 15
or more consecutive glutamine residues and may function as transcription
factors with a potential role
in regulation of neurodevelopment or neuroplasticity.
The immune system responds to infection or trauma by activating a cascade of
events that
coordinate the progressive selection, amplification, and mobilization of
cellular defense mechanisms.
A complex and balanced program of gene activation and repression is involved
in this process.
However, hyperactivity of the immune system as a result of improper or
insufficient regulation of
gene expression may result in considerable tissue or organ damage. This damage
is well documented
in immunological responses associated with arthritis, allergens, heart attack,
stroke, and infections.
(Harrison's Principles of Internal Medicine, 13/e, McGraw Hill, Inc. and Teton
Data Systems
Software, 1996.) In particular, a zinc finger protein termed Staf50 (for
Stimulated trans-acting factor
of 50 kDa) is a transcriptional regulator and is induced in various cell lines
by interferon-I and -II.
Staf50 appears to mediate the antiviral activity of interferon by down-
regulating the viral transcription
directed by the long terminal repeat promoter region of human immunodeficiency
virus type-1 in
transfected cells. (Tissot, C. (1995) J. Biol. Chem. 270:14891-14898.)
Furthermore, the generation of multicellular organisms is based upon the
induction and
coordination of cell differentiation at the appropriate stages of development.
Central to this process is
differential gene expression, which confers the distinct identities of cells
and tissues throughout the
body. Failure to regulate gene expression during development could result in
developmental
disorders.
The discovery of new nucleic-acid binding 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 reproductive, immune, and neurological disorders,
and cell proliferative
disorders including cancer.
SUMMARY OF THE INVENTION
The invention features purified polypeptides, protnames, referred to
collectively as "ABBR"
and individually as "NuABP-1," "NuABP-2," "NuABP-3," "NuABP-4," "NuABP-5,"
"NuABP-6,"
"NuABP-7," "NuABP-8," "NuABP-9," "NuABP-10" "NuABP-11," "NuABP-12," "NuABP-
13,"
"NuABP-14," "NuABP-15," "NuABP-16," "NuABP-17," "NuABP-18," "NuABP-19," "NuABP-
20,"
"NuABP-21," ''NuABP-22," "NuABP-23," "NuABP-24," "NuABP-25," "NuABP-26,"
"NuABP-
27," "NuABP-28," "NuABP-29," "NuABP-30," "NuABP-31," "NuABP-32," "NuABP-33,"
4
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"NuABP-34," "NuABP-35," "NuABP-36," "NuABP-37," "NuABP-38," "NuABP-39," "NuABP-
40" "NuABP-41," "NuABP-42," "NuABP-43," "NuABP-44," ''NuABP-45," "NuABP-46,"
"NuABP-
47," "IVuABP-48," "NuABP-49," "NuABP-50" "NuABP-51," ''NuABP-52," "NuABP-53,"
"NuABP-
54," and "NuABP-55." In one aspect, the invention provides an isolated
polypeptide comprising a) an
amino acid sequence selected from the group consisting of SEQ ID NO:1-55, b) a
naturally occurring
amino acid sequence having at least 90% sequence identity to an amino acid
sequence selected from
the group consisting of SEQ ID NO:1-55, c) a biologically active fragment of
an amino acid sequence
selected from the group consisting of SEQ ID NO:1-55, or d) an immunogenic
fragment of an amino
acid sequence selected from the group consisting of SEQ ID NO:1-55. In one
alternative, the
invention provides an isolated polypeptide comprising the amino acid sequence
of SEQ ID NO:1-55.
The invention further provides an isolated polynucleotide encoding a
polypeptide comprising
a) an amino acid sequence selected from the group consisting of SEQ ID NO:1-
55, b) a naturally
occurring amino acid sequence having at least 90% sequence identity to an
amino acid sequence
selected from the group consisting of SEQ ID NO:1-55, c) a biologically active
fragment of an amino
acid sequence selected from the group consisting of SEQ ID NO:1-55, or d) an
immunogenic
fragment of an amino acid sequence selected from the group consisting of SEQ
ID NO:1-55. In one
alternative, the polynucleotide is selected from the group consisting of SEQ
ID N0:56-110.
Additionally, the invention provides a recombinant polynucleotide comprising a
promoter
sequence operably linked to a polynucleotide encoding a polypeptide comprising
a) an amino acid
sequence selected from the group consisting of SEQ ID NO:1-55, b) a naturally
occurring amino acid
sequence having at least 90% sequence identity to an amino acid sequence
selected from the group
consisting of SEQ ID NO:1-55, c) a biologically active fragment of an amino
acid sequence selected
from the group consisting of SEQ ID NO:1-55, or d) an immunogenic fragment of
an amino acid
sequence selected from the group consisting of SEQ ID NO:I-55. 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 comprising a)
an amino
acid sequence selected from the group consisting of SEQ ID NO:1-55, b) a
naturally occurring amino
acid sequence having at least 90% sequence identity to an amino acid sequence
selected from the
group consisting of SEQ ID NO:1-55, c) a biologically active fragment of an
amino acid sequence
selected from the group consisting of SEQ ID NO:1-55, or d) an immunogenic
fragment of an amino
acid sequence selected from the group consisting of SEQ ID NO: l-55. 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.
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Additionally, the invention provides an isolated antibody which specifically
binds to a
polypeptide comprising a) an amino acid sequence selected from the group
consisting of SEQ ID
NO:1-55, b) a naturally occurring amino acid sequence having at least 90%
sequence identity to an
amino acid sequence selected from the group consisting of SEQ ID NO:1-55, c) a
biologically active
fragment of an amino acid sequence selected from the group consisting of SEQ
ID NO:1-55, or d) an
immunogenic fragment of an amino acid sequence selected from the group
consisting of SEQ ID
NO:1-55.
The invention further provides an isolated polynucleotide comprising a) a
polynucleotide
sequence selected from the group consisting of SEQ ID N0:56-110, b) a
naturally occurring
polynucleotide sequence having at least 90% sequence identity to a
polynucleotide sequence selected
from the group consisting of SEQ ID N0:56-110, c) a polynucleotide sequence
complementary to a),
or d) a polynucleotide sequence complementary to b). 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
comprising a) a
polynucleotide sequence selected from the group consisting of SEQ ID N0:56-
110, b) a naturally
occurring polynucleotide sequence having at least 90% sequence identity to a
polynucleotide
sequence selected from the group consisting of SEQ ID N0:56-110, c) a
polynucleotide sequence
complementary to a), or d) a polynucleotide sequence complementary to b). The
method comprises a)
hybridizing the sample with a probe comprising at least 16 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, 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 30 contiguous nucleotides. In another alternative, the
probe comprises at least 60
contiguous nucleotides.
The invention further provides a pharmaceutical composition comprising an
effective amount
of a polypeptide comprising a) an amino acid sequence selected from the group
consisting of SEQ ID
NO:I-55, b) a naturally occurring amino acid sequence having at least 90%
sequence identity to an
amino acid sequence selected from the group consisting of SEQ ID NO:1-55, c) a
biologically active
fragment of an amino acid sequence selected from the group consisting of SEQ
ID NO:1-55, or d) an
immunogenic fragment of an amino acid sequence selected from the group
consisting of SEQ ID
NO:1-S5, and a pharmaceutically acceptable excipient. The invention
additionally provides a method
of treating a disease or condition associated with decreased expression of
functional NuABP,
comprising administering to a patient in need of such treatment the
pharmaceutical composition.
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The invention also provides a method for screening a compound for
effectiveness as an
agonist of a polypeptide comprising a) an amino acid sequence selected from
the group consisting of
SEQ ID NO: l-55, b) a naturally occurring amino acid sequence having at least
90% sequence identity
to an amino acid sequence selected from the group consisting of SEQ ID NO:I-
S5, c) a biologically
active fragment of an amino acid sequence selected from the group consisting
of SEQ ID NO: l-S5, or
d) an immunogenic fragment of an amino acid sequence selected from the group
consisting of SEQ
ID NO: I-55. 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
pharmaceutical 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 NuABP, comprising
administering to a patient in need of such treatment the pharmaceutical
composition.
Additionally, the invention provides a method for screening a compound for
effectiveness as
an antagonist of a polypeptide comprising a) an amino acid sequence selected
from the group
consisting of SEQ ID NO:I-55, b) a naturally occurring amino acid sequence
having at least 90%
sequence identity to an amino acid sequence selected from the group consisting
of SEQ ID NO:I-S5,
c) a biologically active fragment of an amino acid sequence selected from the
group consisting of
SEQ ID NO:1-55, or d) an immunogenic fragment of an amino acid sequence
selected from the group
consisting of SEQ ID NO:1-55. 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 pharmaceutical 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
NuABP, comprising administering to a patient in need of such treatment the
pharmaceutical
composition.
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 N0:56-110, the method
comprising a)
exposing a sample comprising the target polynucleotide to a compound, and b)
detecting altered
expression of the target polynucleotide.
BRIEF DESCRIPTION OF THE TABLES
Table 1 shows polypeptide and nucleotide sequence identification numbers (SEQ
ID NOs),
clone identification numbers (clone IDs), cDNA libraries, and cDNA fragments
used to assemble full-
length sequences encoding NuABP.
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Table 2 shows features of each polypeptide sequence, including potential
motifs. homologous
sequences, and methods, algorithms. and searchable databases used for analysis
of NuABP.
Table 3 shows selected fragments of each nucleic acid sequence: the tissue-
specific
expression patterns of each nucleic acid sequence as determined by northern
analysis; diseases,
disorders, or conditions associated with these tissues; and the vector into
which each cDNA was
cloned.
Table 4 describes the tissues used to construct the cDNA libraries from which
cDNA clones
encoding NuABP were isolated.
Table 5 shows the tools, programs, and algorithms used to analyze NuABP, 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
IS may vary. It is also to be understood that the terminology used herein is
for the purpose of describing
particular embodiments only, and is not intended to limit the scope of the
present invention which will
be limited only by the appended claims.
It must be noted that as used herein and in the appended claims, the singular
forms "a," "an,"
and "the" include plural reference unless the context clearly dictates
otherwise. Thus, for example, a
reference to "a host cell" includes a plurality of such host cells, and a
reference to ''an antibody" is a
reference to one or more antibodies and equivalents thereof known to those
skilled in the art, and so
forth.
Unless defined otherwise, all technical and scientific terms used herein have
the same
meanings as commonly understood by one of ordinary skill in the art to which
this invention belongs.
Although any machines, materials, and methods similar or equivalent to those
described herein can be
used to practice or test the present invention, the preferred machines,
materials and methods are now
described. All publications mentioned herein are cited for the purpose of
describing and disclosing
the cell lines, protocols, reagents and vectors which are reported in the
publications and which might
be used in connection with the invention. Nothing herein is to be construed as
an admission that the
invention is not entitled to antedate such disclosure by virtue of prior
invention.
DEFINITIONS
"NuABP" refers to the amino acid sequences of substantially purified NuABP
obtained from
any species, particularly a mammalian species, including bovine, ovine,
porcine, murine, equine, and
human, and from any source, whether natural, synthetic, semi-synthetic, or
recombinant.
The term "agonist" refers to a molecule which intensifies or mimics the
biological activity of
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NuABP. Agonists may include proteins, nucleic acids. carbohydrates, small
molecules, or any other
compound or composition which modulates the activity of NuABP either by
directly interacting with
NuABP or by acting on components of the biological pathway in which NuABP
participates.
An "allelic variant" is an alternative form of the gene encoding NuABP.
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 NuABP include those sequences with
deletions,
insertions, or substitutions of different nucleotides, resulting in a
polypeptide the same as NuABP or a
polypeptide with at least one functional characteristic of NuABP. Included
within this definition are
polymorphisms which may or may not be readily detectable using a particular
oligonucleotide probe
of the polynucleotide encoding NuABP, and improper or unexpected hybridization
to allelic variants,
with a locus other than the normal chromosomal locus for the polynucleotide
sequence encoding
NuABP. 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 NuABP. 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 NuABP 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 an amino acid
sequence of a naturally
occurring protein molecule, "amino acid sequence" and like terms are not meant
to limit the amino
acid sequence to the complete native amino acid sequence associated with the
recited protein
molecule.
"Amplification" relates to the production of additional copies of a nucleic
acid sequence.
Amplification is generally carried out using polymerase chain reaction (PCR)
technologies well
known in the art.
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The term "antagonist" refers to a molecule which inhibits or attenuates the
biological activity
ofNuABP. Antagonists may include proteins such as antibodies, nucleic acids,
carbohydrates, small
molecules, or any other compound or composition which modulates the activity
of NuABP either by
directly interacting with NuABP or by acting on components of the biological
pathway in which
NuABP participates.
The term ''antibody' refers to intact immunoglobulin molecules as well as to
fragments
thereof, such as Fab, F(ab')=, and Fv fragments, which are capable of binding
an epitopic determinant.
Antibodies that bind NuABP 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 containing a nucleic acid
sequence which is
complementary to the "sense" strand of a specific nucleic acid sequence.
Antisense molecules may be
produced by any method including synthesis or transcription. Once introduced
into a cell, the
complementary nucleotides combine with natural sequences produced by the cell
to form duplexes
and to block either transcription or translation. The designation ''negative"
or "minus" can refer to the
antisense strand, and the designation "positive" or "plus" can refer to the
sense strand.
The term "biologically active" refers to a protein having structural,
regulatory, or biochemical
functions of a naturally occurring molecule. Likewise, "immunologically
active" refers to the
capability of the natural, recombinant, or synthetic NuABP, or of any
oligopeptide thereof, to induce a
specific immune response in appropriate animals or cells and to bind with
specific antibodies.
The terms "complementary" and "complementarity" refer to the natural binding
of
polynucleotides by base pairing. For example, the sequence "5' A-G-T 3"' bonds
to the
complementary sequence "3' T-C-A 5'." Complementarity between two single-
stranded molecules
may be "partial," such that only some of the nucleic acids bind, or it may be
"complete," such that
total eomplementarity exists between the single stranded molecules. The degree
of complementarity
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between nucleic acid strands has significant effects on the efficiency and
strength of the hybridization
between the nucleic acid strands. This is of particular importance in
amplification reactions, which
depend upon binding between nucleic acid strands, and in the design and use of
peptide nucleic acid
(PNA) molecules.
A "composition comprising a given polynucleotide sequence" and a "composition
comprising
a given amino acid sequence" refer broadly to any composition containing the
given polynucleotide or
amino acid sequence. The composition may comprise a dry formulation or an
aqueous solution.
Compositions comprising polynucleotide sequences encoding NuABP or fragments
of NuABP may
be employed as hybridization probes. The probes may be stored in freeze-dried
form and may be
associated with a stabilizing agent such as a carbohydrate. In hybridizations,
the probe may be
deployed in an aqueous solution containing salts (e.g., NaCI), detergents
(e.g., sodium dodecyl
sulfate; SDS), and other components (e.g., Denhardt's solution, dry milk,
salmon sperm DNA, etc.).
"Consensus sequence" refers to a nucleic acid sequence which has been
resequenced to
resolve uncalled bases, extended using the XL-PCR kit (Perkin-Elmer, Norwalk
CT) in the ~' and/or
the 3' direction, and resequenced, or which has been assembled from the
overlapping sequences of
one or more Incyte Clones and, in some cases, one or more public domain ESTs,
using a computer
program for fragment assembly, such as the GELVIEW fragment assembly system
(GCG, Madison
WI). Some sequences have been both extended and assembled to produce the
consensus sequence.
"Conservative amino acid substitutions'' are those substitutions that, when
made, least
interfere with the properties of the original protein, i.e., the structure and
especially the function of 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 Ile, Val
Lys Arg, Gln, Glu
Met Leu, Ile
Phe His, Met, Leu, Trp, Tyr
Ser Cys, Thr
Thr Ser, Val
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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 the chemical modification of a polypeptide
sequence, or a
polynucleotide sequence. Chemical modifications of a polynucleotide sequence
can include, for
example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group.
A derivative
polynucleotide encodes a polypeptide which retains at least one biological or
immunological function
of the natural molecule. A derivative polypeptide is one modified by
glycosylation, pegylation, or any
similar process that retains at least one biological or immunological function
of the polypeptide from
which it was derived.
A "fragment" is a unique portion of NuABP or the polynucleotide encoding NuABP
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,
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 N0:56-1 10 comprises a region of unique polynucleotide
sequence that
specifically identifies SEQ ID N0:56-110, for example, as distinct from any
other sequence in the
same genome. A fragment of SEQ ID N0:56-1 10 is useful, for example, in
hybridization and
amplification technologies and in analogous methods that distinguish SEQ ID
N0:56-110 from
related polynucleotide sequences. The precise length of a fragment of SEQ ID
N0:56-110 and the
region of SEQ ID N0:56-110 to which the fragment corresponds are routinely
determinable by one of
ordinary skill in the art based on the intended purpose for the fragment.
A fragment of SEQ ID NO:I-55 is encoded by a fragment of SEQ ID N0:56-110. A
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fragment of SEQ ID NO:1-55 comprises a region of unique amino acid sequence
that specifically
identifies SEQ ID NO:1-55. For example, a fragment of SEQ ID NO:1-5~ is useful
as an
immunogenic peptide for the development of antibodies that specifically
recognize SEQ ID NO: I-55.
The precise length of a fragment of SEQ ID NO:I-55 and the region of SEQ ID
NO:1-SS to which the
fragment corresponds are routinely determinable by one of ordinary skill in
the art based on the
intended purpose for the fragment.
The term "similarity" refers to a degree of complementarity. There may be
partial similarity
or complete similarity. The word "identity" may substitute for the word
"similarity." A partially
complementary sequence that at least partially inhibits an identical sequence
from hybridizing to a
target nucleic acid is referred to as "substantially similar." The inhibition
of hybridization of the
completely complementary sequence to the target sequence may be examined using
a hybridization
assay (Southern or northern blot, solution hybridization, and the like) under
conditions of reduced
stringency. A substantially similar sequence or hybridization probe will
compete for and inhibit the
binding of a completely similar (identical) sequence to the target sequence
under conditions of
IS reduced stringency. This is not to say that conditions of reduced
stringency are such that non-specific
binding is permitted, as reduced stringency conditions require that the
binding of two sequences to
one another be a specific (i.e., a selective) interaction. The absence of non-
specific binding may be
tested by the use of a second target sequence which lacks even a partial
degree of complementarity
(e.g., less than about 30% similarity or identity). In the absence of non-
specific binding, the
substantially similar sequence or probe will not hybridize to the second non-
complementary target
sequence.
The phrases "percent identity" and "% identity," as applied to polynucleotide
sequences, refer
to the percentage of residue matches between at least two 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
Higgins, D.G. and P.M. Sharp (1989) CABIOS 5:151-153 and in Higgins, D.G. et
al. (1992) CABIOS
8:189-191. For pairwise alignments of polynucleotide sequences, the default
parameters are set as
follows: Ktuple=2, gap penalty=5, window=4, and "diagonals saved"=4. The
"weighted" residue
weight table is selected as the default. Percent identity is reported by
CLUSTAL V as the ''percent
similarity" between aligned polynucleotide sequence pairs.
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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 accessed 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
2Ø9 (May-07-1999) set at default parameters. Such default parameters may be,
for example:
Matrix: BLOSUM62
I 5 Reward for match: I
Penalty for mismatch: -2
Open Gap: 5 and Extension Gap: 2 penalties
Gap x drop-ofj.~ 50
Expect. 10
Word Size: Il
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
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alignment methods take into account conservative amino acid substitutions.
Such conservative
substitutions, explained in more detail above, generally preserve the
hydrophobicity and acidity at the
site of substitution, thus preserving the structure (and therefore function)
of the polypeptide.
Percent identity between polypeptide sequences may be determined using the
default
parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e
sequence alignment program (described and referenced above). For pairwise
alignments of
polypeptide sequences using CLUSTAL V, the default parameters are set as
follows: Ktuple=l, gap
penalty=3, window=5, and "diagonals saved"=5. The PAM250 matrix is selected as
the default
residue weight table. As with polynucleotide alignments, the percent identity
is reported by
CLUSTAL V as the "percent similarity" between aligned polypeptide sequence
pairs.
Alternatively the NCBI BLAST software suite may be used. For example. for a
pairwise
comparison of two polypeptide sequences, one may use the "BLAST 2 Sequences"
tool Version 2Ø9
(May-07-1999) with blastp set at default parameters. Such default parameters
may be, for example:
Matrix: BLOSUM62
Open Gap: 11 and Extension Gap: I penalties
Gap x drop-off. 50
Expect: 10
Word Size: 3
Filter.' on
Percent identity may be measured over the length of an entire defined
polypeptide sequence,
for example, as defined by a particular SEQ ID number, or may be measured over
a shorter length, for
example, over the length of a fragment taken from a larger, defined
polypeptide sequence, for
instance, a fragment of at least I 5, 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
stable mitotic chromosome segregation and maintenance.
The term "humanized antibody" refers to antibody molecules in which the amino
acid
sequence in the non-antigen binding regions has been altered so that the
antibody more closely
resembles a human antibody, and still retains its original binding ability.
"Hybridization" refers to the process by which a polynucleotide strand anneals
with a
complementary strand through base pairing under defined hybridization
conditions. Specific
hybridization is an indication that two nucleic acid sequences share a high
degree of identity. Specific
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hybridization complexes form under permissive annealing conditions and remain
hybridized after the
"washing" step(s). The washing steps) is particularly important in determining
the stringency of the
hybridization process, with more stringent conditions allowing less non-
specific binding, i.e., binding
between pairs of nucleic acid strands that are not perfectly matched.
Permissive conditions for
annealing of nucleic acid sequences are routinely determinable by one of
ordinary 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 pg/ml denatured salmon sperm DNA.
Generally, stringency of hybridization is expressed, in part, with reference
to the temperature
under which the wash step is carried out. Generally, such wash temperatures
are selected to be about
5°C to 20°C lower than the thermal melting point (Tm) for the
specific sequence at a defined ionic
strength and pH. The Tm is the temperature (under defined ionic strength and
pH) at which 50% 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 et al., 1989,
Molecular Cloning: A Laboratory Manual, 2"d 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,
denatured salmon sperm DNA at about 100-200 pg/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., C°t or
R°t analysis) or formed between one
nucleic acid sequence present in solution and another nucleic acid sequence
immobilized on a solid
support (e.g., paper, membranes, filters, chips, pins or glass slides, or any
other appropriate substrate
to which cells or their nucleic acids have been fixed).
The words "insertion" and "addition" refer to changes in an amino acid or
nucleotide
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sequence resulting in the addition of one or more amino acid residues or
nucleotides, respectively.
"Immune response'' can refer to conditions associated with inflammation,
trauma, immune
disorders, or infectious or genetic disease, etc. These conditions can be
characterized by expression
of various factors, e.g., cytokines, chemokines, and other signaling
molecules, which may affect
cellular and systemic defense systems.
The term "microarray" refers to an arrangement of distinct polynucleotides on
a substrate.
The terms "element" and "array element" in a microarray context, refer to
hybridizable
polynucleotides arranged on the surface of a substrate.
The term "modulate" refers to a change in the activity of NuABP. For example,
modulation
may cause an increase or a decrease in protein activity, binding
characteristics, or any other
biological, functional, or immunological properties of NuABP.
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 the second nucleic acid sequence. For instance, a
promoter is operably
linked to a coding sequence if the promoter affects the transcription or
expression of the coding
sequence. Generally, operably linked DNA sequences may be in close proximity
or contiguous and,
where necessary to join two protein coding regions, in the same reading frame.
"Peptide nucleic acid" (PNA) refers to an antisense molecule or anti-gene
agent which
comprises an oligonucleotide of at least about 5 nucleotides in length linked
to a peptide backbone of
amino acid residues ending in lysine. The terminal lysine confers solubility
to the composition.
PNAs preferentially bind complementary single stranded DNA or RNA and stop
transcript elongation,
and may be pegylated to extend their lifespan in the cell.
"Probe" refers to nucleic acid sequences encoding NuABP, 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 I S contiguous
nucleotides of a known sequence. In order to enhance specificity, longer
probes and primers may also
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be employed, such as probes and primers that comprise at least 20, 25, 30, 40,
50, 60, 70, 80, 90, 100,
or at least 1 SO consecutive nucleotides of the disclosed nucleic acid
sequences. Probes and primers
may be considerably longer than these examples. and it is understood that any
length supported by the
specification, including the tables, figures, and Sequence Listing, may be
used.
Methods for preparing and using probes and primers are described in the
references, for
example Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, 2"d
ed., vol. 1-3, Cold
Spring Harbor Press, Plainview NY; Ausubel et al.,1987, Current Protocols in
Molecular Biolo~y,
Greene Publ. Assoc. & Wiley-Intersciences, New York NY; Innis et al., 1990,
PCR Protocols. A
Guide to Methods and Applications, Academic Press, San Diego CA. PCR primer
pairs can be
derived from a known sequence, for example, by using computer programs
intended for that purpose
such as Primer (Version 0.5, 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
l5 5,000 nucleotides from an input polynucleotide sequence of up to 32
kilobases. Similar primer
selection programs have incorporated additional features for expanded
capabilities. For example, the
PrimOU primer selection program (available to the public from the Genome
Center at University of
Texas South West Medical Center, Dallas TX) is capable of choosing specific
primers from megabase
sequences and is thus useful for designing primers on a genome-wide scope. The
Primer3 primer
selection program (available to the public from the Whitehead Institute/MIT
Center for Genome
Research, Cambridge MA) allows the user to input a "mispriming library," in
which sequences to
avoid as primer binding sites are user-specified. Primer3 is useful, in
particular, for the selection of
oligonucleotides for microarrays. (The source code for the latter two primer
selection programs may
also be obtained from their respective sources and modified to meet the user's
specific needs.) The
PrimeGen program (available to the public from the UK Human Genome Mapping
Project Resource
Centre, Cambridge UK) designs primers based on multiple sequence alignments,
thereby allowing
selection of primers that hybridize to either the most conserved or least
conserved regions of aligned
nucleic acid sequences. Hence, this program is useful for identification of
both unique and conserved
oligonucleotides and polynucleotide fragments. The oligonucleotides and
polynucleotide fragments
identified by any of the above selection methods are useful in hybridization
technologies, for
example, as PCR or sequencing primers, microarray elements, or specific probes
to identify fully or
partially complementary polynucleotides in a sample of nucleic acids. Methods
of oligonucleotide
selection are not limited to those described above.
A "recombinant nucleic acid" is a sequence that is not naturally occurring or
has a sequence
that is made by an artificial combination of two or more otherwise separated
segments of sequence.
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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.
The term "sample" is used in its broadest sense. A sample suspected of
containing nucleic
acids encoding NuABP, or fragments thereof, or NuABP itself, 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
containing the epitope A, or the presence of free unlabeled A, in a reaction
containing free labeled A
and the antibody will reduce the amount of labeled A that binds to the
antibody.
The term ''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 acids or
nucleotides by
different amino acids 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.
"Transformation" describes a process by which exogenous DNA enters and changes
a
recipient cell. Transformation may occur under natural or artificial
conditions according to various
methods well known in the art, and may rely on any known method for the
insertion of foreign nucleic
acid sequences into a prokaryotic or eukaryotic host cell. The method for
transformation is selected
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based on the type of host cell being transformed and may include, but is not
limited to, viral infection,
electroporation, heat shock, lipofection, and particle bombardment. The term
"transformed" cells
includes stably transformed cells in which the inserted DNA is capable of
replication either as an
autonomously replicating plasmid or as part of the host chromosome, as well as
transiently
transformed cells which express the inserted DNA or RNA for limited periods of
time.
A "variant" of a particular nucleic acid sequence is defined as a nucleic acid
sequence having
at least 40% sequence identity to the particular nucleic acid sequence over a
certain length of one of
the nucleic acid sequences using blastn with the "BLAST 2 Sequences" tool
Version 2Ø9 (May-07-
1999) set at default parameters. Such a pair of nucleic acids may show, for
example, at least 50%, at
least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least
95% or at least 98% or
greater sequence identity over a certain defined length. A variant may be
described as, for example,
an "allelic" (as defined above), ''splice," "species," or "polymorphic"
variant. A splice variant may
have significant identity to a reference molecule, but will generally have a
greater or lesser number of
polynucleotides due to alternate splicing of exons during mRNA processing. The
corresponding
polypeptide may possess additional functional domains or lack domains that are
present in the
reference molecule. Species variants are polynucleotide sequences that vary
from one species to
another. The resulting polypeptides generally will 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 95%, or at least
98% or greater sequence
identity over a certain defined length of one of the polypeptides.
THE INVENTION
The invention is based on the discovery of new human nucleic-acid binding
proteins
(NuABP), the polynucleotides encoding NuABP, and the use of these compositions
for the diagnosis,
treatment, or prevention of reproductive, immune, and neurological disorders,
and cell proliferative
disorders including cancer.
Table 1 lists the Incyte clones used to assemble full length nucleotide
sequences encoding
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NuABP. Columns I and 2 show the sequence identification numbers (SEQ ID NOs)
of the
polypeptide and nucleotide sequences, respectively. Column 3 shows the clone
IDs of the Incyte
clones in which nucleic acids encoding each NuABP were identified, and column
4 shows the cDNA
libraries from which these clones were isolated. Column 5 shows Incyte clones
and their
corresponding cDNA libraries. Clones for which cDNA libraries are not
indicated were derived from
pooled cDNA libraries. The Incyte clones in column 5 were used to assemble the
consensus
nucleotide sequence of each NuABP and are useful as fragments in hybridization
technologies.
The columns of Table 2 show various properties of each of the polypeptides of
the invention:
column 1 references the SEQ ID NO; column 2 shows the number of amino acid
residues in each
polypeptide; column 3 shows potential phosphorylation sites; column 4 shows
potential glycosylation
sites; column S shows the amino acid residues comprising signature sequences
and motifs; column 6
shows identification or homologous sequences as identified by BLAST analysis;
and column 7 shows
analytical methods and in some cases, searchable databases to which the
analytical methods were
applied. The methods of column 7 were used to characterize each polypeptide
through sequence
homology and protein motifs.
The columns of Table 3 show the tissue-specificity and diseases, disorders, or
conditions
associated with nucleotide sequences encoding NuABP. The first column of Table
3 lists the
nucleotide SEQ ID NOs. Column 2 lists fragments of the nucleotide sequences of
column 1. These
fragments are useful, for example, in hybridization or amplification
technologies to identify SEQ ID
N0:56-I 10 and to distinguish between SEQ ID N0:56-I 10 and related
polynucleotide sequences.
The polypeptides encoded by these fragments are useful, for example, as
immunogenic peptides.
Column 3 lists tissue categories which express NuABP as a fraction of total
tissues expressing
NuABP. Column 4 lists diseases, disorders, or conditions associated with those
tissues expressing
NuABP as a fraction of total tissues expressing NuABP. Of particular note is
the expression of SEQ
ID N0:83 and SEQ ID NO:I 10 in neurological tissue. About 53% of the cDNA
libraries expressing
SEQ ID N0:83 are derived from neurological tissue. Furthermore, SEQ ID NO:1 10
expression is
detected exclusively in a cDNA library derived from brain tissue afflicted
with Huntington's disease.
Column 5 lists the vectors used to subclone each cDNA library.
The columns of Table 4 show descriptions of the tissues used to construct the
cDNA libraries
from which eDNA clones encoding NuABP were isolated. Column I references the
nucleotide SEQ
ID NOs, column 2 shows the cDNA libraries from which these clones were
isolated, and column 3
shows the tissue origins and other descriptive information relevant to the
cDNA libraries in column 2.
Fragments of the nucleotide sequences encoding NuABP are useful, for example,
in
hybridization or amplification technologies to identify SEQ ID NOS:56-I 10 and
to distinguish
between SEQ ID NOS:56-I 10 and related polynucleotide sequences. The
polypeptides encoded by
21
CA 02359701 2001-07-17
WO 00144900 PCTNS00/D2237
these fragments are useful, for example, as immunogenic peptides.
The invention also encompasses NuABP variants. A preferred NuABP variant is
one which
has at least about 80%, or alternatively at least about 90%, or even at least
about 9~% amino acid
sequence identity to the NuABP amino acid sequence, and which contains at
least one functional or
structural characteristic of NuABP.
The invention also encompasses polynucleotides which encode NuABP. In a
particular
embodiment, the invention encompasses a polynucleotide sequence comprising a
sequence selected
from the group consisting of SEQ ID N0:56-110, which encodes NuABP.
The invention also encompasses a variant of a polynucleotide sequence encoding
NuABP. 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 NuABP. A particular aspect of the invention encompasses a
variant of a
polynucleotide sequence comprising a sequence selected from the group
consisting of SEQ ID
N0:56-1 10 which has at least about 70%, or alternatively at least about 85%,
or even at least about
IS 95% polynucleotide sequence identity to a nucleic acid sequence selected
from the group consisting
of SEQ ID N0:56-1 10. Any one of the polynucleotide variants described above
can encode an amino
acid sequence which contains at least one functional or structural
characteristic of NuABP.
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 NuABP, 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 NuABP, and all such variations
are to be considered
as being specifically disclosed.
Although nucleotide sequences which encode NuABP and its variants are
generally capable
of hybridizing to the nucleotide sequence of the naturally occurring NuABP
under appropriately
selected conditions of stringency, it may be advantageous to produce
nucleotide sequences encoding
NuABP or its derivatives possessing a substantially different codon usage,
e.g., inclusion of non-
naturally occurring codons. Codons may be selected to increase the rate at
which expression of the
peptide occurs in a particular prokaryotic or eukaryotic host in accordance
with the frequency with
which particular codons are utilized by the host. Other reasons for
substantially altering the
nucleotide sequence encoding NuABP 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.
22
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WO 00/44900 PCTNS00/02237
The invention also encompasses production of DNA sequences which encode NuABP
and
NuABP 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 NuABP 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
N0:56-110 and fragments thereof under various conditions of stringency. (See,
e.g., Wahl, G.M. and
S.L. Berger (1987) Methods Enzymol. 152:399-407; Kimmel, A.R. (1987) Methods
Enzymol.
152:507-511.) Hybridization conditions, including annealing and wash
conditions, are described in
"Definitions."
Methods for DNA sequencing are well known in the art and may be used to
practice any of
the embodiments of the invention. The methods may employ such enzymes as the
Klenow fragment
of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase
(Perkin-
IS Elmer), thermostable T7 polymerase (Amersham Pharmacia Biotech, Piscataway
NJ), or
combinations of polymerases and proofreading exonucleases such as those found
in the ELONGASE
amplification system (Life Technologies, Gaithersburg MD). Preferably,
sequence preparation is
automated with machines such as the MICROLAB 2200 liquid transfer system
(Hamilton, Reno NV),
PTC200 thermal cycler (MJ Research, Watertown MA) and ABI CATALYST 800 thermal
cycler
(Perkin-Elmer). Sequencing is then carried out using either the ABI 373 or 377
DNA sequencing
system (Perkin-Elmer), the MEGABACE 1000 DNA sequencing system (Molecular
Dynamics,
Sunnyvale CA), or other systems known in the art. The resulting sequences are
analyzed using a
variety of algorithms which are well known in the art. (See, e.g., Ausubel,
F.M. ( 1997) Short
Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY, unit 7.7;
Meyers, R.A. (1995)
Molecular Biology and Biotechnolo~y, Wiley VCH, New York NY, pp. 856-853.)
The nucleic acid sequences encoding NuABP may be extended utilizing a partial
nucleotide
sequence and employing various PCR-based methods known in the art to detect
upstream sequences,
such as promoters and regulatory elements. For example, one method which may
be employed,
restriction-site PCR, uses universal and nested primers to amplify unknown
sequence from genomic
DNA within a cloning vector. (See, e.g., Sarkar, G. (1993) PCR Methods Applic.
2:318-322.)
Another method, inverse PCR, uses primers that extend in divergent directions
to amplify unknown
sequence from a circularized template. The template is derived from
restriction fragments comprising
a known genomic locus and surrounding sequences. (See, e.g., Triglia, T. et
al. (1988) Nucleic Acids
Res. 16:8186.) A third method, capture PCR, involves PCR amplification of DNA
fragments adjacent
to known sequences in human and yeast artificial chromosome DNA. (See, e.g.,
Lagerstrom, M. et al.
23
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
(1991 ) PCR Methods Applic. 1:1 1 1-119.) 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 S' 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, Perkin-Elmer), 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 NuABP may be cloned in recombinant DNA molecules that direct
expression of
NuABP, 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 NuABP.
The nucleotide sequences of the present invention can be engineered using
methods generally
known in the art in order to alter NuABP-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-
24
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
mediated site-directed mutagenesis may be used to introduce mutations that
create new restriction
sites, alter glycosylation patterns, change codon preference, produce splice
variants, and so forth.
In another embodiment. sequences encoding NuABP 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, NuABP itself or a fragment thereof may be synthesized using
chemical methods. For
example, peptide synthesis can be performed using various solid-phase
techniques. (See, e.g.,
Roberge, J.Y. et al. ( 1995) Science 269:202-204.) Automated synthesis may be
achieved using the
ABI 431A peptide synthesizer (Perkin-Elmer). Additionally, the amino acid
sequence ofNuABP, 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.
The peptide may be substantially purified by preparative high performance
liquid
chromatography. (See, e.g., Chiez, R.M. and F.Z. Regnier (1990) Methods
Enzymol. 182:392-421.)
The composition of the synthetic peptides may be confirmed by amino acid
analysis or by sequencing.
(See, e.g., Creighton, T. (1984) Proteins, Structures and Molecular
Properties, WH Freeman, New
York NY.)
In order to express a biologically active NuABP, the nucleotide sequences
encoding NuABP
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 NuABP. Such elements may vary in their
strength and
specificity. Specific initiation signals may also be used to achieve more
efficient translation of
sequences encoding NuABP. Such signals include the ATG initiation codon and
adjacent sequences,
e.g. the Kozak sequence. In cases where sequences encoding NuABP 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 NuABP and appropriate transcriptional
and translational
control elements. These methods include in vitro recombinant DNA techniques,
synthetic techniques,
CA 02359701 2001-07-17
WO 00144900 PCT/US00/02237
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 NuABP. These include, but are not limited to, microorganisms such as
bacteria transformed
with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors;
yeast transformed with
yeast expression vectors; insect cell systems infected with viral expression
vectors (e.g., baculovirus);
plant cell systems transformed with viral expression vectors (e.g.,
cauliflower mosaic virus, CaMV, or
tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or
pBR322 plasmids); or
animal cell systems. The invention is not limited by the host cell employed.
In bacterial systems, a number of cloning and expression vectors may be
selected depending
upon the use intended for polynucleotide sequences encoding NuABP. For
example, routine cloning,
subcloning, and propagation of polynucleotide sequences encoding NuABP can be
achieved using a
IS multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla
CA) or PSPORTI
plasmid (Life Technologies). Ligation of sequences encoding NuABP 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 NuABP are needed, e.g. for the
production of
antibodies, vectors which direct high level expression of NuABP may be used.
For example, vectors
containing the strong, inducible TS or T7 bacteriophage promoter may be used.
Yeast expression systems may be used for production of NuABP. 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. I 53:516-544; and
Scorer, C.A. et al. ( 1994)
Bio/Technology 12:181-184.)
Plant systems may also be used for expression of NuABP. Transcription of
sequences
encoding NuABP may be driven 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; Broglie, R. et al.
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
(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 Technoloey
(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 NuABP
may be ligated into
an adenovirus transcription/translation complex consisting of the late
promoter and tripartite leader
sequence. Insertion in a non-essential E1 or E3 region of the viral genome may
be used to obtain
infective virus which expresses NuABP in host cells. (See, e.g., Logan, J. and
T. Shenk ( 1984) Proc.
Natl. Acad. Sci. USA 81:3655-3659.) In addition, transcription enhancers, such
as the Rous sarcoma
virus (RSV) enhancer, may be used to increase expression in mammalian host
cells. SV40 or EBV-
based vectors may also be used for high-level protein expression.
Human artificial chromosomes (HACs) may also be employed to deliver larger
fragments of
DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb
to 10 Mb are
constructed and delivered via conventional delivery methods (liposomes,
polycationic amino
polymers, or vesicles) for therapeutic purposes. (See, e.g., Harrington, J.J.
et al. ( 1997) Nat. Genet.
15:345-355.)
For long term production of recombinant proteins in mammalian systems, stable
expression of
NuABP in cell lines is preferred. For example, sequences encoding NuABP 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,
dhfr confers resistance to
methotrexate; neo confers resistance to the aminoglycosides neomycin and G-
418; and als and pat
confer resistance to chlorsulfuron and phosphinotricin acetyltransferase,
respectively. (See, e.g.,
Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-
Garapin, F. et al. (1981)
J. Mol. Biol. 150:1-14.) Additional selectable genes have been described,
e.g., trpB and hisD, which
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CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
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), f3 glucuronidase and its substrate f3-glucuronide. or
luciferase and its substrate
luciferin may be used. These markers can be used not only to identify
transformants, but also to
quantify the amount of transient or stable protein expression attributable to
a specific vector system.
(See, e.g., Rhodes, C.A. (1995) Methods Mol. Biol. 55:121-131.)
Although the presence/absence of marker gene expression suggests that the gene
of interest is
also present, the presence and expression of the gene may need to be
confirmed. For example, if the
sequence encoding NuABP is inserted within a marker gene sequence, transformed
cells containing
sequences encoding NuABP can be identified by the absence of marker gene
function. Alternatively,
a marker gene can be placed in tandem with a sequence encoding NuABP 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 NuABP
and that express
NuABP 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 NuABP
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 NuABP 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) Seroloeical Methods, a Laboratory Manual, APS
Press, St. Paul MN,
Sect. IV; Coligan, J.E. et al. (1997) Current Protocols in Immunoloey, 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 NuABP
include oligolabeling, nick translation, end-labeling, or PCR amplification
using a labeled nucleotide.
Alternatively, the sequences encoding NuABP, 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
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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 NuABP 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 NuABP may be designed to contain
signal sequences which
direct secretion of NuABP through a prokaryotic or eukaryotic cell membrane.
In addition, a host cell strain may be chosen for its ability to modulate
expression of the
inserted sequences or to process the expressed protein in the desired fashion.
Such modifications of
the polypeptide include, but are not limited to, acetylation, carboxylation,
glycosylation,
phosphorylation, lipidation, and acylation. Post-translational processing
which cleaves a "prepro" or
"pro" form of the protein may also be used to specify protein targeting,
folding, and/or activity.
Different host cells which have specific cellular machinery and characteristic
mechanisms for
post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are
available from the
American Type Culture Collection (ATCC, Manassas VA) and may be chosen to
ensure the correct
modification and processing of the foreign protein.
In another embodiment of the invention, natural, modified, or recombinant
nucleic acid
sequences encoding NuABP 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 NuABP protein
containing a heterologous moiety that can be recognized by a commercially
available antibody may
facilitate the screening of peptide libraries for inhibitors of NuABP
activity. Heterologous protein and
peptide moieties may also facilitate purification of fusion proteins using
commercially available
affinity matrices. Such moieties include, but are not limited to, glutathione
S-transferase (GST),
maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide
(CBP), 6-His, FLAG,
c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable
purification of their cognate
fusion proteins on immobilized glutathione, maltose, phenylarsine oxide,
calmodulin, and metal-
chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA) enable
immunoaffinity
purification of fusion proteins using commercially available monoclonal and
polyclonal antibodies
that specifically recognize these epitope tags. A fusion protein may also be
engineered to contain a
proteolytic cleavage site located between the NuABP encoding sequence and the
heterologous protein
sequence, so that NuABP may be cleaved away from the heterologous moiety
following purification.
29
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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 NuABP may
be achieved
in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system
(Promega). These
systems couple transcription and translation of protein-coding sequences
operably associated with the
T7, T3, or SP6 promoters. Translation takes place in the presence of a
radiolabeled amino acid
precursor, for example, 'SS-methionine.
Fragments of NuABP may be produced not only by recombinant means, but also by
direct
peptide synthesis using solid-phase techniques. (See, e.g., Creighton, su ra
pp. ~5-60.) Protein
synthesis may be performed by manual techniques or by automation. Automated
synthesis may be
achieved, for example, using the ABI 43 I A peptide synthesizer (Perkin-
Elmer). Various fragments of
NuABP may be synthesized separately and then combined to produce the full
length molecule.
THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and
motifs, exists between
regions of NuABP and nucleic-acid binding proteins. In addition, the
expression of NuABP is closely
associated with proliferative, neuronal, inflamed, and cancerous tissues and
tissues of the reproductive
system. Therefore, NuABP appears to play a role in reproductive, immune, and
neurological
disorders, and cell proliferative disorders including cancer. In the treatment
of disorders associated
with increased NuABP expression or activity, it is desirable to decrease the
expression or activity of
NuABP. In the treatment of disorders associated with decreased NuABP
expression or activity, it is
desirable to increase the expression or activity of NuABP.
Therefore, in one embodiment, NuABP 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 NuABP. Examples of such disorders include, but are not limited to, a
reproductive disorder such
as disorders of prolactin production, infertility, including tubal disease,
ovulatory defects, and
endometriosis, disruptions of the estrous cycle, disruptions of the menstrual
cycle, polycystic ovary
syndrome, ovarian hyperstimulation syndrome, endometrial and ovarian tumors,
uterine fibroids,
autoimmune disorders, ectopic pregnancies, and teratogenesis; cancer of the
breast, fibrocystic breast
disease, and galactorrhea; disruptions of spermatogenesis, abnormal sperm
physiology, cancer of the
testis, cancer of the prostate, benign prostatic hyperplasia, prostatitis,
Peyronie's disease, impotence,
carcinoma of the male breast, and gynecomastia; an immune disorder such as
inflammation, actinic
keratosis, acquired immunodeficiency syndrome (AIDS), Addison's disease, adult
respiratory distress
syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia,
arteriosclerosis, asthma,
atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis,
bronchitis, bursitis,
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cholecystitis, cirrhosis, contact dermatitis, Crohn's disease, atopic
dermatitis, dermatomyositis,
diabetes mellitus, emphysema, erythroblastosis fetalis, erythema nodosum,
atrophic gastritis,
glomerulonephritis. Goodpasture's syndrome, gout, Graves' disease. Hashimoto's
thyroiditis,
paroxysmal nocturnal hemoglobinuria, hepatitis, hypereosinophilia, irritable
bowel syndrome,
episodic lymphopenia with lymphocytotoxins, mixed connective tissue disease
(MCTD), multiple
sclerosis, myasthenia gravis, myocardial or pericardial inflammation,
myelofibrosis, osteoarthritis,
osteoporosis, pancreatitis, polycythemia vera, polymyositis, psoriasis,
Reiter's syndrome, rheumatoid
arthritis. scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic
lupus erythematosus,
systemic sclerosis, primary thrombocythemia, thrombocytopenic purpura,
ulcerative colitis, uveitis,
Werner syndrome, complications of cancer, hemodialysis, and extracorporeal
circulation, trauma, and
hematopoietic cancer including lymphoma, leukemia, and myeloma; a neurological
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 disorders of the central nervous system,
cerebral palsy,
neuroskeleta) disorders, autonomic nervous system disorders, cranial nerve
disorders, spinal cord
diseases, muscular dystrophy and other neuromuscular disorders, peripheral
nervous system
disorders. dermatomyositis and polymyositis, inherited, metabolic, endocrine,
and toxic myopathies,
myasthenia gravis, periodic paralysis, mental disorders including mood,
anxiety, and schizophrenic
disorders. akathesia, amnesia, catatonia, diabetic neuropathy, tardive
dyskinesia, dystonias, paranoid
psychoses, postherpetic neuralgia, and Tourette's disorder; and 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.
In another embodiment, a vector capable of expressing NuABP or a fragment or
derivative
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thereof may be administered to a subject to treat or prevent a disorder
associated with decreased
expression or activity of NuABP including, but not limited to. those described
above.
In a further embodiment, a pharmaceutical composition comprising a
substantially purified
NuABP 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
NuABP including, but not
limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of NuABP
may be
administered to a subject to treat or prevent a disorder associated with
decreased expression or activity
of NuABP including, but not limited to, those listed above.
t0 In a further embodiment, an antagonist of NuABP may be administered to a
subject to treat or
prevent a disorder associated with increased expression or activity of NuABP.
Examples of such
disorders include, but are not limited to, those reproductive, immune, and
neurological disorders, and
cell proliferative disorders including cancer, described above. In one aspect,
an antibody which
specifically binds NuABP 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 NuABP.
In an additional embodiment, a vector expressing the complement of the
polynucleotide
encoding NuABP may be administered to a subject to treat or prevent a disorder
associated with
increased expression or activity of NuABP 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 NuABP may be produced using methods which are generally known
in the
art. In particular, purified NuABP may be used to produce antibodies or to
screen libraries of
pharmaceutical agents to identify those which specifically bind NuABP.
Antibodies to NuABP 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 NuABP or with any fragment or
oligopeptide thereof
which has immunogenic properties. Depending on the host species, various
adjuvants may be used to
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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 Corynebacteriumparvum are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce
antibodies to
NuABP have an amino acid sequence consisting of at least about 5 amino acids,
and generally will
consist of at least about 10 amino acids. It is also preferable that these
oligopeptides, peptides, or
fragments are identical to a portion of the amino acid sequence of the natural
protein and contain the
entire amino acid sequence of a small, naturally occurring molecule. Short
stretches of NuABP 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 NuABP 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
NuABP-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 NuABP may also be
generated.
For example, such fragments include, but are not limited to, F(ab'), fragments
produced by pepsin
digestion of the antibody molecule and Fab fragments generated by reducing the
disulfide bridges of
the F(ab')2 fragments. Alternatively, Fab expression libraries may be
constructed to allow rapid and
easy identification of monoclonal Fab fragments with the desired specificity.
(See, e.g., Huse, W.D.
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WO 00/44900 PCT/US00/02237
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
NuABP and its
specific antibody. A two-site, monoclonal-based immunoassay utilizing
monoclonal antibodies
reactive to two non-interfering NuABP 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 NuABP.
Affinity is expressed as an
association constant, Ka, which is defined as the molar concentration of NuABP-
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 NuABP epitopes, represents the average affinity, or
avidity, of the antibodies
l5 for NuABP. The K~ determined for a preparation of monoclonal antibodies,
which are monospecific
for a particular NuABP epitope, represents a true measure of affinity. High-
affinity antibody
preparations with Ka ranging from about 109 to 10'-'' L/mole are preferred for
use in immunoassays in
which the NuABP-antibody complex must withstand rigorous manipulations. Low-
affinity antibody
preparations with Ka ranging from about 106 to 10' L/mole are preferred for
use in
immunopurification and similar procedures which ultimately require
dissociation of NuABP,
preferably in active form, from the antibody (Catty, D. (1988) Antibodies,
Volume I: A Practical
Approach, IRL Press, Washington, DC; Liddell, J.E. and Cryer, A. (1991) A
Practical Guide to
Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity of polyclonal antibody preparations may be further
evaluated to
determine the quality and suitability of such preparations for certain
downstream applications. For
example, a polyclonal antibody preparation containing at least 1-2 mg specific
antibody/ml, preferably
5-10 mg specific antibody/ml, is generally employed in procedures requiring
precipitation ofNuABP-
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. su ra.)
In another embodiment of the invention, the polynucleotides encoding NuABP, or
any
fragment or complement thereof, may be used for therapeutic purposes. In one
aspect, the
complement of the polynucleotide encoding NuABP may be used in situations in
which it would be
desirable to block the transcription of the mRNA. In particular, cells may be
transformed with
sequences complementary to polynucleotides encoding NuABP. Thus, complementary
molecules or
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WO 00/44900 PCT/US00/02237
fragments may be used to modulate NuABP activity, or to achieve regulation of
gene function. Such
technology is now well known in the art, and sense or antisense
oligonucleotides or larger fragments
can be designed from various locations along the coding or control regions of
sequences encoding
NuABP.
Expression vectors derived from retroviruses, adenoviruses, or herpes or
vaccinia viruses, or
from various bacterial plasmids, may be used for delivery of nucleotide
sequences to the targeted
organ, tissue, or cell population. Methods which are well known to those
skilled in the art can be used
to construct vectors to express nucleic acid sequences complementary to the
polynucleotides encoding
NuABP. (See, e.g., Sambrook, supra; Ausubel, 1995, supra.)
Genes encoding NuABP can be turned off by transforming a cell or tissue with
expression
vectors which express high levels of a polynucleotide, or fragment thereof,
encoding NuABP. Such
constructs may be used to introduce untranslatable sense or antisense
sequences into a cell. Even in
the absence of integration into the DNA, such vectors may continue to
transcribe RNA molecules
until they are disabled by endogenous nucleases. Transient expression may last
for a month or more
with a non-replicating vector, and may last even longer if appropriate
replication elements are part of
the vector system.
As mentioned above, modifications of gene expression can be obtained by
designing
complementary sequences or antisense molecules (DNA, RNA, or PNA) to the
control, S', or
regulatory regions of the gene encoding NuABP. Oligonucleotides derived from
the transcription
initiation site, e.g., between about positions -10 and +10 from the start
site, may be employed.
Similarly, inhibition can be achieved using triple helix base-pairing
methodology. Triple helix pairing
is useful because it causes inhibition of the ability of the double helix to
open sufficiently for the
binding of polymerases, transcription factors, or regulatory molecules. Recent
therapeutic advances
using triplet DNA have been described in the literature. (See, e.g., Gee, J.E.
et al. (1994) in Huber,
B.E. and B.I. Carr, Molecular and Immunolo~ic 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 NuABP.
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,
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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 NuABP. 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.
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
pharmaceutical
or sterile composition, in conjunction with a pharmaceutically acceptable
carrier, for any of the
therapeutic effects discussed above. Such pharmaceutical compositions may
consist ofNuABP,
antibodies to NuABP, and mimetics, agonists, antagonists, or inhibitors of
NuABP. The compositions
may be administered alone or in combination with at least one other agent,
such as a stabilizing
compound, which may be administered in any sterile, biocompatible
pharmaceutical carrier including,
but not limited to, saline, buffered saline, dextrose, and water. The
compositions may be administered
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WO 00/44900 PCT/USOO102237
to a patient alone, or in combination with other agents. drugs, or hormones.
The pharmaceutical compositions utilized in this invention may be administered
by any
number of routes including, but not limited to. oral, intravenous,
intramuscular, intra-arterial,
intramedullary, intrathecal, intraventricular, transdermal, subcutaneous,
intraperitoneal, intranasal,
enteral, topical, sublingual, or rectal means.
In addition to the active ingredients, these pharmaceutical compositions may
contain suitable
pharmaceutically-acceptable carriers comprising excipients and auxiliaries
which facilitate processing
of the active compounds into preparations which can be used pharmaceutically.
Further details on
techniques for formulation and administration may be found in the latest
edition of Remineton's
Pharmaceutical Sciences (Maack Publishing, Easton PA).
Pharmaceutical compositions for oral administration can be formulated using
pharmaceutically acceptable carriers well known in the art in dosages suitable
for oral administration.
Such carriers enable the pharmaceutical compositions to be formulated as
tablets, pills, dragees,
capsules, liquids, gels, syrups, slurries, suspensions, and the like, for
ingestion by the patient.
Pharmaceutical preparations for oral use can be obtained through combining
active
compounds with solid excipient and processing the resultant mixture of
granules (optionally, after
grinding) to obtain tablets or dragee cores. Suitable auxiliaries can be
added, if desired. Suitable
excipients include carbohydrate or protein fillers, such as sugars, including
lactose, sucrose, mannitol,
and sorbitol; starch from corn, wheat, rice, potato, or other plants;
cellulose, such as methyl cellulose,
hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; gums,
including arabic and
tragacanth; and proteins, such as gelatin and collagen. 1f desired,
disintegrating or solubilizing agents
may be added, such as the cross-linked polyvinyl pyrrolidone, agar, and
alginic acid or a salt thereof,
such as sodium alginate.
Dragee cores may be used in conjunction with suitable coatings, such as
concentrated sugar
solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone,
carbopol gel, polyethylene
glycol, and/or titanium dioxide, lacquer solutions, and suitable organic
solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee coatings for
product identification or to
characterize the quantity of active compound, i.e., dosage.
Pharmaceutical preparations which can be used orally include push-fit capsules
made of
gelatin, as well as soft, sealed capsules made of gelatin and a coating, such
as glycerol or sorbitol.
Push-fit capsules can contain active ingredients mixed with fillers or
binders, such as lactose or
starches, lubricants, such as talc or magnesium stearate, and, optionally,
stabilizers. In soft capsules,
the active compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid, or
liquid polyethylene glycol with or without stabilizers.
Pharmaceutical formulations suitable for parenteral administration may be
formulated in
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WO 00/44900 PCT/US00/02237
aqueous solutions, preferably in physiologically compatible buffers such as
Hanks' solution, Ringer's
solution, or physiologically buffered saline. Aqueous injection suspensions
may contain substances
which increase the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or
dextran. Additionally, suspensions of the active compounds may be prepared as
appropriate oily
injection suspensions. Suitable lipophilic solvents or vehicles include fatty
oils, such as sesame oil, or
synthetic fatty acid esters, such as ethyl oleate, triglycerides, or
liposomes. Non-lipid polycationic
amino polymers may also be used for delivery. Optionally, the suspension may
also contain suitable
stabilizers or agents to increase the solubility of the compounds and allow
for the preparation of
highly concentrated solutions.
For topical or nasal administration, penetrants appropriate to the particular
barrier to be
permeated are used in the formulation. Such penetrants are generally known in
the art.
The pharmaceutical compositions of the present invention may be manufactured
in a manner
that is known in the art, e.g., by means of conventional mixing, dissolving,
granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping, or
lyophilizing processes.
IS The pharmaceutical composition may be provided as a salt and can be formed
with many
acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic,
tartaric, malic, and succinic
acids. Salts tend to be more soluble in aqueous or other protonic solvents
than are the corresponding
free base forms. In other cases, the preparation may be a lyophilized powder
which may contain any
or all of the following: I mM to 50 mM histidine, 0.1% to 2% sucrose, and 2%
to 7% mannitol, at a
pH range of 4.5 to 5.5, that is combined with buffer prior to use.
After pharmaceutical compositions have been prepared, they can be placed in an
appropriate
container and labeled for treatment of an indicated condition. For
administration of NuABP, such
labeling would include amount, frequency, and method of administration.
Pharmaceutical compositions suitable for use in the invention include
compositions wherein
the active ingredients are contained in an effective amount to achieve the
intended purpose. The
determination of an effective dose is well within the capability of those
skilled in the art.
For any compound, the therapeutically effective dose can be estimated
initially either in cell
culture assays, e.g., of neoplastic cells, or in animal models such as mice,
rats, rabbits, dogs, or pigs.
An animal model may also be used to determine the appropriate concentration
range and route of
administration. Such information can then be used to determine useful doses
and routes for
administration in humans.
A therapeutically effective dose refers to that amount of active ingredient,
for example
NuABP or fragments thereof, antibodies of NuABP, and agonists, antagonists or
inhibitors of
NuABP, 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
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
as by calculating the EDS° (the dose therapeutically effective in 50%
of the population) or LDS° (the
dose lethal to 50% of the population) statistics. The dose ratio of toxic to
therapeutic effects is the
therapeutic index, which can be expressed as the LDS°/EDS°
ratio. Pharmaceutical compositions
which exhibit large therapeutic indices are preferred. The data obtained from
cell culture assays and
animal studies are used to formulate a range of dosage for human use. The
dosage contained in such
compositions is preferably within a range of circulating concentrations that
includes the EDS° with
little or no toxicity. The dosage varies within this range depending upon the
dosage form employed,
the sensitivity of the patient, and the route of administration.
The exact dosage will be determined by the practitioner, in light of factors
related to the
subject requiring treatment. Dosage and administration are adjusted to provide
sufficient levels of the
active moiety or to maintain the desired effect. Factors which may be taken
into account include the
severity of the disease state, the general health of the subject, the age,
weight, and gender of the
subject, time and frequency of administration, drug combination(s), reaction
sensitivities, and
response to therapy. Long-acting pharmaceutical compositions may be
administered every 3 to 4
I S 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 ,ug, up to a
total dose of
about I 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 NuABP may be used
for the
diagnosis of disorders characterized by expression of NuABP, or in assays to
monitor patients being
treated with NuABP or agonists, antagonists, or inhibitors of NuABP.
Antibodies useful for
diagnostic purposes may be prepared in the same manner as described above for
therapeutics.
Diagnostic assays for NuABP include methods which utilize the antibody and a
label to detect
NuABP 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 NuABP, including ELISAs, RIAs, and FACS,
are
known in the art and provide a basis for diagnosing altered or abnormal levels
of NuABP expression.
Normal or standard values for NuABP expression are established by combining
body fluids or cell
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
extracts taken from normal mammalian subjects, for example. human subjects,
with antibody to
NuABP under conditions suitable for complex formation. The amount of standard
complex formation
may be quantitated by various methods, such as photometric means. Quantities
of NuABP 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 NuABP 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 ofNuABP
may be correlated
with disease. The diagnostic assay may be used to determine absence, presence,
and excess
expression of NuABP, and to monitor regulation of NuABP levels during
therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting
polynueleotide
sequences, including genomic sequences, encoding NuABP or closely related
molecules may be used
to identify nucleic acid sequences which encode NuABP. The specificity of the
probe, whether it is
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 NuABP, 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 NuABP encoding sequences. The hybridization
probes of the subject
invention may be DNA or RNA and may be derived from the sequence of SEQ ID
N0:56-I 10 or
from genomic sequences including promoters, enhancers, and introns of the
NuABP gene.
Means for producing specific hybridization probes for DNAs encoding NuABP
include the
cloning of polynucleotide sequences encoding NuABP or NuABP 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 3'-P or 35S,
or by enzymatic labels,
such as alkaline phosphatase coupled to the probe via avidin/biotin coupling
systems, and the like.
Polynucleotide sequences encoding NuABP may be used for the diagnosis of
disorders
associated with expression ofNuABP. Examples of such disorders include, but
are not limited to, a
reproductive disorder such as disorders of prolactin production, infertility,
including tubal disease,
ovulatory defects, and endometriosis, disruptions of the estrous cycle,
disruptions of the menstrual
cycle, polycystic ovary syndrome, ovarian hyperstimulation syndrome,
endometrial and ovarian
tumors, uterine fibroids, autoimmune disorders, ectopie pregnancies, and
teratogenesis; cancer of the
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breast, fibrocystic breast disease, and galactorrhea; disruptions of
spermatogenesis, abnormal sperm
physiology, cancer of the testis, cancer of the prostate, benign prostatic
hyperplasia, prostatitis,
Peyronie's disease, impotence, carcinoma of the male breast, and gynecomastia;
an immune disorder
such as inflammation, actinic keratosis, acquired immunodeficiency syndrome
(AIDS), Addison's
disease. adult respiratory distress syndrome, allergies, ankylosing
spondylitis, amyloidosis, anemia,
arteriosclerosis, asthma, atherosclerosis, autoimmune hemolytic anemia,
autoimmune thyroiditis,
bronchitis, bursitis, cholecystitis, cirrhosis, contact dermatitis, Crohn's
disease, atopic dermatitis,
dermatomyositis, diabetes mellitus, emphysema, erythroblastosis fetalis,
erythema nodosum, atrophic
gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease,
Hashimoto's
thyroiditis, paroxysmal nocturnal hemoglobinuria, hepatitis,
hypereosinophilia, irritable bowel
syndrome, episodic lymphopenia with lymphocytotoxins, mixed connective tissue
disease (MCTD),
multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation,
myelofibrosis,
osteoarthritis, osteoporosis, pancreatitis, polycythemia vera, polymyositis,
psoriasis, Reiter's
syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic
anaphylaxis, systemic
lupus erythematosus, systemic sclerosis, primary thrombocythemia,
thrombocytopenic purpura,
ulcerative colitis, uveitis, Werner syndrome, complications of cancer,
hemodialysis, and
extracorporeal circulation, trauma, and hematopoietic cancer including
lymphoma, leukemia, and
myeloma; a neurological 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, neuroftbromatosis, tuberous sclerosis, cerebelloretinal
hemangioblastomatosis,
encephalotrigeminal syndrome, mental retardation and other developmental
disorders of the central
nervous system, cerebral palsy, neuroskeletal disorders, autonomic nervous
system disorders, cranial
nerve disorders, spinal cord diseases, muscular dystrophy and other
neuromuscular disorders,
peripheral nervous system disorders, dermatomyositis and polymyositis,
inherited, metabolic,
endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental
disorders including
mood, anxiety, and schizophrenic disorders, akathesia, amnesia, catatonia,
diabetic neuropathy,
tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and
Tourette's disorder; and
a cell proliferative disorder such as actinic keratosis, arteriosclerosis,
atherosclerosis, bursitis,
cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis,
paroxysmal nocturnal
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hemoglobinuria, polycvthemia 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. The polynucleotide
sequences encoding NuABP 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 NuABP
expression. Such qualitative or quantitative methods are well known in the
art.
In a particular aspect, the nucleotide sequences encoding NuABP may be useful
in assays that
detect the presence of associated disorders, particularly those mentioned
above. The nucleotide
sequences encoding NuABP 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 NuABP 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
NuABP, 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 NuABP, 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
42
CA 02359701 2001-07-17
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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
NuABP may involve the use of PCR. These oligomers may be chemically
synthesized, generated
enzymatically, or produced in vitro. Oligomers wilt preferably contain a
fragment of a polynucleotide
encoding NuABP, or a fragment of a polynucleotide complementary to the
polynucleotide encoding
NuABP, and will be employed under optimized conditions for identification of a
specific gene or
condition. Oligomers may also be employed under less stringent conditions for
detection or
quantification of closely related DNA or RNA sequences.
Methods which may also be used to quantify the expression of NuABP include
radiolabeling
or biotinylating nucleotides, coamplification of a control nucleic acid, and
interpolating results from
standard curves. (See, e.g., Melby, P.C. et al. (1993) J. Immunol. Methods
159:235-244; Duplaa, C.
et al. (1993) Anal. Biochem. 212:229-236.) The speed of quantitation of
multiple samples may be
accelerated by running the assay in a high-throughput format where the
oligomer of interest is
presented in various dilutions and a spectrophotometric 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 targets in a
microarray. The microarray
can be used to monitor the expression level of large numbers of genes
simultaneously and to identify
genetic variants, mutations, and polymorphisms. This information may be used
to determine gene
function, to understand the genetic basis of a disorder, to diagnose a
disorder, and to develop and
monitor the activities of therapeutic agents.
Microarrays may be prepared, used, and analyzed using methods known in the
art. (See, e.g.,
Brennan, T.M. et al. ( 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 W095/251 I
16; 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.)
In another embodiment of the invention, nucleic acid sequences encoding NuABP
may be
used to generate hybridization probes useful in mapping the naturally
occurring genomic sequence.
The sequences may be mapped to a particular chromosome, to a specific region
of a chromosome, or
to artificial chromosome constructions, e.g., human artificial chromosomes
(HACs), yeast artificial
chromosomes (YACs), 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,
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WO 00/44900 PCT/US00/02237
C.M. (1993) Blood Rev. 7:127-134; and Trask, B.J. (1991) Trends Genet. 7:149-
154.)
Fluorescent in situ hybridization (FISH) may be correlated with other physical
chromosome
mapping techniques and genetic map data. (See. e.g., Heinz-Ulrich, et al.
(1995) in Meyers, supra,
pp. 965-968.) Examples of genetic map data can be found in various scientific
journals or at the
Online Mendelian Inheritance in Man (OMIM) World Wide Web site. Correlation
between the
location of the gene encoding NuABP on a physical chromosomal map and a
specific disorder, or a
predisposition to a specific disorder, may help define the region of DNA
associated with that disorder.
The nucleotide sequences of the invention may be used to detect differences in
gene sequences among
normal, carrier, and affected individuals.
In situ hybridization of chromosomal preparations and physical mapping
techniques, such as
linkage analysis using established chromosomal markers, may be used for
extending genetic maps.
Often the placement of a gene on the chromosome of another mammalian species,
such as mouse,
may reveal associated markers even if the number or arm of a particular human
chromosome is not
known. New sequences can be assigned to chromosomal arms by physical mapping.
This provides
IS valuable information to investigators searching for disease genes using
positional cloning or other
gene discovery techniques. Once the disease or syndrome has been crudely
localized by genetic
linkage to a particular genomic region, e.g., ataxia-telangiectasia to 1 Iq22-
23, any sequences mapping
to that area may represent associated or regulatory genes for further
investigation. (See, e.g., Gatti,
R.A. et al. ( 1988) Nature 336:577-580.) The nucleotide sequence of the
subject invention may also be
used to detect differences in the chromosomal location due to translocation,
inversion, etc., among
normal, carrier, or affected individuals.
In another embodiment of the invention, NuABP, 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 NuABP 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 NuABP,
or fragments thereof,
and washed. Bound NuABP is then detected by methods well known in the art.
Purified NuABP 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
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antibodies capable of binding NuABP specifically compete with a test compound
for binding NuABP.
In this manner, antibodies can be used to detect the presence of any peptide
which shares one or more
antigenic determinants with NuABP.
In additional embodiments, the nucleotide sequences which encode NuABP may be
used in
any molecular biology techniques that have yet to be developed, provided the
new techniques rely on
properties of nucleotide sequences that are currently known, including, but
not limited to, such
properties as the triplet genetic code and specific base pair interactions.
Without further elaboration, it is believed that one skilled in the art can,
using the preceding
description, utilize the present invention to its fullest extent. The
following embodiments are,
therefore, to be construed as merely illustrative, and not limitative of the
remainder of the disclosure
in any way whatsoever.
Without further elaboration, it is believed that one skilled in the art can,
using the preceding
description, utilize the present invention to its fullest extent. The
following preferred specific
embodiments are, therefore, to be construed as 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, in
particular U.S. Ser. No. 60/117,905 and U.S. Ser. No. 60/117,904, are hereby
expressly incorporated
by reference.
EXAMPLES
I. Construction of cDNA Libraries
RNA was purchased from Clontech or isolated from tissues described in Table 4.
Some
tissues were homogenized and lysed in guanidinium isothiocyanate, while others
were homogenized
and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL
(Life Technologies), a
monophasic solution of phenol and guanidine isothiocyanate. The resulting
lysates were centrifuged
over CsCI cushions or extracted with chloroform. RNA was precipitated from the
lysates with either
isopropanol or sodium acetate and ethanol, or by other routine methods.
Phenol extraction and precipitation of RNA were repeated as necessary to
increase RNA
purity. In some cases, RNA was treated with DNase. For most libraries,
poly(A+) RNA was isolated
using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX latex
particles (QIAGEN,
Chatsworth CA), or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively,
RNA was
isolated directly from tissue lysates using other RNA isolation kits, e.g.,
the POLY(A)PURE mRNA
purification kit (Ambion, Austin TX).
In some cases, Stratagene was provided with RNA and constructed the
corresponding cDNA
libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed
with the UNIZAP
CA 02359701 2001-07-17
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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), PSPORTI plasmid (Life Technologies), or
pINCY (Incyte
Pharmaceuticals, Palo Alto CA). Recombinant plasmids were transformed into
competent E. coli
cells including XL1-Blue, XL1-BIueMRF, or SOLR from Stratagene or DHSa, DH10B,
or
ElectroMAX DH l OB from Life Technologies.
II. Isolation of cDNA Clones
Plasmids were recovered from host cells by in vivo excision using the UNIZAP
vector system
(Stratagene) or by cell lysis. Plasmids were purified using at least one of
the following: a Magic or
WIZARD Minipreps DNA purification system (Promega); an AGTC Miniprep
purification kit (Edge
Biosystems, Gaithersburg MD); and QIAWELL 8 Plasmid, QIAWELL 8 Plus Plasmid,
QIAWELL 8
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
cDNA sequencing reactions were processed using standard methods or high-
throughput
instrumentation such as the ABI CATALYST 800 (Perkin-Elmer) thermal cycler or
the PTC-200
thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser
(Robbins Scientific) or
the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions
were prepared
using reagents provided by Amersham Pharmacia Biotech or supplied in ABI
sequencing kits such as
the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Perkin-
Elmer).
Electrophoretic separation of cDNA sequencing reactions and detection of
labeled polynucleotides
were carried out using the MEGABACE 1000 DNA sequencing system (Molecular
Dynamics); the
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ABI PRISM 373 or 377 sequencing system (Perkin-Elmer) in conjunction with
standard ABI
protocols and base calling software: or other sequence analysis systems known
in the art. Reading
frames within the cDNA sequences were identified using standard methods
(reviewed in Ausubel,
1997, supra, unit 7.7). Some of the cDNA sequences were selected for extension
using the techniques
disclosed in Example V.
The polynucleotide sequences derived from cDNA sequencing were assembled and
analyzed
using a combination of software programs which utilize algorithms well known
to those skilled in the
art. Table 5 summarizes the tools, programs, and algorithms used and provides
applicable
descriptions, references. and threshold parameters. The first column of Table
5 shows the tools,
programs, and algorithms used, the second column provides brief descriptions
thereof, the third
column presents appropriate references, all of which are incorporated by
reference herein in their
entirety, and the fourth column presents, where applicable, the scores,
probability values, and other
parameters used to evaluate the strength of a match between two sequences (the
higher the score, the
greater the homology between two sequences). Sequences were analyzed using
MACDNASIS PRO
l5 software (Hitachi Software Engineering, South San Francisco CA) and
LASERGENE software
(DNASTAR). Polynucleotide and polypeptide sequence alignments were generated
using the default
parameters specified by the clustal algorithm as incorporated into the
MEGALIGN multisequence
alignment program (DNASTAR), which also calculates the percent identity
between aligned
sequences.
The polynucleotide sequences were validated by removing vector, linker, and
polyA
sequences and by masking ambiguous bases, using algorithms and programs based
on BLAST,
dynamic programing, and dinucleotide nearest neighbor analysis. The sequences
were then queried
against a selection of public databases such as the GenBank primate, rodent,
mammalian, vertebrate,
and eukaryote databases. and BLOCKS, PRINTS, DOMO, PRODOM, and PFAM to acquire
annotation using programs based on BLAST, FASTA, and BLIMPS. The sequences
were assembled
into full length polynucleotide sequences using programs based on Phred,
Phrap, and Consed, and
were screened for open reading frames using programs based on GeneMark, BLAST,
and FASTA.
The full length polynucleotide sequences were~translated to derive the
corresponding full length
amino acid sequences, and these full length sequences were subsequently
analyzed by querying
against databases such as the GenBank databases (described above), SwissProt,
BLOCKS, PRINTS,
DOMO, PRODOM, Prosite, and Hidden Markov Model (HMM)-based protein family
databases such
as PFAM. HMM is a probabilistic approach which analyzes consensus primary
structures of gene
families. (See, e.g., Eddy, S.R. (1996) Curr. Opin. Struct. Biol. 6:361-365.)
The programs described above for the assembly and analysis of full length
polynucleotide and
amino acid sequences were also used to identify polynucleotide sequence
fragments from SEQ ID
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WO 00/44900 PCT/US00/~2237
N0:56-110. Fragments from about 20 to about 4000 nucleotides which are useful
in hybridization
and amplification technologies were described in The Invention section above.
IV. Northern Analysis
Northern analysis is a laboratory technique used to detect the presence of a
transcript of a
gene and involves the hybridization of a labeled nucleotide sequence to a
membrane on which RNAs
from a particular cell type or tissue have been bound. (See, e.g., Sambrook,
supra, ch. 7; Ausubel,
1995, s_u~ra, ch. 4 and 16.)
Analogous computer techniques applying BLAST were used to search for identical
or related
molecules in nucleotide databases such as GenBank or LIFESEQ (Incyte
Pharmaceuticals). This
analysis is much faster than multiple membrane-based hybridizations. In
addition, the sensitivity of
the computer search can be modified to determine whether any particular match
is categorized as
exact or similar. The basis of the search is the product score, which is
defined as:
sequence identity x % maximum BLAST score
100
The product score takes into account both the degree of similarity between two
sequences and the
length of the sequence match. For example, with a product score of 40, the
match will be exact within
a 1% to 2% error, and, with a product score of 70, the match will be exact.
Similar molecules are
usually identified by selecting those which show product scores between 15 and
40, although lower
scores may identify related molecules.
The results of northern analyses are reported as a percentage distribution of
libraries in which
the transcript encoding NuABP occurred. Analysis involved the categorization
of cDNA libraries by
organ/tissue and disease. The organ/tissue categories included cardiovascular,
dermatologic,
developmental, endocrine, gastrointestinal, hematopoietic/immune,
musculoskeletal, nervous,
reproductive, and urologic. The disease/condition categories included cancer,
inflammation, trauma,
cell proliferation, neurological, and pooled. For each category, the number of
libraries expressing the
sequence of interest was counted and divided by the total number of libraries
across all categories.
Percentage values of tissue-specific and disease- or condition-specific
expression are reported in
Table 3.
V. Extension of NuABP Encoding Polynucleotides
The full length nucleic acid sequences of SEQ ID N0:56-110 were produced by
extension of
an appropriate fragment ofthe full length molecule using oligonucleotide
primers designed from this
fragment. One primer was synthesized to initiate 5' extension of the known
fragment, and the other
primer, to initiate 3' extension of the known fragment. The initial primers
were designed using
OLIGO 4.06 software (National Biosciences), or another appropriate program, to
be about 22 to 30
nucleotides in length, to have a GC content of about 50% or more, and to
anneal to the target
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sequence at temperatures of about 68°C to about 72°C. Any
stretch of nucleotides which would
result in hairpin structures and primer-primer dimerizations was avoided.
Selected human cDNA libraries were used to extend the sequence. If more than
one
extension was necessary or desired. additional or nested sets of primers were
designed.
High fidelity amplification was obtained by PCR using methods well known in
the art. PCR
was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research,
Inc.). The reaction
mix contained DNA template, 200 nmol of each primer, reaction buffer
containing Mg=-. (NHa)ZSO,,
and ~i-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 and PCI B: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec;
Step 3: 60°C, 1 min: Step 4: 68°C,
2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68°C, S
min; Step 7: storage at 4°C. In the
alternative, the parameters for primer pair T7 and SK+ were as follows: Step
1: 94°C, 3 min; Step 2:
94°C, 15 sec; Step 3: 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 pl
PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR)
dissolved in 1 X TE
and 0.5 pl of undiluted PCR product into each well of an opaque fluorimeter
plate (Corning Costar,
Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a
Fluoroskan II
(Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample
and to quantify the
concentration of DNA. A 5 ~l to 10 ~l aliquot of the reaction mixture was
analyzed by
electrophoresis on a 1 % agarose mini-gel to determine which reactions were
successful in extending
the sequence.
The extended nucleotides were desalted and concentrated, transferred to 384-
well plates,
digested with CviJI cholera virus endonuclease (Molecular Biology Research,
Madison WI), and
sonicated or sheared prior to relegation into pUC 18 vector (Amersham
Pharmacia Biotech). For
shotgun sequencing, the digested nucleotides were separated on low
concentration (0.6 to 0.8%)
agarose gels, fragments were excised, and agar digested with Agar ACE
(Promega). Extended clones
were relegated 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, 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; Step3:
60°C, 1 min; Step 4: 72°C, 2 min;
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CA 02359701 2001-07-17
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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 ( I :2, v/v), and sequenced using DYENAMIC energy
transfer sequencing
S primers and the DYENAMIC DIRECT kit (Amersham Pharmacia Biotech) or the ABI
PRISM
BIGDYE Terminator cycle sequencing ready reaction kit (Perkin-Elmer).
In like manner, the nucleotide sequences of SEQ ID N0:56-I 10 are used to
obtain 5'
regulatory sequences using the procedure above, oligonucleotides designed for
such extension, and an
appropriate genomic library.
VI. Labeling and Use of Individual Hybridization Probes
Hybridization probes derived from SEQ ID N0:56-1 10 are employed to screen
cDNAs,
genomie 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 ~cCi of
[y-3-'P] 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 dodeeyl sulfate.
Hybridization patterns are visualized using autoradiography or an alternative
imaging means and
compared.
VII. Microarrays
A chemical coupling procedure and an ink jet device can be used to synthesize
array
elements on the surface of a substrate. (See, e.g., Baldeschweiler, supra.) An
array analogous to a dot
or slot blot may also be used to arrange and link elements to the surface of a
substrate using thermal,
UV, chemical, or mechanical bonding procedures. A typical array may be
produced by hand or using
available methods and machines and contain any appropriate number of elements.
After
hybridization, nonhybridized probes are removed and a scanner used to
determine the levels and
patterns of fluorescence. The degree of complementarity and the relative
abundance of each probe
SO
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
which hybridizes to an element on the microarray may be assessed through
analysis of the scanned
images.
Full-length cDNAs, Expressed Sequence Tags (ESTs). or fragments thereof may
comprise
the elements of the microarray. Fragments suitable for hybridization can be
selected using software
well known in the art such as LASERGENE software (DNASTAR). Full-length cDNAs,
ESTs, or
fragments thereof corresponding to one of the nucleotide sequences of the
present invention, or
selected at random from a cDNA library relevant to the present invention, are
arranged on an
appropriate substrate, e.g., a glass slide. The cDNA is fixed to the slide
using, e.g., UV cross-linking
followed by thermal and chemical treatments and subsequent drying. (See, e.g.,
Schena, M. et al.
( 1995) Science 270:467-470; Shalom D. et al. ( 1996) Genome Res. 6:639-645.)
Fluorescent probes
are prepared and used for hybridization to the elements on the substrate. The
substrate is analyzed by
procedures described above.
VIII. Complementary Polynucleotides
Sequences complementary to the NuABP-encoding sequences, or any parts thereof,
are used
to detect, decrease, or inhibit expression of naturally occurring NuABP.
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 NuABP. 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 NuABP-encoding
transcript.
IX. Expression of NuABP
Expression and purification of NuABP is achieved using bacterial or virus-
based expression
systems. For expression of NuABP in bacteria, cDNA is subcloned into an
appropriate vector
containing an antibiotic resistance gene and an inducible promoter that
directs high levels of cDNA
transcription. Examples of such promoters include, but are not limited to, the
trp-lac (tac) hybrid
promoter and the TS or T7 bacteriophage promoter in conjunction with the lac
operator regulatory
element. Recombinant vectors are transformed into suitable bacterial hosts,
e.g., BL21 (DE3).
Antibiotic resistant bacteria express NuABP upon induction with isopropyl beta-
D-
thiogalactopyranoside (IPTG). Expression ofNuABP 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 NuABP 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
51
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
infect Spodoptera frugiperda (Sfi7) 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.
7:193 7-1945. )
In most expression systems, NuABP 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
NuABP 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,
l5 supra, ch. 10 and 16). Purified NuABP obtained by these methods can be used
directly in the
following activity assay.
X. Demonstration of NuABP Activity
NuABP activity is measured by its ability to stimulate transcription of a
reporter gene (Liu,
H.Y. et al. ( 1997) EMBO J. 16( 17):5289-5298.) The assay entails the use of a
well characterized
reporter gene construct, LexAoP LacZ, that consists of LexA DNA
transcriptional control elements
(LexAoP) fused to sequences encoding the E. coli LacZ enzyme. The methods for
constructing and
expressing fusions genes, introducing them into cells, and measuring LacZ
enzyme activity, are well
known to those skilled in the art. Sequences encoding NuABP are cloned into a
plasmid that directs
the synthesis of a fusion protein, LexA-NuABP, consisting of NuABP and a DNA
binding domain
derived from the LexA transcription factor. The resulting plasmid, encoding a
LexA-NuABP fusion
protein, is introduced into yeast cells along with a plasmid containing the
LexAoP LacZ reporter gene.
The amount of LacZ enzyme activity associated with LexA-NuABP transfected
cells, relative to
control cells, is proportional to the amount of transcription stimulated by
the NuABP.
XI. Functional Assays
NuABP function is assessed by expressing the sequences encoding NuABP 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 ~g of
recombinant vector
are transiently transfected into a human cell line, for example, an
endothelial or hematopoietic cell
52
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
line, using either liposome formulations or electroporation. 1-2 ~g of an
additional plasmid
containing sequences encoding a marker protein are co-transfected. Expression
of a marker protein
provides a means to distinguish transfeeted 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 ofNuABP on gene expression can be assessed using highly purified
populations of cells transfeeted with sequences encoding NuABP 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 NuABP and other genes of interest can be
analyzed by northern
analysis or microarray techniques.
XII. Production of NuABP Specific Antibodies
NuABP 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 NuABP 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. I l.)
Typically, oligopeptides of about 1 S residues in length are synthesized using
an ABI 431 A
peptide synthesizer (Perkin-Elmer) using fmoc-chemistry and coupled to KLH
(Sigma-Aldrich, St.
Louis MO) by reaction with N-maleimidobenzoyl-N-hydroxysuecinimide ester (MBS)
to increase
53
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
immunogenicity. (See. e.g., Ausubel, 1995, supra.) Rabbits are immunized with
the oligopeptide-
KLH complex in complete Freund's adjuvant. Resulting antisera are tested for
antipeptide and anti-
NuABP activity by, for example, binding the peptide or NuABP to a substrate,
blocking with 1
BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated
goat anti-rabbit IgG.
XIII. Purification of Naturally Occurring NuABP Using Specific Antibodies
Naturally occurring or recombinant NuABP is substantially purified by
immunoaffinity
chromatography using antibodies specific for NuABP. An immunoaffinity column
is constructed by
covalently coupling anti-NuABP 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 NuABP are passed over the immunoaffinity column, and the
column is
washed under conditions that allow the preferential absorbance of NuABP (e.g.,
high ionic strength
buffers in the presence of detergent). The column is eluted under conditions
that disrupt
antibodylNuABP 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 NuABP is collected.
XIV. Identification of Molecules Which Interact with NuABP
NuABP, or biologically active fragments thereof, are labeled with '-'SI Bolton-
Hunter reagent.
(See, e.g., Bolton A.E. and W.M. Hunter (1973) Biochem. J. 133:529-539.)
Candidate molecules
previously arrayed in the wells of a multi-well plate are incubated with the
labeled NuABP, washed,
and any wells with labeled NuABP complex are assayed. Data obtained using
different
concentrations of NuABP are used to calculate values for the number, affinity,
and association of
NuABP with the candidate molecules.
Various modifications and variations of the described methods and systems of
the invention
will be apparent to those skilled in the art without departing from the scope
and spirit of the invention.
Although the invention has been described in connection with certain
embodiments, it should be
understood that the invention as claimed should not be unduly limited to such
specific embodiments.
Indeed, various modifications of the described modes for carrying out the
invention which are
obvious to those skilled in molecular biology or related fields are intended
to be within the scope of
the following claims.
54
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/D2237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00102237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00/02237
0
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00102237
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
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CA 02359701 2001-07-17
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
p ~' v
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SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
V ~a
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84/1
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00/02237
SEQUENCE LISTING
<110> INCYTE PHARMACEUTICALS, INC.
TANG, Y. Tom
LAL, Preeti
HILLMAN, Jennifer L.
YUE, Henry
AZIMZAI, Yalda
LU, Aina M.D.
BAUGHN, Mariah R.
TRAN, Bao
SHIH, Leo L.
AU-YOUNG, Janice
<120> NUCLEIC ACID-BINDING PROTEINS
<130> PF-0662 PCT
<140> To Be Assigned
<141> Herewith
<150> 60/117,905; 60/117,904
<151> 1999-01-29; 1999-01-29
<160> 110
<170> PERL Program
<210> 1
<211> 754
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 025733CD1
<400> 1
Met Ala Ala Ala Gly Ser Arg Lys Arg Arg Leu Ala Glu Leu Thr
1 5 10 15
Val Asp Glu Phe Leu Ala Ser Gly Phe Asp Ser Glu Ser Glu Ser
20 25 30
Glu Ser Glu Asn Ser Pro Gln Ala Glu Thr Arg Glu Ala Arg Glu
35 40 45
Ala Ala Arg Ser Pro Asp Lys Pro Gly Gly Ser Pro Ser Ala Ser
50 55 60
Arg Arg Lys Gly Arg Ala Ser Glu His Lys Asp Gln Leu Ser Arg
65 70 75
Leu Lys Asp Arg Asp Pro Glu Phe Tyr Lys Phe Leu Gln Glu Asn
80 85 90
Asp Gln Ser Leu Leu Asn Phe Ser Asp Ser Asp Ser Ser Glu Glu
95 100 105
Glu Glu Gly Pro Phe His Ser Leu Pro Asp Val Leu Glu Glu Ala
110 115 120
Ser Glu Glu Glu Asp Gly Ala Glu Glu Gly Glu Asp Gly Asp Arg
125 130 135
Val Pro Arg Gly Leu Lys Gly Lys Lys Asn Ser Val Pro Val Thr
140 145 150
Val Ala Met Val Glu Arg Trp Lys Gln Aia Ala Lys Gln Arg Leu
155 160 165
1/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Thr Pro Lys Leu Phe His Glu Val Val Gln Ala Phe Arg Ala Ala
170 175 180
Val Ala Thr Thr Arg Gly Asp Gln Glu Ser Ala Glu Ala Asn Lys
185 190 195
Phe Gln Val Thr Asp Ser Ala Ala Phe Asn Ala Leu Val Thr Phe
200 205 210
Cys Ile Arg Asp Leu Ile Gly Cys Leu Gln Lys Leu Leu Phe Gly
215 220 225
Lys Val Ala Lys Asp Ser Ser Arg Met Leu Gln Pro Ser Ser Ser
230 235 240
Pro Leu Trp Gly Lys Leu Arg Val Asp Ile Lys Ala Tyr Leu Gly
245 250 255
Ser Ala Ile Gln Leu Val Ser Cys Leu Ser Glu Thr Thr Val Leu
260 265 270
Ala Ala Val Leu Arg His Ile Ser Val Leu Val Pro Cys Phe Leu
275 280 285
Thr Phe Pro Lys Gln Cys Arg Met Leu Leu Lys Arg Met Val Val
290 295 300
Val Trp Ser Thr Gly Glu Glu Ser Leu Arg Val Leu Ala Phe Leu
305 310 315
Val Leu Ser Arg Val Cys Arg His Lys Lys Asp Thr Phe Leu Gly
320 325 330
Pro Val Leu Lys Gln Met Tyr Ile Thr Tyr Val Arg Asn Cys Lys
335 340 345
Phe Thr Ser Pro Gly Ala Leu Pro Phe Ile Ser Phe Met Gln Trp
350 355 360
Thr Leu Thr Glu Leu Leu Ala Leu Glu Pro Gly Val Ala Tyr Gln
365 370 375
His Ala Phe Leu Tyr Ile Arg Gln Leu Ala Ile His Leu Arg Asn
380 385 390
Ala Met Thr Thr Arg Lys Lys Glu Thr Tyr Gln Ser Val Tyr Asn
395 400 405
Trp Gln Tyr Val His Cys Leu Phe Leu Trp Cys Arg Val Leu Ser
410 415 420
Thr Ala Gly Pro Ser Glu Ala Leu Gln Pro Leu Val Tyr Pro Leu
425 430 435
Ala Gln Val Ile Ile Gly Cys Ile Lys Leu Ile Pro Thr Ala Arg
440 445 450
Phe Tyr Pro Leu Arg Met His Cys Ile Arg Ala Leu Thr Leu Leu
455 460 465
Ser Gly Ser Ser Gly Ala Phe Ile Pro Val Leu Pro Phe Ile Leu
470 475 480
Glu Met Phe Gln Gln Val Asp Phe Asn Arg Lys Pro Gly Arg Met
485 490 495
Ser Ser Lys Pro Ile Asn Phe Ser Val Ile Leu Lys Leu Ser Asn
500 505 510
Val Asn Leu Gln Glu Lys Ala Tyr Arg Asp Gly Leu Val Glu Gln
515 520 525
Leu Tyr Asp Leu Thr Leu Glu Tyr Leu His Ser Gln Ala His Cys
530 535 540
Ile Gly Phe Pro Glu Leu Val Leu Pro Val Val Leu Gln Leu Lys
545 550 555
Ser Phe Leu Arg Glu Cys Lys Val Ala Asn Tyr Cys Arg Gln Val
560 565 570
Gln Gln Leu Leu Gly Lys Val Gln Glu Asn Ser Ala Tyr Ile Cys
575 580 585
Ser Arg Arg Gln Arg Val Ser Phe Gly Val Ser Glu Gln Gln Ala
590 595 600
Val Glu Ala Trp Glu Lys Leu Thr Arg Glu Glu Gly Thr Pro Leu
605 610 615
2/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Thr Leu Tyr Tyr Ser His Trp Arg Lys Leu Arg Asp Arg Glu Ile
620 625 630
Gln Leu Glu Ile Ser Gly Lys Glu Arg Leu Glu Asp Leu Asn Phe
635 640 645
Pro Glu Ile Lys Arg Arg Lys Met Ala Asp Arg Lys Asp Glu Asp
650 655 660
Arg Lys Gln Phe Lys Asp Leu Phe Asp Leu Asn Ser Ser Glu Glu
665 670 675
Asp Asp Thr Glu Gly Phe Ser Glu Arg Gly Ile Leu Arg Pro Leu
680 685 690
Ser Thr Arg His Gly Val Glu Asp Asp Glu Glu Asp Glu Glu Glu
695 700 . 705
Gly Glu Glu Asp Ser Ser Asn Ser Glu Gly Glu Trp Ser Trp Asp
710 715 720
Gly Asp Pro Asp Ala Glu Ala Gly Leu Ala Pro Gly Glu Leu Gln
725 730 735
Gln Leu Ala Gln Gly Pro Glu Asp Glu Leu Glu Asp Leu Gln Leu
740 745 750
Ser Glu Asp Asp
<210> 2
<211> 593
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 079702CD1
<400> 2
Met Arg Asp Ser Thr Gly Ala Gly Asn Ser Leu Val His Lys Arg
1 5 10 15
Ser Pro Leu Arg Arg Asn Gln Lys Thr Pro Thr Ser Leu Thr Lys
20 25 30
Leu Ser Leu Gln Asp Gly His Lys Ala Lys Lys Pro Ala Cys Lys
35 40 45
Phe Glu Glu Gly Gln Asp Val Leu Ala Arg Trp Ser Asp Gly Leu
50 55 60
Phe Tyr Leu Gly Thr Ile Lys Lys Ile Asn Ile Leu Lys Gln Ser
65 70 75
Cys Phe Ile Ile Phe Glu Asp Ser Ser Lys Ser Trp Val Leu Trp
80 85 90
Lys Asp Ile Gln Thr Gly Ala Thr Gly Ser Gly Glu Met Val Cys
95 100 105
Thr Ile Cys Gln Glu Glu Tyr Ser Glu Ala Pro Asn Glu Met Val
110 115 120
Ile Cys Asp Lys Cys Gly Gln Gly Tyr His Gln Leu Cys His Thr
125 130 135
Pro His Ile Asp Ser Ser Val Ile Asp Ser Asp Glu Lys Trp Leu
140 145 150
Cys Arg Gln Cys Val Phe Ala Thr Thr Thr Lys Arg Gly Gly Ala
155 160 165
Leu Lys Lys Gly Pro Asn Ala Lys Ala Leu Gln Val Met Lys Gln
170 175 180
Thr Leu Pro Tyr Ser Val Ala Asp Leu Glu Trp Asp Ala Gly His
185 190 195
Lys Thr Asn Val Gln Gln Cys Tyr Cys Tyr Cys Gly Gly Pro Gly
200 205 210
Asp Trp Tyr Leu Lys Met Leu Gln Cys Cys Lys Cys Lys Gln Trp
3/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
215 220 225
Phe His Glu Ala Cys Val Gln Cys Leu Gln Lys Pro Met Leu Phe
230 235 240
Gly Asp Arg Phe Tyr Thr Phe Ile Cys Ser Val Cys Ser Ser Gly
245 250 255
Pro Glu Tyr Leu Lys Arg Leu Pro Leu Gln Trp Val Asp Ile Ala
260 265 270
His Leu Cys Leu Tyr Asn Leu Ser Val Ile His Lys Lys Lys Tyr
275 280 285
Phe Asp Ser Glu Leu Glu Leu Met Thr Tyr Ile Asn Glu Asn Trp
290 295 300
Asp Arg Leu His Pro Gly Glu Leu Ala Asp Thr Pro Lys Ser Glu
305 310 315
Arg Tyr Glu His Val Leu Glu Ala Leu Asn Asp Tyr Lys Thr Met
320 325 330
Phe Met Ser Gly Lys Glu Ile Lys Lys Lys Lys His Leu Phe Gly
335 340 345
Leu Arg Ile Arg Val Pro Pro Val Pro Pro Asn Val Ala Phe Lys
350 355 360
Ala Glu Lys Glu Pro Glu Gly Thr Ser His Glu Phe Lys Ile Lys
365 370 375
Gly Arg Lys Ala Ser Lys Pro Ile Ser Asp Ser Arg Glu Val Ser
380 385 390
Asn Gly Ile Glu Lys Lys Lys Lys Lys Lys Ser Val Gly Arg Pro
395 400 405
Pro Gly Pro Tyr Thr Arg Lys Met Ile Gln Lys Thr Ala Glu Pro
410 415 420
Leu Leu Asp Lys Glu Ser Ile Ser Glu Asn Pro Thr Leu Asp Leu
425 430 435
Pro Cys Ser Ile Gly Arg Thr Glu Gly Thr Ala His Ser Ser Asn
440 445 450
Thr Ser Asp Val Asp Phe Thr Gly Ala Ser Ser Ala Lys Glu Thr
455 460 465
Thr Ser Ser Ser Ile Ser Arg His Tyr Gly Leu Ser Asp Ser Arg
470 475 480
Lys Arg Thr Arg Thr Gly Arg Ser Trp Pro Ala Ala Ile Pro His
485 490 495
Leu Arg Arg Arg Arg Gly Arg Leu Pro Arg Arg Ala Leu Gln Thr
500 505 510
Gln Asn Ser Glu Ile Val Lys Asp Asp Glu Gly Lys Glu Asp Tyr
515 520 525
Gln Phe Asp Glu Leu Asn Thr Glu Ile Leu Asn Asn Leu Ala Asp
530 535 540
Gln Glu Leu Gln Leu Asn His Leu Lys Asn Ser Ile Thr Ser Tyr
545 550 555
Phe Gly Ala Ala Gly Arg Ile Ala Cys Gly Glu Lys Tyr Arg Val
560 565 570
Leu Ala Arg Arg Val Thr Leu Asp Gly Lys Val Gln Tyr Leu Val
575 580 585
Glu Trp Glu Gly Ala Thr Ala Ser
590
<210> 3
<211> 534
<212> PRT
<213> Homo Sapiens
<220>
4/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<221> misc-feature
<223> Incyte ID No.: 116208CD1
<400> 3
Met Arg Ala Leu His Leu Leu Lys Ser Gly Cys Ser Pro Ala Val
1 5 10 15
Gln Ile Lys Ile Arg Glu Leu Tyr Arg Arg Arg Tyr Pro Arg Thr
20 25 30
Leu Glu Gly Leu Ser Asp Leu Ser Thr Ile Lys Ser Ser Val Phe
35 40 45
Ser Leu Asp Gly Gly Ser Ser Pro Val Glu Pro Asp Leu Ala Val
50 55 60
Ala Gly Ile His Ser Leu Pro Ser Thr Ser Val Thr Pro His Ser
65 70 75
Pro Ser Ser Pro Val Gly Ser Val Leu Leu Gln Asp Thr Lys Pro
80 85 90
Thr Phe Glu Met Gln Gln Pro Ser Pro Pro Ile Pro Pro Val His
95 100 105
Pro Asp Val Gln Leu Lys Asn Leu Pro Phe Tyr Asp Val Leu Asp
110 115 120
Val Leu Ile Lys Pro Thr Ser Leu Val Gln Ser Ser Ile Gln Arg
125 130 135
Phe Gln Glu Lys Phe Phe Ile Phe Ala Leu Thr Pro Gln Gln Val
140 145 150
Arg Glu Ile Cys Ile Ser Arg Asp Phe Leu Pro Gly Gly Arg Arg
155 160 165
Asp Tyr Thr Val Gln Val Gln Leu Arg Leu Cys Leu Ala Glu Thr
170 175 180
Ser Cys Pro Gln Glu Asp Asn Tyr Pro Asn Ser Leu Cys Ile Lys
185 190 195
Val Asn Gly Lys Leu Phe Pro Leu Pro Gly Tyr Ala Pro Pro Pro
200 205 210
Lys Asn Gly Ile Glu Gln Lys Arg Pro Gly Arg Pro Leu Asn Ile
215 220 225
Thr Ser Leu Val Arg Leu Ser Ser Ala Val Pro Asn Gln Ile Ser
230 235 240
Ile Ser Trp Ala Ser Glu I1e Gly Lys Asn Tyr Ser Met Ser Val
245 250 255
Tyr Leu Val Arg Gln Leu Thr Ser Ala Met Leu Leu Gln Arg Leu
260 265 270
Lys Met Lys Gly Ile Arg Asn Pro Asp His Ser Arg Ala Leu Ser
275 280 285
Lys Glu Lys Leu Thr Ala Asp Pro Asp Ser Glu Ile Ala Thr Thr
290 295 300
Ser Leu Arg Val Ser Leu Met Cys Pro Leu Gly Lys Met Arg Leu
305 310 315
Thr Ile Pro Cys Arg Ala Val Thr Cys Thr His Leu Gln Cys Phe
320 325 330
Asp Ala Ala Leu Tyr Leu Gln Met Asn Glu Lys Lys Pro Thr Trp
335 340 345
Ile Cys Pro Val Cys Asp Lys Lys Ala Ala Tyr Glu Ser Leu Ile
350 355 360
Leu Asp Gly Leu Phe Met Glu Ile Leu Asn Asp Cys Ser Asp Val
365 370 375
Asp Glu Ile Lys Phe Gln Glu Asp Gly Ser Trp Cys Pro Met Arg
380 385 390
Pro Lys Lys Glu Ala Met Lys Val Ser Ser Gln Pro Cys Thr Lys
395 400 405
Ile Glu Ser Ser Ser Val Leu Ser Lys Pro Cys Ser Val Thr Val
410 415 420
Ala Ser Glu Ala Ser Lys Lys Lys Val Asp Val Ile Asp Leu Thr
425 430 435
5/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Ile Glu Ser Ser Ser Asp Glu Glu Glu Asp Pro Pro Ala Lys Arg
440 445 450
Lys Cys Ile Phe Met Ser Glu Thr Gln Ser Ser Pro Thr Lys Gly
455 460 465
Val Leu Met Tyr Gln Pro Ser Ser Val Arg Val Pro Ser Val Thr
470 475 480
Ser Val Asp Pro Ala Ala Ile Pro Pro Ser Leu Thr Asp Tyr Ser
485 490 495
Val Pro Phe His His Thr Pro Ile Ser Ser Met Ser Ser Asp Leu
500 505 510
Pro Gly Glu Gln Arg Arg Asn Asp Ile Asn Asn Glu Leu Lys Leu
515 520 525
Gly Thr Ser Ser Asp Thr Val Gln Gln
530
<210> 4
<211> 255
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No.: 179261CD1
<400> 4
Met Lys Ile Ile Ser Glu Asn Val Pro Ser Tyr Lys Thr His Glu
1 5 10 15
Ser Leu Thr Leu Pro Arg Arg 1'hr His Asp Ser Glu Lys Pro Tyr
20 25 30
Glu Tyr Lys Glu Tyr Glu Lys Val Phe Ser Cys Asp Leu Glu Phe
35 40 45
Asp Glu Tyr Gln Lys Ile His Thr Gly Gly Lys Asn Tyr Glu Cys
50 55 60
Asn Gln Cys Trp Lys Thr Phe Gly Ile Asp Asn Ser Ser Met Leu
65 70 75
Gln Leu Asn Ile His Thr Gly Val Lys Pro Cys Lys Tyr Met Glu
80 85 90
Tyr Gly Asn Thr Cys Ser Phe Tyr Lys Asp Phe Asn Val Tyr Gln
95 100 105
Lys Ile His Asn Glu Lys Phe Tyr Lys Cys Lys Glu Tyr Arg Arg
110 115 120
Thr Phe Glu Arg Val Gly Lys Val Thr Pro Leu Gln Arg Val His
125 130 135
Asp Gly Glu Lys His Phe Glu Cys Ser Phe Cys Gly Lys Ser Phe
140 145 150
Arg Val His Ala Gln Leu Thr Arg His Gln Lys Ile His Thr Asp
155 160 165
Glu Lys Thr Tyr Lys Cys Met Glu Cys Gly Lys Asp Phe Arg Phe
170 175 180
His Ser Gln Leu Thr Glu His Gln Arg Ile His Thr Gly Glu Lys
185 190 195
Pro Tyr Lys Cys Met His Cys Glu Lys Val Phe Arg Ile Ser Ser
200 205 210
Gln Leu Ile Glu His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr
215 220 225
Ala Cys Lys Glu Cys Gly Lys Ala Phe Gly Val Cys Arg Glu Leu
230 235 240
Ala Arg His Gln Arg Ile His Thr Gly Lys Tyr Cys Gly Trp Ile
245 250 255
6/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<210> 5
<211> 562
<212> PRT
<213> Homo sapiens
<220>
<221> misc feature
<223> Incyte ID No.: 259161CD1
<400> 5
Met Ala Ser Val Ser Ala Leu Thr Glu Glu Leu Asp Ser Ile Thr
1 5 10 15
Ser Glu Leu His Ala Val Glu Ile Gln Ile Gln Glu Leu Thr Glu
20 25 30
Arg Gln Gln Glu Leu Ile Gln Lys Lys Lys Val Leu Thr Lys Lys
35 40 45
Ile Lys Gln Cys Leu Glu Asp Ser Asp Ala Gly Ala Ser Asn Glu
50 55 60
Tyr Asp Ser Ser Pro Ala Ala Trp Asn Lys Glu Asp Phe Pro Trp
65 70 75
Ser Gly Lys Val Lys Asp Ile Leu Gln Asn Val Phe Lys Leu Glu
80 85 90
Lys Phe Arg Pro Leu Gln Leu Glu Thr Ile Asn Val Thr Met Ala
95 100 105
Gly Lys Glu Val Phe Leu Val Met Pro Thr Gly Gly Gly Lys Ser
110 115 120
Leu Cys Tyr Gln Leu Pro Ala Leu Cys Ser Asp Gly Phe Thr Leu
125 130 135
Val Ile Cys Pro Leu Ile Ser Leu Met Glu Asp Gln Leu Met Val
140 145 150
Leu Lys Gln Leu Gly Ile Ser Ala Thr Met Leu Asn Ala Ser Ser
155 160 165
Ser Lys Glu His Val Lys Trp Val His Ala Glu Met Val Asn Lys
170 175 180
Asn Ser Glu Leu Lys Leu Ile Tyr Val Thr Pro Glu Lys Ile Ala
185 190 195
Lys Ser Lys Met Phe Met Ser Arg Leu Glu Lys Ala Tyr Glu Ala
200 205 210
Arg Arg Phe Thr Arg Ile Ala Val Asp Glu Val His Cys Cys Ser
215 220 225
Gln Trp Gly His Asp Phe Arg Pro Asp Tyr Lys Ala Leu Gly Ile
230 235 240
Leu Lys Arg Gln Phe Pro Asn Ala Ser Leu Ile Gly Leu Thr Ala
245 250 255
Thr Ala Thr Asn His Val Leu Thr Asp Ala Gln Lys Ile Leu Cys
260 265 270
Ile Glu Lys Cys Phe Thr Phe Thr Ala Ser Phe Asn Lys Pro Asp
275 280 285
Val Arg Phe Val Ile His His Ser Met Ser Lys Ser Met Glu Asn
290 295 300
Tyr Tyr Gln Glu Ser Gly Arg Ala Gly Arg Asp Asp Met Lys Ala
305 310 315
Asp Cys Ile Leu Tyr Tyr Gly Phe Gly Asp Ile Phe Arg Ile Ser
320 325 330
Ser Met Val Val Met Glu Asn Val Gly Gln Gln Lys Leu Tyr Glu
335 340 345
Met Val Ser Tyr Cys Gln Asn Ile Ser Lys Cys Arg Arg Val Leu
350 355 360
Met Ala Gln His Phe Asp Glu Val Trp Asn Ser Glu Ala Cys Asn
7/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
365 370 375
Lys Met Cys Asp Asn Cys Cys Lys Asp Ser Ala Phe Glu Arg Lys
380 385 390
Asn Ile Thr Glu Tyr Cys Arg Asp Leu Ile Lys Ile Leu Lys Gln
395 400 405
Ala Glu Glu Leu Asn Glu Lys Leu Thr Pro Leu Lys Leu Ile Asp
410 415 420
Ser Trp Met Gly Lys Gly Ala Ala Lys Leu Arg Val Ala Gly Val
425 430 435
Val Ala Pro Thr Leu Pro Arg Glu Asp Leu Glu Lys Ile Ile Ala
440 445 450
His Phe Leu Ile Gln Gln Tyr Leu Lys Glu Asp Tyr Ser Phe Thr
455 460 465
Ala Tyr Ala Thr Ile Ser Tyr Leu Lys Ile Gly Pro Lys Ala Asn
470 475 480
Leu Leu Asn Asn Glu Ala His Ala Ile Thr Met Gln Val Thr Lys
485 490 495
Ser Thr Gln Asn Ser Phe Arg Ala Glu Ser Ser Gln Thr Cys His
500 505 510
Ser Glu Gln Gly Asp Lys Lys Ile Gly Gly Lys Lys Phe Gln Ala
515 520 525
Thr Ser Arg Arg Arg Leu Gln Thr Cys Phe Ser Asn Leu Val Leu
530 535 540
Arg Ile Gln Glu Leu Arg Lys Glu Lys Ser Met Met Pro Asp Met
545 550 555
Thr Val Thr Lys Phe Ser Asn
560
<210> 6
<211> 432
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 320087CD1
<400> 6
Met Ser Glu Leu Lys Asp Cys Pro Leu Gln Phe His Asp Phe Lys
1 5 10 15
Ser Val Asp His Leu Lys Val Cys Pro Arg Tyr Thr Ala Val Leu
20 25 30
Ala Arg Ser Glu Asp Asp Gly Ile Gly Ile Glu Glu Leu Asp Thr
35 40 45
Leu Gln Leu Glu Leu Glu Thr Leu Leu Ser Ser Ala Ser Arg Arg
50 55 60
Leu Arg Val Leu Glu Ala Glu Thr Gln Ile Leu Thr Asp Trp Gln
65 70 75
Asp Lys Lys Gly Asp Arg Arg Phe Leu Lys Leu Gly Arg Asp His
80 85 90
Glu Leu Gly Ala Pro Pro Lys His Gly Lys Pro Lys Lys Gln Lys
95 100 105
Leu Glu Gly Lys Ala Gly His Gly Pro Gly Pro Gly Pro Gly Arg
110 115 120
Pro Lys Ser Lys Asn Leu Gln Pro Lys Ile Gln G1u Tyr Glu Phe
125 130 135
Thr Asp Asp Pro Ile Asp Val Pro Arg Ile Pro Lys Asn Asp Ala
140 145 150
8/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
Pro Asn Arg Phe Trp Ala Ser Val Glu Pro Tyr Cys Ala Asp Ile
155 160 165
Thr Ser Glu Glu Val Arg Thr Leu Glu Glu Leu Leu Lys Pro Pro
170 175 180
Glu Asp Glu Ala Glu His 'I'~~r Lys Ile Pro Pro Leu Gly Lys His
185 190 195
Tyr Ser Gln Arg Trp Ala Gln Glu Asp Leu Leu Glu Glu Gln Lys
200 205 210
Asp Gly Ala Arg Ala Ala Ala Val Ala Asp Lys Lys Lys Gly Leu
215 220 225
Met Gly Pro Leu Thr Glu Leu Asp Thr Lys Asp Val Asp Ala Leu
230 235 240
Leu Lys Lys Ser Glu Ala Gln His Glu Gln Pro Glu Asp Gly Cys
245 250 255
Pro Phe Gly Ala Leu Thr Gln Arg Leu Leu Gln Ala Leu Val Glu
260 265 270
Glu Asn Ile Ile Ser Pro Met Glu Asp Ser Pro Ile Pro Asp Met
275 280 285
Ser Gly Lys Glu Ser Gly Ala Asp Gly Ala Ser Thr Ser Pro Arg
290 295 300
Asn Gln Asn Lys Pro Phe Ser Val Pro His Thr Lys Ser Leu Glu
305 310 315
Ser Arg Ile Lys Glu Glu Leu Ile Ala Gln Gly Leu Leu Glu Ser
320 325 330
Glu Asp Arg Pro Ala Glu Asp Ser Glu Asp Glu Val Leu Ala Glu
335 340 345
Leu Arg Lys Arg Gln Ala Glu Leu Lys Ala Leu Ser Ala His Asn
350 355 360
Arg Thr Lys Lys His Asp Leu Leu Arg Leu Ala Lys Glu Glu Val
365 370 375
Ser Arg Gln Glu Leu Arg Gln Arg Val Arg Met Ala Asp Asn Glu
380 385 390
Val Met Asp Ala Phe Arg Lys Ile Met Ala Ala Arg Gln Lys Lys
395 400 405
Arg Thr Pro Thr Lys Lys Glu Lys Asp Gln Ala Trp Lys Thr Leu
410 415 420
Lys Glu Arg Glu Ser Ile Leu Lys Leu Leu Asp Gly
425 43 0
<210> 7
<211> 799
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> 491271CD1
<400> 7
Met Pro Ser Gln Asn Tyr Asp Leu Pro Gln Lys Lys Gln Glu Lys
1 5 10 15
Met Thr Lys Phe Gln Glu Ala Val Thr Phe Lys Asp Val Ala Val
20 25 30
Val Phe Ser Arg Glu Glu Leu Arg Leu Leu Asp Leu Thr Gln Arg
35 40 45
Lys Leu Tyr Arg Asp Val Met Val Glu Asn Phe Lys Asn Leu Val
50 55 60
Ala Val Gly His Leu Pro Phe Gln Pro Asp biet Val Ser Gln Leu
65 70 75
9/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Glu Ala Glu Glu Lys Leu Trp Met Met Glu Thr Glu Thr Gln Arg
80 85 90
Ser Ser Lys His Gln Asn Lys Met Glu Thr Leu Gln Lys Phe Ala
95 100 105
Leu Lys 'I"yr Leu Ser Asn Gln Glu Leu Ser Cys Trp Gln Ile Trp
110 115 120
Lys Gln Val Ala Ser Glu Leu Thr Arg Cys Leu Gln Gly Lys Ser
125 130 135
Ser Gln Leu Leu Gln Gly Asp Ser Ile Gln Val Ser Glu Asn Glu
140 145 150
Asn Asn Ile Met Asn Pro Lys Gly Asp Ser Pro Ile Tyr Ile Glu
155 160 165
Asn Gln Glu Phe Pro Phe Trp Arg Thr Gln His Ser Cys Gly Asn
170 175 180
Thr Tyr Leu ser Glu Ser Gln Ile Gln Ser Arg Gly Lys Gln Ile
185 190 195
Asp Val Lys Asn Asn Leu Gln Ile Arg Glu Asp Phe Val Lys Lys
200 205 210
Ser Pro Phe His Glu His Ile Lys Thr Asp Thr Glu Pro Lys Pro
215 220 225
Cys Lys Gly Asn Glu Tyr Gly Lys Ile Ile Ser Asp Gly Ser Asn
230 235 240
Gln Lys Leu Pro Leu Gly Glu Lys Pro His Pro Cys Gly Glu Cys
245 2S0 255
Gly Arg Gly Phe Ser Tyr Ser Pro Arg Leu Pro Leu His Pro Asn
260 265 270
Val His Thr Gly Glu Lys Cys Phe Ser Gln Ser Ser His Leu Arg
275 280 285
Thr His Gln Arg Ile His Pro Gly Glu Lys Leu Asn Arg Cys His
290 295 30U
Glu Ser Gly Asp Cys Phe Asn Lys Ser Ser Phe His Ser Tyr Gln
305 310 315
Ser Asn His Thr Gly Glu Lys Ser Tyr Arg Cys Asp Ser Cys Gly
320 325 330
Lys Gly Phe Ser Ser Ser Thr Gly Leu Ile Ile His Tyr Arg Thr
335 340 345
His Thr Gly Glu Lys Pro Tyr Lys Cys Glu Glu Cys Gly Lys Cys
350 35S 360
Phe Ser Gln Ser Ser Asn Phe Gln Cys His Gln Arg Val His Thr
365 370 375
Glu Glu Lys Pro Tyr Lys Cys Glu Glu Cys Gly Lys Gly Phe Gly
380 385 390
Trp Ser Val Asn Leu Arg Val His Gln Arg Val His Arg Gly Glu
395 400 405
Lys Pro Tyr Lys Cys Glu Glu Cys Gly Lys Gly Phe Thr Gln Ala
410 415 420
Ala His Phe His Ile His G1n Arg Val His Thr Gly Glu Lys Pro
425 430 435
Tyr Lys Cys Asp Val Cys Gly Lys Gly Phe Ser His Asn Ser Pro
440 445 450
Leu Ile Cys His Arg Arg Val His Thr Gly Glu Lys Pro Tyr Lys
455 460 465
Cys Glu Ala Cys Gly Lys Gly Phe Thr Arg Asn Thr Asp Leu His
470 475 480
Ile His Phe Arg Val His Thr Gly Glu Lys Pro Tyr Lys Cys Lys
48S 490 495
Glu Cys Gly Lys Gly Phe Ser Gln Ala Ser Asn Leu Gln Val His
500 50S 510
Gln Asn Val His Thr Gly Glu Lys Arg Phe Lys Cys Glu Thr Cys
515 S20 525
Gly Lys Gly Phe Ser Gln Ser Ser Lys Leu Gln Thr His Gln Arg
10/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
530 535 540
Val His Thr Gly Glu Lys Pro Tyr Arg Cys Asp Val Cys Gly Lys
545 550 555
Asp Phe Ser Tyr Ser Ser Asn Leu Lys Leu His Gln Val Ile His
560 565 570
Thr Gly Glu Lys Pro Tyr Lys Cys Glu Glu Cys Gly Lys Gly Phe
575 580 585
Ser Trp Arg Ser Asn Leu His Ala His Gln Arg Val His Ser Gly
590 595 600
Glu Lys Pro Tyr Lys Cys Glu Gln Cys Asp Lys Ser Phe Ser Gln
605 610 615
Ala Ile Asp Phe Arg Val His Gln Arg Val His Thr G1y Glu Lys
620 625 630
Pro Tyr Lys Cys Gly Val Cys Gly Lys Gly Phe Ser Gln Ser Ser
635 640 645
Gly Leu Gln Ser His Gln Arg Val His Thr Gly Glu Lys Pro Tyr
650 655 660
Lys Cys Asp Val Cys Gly Lys Gly Phe Arg Tyr Ser Ser Gln Phe
665 670 675
Ile Tyr His Gln Arg Gly His Thr Gly Glu Lys Pro Tyr Lys Cys
680 685 690
Glu Glu Cys Gly Lys Gly Phe Gly Arg Ser Leu Asn Leu Arg His
695 700 705
His Gln Arg Val His Thr Gly Glu Lys Pro His Ile Cys Glu Glu
710 715 720
Cys Gly Lys Ala Phe Ser Leu Pro Ser Asn Leu Arg Val His Leu
725 730 735
Gly Val His Thr Arg Glu Lys Leu Phe Lys Cys Glu Glu Cys Gly
740 745 750
Lys Gly Phe Ser Gln Ser Ala Arg Leu Glu Ala His Gln Arg Val
755 760 '765
His Thr Gly Glu Lys Pro Tyr Lys Cys Asp Ile Cys Asp Lys Asp
770 775 780
Phe Arg His Arg Ser Arg Leu Thr Tyr His Gln Lys Val His Thr
785 790 795
Gly Lys Lys Leu
<210> 8
<211> 137
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 585172CD1
<400> 8
Met Leu Ser Gly Arg Leu Val Leu Gly Leu Val Ser Met Ala Gly
1 5 10 15
Arg Val Cys Leu Cys Gln Gly Ser Ala Gly Ser Gly Ala Ile Gly
20 25 30
Pro Val Glu Ala Ala Ile Arg Thr Lys Leu Glu Glu Ala Leu Ser
35 40 45
Pro Glu Val Leu Glu Leu Arg Asn Glu Ser Gly Gly His Ala Val
50 55 60
Pro Pro Gly Ser Glu Thr His Phe Arg Va1 Ala Val Val Ser Ser
65 70 75
Arg Phe Glu Gly Leu Ser Pro Leu Gln Arg His Arg Leu Val His
11/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
80 85 90
Ala Ala Leu Ala Glu Glu Leu Gly Gly Pro Val His Ala Leu Ala
95 100 105
Ile Gln Ala Arg Thr Pro Ala Gln Trp Arg Glu Asn Ser Gln Leu
110 115 120
Asp Thr Ser Pro Pro Cys Leu Gly Gly Asn Lys Lys Thr Leu Gly
125 130 135
Thr Pro
<210> 9
<211> 230
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 615200CD1
<400> 9
Met Val Gly Ala Gly Ile Ser Thr Pro Ser Gly Ile Pro Asp Phe
1 5 10 15
Arg Ser Pro Gly Ser Gly Leu Tyr Ser Asn Leu Gln Gln Tyr Asp
20 25 30
Leu Pro Tyr Pro Glu Ala Ile Phe Glu Leu Pro Phe Phe Phe His
35 40 45
Asn Pro Lys Pro Phe Phe Thr Leu Ala Lys Glu Leu Tyr Pro Gly
50 55 6C
Asn Tyr Lys Pro Asn Ile Thr His Tyr Phe Leu Arg Leu Leu His
65 70 75
Asp Lys Gly Leu Leu Leu Arg Leu Tyr Thr Gln Asn Ile Asp Gly
80 85 90
Leu Glu Arg Val Ser Gly Ile Pro Ala Ser Lys Leu Val Glu Ala
95 100 105
His Gly Thr Phe Ala Ser Ala Thr Cys Thr Val Cys Gln Arg Pro
110 115 120
Phe Pro Gly Glu Asp Ile Arg Ala Asp Val Met Ala Asp Arg Val
125 130 135
Pro Arg Cys Pro Val Cys Thr Gly Val Val Lys Pro Asp Ile Val
140 145 150
Phe Phe Gly Glu Pro Leu Pro Gln Arg Phe Leu Leu His Val Val
155 160 165
Asp Phe Pro Met Ala Asp Leu Leu Leu Ile Leu Gly Thr Ser Leu
170 175 180
Glu Val Glu Pro Phe Ala Ser Leu Thr Glu Ala Val Arg Thr Gln
185 190 195
Phe Pro Asp Cys Ser Ser Thr Gly Thr Trp Trp Gly Pro Trp Leu
200 205 210
Gly Ile Leu Ala Ala Gly Thr Trp Pro Ser Trp Gly Thr Trp Phe
215 220 225
Thr Ala Trp Lys Ala
230
<210> 10
<211> 446
<212> PRT
<213> Homo sapiens
12/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<220>
<221> misc-feature
<223> Incyte ID No.: 997067CD1
<400> 10
Met Glu Thr Gln Ala Asp Leu Val Ser Gln Glu Pro Gln Ala Leu
1 5 10 15
Leu Asp Ser Ala Leu Pro Ser Lys Val Pro Ala Phe Ser Asp Lys
20 25 30
Asp Ser Leu Gly Asp Glu Met Leu Ala Ala Ala Leu Leu Lys Ala
35 40 45
Lys 5er Gln Glu Leu Val Thr Phe Glu Asp Val Ala Val Tyr Phe
50 55 60
Ile Arg Lys Glu Trp Lys Arg Leu Glu Pro Ala Gln Arg Asp Leu
65 70 75
Tyr Arg Asp Val Met Leu Glu Asn Tyr Gly Asn Val Phe Ser Leu
80 85 90
Asp Arg Glu Thr Arg Thr Glu Asn Asp Gln Glu Ile Ser Glu Asp
95 100 105
Thr Arg Ser His Gly Val Leu Leu Gly Arg Phe Gln Lys Asp Ile
110 115 120
Ser Gln Gly Leu Lys Phe Lys Glu Ala Tyr Glu Arg Glu Val Ser
125 130 135
Leu Lys Arg Pro Leu Gly Asn Ser Pro Gly Glu Arg Leu Asn Arg
140 145 150
Lys Met Pro Asp Phe Gly Gln Val Thr Val Glu Glu Lys Leu Thr
155 160 165
Pro Arg Gly Glu Arg Ser Glu Lys Tyr Asn Asp Phe Gly Asn Ser
170 175 180
Phe Thr Val Asn Ser Asn Leu Ile Ser His Gln Arg Leu Pro Val
185 190 195
Gly Asp Arg Pro His Lys Cys Asp Glu Cys Ser Lys Ser Phe Asn
200 205 210
Arg Thr Ser Asp Leu Ile Gln His Gln Arg Ile His Thr Gly Glu
215 220 225
Lys Pro Tyr Glu Cys Asn Glu Cys Gly Lys Ala Phe Ser Gln Ser
230 235 240
Ser His Leu Ile Gln His Gln Arg Ile His Thr Gly Glu Lys Pro
245 250 255
Tyr Glu Cys Ser Asp Cys Gly Lys Thr Phe Ser Cys Ser Ser Ala
260 265 270
Leu Ile Leu His Arg Arg Ile His Thr Gly Glu Lys Pro Tyr Glu
275 280 285
Cys Asn Glu Cys Gly Lys Thr Phe Ser Trp Ser Ser Thr Leu Thr
290 295 300
His His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr Ala Cys Asn
305 310 315
Glu Cys Gly Lys Ala Phe Ser Arg Ser Ser Thr Leu Ile His His
320 325 330
Gln Arg Ile His Thr Gly Glu Lys Pro Tyr Glu Cys Asn Glu Cys
335 340 345
Gly Lys Ala Phe Ser Gln Ser Ser His Leu Tyr Gln His Gln Arg
350 355 360
Ile His Thr Gly Glu Lys Pro Tyr Glu Cys Met Glu Cys Gly Gly
365 370 375
Lys Phe Thr Tyr Ser Ser Gly Leu Ile Gln His Gln Arg Ile His
380 385 390
Thr Gly Glu Asn Pro Tyr Glu Cys Ser Glu Cys Gly Lys Ala Phe
395 400 405
Arg Tyr Ser Ser Ala Leu Val Arg His Gln Arg Ile His Thr Gly
410 415 420
Glu Lys Pro Leu Asn Gly Ile Gly Met Ser Lys Ser Ser Leu Arg
13/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
425 430 435
Val Thr Thr Glu Leu Asn Ile Arg Glu Ser Thr
440 445
<210> 11
<211> 428
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID NO.: 1443262CD1
<400> 11
Met Glu Pro Leu Lys Val Glu Lys Phe Ala Thr Ala Asn Arg Gly
1 5 10 15
Asn Gly Leu Arg Ala Val Thr Pro Leu Arg Pro Gly Glu Leu Leu
20 25 30
Phe Arg Ser Asp Pro Leu Ala Tyr Thr Val Cys Lys Gly Ser Arg
35 40 45
Gly Val Val Cys Asp Arg Cys Leu Leu Gly Lys Glu Lys Leu Met
50 55 60
Arg Cys Ser Gln Cys Arg Val Ala Lys Tyr Cys Ser Ala Lys Cys
65 70 75
Gln Lys Lys Ala Trp Pro Asp His Lys Arg Glu Cys Lys Cys Leu
80 85 90
Lys Ser Cys Lys Pro Arg Tyr Pro Pro Asp Ser Val Arg Leu Leu
95 100 105
Gly Arg Val Val Phe Lys Leu Met Asp Gly Ala Pro Ser Glu Ser
110 115 120
Glu Lys Leu Tyr Ser Phe Tyr Asp Leu Glu Ser Asn Ile Asn Lys
125 130 135
Leu Thr Glu Asp Lys Lys Glu Gly Leu Arg Gln Leu Val Met Thr
140 145 150
Phe Gln His Phe Met Arg Glu Glu Ile Gln Asp Ala Ser Gln Leu
155 160 165
Pro Pro Ala Phe Asp Leu Phe Glu Ala Phe Ala Lys Val Ile Cys
170 175 180
Asn Ser Phe Thr Ile Cys Asn Ala Glu Met Gln Glu Val Gly Val
185 190 195
Gly Leu Tyr Pro Ser Ile Ser Leu Leu Asn His Ser Cys Asp Pro
200 205 210
Asn Cys Ser Ile Val Phe Asn Gly Pro His Leu Leu Leu Arg Ala
215 220 225
Val Arg Asp Ile Glu Val Gly Glu Glu Leu Thr Ile Cys Tyr Leu
230 235 240
Asp Met Leu Met Thr Ser Glu Glu Arg Arg Lys Gln Leu Arg Asp
245 250 255
Gln Tyr Cys Phe Glu Cys Asp Cys Phe Arg Cys Gln Thr Gln Asp
260 265 270
Lys Asp Ala Asp Met Leu Thr Gly Asp Glu Gln Val Trp Lys Glu
275 280 285
Val Gln Glu Ser Leu Lys Lys Ile Glu Glu Leu Lys Ala His Trp
290 295 300
Lys Trp Glu Gln Val Leu Ala Met Cys Gln Ala Ile Ile Ser Ser
305 310 315
Asn Ser Glu Arg Leu Pro Asp Ile Asn Ile Tyr Gln Leu Lys Val
320 325 330
14/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Leu Asp Cys Ala Met Asp Ala Cys Ile Asn Leu Gly Leu Leu Glu
335 340 345
Glu Ala Leu Phe Tyr Gly Thr Arg Thr Met Glu Pro Tyr Arg Ile
350 355 360
Phe Phe Pro Gly Ser His Pro Val Arg Gly Val Gln Val Met Lys
365 370 375
Val Gly Lys Leu Gln Leu His Gln Gly Met Phe Pro Gln Ala Met
380 385 390
Lys Asn Leu Arg Leu Ala Phe Asp Ile Met Arg Val Thr His Gly
395 400 405
Arg Glu His Ser Leu Ile Glu Asp Leu Ile Leu Leu Leu Glu Glu
410 415 420
Cys Asp Ala Asn Ile Arg Ala Ser
425
<210> 12
<211> 590
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1521648CD1
<400> 12
Met Ala Glu Asp Trp Leu Asp Cys Pro Ala Leu Gly Pro Gly Trp
1 5 10 15
Lys Arg Arg Glu Val Phe Arg Lys Ser Gly Ala Thr Cys Gly Arg
20 25 30
Ser Asp Thr Tyr Tyr Gln Ser Pro Thr Gly Asp Arg Ile Arg Ser
35 40 45
Lys Val Glu Leu Thr Arg Tyr Leu Gly Pro Ala Cys Asp Leu Thr
50 55 60
Leu Phe Asp Phe Lys Gln Gly Ile Leu Cys Tyr Pro Ala Pro Lys
65 70 75
Ala His Pro Val Ala Val Ala Ser Lys Lys Arg Lys Lys Pro Ser
80 85 90
Arg Pro Ala Lys Thr Arg Lys Arg Gln Val Gly Pro Gln Ser Gly
95 100 105
Glu Val Arg Lys Glu Ala Pro Arg Asp Glu Thr Lys Ala Asp Thr
110 115 120
Asp Thr Ala Pro Ala Ser Phe Pro Ala Pro Gly Cys Cys Glu Asn
125 130 135
Cys Gly Ile Ser Phe Ser Gly Asp Gly Thr Gln Arg Gln Arg Leu
140 145 150
Lys Thr Leu Cys Lys Asp Cys Arg Ala Gln Arg Ile Ala Phe Asn
155 160 165
Arg Glu Gln Arg Met Phe Lys Arg Val Gly Cys Gly Glu Cys Ala
170 175 180
Ala Cys Gln Val Thr Glu Asp Cys Gly Ala Cys Ser Thr Cys Leu
185 190 195
Leu Gln Leu Pro His Asp Val Ala Ser Gly Leu Phe Cys Lys Cys
200 205 210
Glu Arg Arg Arg Cys Leu Arg Ile Val Glu Arg Ser Arg Gly Cys
215 220 225
Gly Val Cys Arg Gly Cys Gln Thr Gln Glu Asp Cys Gly His Cys
230 235 240
Pro Ile Cys Leu Arg Pro Pro Arg Pro Gly Leu Arg Arg Gln Trp
245 250 255
1 S/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Lys Cys Val Gln Arg Arg Cys Leu Arg Gly Lys His Ala Arg Arg
260 265 270
Lys Gly Gly Cys Asp Ser Lys Met Ala Ala Arg Arg Arg Pro Gly
275 280 285
Ala Gln Pro Leu Pro Pro Pro Pro Pro Ser Gln Ser Pro Glu Pro
290 295 300
Thr Glu Pro His Pro Arg Ala Leu Ala Pro Ser Pro Pro Ala Glu
305 310 315
Phe Ile Tyr Tyr Cys Val Asp Glu Asp Glu Leu Gln Pro Tyr Thr
320 325 330
Asn Arg Arg Gln Asn Arg Lys Cys Gly Ala Cys Ala Ala Cys Leu
335 340 345
Arg Arg Met Asp Cys Gly Arg Cys Asp Phe Cys Cys Asp Lys Pro
350 355 360
Lys Phe Gly Gly Ser Asn Gln Lys Arg Gln Lys Cys Arg Trp Arg
365 370 375
Gln Cys Leu Gln Phe Ala Met Lys Arg Leu Leu Pro Ser Val Trp
380 385 390
Ser Glu Ser Glu Asp Gly Ala Gly Ser Pro Pro Pro Tyr Arg Arg
395 400 405
Arg Lys Arg Pro Ser Ser Ala Arg Arg His His Leu Gly Pro Thr
410 415 420
Leu Lys Pro Thr Leu Ala Thr Arg Thr Ala Gln Pro Asp His Thr
425 430 435
Gln Ala Pro Thr Lys Gln Glu Ala Gly Gly Gly Phe Val Leu Pro
440 445 450
Pro Pro Gly Thr Asp Leu Val Phe Leu Arg Glu Gly Ala Ser Ser
455 460 465
Pro Val Gln Val Pro Gly Pro Val Ala Ala Ser Thr Glu Ala Leu
470 475 480
Leu Gln Val Lys Gln Glu Lys Ala Asp Thr Gln Asp Glu Trp Thr
485 490 495
Pro Gly Thr Ala Val Leu Thr Ser Pro Val Leu Val Pro Gly Cys
500 505 510
Pro Ser Lys Ala Val Asp Pro Gly Leu Pro Ser Val Lys Gln Glu
515 520 525
Pro Pro Asp Pro Glu Glu Asp Lys Glu Glu Asn Lys Asp Asp Ser
530 535 540
Ala Ser Lys Leu Ala Pro Glu Glu Glu Ala Gly Gly Ala Gly Thr
545 550 555
Pro Val Ile Thr Glu Ile Phe Ser Leu Gly Gly Thr Arg Phe Arg
560 565 570
Asp Thr Ala Val Trp Leu Pro Arg Ser Lys Asp Leu Lys Lys Pro
575 580 585
Gly Ala Arg Lys Gln
590
<210> 13
<211> 479
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1685494CD1
<400> 13
Met Ala Thr Ala Leu Val Ser Ala His Ser Leu Ala Pro Leu Ser
16/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
1 5 10 15
Leu Lys Lys Glu Gly Leu Arg Val Val Arg Glu Asp His Tyr Ser
20 25 30
Thr Trp Glu Gln Gly Phe Lys Leu Gln Gly Asn Ser Lys Gly Leu
35 40 45
Gly Gln Glu Pro Leu Cys Lys Gln Phe Arg Gln Leu Arg Tyr Glu
50 55 60
Glu Thr Thr Gly Pro Arg Glu Ala Leu Ser Arg Leu Arg Glu Leu
65 70 75
Cys Gln Gln Trp Leu Gln Pro Glu Thr His Thr Lys Glu Gln Ile
80 85 90
Leu Glu Leu Leu Val Leu Glu Gln Phe Leu Ile Ile Leu Pro Lys
95 100 105
Glu Leu Gln Ala Arg Val Gln Glu His His Pro Glu Ser Arg Glu
110 115 120
Asp Val Val Val Val Leu Glu Asp Leu Gln Leu Asp Leu Gly Glu
125 130 135
Thr Gly Gln Gln Val Asp Pro Asp Gln Pro Lys Lys Gln Lys Ile
140 145 150
Leu Val Glu Glu Met Ala Pro Leu Lys Gly Val Gln Glu Gln Gln
155 160 165
Val Arg His Glu Cys Glu Val Thr Lys Pro Glu Lys Glu Lys Gly
170 175 180
Glu Glu Thr Arg Ile Glu Asn Gly Lys Leu Ile Val Val Thr Asp
185 190 195
Ser Cys Gly Arg Val Glu Ser Ser Gly Lys Ile Ser Glu Pro Met
200 205 210
Glu Ala His Asn Glu Gly Ser Asn Leu Glu Arg His Gln Ala Lys
215 220 225
Pro Lys Glu Lys Ile Glu Tyr Lys Cys Ser Glu Arg Glu Gln Arg
230 235 240
Phe Ile Gln His Leu Asp Leu Ile Glu His Ala Ser Thr His Thr
245 250 255
Gly Lys Lys Leu Cys Glu Ser Asp Val Cys Gln Ser Ser Ser Leu
260 265 270
Thr Gly His Lys Lys Val Leu Ser Arg Glu Lys Gly His Gln Cys
275 280 285
His Glu Cys Gly Lys Ala Phe Gln Arg Ser Ser His Leu Val Arg
290 295 300
His Gln Lys Ile His Leu Gly Glu Lys Pro Tyr Gln Cys Asn Glu
305 310 315
Cys Gly Lys Val Phe Ser Gln Asn Ala Gly Leu Leu Glu His Leu
320 325 330
Arg Ile His Thr Gly Glu Lys Pro Tyr Leu Cys Ile His Cys Gly
335 340 345
Lys Asn Phe Arg Arg Ser Ser His Leu Asn Arg His Gln Arg Ile
350 355 360
His Ser Gln Glu Glu Pro Cys Glu Cys Lys Glu Cys Gly Lys Thr
365 370 375
Phe Ser Gln Ala Leu Leu Leu Thr His His Gln Arg Ile His Ser
380 385 390
His Ser Lys Ser His Gln Cys Asn Glu Cys Gly Lys Ala Phe Ser
395 400 405
Leu Thr Ser Asp Leu Ile Arg His His Arg Ile His Thr Gly Glu
410 415 420
Lys Pro Phe Lys Cys Asn Ile Cys Gln Lys Ala Phe Arg Leu Asn
425 430 435
Ser His Leu Ala Gln His Val Arg Ile His Asn Glu Glu Lys Pro
440 445 450
Tyr Gln Cys Ser Glu Cys Gly Glu Ala Phe Arg Gln Arg Ser Gly
455 460 465
Leu Phe Gln His Gln Arg Tyr His His Lys Asp Lys Leu Ala
17/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
470 475
<210> 14
<211> 433
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1730829CD1
<400> 14
Met Glu Ala Val Tyr Leu Val Val Asn Gly Leu Gly Leu Val Leu
1 5 10 15
Asp Val Leu Thr Leu Val Leu Asp Leu Asn Phe Leu Leu Val Ser
20 25 30
Ser Leu Leu Ala Ser Leu Ala Trp Leu Leu Ala Phe Val Tyr Asn
35 40 45
Leu Pro His Thr Val Leu Thr Ser Leu Leu His Leu Gly Arg Gly
50 55 60
Val Leu Leu Ser Leu Leu Ala Leu Ile Glu Ala Val Val Arg Phe
65 70 75
Thr Cys Gly Gly Leu Gln Ala Leu Cys Thr Leu Leu Tyr Ser Cys
80 85 90
Cys Ser Gly Leu Glu Ser Leu Lys Leu Leu Gly His Leu Ala Ser
95 100 105
His Gly Ala Leu Arg Ser Arg Glu Ile Leu His Arg Gly Val Leu
110 115 120
Asn Val Val Ser Ser Gly His Ala Leu Leu Arg Gln Ala Cys Asp
125 130 135
Ile Cys Ala Ile Ala Met Ser Leu Val Ala Tyr Val Ile Asn 5er
140 145 150
Leu Val Asn Ile Cys Leu Ile Gly Thr Gln Asn Leu Phe Ser Leu
155 160 165
Val Leu Ala Leu Trp Asp Ala Val Thr Gly Pro Leu Trp Arg Met
170 175 180
Thr Asp Val Val Ala Ala Phe Leu Ala His Ile Ser Ser Ser Ala
185 190 195
Val Ala Met Ala Ile Leu Leu Trp Thr Pro Cys Gln Leu Ala Leu
200 205 210
Glu Leu Leu Ala Ser Ala Ala Arg Leu Leu Ala Ser Phe Val Leu
215 220 225
Val Asn Leu Thr Gly Leu Val Leu Leu Ala Cys Val Leu Ala Val
230 235 240
Thr Val Thr Val Leu His Pro Asp Phe Thr Leu Arg Leu Ala Thr
245 250 255
Gln Ala Leu Ser Gln Leu His Ala Arg Pro Ser Tyr His Arg Leu
260 265 270
Arg Glu Asp Val Met Arg Leu Ser Arg Leu Ala Leu Gly Ser Glu
275 280 285
Ala Trp Arg Arg Val Trp Ser Arg Ser Leu Gln Leu Ala Ser Trp
290 295 300
Pro Asn Arg Gly Gly Ala Pro Gly Ala Pro Gln Gly Asp Pro Met
305 310 315
Arg Val Phe Ser Val Arg Thr Arg Arg Gln Asp Thr Leu Pro Glu
320 325 330
Ala Gly Arg Arg Ser Glu Ala Glu Glu Glu Glu Ala Arg Thr Ile
335 340 345
Arg Val Thr Pro Val Arg Gly Arg Glu Arg Leu Asn Glu Glu Glu
18/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
350 355 360
Pro Pro Gly Gly Gln Asp Pro Trp Lys Leu Leu Lys Glu Gln Glu
365 370 375
Glu Arg Lys Lys Cys Val Ile Cys Gln Asp Gln Ser Lys Thr Val
380 385 390
Leu Leu Leu Pro Cys Arg His Leu Cys Leu Cys Gln Ala Cys Thr
395 400 405
Glu Ile Leu Met Arg His Pro Val Tyr His Arg Asn Cys Pro Leu
410 415 420
Cys Arg Arg Gly Ile Leu Gln Thr Leu Asn Val Tyr Leu
425 430
<210> 15
<211> 320
<212> PRT
<213> Homo sapiens
<220>
<221> misc feature
<223> Incyte ID No.: 1864641CD1
<400> 15
Met Pro Lys Lys Lys Thr Gly Ala Arg Lys Lys Ala Glu Asn Arg
1 5 10 15
Arg Glu Arg Glu Lys Gln Leu Arg Ala Ser Arg Ser Thr Ile Asp
20 25 30
Leu Ala Lys His Pro Cys Asn Ala Ser Met Glu Cys Asp Lys Cys
35 40 45
Gln Arg Arg Gln Lys Asn Arg Ala Phe Cys Tyr Phe Cys Asn Ser
50 55 60
Val Gln Lys Leu Pro Ile Cys Ala Gln Cys Gly Lys Thr Lys Cys
65 70 75
Met Met Lys Ser Ser Asp Cys Val Ile Lys His Ala Gly Val Tyr
80 85 90
Ser Thr Gly Leu Ala Met Val Gly Ala Ile Cys Asp Phe Cys Glu
95 100 105
Ala Trp Val Cys His Gly Arg Lys Cys Leu Ser Thr His Ala Cys
110 115 120
Ala Cys Pro Leu Thr Asp Ala Glu Cys Val Glu Cys Glu Arg Gly
125 130 135
Val Trp Asp His Gly Gly Arg Ile Phe Ser Cys Ser Phe Cys His
140 145 150
Asn Phe Leu Cys Glu Asp Asp Gln Phe Glu His Gln Ala Ser Cys
155 160 165
Gln Val Leu Glu Ala Glu Thr Phe Lys Cys Val Ser Cys Asn Arg
170 175 180
Leu Gly Gln His Ser Cys Leu Arg Cys Lys Ala Cys Phe Cys Asp
185 190 195
Asp His Thr Arg Ser Lys Val Phe Lys Gln Glu Lys Gly Lys Gln
200 205 210
Pro Pro Cys Pro Lys Cys Gly His Glu Thr Gln Glu Thr Lys Asp
215 220 225
Leu Ser Met Ser Thr Arg Ser Leu Lys Phe Gly Arg Gln Thr Gly
230 235 240
Gly Glu Glu Gly Asp Gly Ala Ser Gly Tyr Asp Ala Tyr Trp Lys
245 250 255
Asn Leu Ser Ser Asp Lys Tyr Gly Asp Thr Ser Tyr His Asp Glu
260 265 270
Glu Glu Asp Glu Tyr Glu Ala Glu Asp Asp Glu Glu Glu Glu Asp
19/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
275 280 285
Glu Gly Arg Lys Asp Ser Asp Thr Glu Ser Ser Asp Leu Phe Thr
290 295 300
Asn Leu Asn Leu Gly Arg Thr T~,rr Ala Ser Gly Tyr Ala His Tyr
305 310 315
Glu Glu Gln Glu Asn
320
<210> 16
<211> 179
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2444604CD1
<400> 16
Met Ala Ala Gly Phe Phe Gln Pro Phe Met Ser Pro Arg Phe Pro
1 5 10 15
Gly Gly Pro Arg Pro Thr Leu Arg Met Pro Ser Gln Pro Pro Ala
20 25 30
Cys Leu Pro Gly Ser Gln Pro Leu Leu Pro Gly Ala Met Glu Pro
35 40 45
Ser Pro Arg Ala Gln Gly His Pro Ser Met Gly Gly Pro Met Gln
50 55 60
Arg Va.l Thr Pro Pro Arg Gly Met Ala Ser Val Gly Pro Gln Ser
65 70 75
Tyr Gly Gly Gly Met Arg Pro Pro Pro Asn Ser Leu Ala Gly Pro
80 85 90
Gly Leu Pro Ala Met Asn Met Gly Pro Gly Val Arg Gly Pro Trp
95 100 105
Ala Ser Pro Ser Gly Asn Ser Ile Pro Tyr Ser Ser Ser Ser Pro
110 115 120
Gly Ser Tyr Thr Gly Pro Pro Gly Gly Gly Gly Pro Pro Gly Thr
125 13 0 135
Pro Ile Met Pro Ser Pro Gly Asp Ser Thr Asn Ser Ser Glu Asn
140 145 150
Met Tyr Thr Ile Met Asn Pro Ile Gly Gln Gly Ala Gly Arg Ala
155 160 165
Asn Phe Pro Leu Gly Pro Gly Pro Glu Gly Pro Trp Pro Pro
170 175
<210> 17
<211> 494
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2445008CD1
<400> 17
Met Gly Arg Lys Lys Lys Lys Gln Leu Lys Pro Trp Cys Trp Tyr
1 5 10 15
Cys Asn Arg Asp Phe Asp Asp Glu Lys Ile Leu Ile Gln His Gln
20/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/D2237
20 25 30
Lys Ala Lys His Phe Lys Cys His Ile Cys His Lys Lys Leu Tyr
35 40 45
Thr Gly Pro Gly Leu Ala Ile His Cys Met Gln Val His Lys Glu
50 55 60
Thr Ile Asp Ala Val Pro Asn Ala Ile Pro Gly Arg Thr Asp Ile
65 70 75
Glu Leu Glu Ile Tyr Gly Met Glu Gly Ile Pro Glu Lys Asp Met
80 85 90
Asp Glu Arg Arg Arg Leu Leu Glu Gln Lys Thr Gln Glu Ser Gln
95 100 105
Lys Lys Lys Gln Gln Asp Asp Ser Asp Glu Tyr Asp Asp Asp Asp
110 115 120
Ser Ala Ala Ser Thr Ser Phe Gln Pro Gln Pro Val Gln Pro Gln
125 130 135
Gln Gly Tyr Ile Pro Pro Met Ala Gln Pro Gly Leu Pro Pro Val
140 145 150
Pro Gly Ala Pro Gly Met Pro Pro Gly Ile Pro Pro Leu Met Pro
155 160 165
Gly Val Pro Pro Leu Met Pro Gly Met Pro Pro Val Met Pro Gly
170 175 180
Met Pro Pro Gly Leu His His Gln Arg Lys Tyr Thr Gln Ser Phe
185 190 195
Cys Gly Glu Asn Ile Met Met Pro Met Gly Gly Met Met Pro Pro
200 205 210
Gly Pro Gly Ile Pro Pro Leu Met Pro Gly Met Pro Pro Gly Met
215 220 225
Pro Pro Pro Val Pro Arg Pro Gly Ile Pro Pro Met Thr Gln Ala
230 235 240
Gln Ala Val Ser Ala Pro Gly Ile Leu Asn Arg Pro Pro Ala Pro
245 250 255
Thr Ala Thr Val Pro Ala Pro Gln Pro Pro Val Thr Lys Pro Leu
260 265 270
Phe Pro Ser Ala Gly Gln Met Gly Thr Pro Val Thr Ser Ser Ser
275 280 285
Thr Ala Ser Ser Asn Ser Glu Ser Leu Ser Ala Ser Ser Lys Ala
290 295 300
Leu Phe Pro Ser Thr Ala Gln Ala Gln Ala Ala Val Gln Gly Pro
305 310 315
Val Gly Thr Asp Phe Lys Pro Leu Asn Ser Thr Pro Ala Thr Thr
320 325 330
Thr Glu Pro Pro Lys Pro Thr Phe Pro Ala Tyr Thr Gln Ser Thr
335 340 345
Ala Ser Thr Thr Ser Thr Thr Asn Ser Thr Ala Ala Lys Pro Ala
350 355 360
Ala Ser Ile Thr Ser Lys Pro Ala Thr Leu Thr Thr Thr Ser Ala
365 370 375
Thr Ser Lys Leu Ile His Pro Asp Glu Asp Ile Ser Leu Glu Glu
380 385 390
Arg Arg Ala Gln Leu Pro Lys Tyr Gln Arg Asn Leu Pro Arg Pro
395 400 405
Gly Gln Ala Pro Ile Gly Asn Pro Pro Val Gly Pro Ile Gly Gly
410 415 420
Met Met Pro Pro Gln Pro Gly Ile Pro Gln Gln Gln Gly Met Arg
425 430 435
Pro Pro Met Pro Pro His Gly Gln Tyr Gly Gly His His Gln Gly
440 445 450
Met Pro Gly Tyr Leu Pro Gly Ala Met Pro Pro Tyr Gly Gln Gly
455 460 465
Pro Pro Met Val Pro Pro ~'~r Gln Gly Gly Pro Pro Arg Pro Pro
470 475 480
21/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Met Gly Met Arg Pro Pro Val Met Ser Gln Gly Gly Arg Tyr
485 490
<210> 18
<211> 401
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2572462CD1
<400> 18
Met Ala Ser Ser Pro Arg Pro Lys Met Asp Ala Ile Leu Thr Glu
1 5 10 15
Ala Ile Lys Ala Cys Phe Gln Lys Ser Gly Ala Ser Val Val Ala
20 25 30
Ile Arg Lys Tyr Ile Ile His Lys Tyr Pro Ser Leu Glu Leu Glu
35 40 45
Arg Arg Gly Tyr Leu Leu Lys Gln Ala Leu Lys Arg Glu Leu Asn
50 55 60
Arg Gly Val Ile Lys Gln Val Lys Gly Lys Gly Ala Ser Gly Ser
65 70 75
Phe Val Val Val Gln Lys Ser Arg Lys Thr Pro Gln Lys Ser Arg
80 85 90
Asn Arg Lys Asn Arg Ser Ser Ala Val Asp Pro Glu Pro Gln Val
95 100 105
Lys Leu Glu Asp Val Leu Pro Leu Ala Phe Thr Arg Leu Cys Glu
110 115 120
Pro Lys Glu Ala Ser Tyr Ser Leu Ile Arg Lys Tyr Val Ser Gln
125 130 135
Tyr Tyr Pro Lys Leu Arg Val Asp Ile Arg Pro Gln Leu Leu Lys
140 145 150
Asn Ala Leu Gln Arg Ala Val Glu Arg Gly Gln Leu Glu Gln Ile
155 160 165
Thr Gly Lys Gly Ala Ser Gly Thr Phe Gln Leu Lys Lys Ser Gly
170 175 180
Glu Lys Pro Leu Leu Gly Gly Ser Leu Met Glu Tyr Ala Ile Leu
185 190 195
Ser Ala Ile Ala Ala Met Asn Glu Pro Lys Thr Cys Ser Thr Thr
200 205 210
Ala Leu Lys Lys Tyr Val Leu Glu Asn His Pro Gly Thr Asn Ser
215 220 225
Asn Tyr Gln Met His Leu Leu Lys Lys Thr Leu Gln Lys Cys Glu
230 235 240
Lys Asn Gly Trp Met Glu Gln Ile Ser Gly Lys Gly Phe Ser Gly
245 250 255
Thr Phe Gln Leu Cys Phe Pro Tyr Tyr Pro Ser Pro Gly Val Leu
260 265 270
Phe Pro Lys Lys Glu Pro Asp Asp Ser Arg Asp Glu Asp Glu Asp
275 280 285
Glu Asp Glu Ser Ser Glu Glu Asp Ser Glu Asp Glu Glu Pro Pro
290 295 300
Pro Lys Arg Arg Leu Gln Lys Lys Thr Pro Ala Lys Ser Pro Gly
305 310 315
Lys Ala Ala Ser Val Lys G1n Arg Gly Ser Lys Pro Ala Pro Lys
320 325 330
Val Ser Ala Ala Gln Arg Gly Lys Ala Arg Pro Leu Pro Lys Lys
335 340 345
22/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Ala Pro Pro Lys Ala Lys Thr Pro Ala Lys Lys Thr Arg Pro Ser
350 355 360
Ser Thr Val Ile Lys Lys Pro Ser Gly Gly Ser Ser Lys Lys Pro
365 370 375
Ala Thr Ser Ala Arg Lys Glu Va1 Lys Leu Pro Gly Lys Gly Lys
380 385 390
Ser Thr Met Lys Lys Ser Phe Arg Val Lys Lys
395 400
<210> 19
<211> 264
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2572892CD1
<400> 19
Met Pro Arg Ser Phe Leu Val Arg Lys Pro Ser Asp Pro Asn Arg
1 5 10 15
Lys Pro Asn Tyr Ser Glu Leu Gln Asp Ser Asn Pro Glu Phe Thr
20 25 30
Phe Gln Gln Pro Tyr Asp Gln Ala His Leu Leu Ala Ala Ile Pro
35 40 45
Pro Pro Glu Ile Leu Asn Pro Thr Ala Ser Leu Pro Met Leu Ile
50 55 60
Trp Asp Ser Val Leu Ala Pro Gln Ala Gln Pro Ile Ala Trp Ala
65 70
Ser Leu Arg Leu Gln Glu Ser Pro Arg Val Ala Glu Leu Thr Ser
80 85 90
Leu Ser Asp Glu Asp Ser Gly Lys Gly Ser Gln Pro Pro Ser Pro
95 100 105
Pro Ser Pro Ala Pro Ser Ser Phe Ser Ser Thr Ser Ala Ser Ser
110 115 120
Leu Glu Ala Glu Ala Tyr Ala Ala Phe Pro Gly Leu Gly Gln Val
125 130 135
Pro Lys Gln Leu Ala Gln Leu Ser Glu Ala Lys Asp Leu Gln Ala
140 145 150
Arg Lys Ala Phe Asn Cys Lys Tyr Cys Asn Lys Glu Tyr Leu Ser
155 160 165
Leu Gly Ala Leu Lys Met His Ile Arg Ser His Thr Leu Pro Cys
170 175 180
Val Cys Gly Thr Cys Gly Lys Ala Phe Ser Arg Pro Trp Leu Leu
185 190 195
Gln Gly His Val Arg Thr His Thr Gly Glu Lys Pro Phe Ser Cys
200 205 210
Pro His Cys Ser Arg Ala Phe Ala Asp Arg Ser Asn Leu Arg Ala
215 220 225
His Leu Gln Thr His Ser Asp Val Lys Lys Tyr Gln Cys Gln Ala
230 235 240
Cys Ala Arg Thr Phe Ser Arg Met Ser Leu Leu His Lys His Gln
245 250 255
Glu Ser Gly Cys Ser Gly Cys Pro Arg
260
23/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<210> 20
<211> 153
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2785674CD1
<400> 20
Met Thr Lys Ile Lys Ala Asp Pro Asp Gly Pro Glu Ala Gln Ala
1 5 10 15
Glu Ala Cys Ser Gly Glu Arg Thr Tyr Gln Glu Leu Leu Val Asn
20 25 30
Gln Asn Pro Ile Ala Gln Pro Leu Ala Ser Arg Arg Leu Thr Arg
35 40 45
Lys Leu Tyr Lys Cys Ile Lys Lys Ala Val Lys Gln Lys Gln Ile
50 55 - 60
Arg Arg Gly Val Lys Glu Val Gln Lys Phe Val Asn Lys Gly Glu
65 70 75
Lys Gly Ile Met Val Leu Ala Gly Asp Thr Leu Pro Ile Glu Val
80 85 90
Tyr Cys His Leu Pro Val Met Cys Glu Asp Arg Asn Leu Pro Tyr
95 100 105
Val Tyr Ile Pro Ser Lys Thr Asp Leu Gly Ala Ala Ala Gly Ser
110 115 120
Lys Arg Pro Thr Cys Val Ile Met Val Lys Pro His Glu Glu Tyr
125 130 135
Gln Glu Ala Tyr Asp Glu Cys Leu Glu Glu Val Gln Ser Leu Pro
140 145 150
Leu Pro Leu
<210> 21
<211> 243
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2797479CD1
<400> 21
Met Gly Asp Asp Ile Ser Thr His Ile Ala Pro Lys Glu Leu Arg
1 5 10 15
His Lys His Pro Ser Ser Val Asp Glu Val Ala Gln Val Val Lys
20 25 30
Gln Leu Arg Ile Ile Leu Gln Gln Gln Val Arg Pro Gly Glu Ser
35 40 45
Thr Val Leu Ala Leu Arg Pro Asn Val Gln Gln Ile Glu Ala Pro
50 55 60
Asp Val Ser Arg Asp Pro Arg Val Leu Gly Phe Asp Phe Pro Gly
65 ?0 75
Ser Ala Arg I1e His Glu Gly Thr His Thr Leu Glu Lys Pro Tyr
80 85 90
Glu Cys Lys Gln Cys Gly Lys Leu Leu Ser His Arg Ser Ser Phe
95 100 105
Arg Arg His Met Met Ala His Thr Gly Asp G1y Pro His Lys Cys
110 115 120
Thr Val Cys Gly Lys Ala Phe Asp Ser Pro Ser Val Phe Gln Arg
24/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
125 130 135
His Glu Arg Thr His Thr Gly Glu Lys Pro Tyr Glu Cys Lys Gln
140 145 150
Cys Gly Lys Ala Phe Arg Thr Ser Ser Ser Leu Arg Lys His Glu
155 160 165
Thr Thr His Thr Gly Glu Gln Pro Tyr Lys Cys Lys Cys Gly Lys
170 175 180
Ala Phe Ser Asp Leu Phe Ser Phe Gln Ser His Glu Thr Thr His
185 190 195
Ser Glu Glu Glu Pro Tyr Glu Cys Lys Glu Cys Gly Lys Ala Phe
200 205 210
Ser Ser Phe Lys Tyr Phe Cys Arg His Glu Arg Thr His Ser Glu
215 220 225
Glu Lys Ser Tyr Glu Cys Gln Ile Cys Gly Lys Leu Ser Val Val
230 235 240
Ser Val Thr
<210> 22
<211> 485
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2960640CD1
<400> 22
Met Arg Asp Asn Arg Ala Val Ser Leu Cys Gln Gln Glu Trp Met
1 5 10 15
Cys Pro Gly Pro Ala Gln Arg Ala Leu Tyr Arg Gly Ala Thr Gln
20 25 30
Arg Lys Asp Ser His Val Ser Leu Ala Thr Gly Val Pro Trp Gly
35 40 45
Tyr Glu Glu Thr Lys Thr Leu Leu Ala Ile Leu Ser Ser Ser Gln
50 55 60
Phe Tyr Gly Lys Leu Gln Thr Cys Gln Gln Asn Ser Gln Ile Tyr
65 70 75
Arg Ala Met Ala Glu Gly Leu Trp Glu Gln Gly Phe Leu Arg Thr
80 85 90
Pro Glu Gln Cys Arg Thr Lys Phe Lys Ser Leu Gln Leu Ser Tyr
95 100 105
Arg Lys Val Arg Arg Gly Arg Val Pro Glu Pro Cys Ile Phe Tyr
110 115 120
Glu Glu Met Asn Ala Leu Ser Gly Ser Trp Ala Ser Ala Pro Pro
125 130 135
Met Ala Ser Asp Ala Val Pro Gly Gln Glu Gly Ser Asp Ile Glu
140 145 150
Ala Gly Glu Leu Asn His Gln Asn Gly Glu Pro Thr Glu Val Glu
155 160 165
Asp Gly Thr Val Asp Gly Ala Asp Arg Asp Glu Lys Asp Phe Arg
170 175 180
Asn Pro Gly Gln Glu Val Arg Lys Leu Asp Leu Pro Val Leu Phe
185 190 195
Pro Asn Arg Leu Gly Phe Glu Phe Lys Asn Glu Ile Lys Lys Glu
200 205 210
Asn Leu Lys Trp Asp Asp Ser Glu Glu Val Glu Ile Asn Lys Ala
215 220 225
Leu Gln Arg Lys Ser Arg Gly Val Tyr Trp His Ser Glu Leu Gln
25/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
230 235 240
Lys Gly Leu Glu Ser Glu Pro Thr Ser Arg Arg Gln Cys Arg Asn
245 250 255
Ser Pro Gly Glu Ser Glu Glu Lys Thr Pro Ser Gln Glu Lys Met
260 265 270
Ser His Gln Ser Phe Cys Ala Arg Asp Lys Ala Cys Thr His Ile
275 280 285
Leu Cys Gly Lys Asn Cys Ser Gln Ser Val His Ser Pro His Lys
290 295 300
Pro Ala Leu Lys Leu Glu Lys Val Ser Gln Cys Pro Glu Cys Gly
305 310 315
Lys Thr Phe Ser Arg Ser Ser Tyr Leu Val Arg His Gln Arg Ile
320 325 330
His Thr Gly Glu Lys Pro His Lys Cys Ser Glu Cys Gly Lys Gly
335 340 345
Phe Ser Glu Arg Ser Asn Leu Thr Ala His Leu Arg Thr His Thr
350 355 360
Gly Glu Arg Pro Tyr Gln Cys Gly Gln Cys Gly Lys Ser Phe Asn
365 370 375
Gln Ser Ser Ser Leu Ile Val His Gln Arg Thr His Thr G1y Glu
380 385 390
Lys Pro Tyr Gln Cys Ile Val Cys Gly Lys Arg Phe Asn Asn Ser
395 400 405
Ser Gln Phe Ser Ala His Arg Arg Ile His Thr Gly Glu Ser Pro
410 415 420
Tyr Lys Cys Ala Val Cys Gly Lys Ile Phe Asn Asn Ser Ser His
425 430 435
Phe Ser Ala His Arg Lys Thr His Thr Gly Glu Lys Pro Tyr Arg
440 445 450
Cys Ser His Cys Glu Arg Gly Phe Thr Lys Asn Ser Ala Leu Thr
455 460 465
Arg His Gln Thr Val His Met Lys Ala Val Leu Ser Ser Gln Glu
470 475 480
Gly Arg Asp Ala Leu
485
<210> 23
<211> 160
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3454051CD1
<400> 23
Met Ser Trp Thr Cys Pro Arg Cys Gln Gln Pro Val Phe Phe Ala
1 5 10 15
Glu Lys Val Ser Ser Leu Gly Lys Asn Trp His Arg Phe Cys Leu
20 25 30
Lys Cys Glu Arg Cys His Ser I1e Leu Ser Pro Gly Gly His Ala
35 40 45
Glu His Asn Gly Arg Pro Tyr Cys His Lys Pro Cys Tyr Gly Ala
50 55 60
Leu Phe Gly Pro Arg Gly Pro Pro His Met Lys Thr Phe Thr Gly
65 70 75
Glu Thr Ser Leu Cys Pro Gly Cys Gly Glu Pro Val 'I'~~rr Phe A1a
80 85 90
26/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Glu Lys Val Met Ser Leu Gly Arg Asn Trp His Arg Pro Cys Leu
95 100 105
Arg Cys Gln Arg Cys His Lys Thr Leu Thr Ala Gly Ser His Ala
110 115 120
Glu His Asp Gly Val Pro Tyr Cys His -,lal Pro Cys Tyr Gly Tyr
125 130 135
Leu Phe Gly Pro Lys Gly Val Asn Ile Gly Asp Val Gly Cys Tyr
140 145 150
Ile Tyr Asp Pro Val Lys Ile Lys Phe Lys
155 160
<210> 24
<211> 511
<212> PRT
<213> Homo sapiens
<220>
<221>
<223> Incyte ID No.: 3510640CD1
<400> 24
Met Gln Glu Leu Tyr Ser Thr Pro Ala Ser Arg Leu Asp Ser Phe
1 5 10 15
Val Ala Gln Trp Leu Gln Pro His Arg Glu Trp Lys Glu Glu Val
20 25 30
Leu Asp Ala Val Arg Thr Val Glu Glu Phe Leu Arg Gln Glu His
35 40 45
Phe Gln Gly Lys Arg Gly Leu Asp Gln Asp Val Arg Val Leu Lys
50 55 60
Val Val Lys Val Gly Ser Phe Gly Asn Gly Thr Val Leu Arg Ser
65 70 75
Thr Arg Glu Val Glu Leu Val Ala Phe Leu Ser Cys Phe His Ser
80 85 90
Phe Gln Glu Ala Ala Lys His His Lys Asp Val Leu Arg Leu Ile
95 100 105
Trp Lys Thr Met Trp Gln Ser Gln Asp Leu Leu Asp Leu Gly Leu
110 115 120
Glu Asp Leu Arg Met Glu Gln Arg Val Pro Asp Ala Leu Val Phe
125 130 135
Thr Ile Gln Thr Arg Gly Thr Ala Glu Pro Ile Thr Val Thr Ile
140 145 150
Val Pro Ala Tyr Arg Ala Leu Gly Pro Ser Leu Pro Asn Ser Gln
155 160 165
Pro Pro Pro Glu Val Tyr Val Ser Leu Ile Lys Ala Cys Gly Gly
170 175 180
Pro Gly Asn Phe Cys Pro Phe Phe Ser Glu Leu Gln Arg Asn Phe
185 190 195
Val Lys His Arg Pro Thr Lys Leu Lys Ser Leu Leu Arg Leu Val
200 205 210
Lys His Trp Tyr Gln Gln Tyr Val Lys Ala Arg Ser Pro Arg Ala
215 220 225
Asn Leu Pro Pro Leu Tyr Ala Leu Glu Leu Leu Thr Ile Tyr Ala
230 235 240
Trp Glu Met Gly Thr Glu Glu Asp Glu Asn Phe Met Leu Asp Glu
245 250 255
Gly Phe Thr Thr Val Met Asp Leu Leu Leu Glu Tyr Glu Val Ile
260 265 270
Cys Ile Tyr Trp Thr Lys Tyr Tyr Thr Leu His Asn Ala Ile Ile
27/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
275 280 285
Glu Asp Cys Val Arg Lys Gln Leu Lys Lys Glu Arg Pro Ile Ile
290 295 300
Leu Asp Pro Ala Asp Pro Thr Leu Asn Val Ala Glu Gly Tyr Arg
305 310 315
Trp Asp Ile Val Ala Gln Arg Ala Ser Gln Cys Leu Lys Gln Asp
320 325 330
Cys Cys Tyr Asp Asn Arg Glu Asn Pro Ile Ser Ser Trp Asn Val
335 340 345
Lys Arg Ala Arg Asp Ile His Leu Thr Val Glu Gln Arg Gly Tyr
350 355 360
Pro Asp Phe Asn Leu Ile Val Asn Pro Tyr Glu Pro Ile Arg Lys
365 370 375
Val Lys Glu Lys Ile Arg Arg Thr Arg Gly Tyr Ser Gly Leu Gln
380 385 390
Arg Leu Ser Phe Gln Val Pro Gly Ser Glu Arg Gln Leu Leu Ser
395 400 405
Ser Arg Cys Ser Leu Ala Lys Tyr Gly Ile Phe Ser His Thr His
410 415 420
Ile Tyr Leu Leu Glu Thr Ile Pro Ser Glu Ile Gln Val Phe Val
425 430 435
Lys Asn Pro Asp Gly Gly Ser Tyr Ala Tyr Ala Ile Asn Pro Asn
440 445 450
Ser Phe Ile Leu Gly Leu Lys Gln Gln Ile Glu Asp Gln Gln Gly
455 460 465
Leu Pro Lys Lys Gln Gln Gln Leu Glu Phe Gln Gly Gln Val Leu
470 475 480
Gln Asp Trp Leu Gly Leu Gly Ile Tyr Gly Ile Gln Asp Ser Asp
485 490 495
Thr Leu Ile Leu Ser Lys Lys Lys Gly Glu Ala Leu Phe Pro Ala
500 505 510
Ser
<210> 25
<211> 310
<212> PRT
<213> Homo sapiens
<220> -
<223> Incyte ID No.: 3815083CD1
<400> 25
Met Arg Pro Leu Gln Ile Val Pro Ser Arg Leu Ile Ser Gln Leu
1 5 10 15
Tyr Cys Gly Leu Lys Pro Pro Ala Ser Thr Arg Asn Gln Ile Cys
20 25 30
Leu Lys Met Ala Arg Pro Ser Ser Ser Met Ala Asp Phe Arg Lys
35 40 45
Phe Phe Ala Lys Ala Lys His Ile Val Ile Ile Ser Gly Ala Gly
50 55 60
Val Ser Ala Glu Ser Gly Val Pro Thr Phe Arg Gly Ala Gly Gly
65 70 75
Tyr Trp Arg Lys Trp Gln A1a Gln Asp Leu Ala Thr Pro Leu Ala
80 85 90
Phe Ala His Asn Pro Ser Arg Val Trp Glu Phe Tyr His Tyr Arg
95 100 105
Arg Glu Val Met Gly Ser Lys Glu Pro Asn Ala Gly His Arg Ala
110 115 120
28/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Ile Ala Glu Cys Glu Thr Arg Leu Gly Lys Gln Gly Arg Arg Val
125 130 135
Val Val Ile Thr Gln Asn Ile Asp Glu Leu His Arg Lys Ala Gly
140 145 150
Thr Lys Asn Leu Leu Glu Ile His Gly Ser Leu Phe Lys Thr Arg
155 160 165
Cys Thr Ser Cys Gly Val Val Ala Glu Asn Tyr Lys Ser Pro Ile
170 175 180
Cys Pro Ala Leu Ser Gly Lys Gly Ala Pro Glu Pro Gly Thr Gln
185 190 195
Asp Ala Ser Ile Pro Val Glu Lys Leu Pro Arg Cys Glu Glu Ala
200 205 210
Gly Cys Gly Gly Leu Leu Arg Pro His Val Val Trp Phe Gly Glu
215 220 225
Asn Leu Asp Pro Ala Ile Leu Glu Glu Val Asp Arg Glu Leu Ala
230 235 240
His Cys Asp Leu Cys Leu Val Val Gly Thr Ser Ser Val Val Tyr
245 250 255
Pro Ala Ala Met Phe Ala Pro Gln Val Ala Ala Arg Gly Val Pro
260 265 270
Val Ala Glu Phe Asn Thr Glu Thr Thr Pro Ala Thr Asn Arg Phe
275 280 285
Arg Phe His Phe Gln Gly Pro Cys Gly Thr Thr Leu Pro Glu Ala
290 295 300
Leu Ala Cys His Glu Asn Glu Thr Val Ser
305 310
<210> 26
<211> 331
<212> PRT
<213> Homo sapiens
<220> -
<221> misc-feature
<223> Incyte ID No.: 3988457CD1
<400> 26
Met Ala Ile Asn Arg Phe Arg Leu Glu Asn Asp Leu Glu Glu Leu
1 5 10 15
Ala Leu Tyr Gln Ile Gln Leu Leu Lys Asp Leu Arg His Thr Glu
20 25 30
Asn Glu Glu Asp Lys Val Ser Ser Ser Ser Phe Arg Gln Arg Met
35 40 45
Leu Gly Asn Leu Leu Arg Pro Pro Tyr Glu Arg Pro Glu Leu Pro
50 55 60
Thr Cys Leu Tyr Val Ile Gly Leu Thr Gly Ile Ser Gly Ser Gly
65 70 75
Lys Ser Ser Ile Ala Gln Arg Leu Lys Gly Leu Gly Ala Phe Val
80 85 90
Ile Asp Ser Asp His Leu Gly His Arg Ala Tyr Ala Pro Gly Gly
95 100 105
Pro Ala Tyr Gln Pro Val Val Glu Ala Phe Gly Thr Asp Ile Leu
110 115 120
His Lys Asp Gly Ile Ile Asn Arg Lys Val Leu Gly Ser Arg Val
125 130 135
Phe Gly Asn Lys Lys Gln Leu Lys Ile Leu Thr Asp Ile Met Trp
140 145 150
Pro Ile Ile Ala Lys Leu Ala Arg Glu Glu Met Asp Arg Ala Val
155 160 165
Ala Glu Gly Lys Arg Val Cys Val Ile Asp Ala Ala Val Leu Leu
170 175 180
29/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Glu Ala Gly Trp Gln Asn Leu Val His Glu Val Trp Thr Ala Val
185 190 195
Ile Pro Glu Thr Glu Ala Val Arg Arg Ile Val Glu Arg Asp Gly
200 205 210
Leu Ser Glu Ala Ala Ala Gln Ser Arg Leu Gln Ser Gln Met Ser
215 220 225
Gly Gln Gln Leu Val Glu Gln Ser His Val Val Leu Ser Ser Pro
230 235 240
Cys Gly Ser Arg Ile Ser Pro Asn Ala Arg Trp Arg Lys Pro Gly
245 250 255
Pro Ser Cys Arg Ser Ala Phe Pro Arg Leu Ile Arg Pro Ser Thr
260 265 270
Glu Lys Phe Ser Val Gly Pro Asp Trp Leu Leu Glu Leu Thr Ser
275 280 285
Asp Pro Val Val Arg Arg Asn Gly Gly Leu Asp Ala His Pro Gly
290 295 300
Ser Gly Pro Glu Val Gln Ala Ile Leu Cys Arg Thr Trp Pro Gly
305 310 315
Leu Val Asp Thr Gly Ser Leu Pro Asn Thr Leu Val Phe Gly Gln
320 325 330
His
<210> 27
<211> 200
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 131890CD1
<400> 27
Met Met Thr Ala Glu Ser Arg Glu Ala Thr Gly Leu Ser Pro Gln
1 5 10 15
Ala Ala Gln Glu Lys Asp Gly Ile Val Ile Val Lys Val Glu Glu
20 25 30
Glu Asp Glu Glu Asp His Met Trp Gly Gln Asp Ser Thr Leu G1n
35 40 45
Asp Thr Pro Pro Pro Asp Pro Glu Ile Phe Arg Gln Arg Phe Arg
50 55 60
Arg Phe Cys Tyr Gln Asn Thr Phe Gly Pro Arg Glu Ala Leu Ser
65 70 75
Arg Leu Lys Glu Leu Cys His Gln Trp Leu Arg Pro Glu Ile Asn
80 85 90
Thr Lys Glu Gln Ile Leu Glu Leu Leu Val Leu Glu Gln Phe Leu
95 100 105
Ser Ile Leu Pro Lys Glu Leu Gln Val Trp Leu Gln Glu Tyr Arg
110 115 120
Pro Asp Ser Gly Glu Glu Ala Val Thr Leu Leu Glu Asp Leu Glu
125 130 135
Leu Asp Leu Ser Gly Gln Gln Val Pro Gly Gln Val His Gly Pro
140 145 150
Glu Met Leu Ala Arg Gly Met Val Pro Leu Asp Pro Val Gln Glu
155 160 165
Ser Ser Ser Phe Asp Leu His His Glu Ala Thr Gln Ser His Phe
170 175 180
Lys His Ser Ser Arg Lys Pro Arg Leu Leu Gln Ser Arg Gly Lys
185 190 195
Lys Gln Gly Phe Ile
30/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
200
<210> 28
<211> 100
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 238642CD1
<400> 28
Met Gln Lys Pro Cys Lys Glu Asn Glu Gly Lys Pro Lys Cys Ser
1 S 10 15
Val Pro Lys Arg Glu Glu Lys Arg Pro Tyr Gly Glu Phe Glu Arg
20 25 30
Gln Gln Thr Glu Gly Asn Phe Arg Gln Arg Leu Leu Gln Ser Leu
35 40 45
Glu Glu Phe Lys Glu Asp Ile Asp Tyr Arg His Phe Lys Asp Glu
50 55 60
Glu Met Thr Arg Glu Gly Asp Glu Met Glu Arg Cys Leu Glu Glu
65 70 75
Ile Arg Gly Leu Arg Lys Lys Phe Arg Ala Leu His Ser Asn His
80 85 90
Arg His Ser Arg Asp Arg Pro Tyr Pro Ile
95 100
<210> 29
<211> 528
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 669862CD1
<400> 29
Met Ser Ser Pro Tyr Pro Leu Leu Leu Glu Asn Ser Ile Cys Leu
1 5 10 15
Phe Phe His Phe Leu Pro Asp Phe Asn Phe Thr Thr Glu Ser Asn
20 25 30
Lys Leu Ser Ser Glu Lys Arg Asn Tyr Glu Val Asn Ala Tyr His
35 40 45
Gln Glu Thr Trp Lys Arg Asn Lys Thr Phe Asn Leu Met Arg Phe
50 55 60
Ile Phe Arg Thr Asp Pro Gln Tyr Thr Ile Glu Phe Gly Arg Gln
65 70 75
Gln Arg Pro Lys Val Gly Cys Phe Ser Gln Met Ile Phe Lys Lys
80 85 90
His Lys Ser Leu Pro Leu His Lys Arg Asn Asn Thr Arg Glu Lys
95 100 105
Ser Tyr Glu Cys Lys Glu Tyr Lys Lys Gly Phe Arg Lys Tyr Leu
110 115 120
His Leu Thr Glu His Leu Arg Asp His Thr Gly Val Ile Pro Tyr
125 130 135
Glu Cys Asn Glu Cys Gly Lys Ala Phe Val Val Phe Gln His Phe
31/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
140 145 150
Ile Arg His Arg Lys Ile His Thr Asp Leu Lys Pro Tyr Glu Cys
155 160 165
Asn Gly Cys Glu Lys Ala Phe Arg Phe Tyr Ser G1n Leu Ile Gln
170 175 180
His Gln Ile Ile His Thr Gly Met Lys Pro Tyr Glu Cys Lys Gln
185 190 195
Cys Gly Lys Ala Phe Arg Arg His Ser His Leu Thr Glu His Gln
200 205 210
Lys Ile His Val Gly Leu Lys Pro Phe Glu Cys Lys Glu Cys Gly
215 220 225
Glu Thr Phe Arg Leu Tyr Arg His Met Cys Leu His Gln Lys Ile
230 235 240
His His Gly Val Lys Pro Tyr Lys Cys Lys Glu Cys Gly Lys Ala
245 250 255
Phe Gly His Arg Ser Ser Leu Tyr Gln His Lys Lys Ile His Ser
260 265 270
Gly Glu Lys Pro Tyr Lys Cys Glu Gln Cys Glu Lys Ala Phe Val
275 280 285
Arg Ser Tyr Leu Leu Val Glu His Gln Arg Ser His Thr Gly Glu
290 295 300
Lys Pro His Glu Cys Met Glu Cys Gly Lys Ala Phe Ser Lys Gly
305 310 315
Ser Ser Leu Leu Lys His Lys Arg Ile His Ser Ser Glu Lys Leu
320 325 330
Tyr Asp Cys Lys Asp Cys Gly Lys Ala Phe Cys Arg Gly Ser Gln
335 340 345
Leu Thr Gln His Gln Arg Ile His Thr Gly Glu Lys Pro His Glu
350 355 360
Cys Lys Glu Cys Gly Lys Thr Phe Lys Leu His Ser Tyr Leu Ile
365 370 375
Gln His ~ln ile Ile His Thr Asp Leu Lys Pro Tyr Glu Cys Lys
380 385 390
Gln Cys Gly Lys Ala Phe Ser Arg Val Gly Asp Leu Lys Thr His
395 400 405
Gln Ser Ile His Ala Gly Glu Lys Pro Tyr Glu Cys Lys Glu Cys
410 415 420
Gly Lys Thr Phe Arg Leu Asn Ser Gln Leu Ile Tyr His Gln Thr
425 430 435
Ile His Thr Gly Leu Lys Pro Tyr Val Cys Lys Glu Cys Lys Lys
440 445 450
Ala Phe Arg Ser Ile Ser Gly Leu Ser Gln His Lys Arg Ile His
455 460 465
Thr Gly Glu Lys Pro Tyr Glu Cys Lys Glu Cys Asp Lys Ala Phe
470 475 480
Asn Arg Ser Asp Arg Leu Thr Gln His Glu Thr Ile His Thr Gly
485 490 495
Val Lys Pro Gln Lys Cys Lys Glu Cys Gly Lys Ala Phe Ser His
500 505 510
Cys Tyr Gln Leu Ser Gln His Gln Arg Phe His His Gly Glu Arg
515 520 525
Leu Leu Met
<210> 30
<211> 350
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1003663CD1
32/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<400> 30
Met His Pro Ala Ala Phe Pro Leu Pro Val Val Val Ala Ala Val
1 5 10 15
Leu Trp Gly Ala Ala Pro Thr Arg Gly Leu Ile Arg Ala Thr Ser
20 25 30
Asp His Asn Ala Ser Met Asp Phe Ala Asp Leu Pro Ala Leu Phe
35 40 45
Gly Ala Thr Leu Ser Gln Glu Gly Leu Gln Gly Phe Leu Val Glu
SO 55 60
Ala His Pro Asp Asn Ala Cys Ser Pro Ile Ala Pro Pro Pro Pro
65 70 75
Ala Pro Val Asn Gly Ser Val Phe Ile Ala Leu Leu Arg Arg Phe
80 85 90
Asp Cys Asn Phe Asp Leu Lys Val Leu Asn Ala Gln Lys Ala Gly
95 100 105
Tyr Gly Ala Ala Val Val His Asn Val Asn Ser Asn Glu Leu Leu
110 115 120
Asn Met Val Trp Asn Ser Glu Glu Ile Gln Gln Gln Ile Trp Ile
125 130 135
Pro Ser Val Phe Ile Gly Glu Arg Ser Ser Glu Tyr Leu Arg Ala
140 145 150
Leu Phe Val Tyr Glu Lys Gly Ala Arg Val Leu Leu Val Pro Asp
155 160 165
Asn Thr Phe Pro Leu Gly Tyr Tyr Leu Ile Pro Phe Thr Gly Ile
170 175 180
Val Gly Leu Leu Val Leu Ala Met Gly Ala Val Met Ile Ala Arg
185 190 195
Cys Ile Gln His Arg Lys Arg Leu Gln Arg Asn Arg Leu Thr Lys
200 205 210
Glu Gln :~eu Lys Gln Ile Pro Thr His Asp Tyr Gln Lys Gly Asp
215 220 225
Gln Tyr Asp Val Cys Ala Ile Cys Leu Asp Glu Tyr Glu Asp Gly
230 235 240
Asp Lys Leu Arg Val Leu Pro Cys Ala His Ala Tyr His Ser Arg
245 250 255
Cys Val Asp Pro Trp Leu Thr Gln Thr Arg Lys Thr Cys Pro Ile
260 265 270
Cys Lys Gln Pro Val His Arg Gly Pro Gly Asp Glu Asp Gln Glu
275 280 285
Glu Glu Thr Gln Gly Gln Glu Glu Gly Asp Glu Gly Glu Pro Arg
290 295 300
Asp His Pro Ala Ser G1u Arg Thr Pro Leu Leu Gly Ser Ser Pro
305 310 315
Thr Leu Pro Thr Ser Phe Gly Ser Leu Ala Pro Ala Pro Leu Val
320 325 330
Phe Pro Gly Pro Ser Thr Asp Pro Pro Leu Ser Pro Pro Ser Ser
335 340 345
Pro Val Ile Leu Val
350
<210> 31
<211> 315
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1432557CD1
33/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<400> 31
Met Ala Ala Leu Gly Val Leu Glu Ser Asp Leu Pro Ser Ala Val
1 5 10 15
Thr Leu Leu Lys Asn Leu Gln Glu G1n Val Met Ala Val Thr Ala
20 25 30
Gln Val Lys Ser Leu Thr Gln Lys Val Gln Ala Gly Ala Tyr Pro
35 40 45
Thr Glu Lys Gly Leu Ser Phe Leu Glu Val Lys Asp Gln Leu Leu
50 55 60
Leu Met Tyr Leu Met Asp Leu Thr His Leu Ile Leu Asp Lys Ala
65 70 75
Ser Gly Gly Ser Leu Gln Gly His Asp Ala Val Leu Arg Leu Va1
80 85 90
Glu Ile Arg Thr Val Leu Glu Lys Leu Arg Pro Leu Asp Gln Lys
95 100 105
Leu Lys Tyr Gln Ile Asp Lys Leu Ile Lys Thr Ala Val Thr Gly
110 115 120
Ser Leu Ser Glu Asn Asp Pro Leu Arg Phe Lys Pro His Pro Ser
125 130 135
Asn Met Met Ser Lys Leu Ser Ser Glu Asp Glu Glu Glu Asp Glu
140 145 150
Ala Glu Asp Asp Gln Ser Glu Ala Ser Gly Lys Lys Ser Val Lys
155 160 165
Gly Val Ser Lys Lys Tyr Val Pro Pro Arg Leu Val Pro Val His
170 175 180
Tyr Asp Glu Thr Glu Ala Glu Arg Glu Lys Lys Arg Leu Glu Arg
185 190 195
Ala Lys Arg Arg Ala Leu Ser Ser Ser Val Ile Arg Glu Leu Lys
200 205 210
Glu Gln Tyr Ser Asp Ala Pro Glu Glu Ile Arg Asp Ala Arg His
215 220 225
Pro His Val Thr Arg Gln Ser Gln Glu Asp Gln His Arg Ile Asn
230 235 240
Tyr Glu Glu Ser Met Met Val Arg Leu Ser Val Ser Lys Arg Glu
245 250 255
Lys Gly Arg Arg Lys Arg Ala Asn Val Met Ser Ser Gln Leu His
260 265 270
Ser Leu Thr His Phe Ser Asp Ile Ser Ala Leu Thr Gly Gly Thr
275 280 285
Val His Leu Asp Glu Asp Gln Asn Pro Ile Lys Lys Arg Lys Lys
290 295 300
Ile Pro Gln Lys Gly Arg Lys Lys Lys Gly Phe Arg Arg Arg Arg
305 310 315
<210> 32
<211> 120
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> 1441770CD1
<400> 32
Met Asp Asp Ser Lys Val Val Gly Gly Lys Val Lys Lys Pro Gly
1 5 10 15
Lys Arg Gly Arg Lys Pro Ala Lys Ile Asp Leu Lys Ala Lys Leu
20 25 30
Glu Arg Ser Arg Gln Ser Ala Arg Glu Cys Arg Ala Arg Lys Lys
35 40 45
34/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Leu Arg Tyr Gln Tyr Leu Glu Glu Leu Val Ser Ser Arg Glu Arg
50 55 60
Ala Ile Cys Ala Leu Arg Glu Glu Leu Glu Met Tyr Lys Gln Trp
65 70 75
Cys Met Ala Met Asp Gln Gly Lys Ile Prc Ser Glu Ile Lys Ala
80 85 90
Leu Leu Thr Gly Glu Glu Gln Asn Lys Ser Gln Gln Asn Ser Ser
95 100 105
Arg His Thr Lys Ala Gly Lys Thr Asp Ala Asn Ser Asn Ser Trp
110 115 120
<210> 33
<211> 326
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1456684CD1
<400> 33
Met Gln Glu Glu Pro Leu Pro Gln Gly Asn Asp Pro Glu Pro Ser
1 5 10 15
Gly Asp Ser Pro Leu Gly Leu Cys Gln Ser Glu Cys Met Glu Met
20 25 30
Ser Glu Val Phe Asp Asp Ala Ser Asp Gln Asp Ser Thr Asp Lys
35 40 4.~
Pro ~rrp Arg Pro Tyr Tyr Asn Tyr Lys Pro Lys Lys Lys Ser Arg
50 55 60
Gln Leu Lys Lys Met Arg Lys Val Asn Trp Arg Lys Glu His Gly
65 70 75
Asn Arg Ser Pro Ser His Lys Cys Lys Tyr Pro Ala Glu Leu Asp
80 85 90
Cys Ala Val G1y Lys Ala Pro Gln Asp Lys Pro Phe Glu Glu Glu
95 100 105
Glu Thr Lys Glu Met Pro Lys Leu Gln Cys Glu Leu Cys Asp Gly
110 115 120
Asp Lys Ala Val Gly Ala Gly Asn Gln Gly Arg Pro His Arg His
125 130 135
Leu Thr Ser Arg Pro Tyr Ala Cys Glu Leu Cys Ala Lys Gln Phe
140 145 150
Gln Ser Pro Ser Thr Leu Lys Met His Met Arg Cys His Thr Gly
155 160 165
Glu Lys Pro Tyr Gln Cys Lys Thr Cys Gly Arg Cys Phe Ser Val
170 175 180
Gln Gly Asn Leu Gln Lys His Glu Arg Ile His Leu Gly Leu Lys
185 190 195
Glu Phe Val Cys Gln Tyr Cys Asn Lys Ala Phe Thr Leu Asn Glu
200 205 210
Thr Leu Lys Ile His Glu Arg Ile His Thr Gly Glu Lys Arg Tyr
215 220 225
His Cys Gln Phe Cys Phe Gln Arg Phe Leu Tyr Leu Ser Thr Lys
230 235 240
Arg Asn His Glu Gln Arg His Ile Arg Glu His Asn Gly Lys Gly
245 250 255
Tyr Ala Cys Phe Gln Cys Pro Lys Ile Cys Lys Thr Ala Ala Ala
260 265 270
Leu Gly Met His Gln Lys Lys His Leu P:~ Lys Ser Pro Ser Gln
275 280 285
35/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Gln Glu Lys Ile Gly Asp Val Cys His Glu Asn Ser Asn Pro Leu
290 295 300
Glu Asn Gln His Phe Ile Gly Ser Glu Asp Asn Asp Gln Lys Asp
305 310 315
Asn Ile Gln Thr Gly Val Glu Asn Val Val Leu
320 325
<210> 34
<211> 106
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1602916CD1
<400> 34
Met Phe Pro Trp Met Arg Pro Gln Ala Ala Pro Gly Arg Arg Arg
1 5 10 15
Gly Arg Gln Thr Tyr Ser Arg Phe Gln Thr Leu Glu Leu Glu Lys
20 25 30
Glu Phe Leu Phe Asn Pro Tyr Leu Thr Arg Lys Arg Arg Ile Glu
35 40 45
Val Ser His Ala Leu Ala Leu Thr Glu Arg Gln Val Lys Ile Trp
50 55 60
Phe Gln Asn Arg Arg Met Lys Trp Lys Lys Glu Asn Asn Lys Asp
65 70 75
Lys Phe Pro Val Ser Arg Gln Glu Val Lys Asp Gly Glu Thr Lys
80 85 90
Lys Glu Ala Gln Glu Leu Glu Glu Asp Arg Ala Glu Arg Leu Thr
95 100 105
Asn
<210> 35
<211> 209
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1692816CD1
<400> 35
Met Asn Pro Ser Met Lys Gln Lys Gln Glu Glu Ile Lys Glu Asn
1 5 10 15
Ile Lys Asn Ser Ser Val Pro Arg Arg Thr Leu Lys Met Ile Gln
20 25 30
Pro Ser Ala Ser Gly Ser Leu Val Gly Arg Glu Asn Glu Leu Ser
35 40 45
Ala Gly Leu Ser Lys Arg Lys His Arg Asn Asp His Leu Thr Ser
50 55 60
Thr Thr Ser Ser Pro Gly Val Ile Val Pro Glu Ser Ser Glu Asn
65 70 75
Lys Asn Leu Gly Gly Val Thr Gln Glu Ser Phe Asp Leu Met Ile
80 85 90
Lys Glu Asn Pro Ser Ser Gln Tyr Trp Lys Glu Val Ala Glu Lys
36/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
95 100 105
Arg Arg Lys Ala Leu Tyr Glu Ala Leu Lys Glu Asn Glu Lys Leu
110 115 120
His Lys Glu Ile Glu Gln Lys Asp Asn Glu Ile Ala Arg Leu Lys
125 130 135
Lys Glu Asn Lys Glu Leu Ala Glu Val Ala Glu His Val Gln Tyr
140 145 150
Met Ala Glu Leu Ile Glu Arg Leu Asn Gly Glu Pro Leu Asp Asn
155 160 165
Phe Glu Ser Leu Asp Asn Gln Glu Phe Asp Ser Glu Glu Glu Thr
170 175 180
Val Glu Asp Ser Leu Val Glu Asp Ser Glu Ile Gly Thr Cys Ala
185 190 195
Glu Gly Thr Val Ser Ser Ser Thr Asp Ala Lys Pro Cys Ile
200 205
<210> 36
<211> 212
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1968191CD1
<400> 36
Met Leu Gly Asn Glu Trp Ser Lys Leu Pro Pro Glu Glu Lys Gln
1 5 10 15
Arg Tyr Leu Asp Glu Ala Asp Arg Asp Lys Glu Arg Tyr Met Lys
20 25 30
Glu Leu Glu Gln Tyr Gln Lys Thr Glu Ala Tyr Lys Val Phe Ser
35 40 45
Arg Lys Thr Gln Asp Arg Gln Lys Gly Lys Ser His Arg Gln Asp
50 55 60
Ala Ala Arg Gln Ala Thr His Asp His Glu Lys Glu Thr Glu Val
65 70 75
Lys Glu Arg Ser Val Phe Asp Ile Pro Ile Phe Thr Glu Glu Phe
80 85 90
Leu Asn His Ser Lys Ala Arg Glu Ala Glu Leu Arg Gln Leu Arg
95 100 105
Lys Ser Asn Met Glu Phe Glu Glu Arg Asn Ala Ala Leu Gln Lys
110 115 120
His Val Glu Ser Met Arg Thr Ala Val Glu Lys Leu Glu Val Asp
125 130 135
Val Ile Gln Glu Arg Ser Arg Asn Thr Val Leu Gln Gln His Leu
140 145 150
Glu Thr Leu Arg Gln Val Leu Thr Ser Ser Phe Ala Ser Met Pro
155 160 165
Leu Pro Gly Ser Gly Glu Thr Pro Thr Val Asp Thr Ile Asp Ser
170 175 180
Tyr Met Asn Arg Leu His Ser Ile Ile Leu Ala Asn Pro Gln Asp
185 190 195
Asn Glu Asn Phe Ile Ala Thr Val Arg Glu Val Val Asn Arg Leu
200 205 210
Asp Arg
37/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<210> 37
<211> 359
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2052061CD1
<400> 37
Met Val Asp Met Asp Lys Leu Ile Asn Asn Leu Glu Val Gln Leu
1 5 10 15
Asn Ser Glu Gly Gly Ser Met Gln Val Phe Lys Gln Val Thr Ala
20 25 30
Ser Val Arg Asn Arg Asp Pro Pro Glu Ile Glu Tyr Thr Ser Asn
35 40 45
Met Thr Ser Pro Thr Leu Leu Asp Ala Asn Pro Met Glu Asn Pro
50 55 60
Ala Leu Phe Asn Asp Ile Lys Ile Glu Pro Pro Glu Glu Leu Leu
65 70 75
Ala Ser Asp Phe Ser Leu Pro Gln Val Glu Pro Val Asp Leu Ser
80 85 90
Phe His Lys Pro Lys Ala Pro Leu Gln Pro Ala Ser Met Leu Gln
95 100 105
Ala Pro Ile Arg Pro Pro Lys Pro Gln Ser Ser Pro Gln Thr Leu
110 115 120
Val Val Ser Thr Ser Thr Ser Asp Met Ser Thr Ser Ala Asn Ile
125 130 135
Pro Thr Val Leu Thr Pro Gly Ser Val Leu Thr Ser Ser Gln Ser
140 145 150
Thr Gly Ser Gln Gln Ile Leu His Val Ile His Thr Ile Pro Ser
155 160 165
Val Ser Leu Pro Asn Lys Met Gly Gly Leu Lys Thr Ile Pro Val
170 175 180
Val Val Gln Ser Leu Pro Met Val Tyr Thr Thr Leu Pro Ala Asp
185 190 195
Gly Gly Pro Ala Ala Ile Thr Val Pro Leu Ile Gly Gly Asp Gly
200 205 210
Lys Asn Ala Gly Ser Val Lys Val Asp Pro Thr Ser Met Ser Pro
215 220 225
Leu Glu Ile Pro Ser Asp Ser Glu Glu Ser Thr Ile Glu Ser Gly
230 235 240
Ser Ser Ala Leu Gln Ser Leu Gln Gly Leu Gln Gln Glu Pro Ala
245 250 255
Ala Met Ala Gln Met Gln Gly Glu Glu Ser Leu Asp Leu Lys Arg
260 265 270
Arg Arg Ile His Gln Cys Asp Phe Ala Gly Cys Ser Lys Val Tyr
275 280 285
Thr Lys Ser Ser His Leu Lys Ala His Arg Arg Ile His Thr Gly
290 295 300
Glu Lys Pro Tyr Lys Cys Thr Trp Asp Gly Cys Ser Trp Lys Phe
305 310 315
Ala Arg Ser Asp Glu Leu Thr Arg His Phe Arg Lys His Thr Gly
320 325 330
Ile Lys Pro Phe Arg Cys Thr Asp Cys Asn Arg Ser Phe Ser Arg
335 340 345
Ser Asp His Leu Ser Leu His Arg Arg Arg His Asp Thr Met
350 355
38/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<210> 38
<211> 445
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2056207CD1
<400> 38
Met Val Glu Cys Ile Arg Glu Val Asn Glu Val Ile Gln Asn Pro
1 5 10 15
Ala Thr Ile Thr Arg Ile Leu Leu Ser His Phe Asn Trp Asp Lys
20 25 30
Glu Lys Leu Met Glu Arg Tyr Phe Asp Gly Asn Leu Glu Lys Leu
35 40 45
Phe Ala Glu Cys His Val Ile Asn Pro Ser Lys Lys Ser Arg Thr
50 55 60
Arg Gln Met Asn Thr Arg Ser Ser Ala Gln Asp Met Pro Cys Gln
65 70 75
Ile Cys Tyr Leu Asn Tyr Pro Asn Ser Tyr Phe Thr Gly Leu Glu
80 85 90
Cys Gly His Lys Phe Cys Met Gln Cys Trp Ser Glu Tyr Leu Thr
95 100 105
Thr Lys Ile Met Glu Glu Gly Met Gly Gln Thr Ile Ser Cys Pro
110 115 120
Ala His Gly Cys Asp Ile Leu Val Asp Asp Asn Thr Val Met Arg
125 130 135
Leu Ile Thr Asp Ser Lys Val Lys Leu Lys Tyr Gln His Leu Ile
140 145 150
Thr Asn Ser Phe Val Glu Cys Asn Arg Leu Leu Lys Trp Cys Pro
155 160 165
Ala Pro Asp Cys His His Val Val Lys Val Gln Tyr Pro Asp Ala
170 175 180
Lys Pro Val Arg Cys Lys Cys Gly Arg Gln Phe Cys Phe Asn Cys
185 190 195
Gly Glu Asn Trp His Asp Pro Val Lys Cys Lys Trp Leu Lys Lys
200 205 210
Trp Ile Lys Lys Cys Asp Asp Asp Ser Glu Thr Ser Asn Trp Ile
215 220 225
Ala Ala Asn Thr Lys Glu Cys Pro Lys Cys His Val Thr Ile Glu
230 235 240
Lys Asp Gly Gly Cys Asn His Met Val Cys Arg Asn Gln Asn Cys
245 250 255
Lys Ala Glu Phe Cys Trp Val Cys Leu Gly Pro Trp Glu Pro His
260 265 270
Gly Ser Ala Trp Tyr Asn Cys Asn Arg Tyr Asn Glu Asp Asp Ala
275 280 285
Lys Ala Ala Arg Asp Ala Gln Glu Arg Ser Arg Ala Ala Leu Gln
290 295 300
Arg Tyr Leu Phe Tyr Cys Asn Arg Tyr Met Asn His Met Gln Ser
305 310 315
Leu Arg Phe Glu His Lys Leu Tyr Ala Gln Val Lys Gln Lys Met
320 325 330
Glu Glu Met Gln Gln His Asn Met Ser Trp Ile Glu Val Gln Phe
335 340 345
Leu Lys Lys Ala Val Asp Val Leu Cys Gln Cys Arg Ala Thr Leu
350 355 360
Met Tyr Thr Tyr Val Phe Ala Phe Tyr Leu Lys Lys Asn Asn Gln
365 370 375
Ser Ile Ile Phe Glu Asn Asn Gln Ala Asp Leu Glu Asn Ala Thr
380 385 390
39/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00/02237
Glu Val Leu Ser Gly Tyr Leu Glu Arg Asp Ile Ser Gln Asp Ser
395 400 405
Leu Gln Asp Ile Lys Gln Lys Val Gln Asp Lys Tyr Arg Tyr Cys
410 415 420
Glu Ser Arg Arg Arg Val Leu Leu Gln His Val His Glu Gly Tyr
425 430 435
Glu Lys Asp Leu Trp Glu Tyr Ile Glu Asp
440 445
<210> 39
<211> 433
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2101803CD1
<400> 39
Met Arg Ala Glu Gly Leu Gly Gly Leu Glu Arg Phe Cys Ser Pro
1 5 10 15
Gly Lys Gly Arg Gly Leu Arg Ala Leu Gln Pro Phe Gln Val Gly
20 25 30
Asp Leu Leu Phe Ser Cys Pro Ala Tyr Ala Tyr Val Leu Thr Val
35 40 45
Asn Glu Arg Gly Asn His Cys Glu Tyr Cys Phe Thr Arg Lys Glu
50 55 60
Gly Leu Ser Lys Cys Gly Arg Cys Lys Gln Ala Phe Tyr Cys Asn
65 70 75
Val Glu Cys Gln Lys Glu Asp Trp Pro Met His Lys Leu Glu Cys
80 85 90
Ser Pro Met Val Val Phe Gly Glu Asn Trp Asn Pro Ser Glu Thr
95 100 105
Val Arg Leu Thr Ala Arg Ile Leu Ala Lys Gln Lys Ile His Pro
110 115 120
Glu Arg Thr Pro Ser Glu Lys Leu Leu Ala Val Lys Glu Phe Glu
125 130 135
Ser His Leu Asp Lys Leu Asp Asn Glu Lys Lys Asp Leu Ile Gln
140 145 150
Ser Asp Ile Ala Ala Leu His His Phe Tyr Ser Lys His Leu Glu
155 160 165
Phe Pro Asp Asn Asp Ser Leu Val Val Leu Phe Ala Gln Val Asn
170 175 180
Cys Asn Gly Phe Thr Ile Glu Asp Glu Glu Leu Ser His Leu Gly
185 190 195
Ser Ala Ile Phe Pro Asp Val Ala Leu Met Asn His Ser Cys Cys
200 205 210
Pro Asn Val Ile Val Thr Tyr Lys Gly Thr Leu Ala Glu Val Arg
215 220 225
Ala Val Gln Glu Ile Lys Pro Gly Glu Glu Val Phe Thr Ser Tyr
230 235 240
Ile Asp Leu Leu Tyr Pro Thr Glu Asp Arg Asn Asp Arg Leu Arg
245 250 255
Asp Ser Tyr Phe Phe Thr Cys Glu Cys Gln Glu Cys Thr Thr Lys
260 265 270
Asp Lys Asp Lys Ala Lys Val Glu Ile Arg Lys Leu Ser Asp Pro
275 280 285
Pro Lys Ala Glu Ala Ile Arg Asp Met Val Arg Tyr Ala Arg Asn
290 295 300
40/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Val Ile Glu Glu Phe Arg Arg Ala Lys His Tyr Lys Ser Pro Ser
305 310 315
Glu Leu Leu Glu Ile Cys Glu Leu Ser Gln Glu Lys Met Ser Ser
320 325 330
Val Phe Glu Asp Ser Asn Val Tyr Met Leu His Met Met Tyr Gln
335 340 345
Ala Met Gly Val Cys Leu Tyr Met Gln Asp Trp Glu Gly Ala Leu
350 355 360
Gln Tyr Gly Gln Lys Ile Ile Lys Pro Tyr Ser Lys His Tyr Pro
365 370 375
Leu Tyr Ser Leu Asn Val Ala Ser Met Trp Leu Lys Leu Gly Arg
380 385 390
Leu Tyr Met Gly Leu Glu His Lys Ala Ala Gly Glu Lys Ala Leu
395 400 405
Lys Lys Ala Ile Ala Ile Met Glu Val Ala His Gly Lys Asp His
410 415 420
Pro Tyr Ile Ser Glu Ile Lys Gln Glu Ile Glu Ser His
425 430
<210> 40
<211> 355
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2112362CD1
<400> 40
Met Ser Val Asn Tyr Ala Ala Gly Leu Ser Pro Tyr Ala Asp Lys
1 5 10 15
Gly Lys Cys Gly Leu Pro Glu Ile Phe Asp Pro Pro Glu Glu Leu
20 25 30
Glu Arg Lys Val Trp Glu Leu Ala Arg Leu Val Trp Gln Ser Ser
35 40 45
Asn Val Val Phe His Thr Gly Ala Gly Ile Ser Thr Ala Ser Gly
50 55 60
Ile Pro Asp Phe Arg Gly Pro His Gly Val Trp Thr Met Glu Glu
65 70 75
Arg Gly Leu Ala Pro Lys Phe Asp Thr Thr Phe Glu Ser Ala Arg
80 85 90
Pro Thr Gln Thr His Met Ala Leu Val Gln Leu Glu Arg Val Gly
95 100 105
Leu Leu Arg Phe Leu Val Ser Gln Asn Val Asp Gly Leu His Val
110 115 120
Arg Ser Gly Phe Pro Arg Asp Lys Leu Ala Glu Leu His Gly Asn
125 130 135
Met Phe Val Glu Glu Cys Ala Lys Cys Lys Thr Gln Tyr Val Arg
140 145 150
Asp Thr Val Val Gly Thr Met Gly Leu Lys Ala Thr Gly Arg Leu
155 160 165
Cys Thr Val Ala Lys Ala Arg Gly Leu Arg Ala Cys Arg Gly Glu
170 175 180
Leu Arg Asp Thr Ile Leu Asp Trp Glu Asp Ser Leu Pro Asp Arg
185 190 195
Asp Leu Ala Leu Ala Asp Glu Ala Ser Arg Asn Ala Asp Leu Ser
200 205 210
Ile Thr Leu Gly Thr Ser Leu Gln Ile Arg Pro Ser Gly Asn Leu
215 220 225
41/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCTNS00/02237
Pro Leu Ala Thr Lys Arg Arg Gly Gly Arg Leu Val Ile Val Asn
230 235 240
Leu Gln Pro Thr Lys His Asp Arg His Ala Asp Leu Arg Ile His
245 250 255
Gly Tyr Val Asp Glu Val Met Thr Arg Leu Met Lys His Leu Gly
260 265 270
Leu Glu Ile Pro Ala Trp Asp Gly Pro Arg Val Leu Glu Arg Ala
275 280 285
Leu Pro Pro Leu Pro Arg Pro Pro Thr Pro Lys Leu Glu Pro Lys
290 295 300
Glu Glu Ser Pro Thr Arg Ile Asn Gly Ser Ile Pro Ala Gly Pro
305 310 315
Lys Gln Glu Pro Cys Ala Gln His Asn Gly Ser Glu Pro Ala Ser
320 325 330
Pro Lys Arg Glu Arg Pro Thr Ser Pro Ala Pro His Arg Pro Pro
335 340 345
Lys Arg Val Lys Ala Lys Ala Val Pro Ser
350 355
<210> 41
<211> 443
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2117346CD1
<400> 41
Met Asp Arg Leu Gly Ser Phe Ser Asn Asp Pro Ser Asp Lys Pro
1 5 10 15
Pro Cys Arg Gly Cys Ser Ser Tyr Leu Met Glu Pro Tyr Ile Lys
20 25 30
Cys Ala Glu Cys Gly Pro Pro Pro Phe Phe Leu Cys Leu Gln Cys
35 40 45
Phe Thr Arg Gly Phe Glu Tyr Lys Lys His Gln Ser Asp His Thr
50 55 60
Tyr Glu Ile Met Thr Ser Asp Phe Pro Val Leu Asp Pro Ser Trp
65 70 75
Thr Ala Gln Glu Glu Met Ala Leu Leu Glu Ala Val Met Asp Cys
80 85 90
Gly Phe Gly Asn Trp Gln Asp Val Ala Asn Gln Met Cys Thr Lys
95 100 105
Thr Lys Glu Glu Cys Glu Lys His Tyr Met Lys His Phe Ile Asn
110 115 120
Asn Pro Leu Phe Ala Ser Thr Leu Leu Asn Leu Lys Gln Ala Glu
125 130 135
Glu Ala Lys Thr Ala Asp Thr Ala Ile Pro Phe His Ser Thr Asp
140 145 150
Asp Pro Pro Arg Pro Thr Phe Asp Ser Leu Leu Ser Arg Asp Met
155 160 165
Ala Gly Tyr Met Pro Ala Arg Ala Asp Phe Ile Glu Glu Phe Asp
170 175 180
Asn Tyr Ala Glu Trp Asp Leu Arg Asp Ile Asp Phe Val Glu Asp
185 190 195
Asp Ser Asp Ile Leu His A1a Leu Lys Met Ala Val Val Asp Ile
200 205 210
Tyr His Ser Arg Leu Lys Glu Arg Gln Arg Arg Lys Lys Ile Ile
215 220 225
42/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
Arg Asp His Gly Leu Ile Asn Leu Arg Lys Phe Gln Leu Met Glu
230 235 240
Arg Arg Tyr Pro Lys Glu Val Gln Asp Leu Tyr Glu Thr Met Arg
245 250 255
Arg Phe Ala Arg Ile Val Gly Pro Val Glu His Asp Lys Phe Ile
260 265 270
Glu Ser His Ala Leu Glu Phe Glu Leu Arg Arg Glu Ile Lys Arg
275 280 285
Leu Gln Glu Tyr Arg Thr Ala Gly Ile Thr Asn Phe Cys Ser Ala
290 295 300
Arg Thr Tyr Asp His Leu Lys Lys Thr Arg Glu Glu Glu Arg Leu
305 310 315
Lys Arg Thr Met Leu Ser Glu Val Leu Gln Tyr Ile Gln Asp Ser
320 325 330
Ser Ala Cys Gln Gln Trp Leu Arg Arg Gln Ala Asp Ile Asp Ser
335 340 345
Gly Leu Ser Pro Ser Ile Pro Met Ala Ser Asn Ser Gly Arg Arg
350 355 360
Ser Ala Pro Pro Leu Asn Leu Thr Gly Leu Pro Gly Thr Glu Lys
365 370 375
Leu Asn Glu Lys Glu Lys Glu Leu Cys Gln Met Val Arg Leu Val
380 385 390
Pro Gly Ala Tyr Leu Glu Tyr Lys Ser Ala Leu Leu Asn Glu Cys
395 400 405
Asn Lys Gln Gly Gly Leu Arg Leu Ala Gln Ala Arg Ala Leu Ile
410 415 420
Lys Ile Asp Val Asn Lys Thr Arg Lys Ile Tyr Asp Phe Leu Ile
425 430 435
Arg Glu Gly Tyr Ile Thr Lys Gly
440
<210> 42
<211> 164
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2119917CD1
<400> 42
Met Thr Ala Ser Ala Gln Pro Arg Gly Arg Arg Pro G1y Val Gly
1 5 10 15
Val Gly Val Val Val Thr Ser Cys Lys His Pro Arg Cys Val Leu
20 25 30
Leu Gly Lys Arg Lys Gly Ser Val Gly Ala Gly Ser Phe Gln Leu
35 40 45
Pro Gly Gly His Leu Glu Phe Gly Glu Thr Trp Glu Glu Cys Ala
50 55 60
Gln Arg Glu Thr Trp Glu Glu Ala Ala Leu His Leu Lys Asn Val
65 70 75
His Phe Ala Ser Val Val Asn Ser Phe Ile Glu Lys Glu Asn Tyr
80 85 90
His Tyr Val Thr Ile Leu Met Lys Gly Glu Val Asp Val Thr His
95 100 105
Asp Ser Glu Pro Lys Asn Val Glu Pro Glu Lys Asn Glu Ser Trp
110 115 120
Glu Trp '.'al Pro Trp Glu Glu Leu Pro Pro Leu Asp Gln Leu Phe
125 130 135
43/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Trp Gly Leu Arg Cys Leu Lys Glu Gln Gly Tyr Asp Pro Phe Lys
140 145 150
Glu Asp Leu Asn His Leu Val Gly Tyr Lys Gly Asn His Leu
155 160
<210> 43
<211> 215
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2123456CD1
<400> 43
Met Leu Gly Ala Glu Trp Ser Lys Leu Gln Pro Thr Glu Lys Gln
1 5 10 15
Arg Tyr Leu Asp Glu Ala Glu Arg Glu Lys Gln Gln Tyr Met Lys
20 25 30
Glu Leu Arg Ala Tyr Gln Gln Ser Glu Ala Tyr Lys Met Cys Thr
35 40 45
Glu Lys Ile Gln Glu Lys Lys Ile Lys Lys Glu Asp Ser Ser Ser
50 55 60
Gly Leu Met Asn Thr Leu Leu Asn Gly His Lys Gly Gly Asp Cys
65 70 75
Asp Gly Phe Ser Thr Phe Asp Val Pro Ile Phe Thr Glu Glu Phe
80 85 90
Leu Asp Gln Asn Lys Aia Arg Glu Ala Glu Leu Arg Arg Leu Arg
95 100 105
Lys Met Asn Val Ala Phe Glu Glu Gln Asn Ala Val Leu Gln Arg
110 115 120
His Thr Gln Ser Met Ser Ser Ala Arg Glu Arg Leu Glu Gln Glu
125 130 135
Leu Ala Leu Glu Glu Arg Arg Thr Leu Ala Leu Gln Gln Gln Leu
140 145 150
Gln Ala Val Arg Gln Ala Leu Thr Ala Ser Phe Ala Ser Leu Pro
155 160 165
Val Pro Gly Thr Gly Glu Thr Pro Thr Leu Gly Thr Leu Asp Phe
170 175 180
Tyr Met Ala Arg Leu His Gly Ala Ile Glu Arg Asp Pro Ala Gln
185 190 195
His Glu Lys Leu Ile Val Arg Ile Lys Glu Ile Leu Ala Gln Val
200 205 210
Ala Ser Glu His Leu
215
<210> 44
<211> 539
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2148792CD1
<400> 44
44/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Met Ala Ala Leu Phe Leu Ser Ala Pro Pro Gln Ala Glu Val Thr
1 5 10 15
Phe Glu Asp Val Ala Val Tyr Leu Ser Arg Glu Glu Trp Gly Arg
20 25 30
Leu Gly Pro Ala Gln Arg Gly Leu Tyr Arg Asp Val Met Leu Glu
35 40 45
Thr Tyr Gly Asn Leu Val Ser Leu Gly Val Gly Pro Ala Gly Pro
50 55 60
Lys Pro Gly Val Ile Ser Gln Leu Glu Arg Gly Asp Glu Pro Trp
65 70 75
Val Leu Asp Val Gln Gly Thr Ser Gly Lys Glu His Leu Arg Val
80 85 90
Asn Ser Pro Ala Leu Gly Thr Arg Thr Glu Tyr Lys Glu Leu Thr
95 100 105
Ser Gln Glu Thr Phe Gly Glu Glu Asp Pro Gln Gly Ser Glu Pro
110 115 120
Val Glu Ala Cys Asp His Ile Ser Lys Ser Glu Gly Ser Leu Glu
125 130 135
Lys Leu Val Glu Gln Arg Gly Pro Arg Ala Val Thr Leu Thr Asn
140 145 150
Gly Glu Ser Ser Arg Glu Ser Gly Gly Asn Leu Arg Leu Leu Ser
155 160 165
Arg Pro Val Pro Asp Gln Arg Pro His Lys Cys Asp Ile Cys Glu
170 175 180
Gln Ser Phe Glu Gln Arg Ser Tyr Leu Asn Asn His Lys Arg Val
185 190 195
His Arg Ser Lys Lys Thr Asn Thr Val Arg Asn Ser Gly Glu Ile
200 205 210
Phe Ser Ala Asn Leu Val Val Lys Glu Asp Gln Lys Ile Pro Thr
21.5 220 225
Gly Lys Lys Leu His Tyr Cys Ser Tyr Cys Gly Lys Thr Phe Arg
230 235 240
Tyr Ser Ala Asn Leu Val Lys His Gln Arg Leu His Thr Glu Glu
245 250 255
Lys Pro Tyr Lys Cys Asp Glu Cys Gly Lys Ala Phe Ser Gln Ser
260 265 270
Cys Glu Phe Ile Asn His Arg Arg Met His Ser Gly Glu Ile Pro
275 280 285
Tyr Arg Cys Asp Glu Cys Gly Lys Thr Phe Thr Arg Arg Pro Asn
290 295 300
Leu Met Lys His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr Lys
305 310 315
Cys Gly Glu Cys Gly Lys His Phe Ser Ala Tyr Ser Ser Leu Ile
320 325 330
Tyr His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr Lys Cys Asn
335 340 345
Asp Cys Gly Lys Ala Phe Ser Asp Gly Ser Ile Leu Ile Arg His
350 355 360
Arg Arg Thr His Thr Gly Glu Lys Pro Phe Glu Cys Lys Glu Cys
365 370 375
Gly Lys Gly Phe Thr Gln Ser Ser Asn Leu Ile Gln His Gln Arg
380 385 390
Ile His Thr Gly Glu Lys Pro Tyr Lys Cys Asn Glu Cys Glu Lys
395 400 405
Ala Phe Ile Gln Lys Thr Lys Leu Val Glu His Gln Arg Ser His
410 415 420
Thr Gly Glu Lys Pro Tyr Glu Cys Asn Asp Cys Gly Lys Val Phe
425 430 435
Ser Gln Ser Thr His Leu Ile Gln His G1n Arg Ile His Thr Gly
440 445 450
Glu Lys Pro Tyr Lys Cys Ser Glu Cys Gly Lys Ala Phe His Asn
455 460 465
45/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
Ser Ser Arg Leu Ile His His Gln Arg Leu His His Gly Glu Lys
470 475 480
Pro Tyr Arg Cys Ser Asp Cys Lys Lys Ala Phe Ser Gln Ser Thr
485 490 495
Tyr Leu Ile Gln His Arg Arg Ile His ~hr Gly Glu Lys Pro Tyr
500 505 510
Lys Cys Ser Glu Cys Gly Lys Ala Phe Arg His Ser Ser Asn Met
515 520 525
Cys Gln His Gln Arg Ile His Leu Arg Glu Asp Phe Ser Met
530 535
<210> 45
<211> 182
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2751943CD1
<400> 45
Met Ala Arg Leu Leu Trp Leu Leu Arg Gly Leu Thr Leu Gly Thr
1 5 10 15
Ala Pro Arg Arg Ala Val Arg Gly Gln Ala Gly Gly Gly Gly Pro'
20 25 30
Gly Thr Gly Pro Gly Leu Gly Glu Ala Gly Ser Leu Ala Thr Cys
35 40 45
Glu Leu Pro Leu Ala Lys Ser Glu Trp Gln Lys Lys Leu Thr Pro
50 55 60
Glu Gln Phe Tyr Val Thr Arg Glu Lys Gly Thr Glu Pro Pro Phe
65 70 75
Ser Gly Ile Tyr Leu Asn Asn Lys Glu Ala Gly Met Tyr His Cys
80 85 90
Val Cys Cys Asp Ser Pro Leu Phe Ser Ser Glu Lys Lys Tyr Cys
95 100 105
Ser Gly Thr Gly Trp Pro Ser Phe Ser Glu Ala His Gly Thr Ser
110 115 120
Gly Ser Asp Glu Ser His Thr Gly I1~ Leu Arg Arg Leu Asp Thr
125 130 135
Ser Leu Gly Ser Ala Arg Thr Glu Val Val Cys Lys Gln Cys Glu
140 145 150
Ala His Leu Gly His Val Phe Pro Asp Gly Pro Gly Pro Asn Gly
155 160 165
Gln Arg Phe Cys Ile Asn Ser Val Ala Leu Lys Phe Lys Pro Arg
170 175 180
Lys His
<210> 46
<211> 534
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3128913CD1
46/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
<400> 46
Met Ala Val Glu Ser Gly Val Ile Ser Thr Leu Ile Pro Gln Asp
1 5 10 15
Pro Pro Glu Gln Glu Leu Ile Leu Val Lys Val Glu Asp Asn Phe
20 25 30
Ser Trp Asp Glu Lys Phe Lys Gln Asn Gly Ser Thr Gln Ser Cys
35 40 45
Gln Glu Leu Phe Arg Gln Gln Phe Arg Lys Phe Cys Tyr Gln Glu
50 55 60
Thr Pro Gly Pro Arg Glu Ala Leu Ser Arg Leu Gln Glu Leu Cys
65 70 75
Tyr Gln Trp Leu Met Pro Glu Leu His Thr Lys Glu Gln Ile Leu
80 85 90
Glu Leu Leu Val Leu Glu Gln Phe Leu Ser Ile Leu Pro Glu Glu
95 100 105
Leu Gln Ile Trp Val Gln Gln His Asn Pro Glu Ser Gly Glu Glu
110 115 120
Ala Val Thr Leu Leu Glu Asp Leu Glu Arg Glu Phe Asp Asp Pro
125 130 135
Gly Gln Gln Val Pro Ala Ser Pro Gln Gly Pro Ala Val Pro Trp
140 145 150
Lys Asp Leu Thr Cys Leu Arg Ala Ser Gln Glu Ser Thr Asp Ile
155 160 165
His Leu Gln Pro Leu Lys Thr Gln Leu Lys Ser Trp Lys Pro Cys
170 175 180
Leu Ser Pro Lys Ser Asp Cys Glu Asn Ser Glu Thr Ala Thr Lys
185 190 195
Glu Gly Ile Ser Glu Glu Lys Ser Gln Gly Leu Pro Gln Glu Pro
_ 200 205 210
Ser Phe Arg Gly Ile Ser Glu His Glu Ser Asn Leu Val Trp Lys
215 220 225
Gln Gly Ser Ala Thr Gly Glu Lys Leu Arg Ser Pro Ser Gln Gly
230 235 240
Gly Ser Phe Ser Gln Val Ile Phe Thr Asn Lys Ser Leu Gly Lys
245 250 255
Arg Asp Leu Tyr Asp Glu Ala Glu Arg Cys Leu Ile Leu Thr Thr
260 265 270
Asp Ser Ile Met Cys Gln Lys Val Pro Pro Glu Glu Arg Pro Tyr
275 280 X85
Arg Cys Asp Val Cys Gly His Ser Phe Lys Gln His Ser Ser Leu
290 295 300
Thr Gln His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr Lys Cys
305 310 315
Asn Gln Cys Gly Lys Ala Phe Ser Leu Arg Ser Tyr Leu Ile Ile
320 325 330
His Gln Arg Ile His Ser Gly Glu Lys Ala Tyr Glu Cys Ser Glu
335 340 345
Cys Gly Lys Ala Phe Asn Gln Ser Ser Ala Leu Ile Arg His Arg
350 355 360
Lys Ile His Thr Gly Glu Lys Ala Cys Lys Cys Asn Glu Cys Gly
365 370 375
Lys Ala Phe Ser Gln Ser Ser Tyr Leu Ile Ile His Gln Arg Ile
380 385 390
His Thr Gly Glu Lys Pro Tyr Glu Cys Asn Glu Cys Gly Lys Thr
395 400 405
Phe Ser Gln Ser Ser Lys Leu Ile Arg His Gln Arg Ile His Thr
410 415 420
Gly Glu Arg Pro Tyr Glu Cys Asn Glu Cys Gly Lys Ala Phe Arg
425 430 435
Gln Ser Ser Glu Leu Ile Thr His Gln Arg Ile His Ser Gly Glu
440 445 450
Lys Pro Tyr Glu Cys Ser Glu Cys Gly Lys Ala Phe Ser Leu Ser
47/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
455 460 465
Ser Asn Leu Ile Arg His Glri Arg Ile His Ser Gly Glu Glu Pro
470 475 480
Tyr Gln Cys Asn Glu Cys Gly Lys Thr Phe Lys Arg Ser Ser Ala
485 490 495
Leu Val Gln His Gln Arg Ile His Ser Gly Asp Glu Ala Tyr Ile
500 505 510
Cys Asn Glu Cys Gly Lys Ala Phe Arg His Arg Ser Val Leu Met
515 520 525
Arg His Gln Arg Val His Thr Ile Lys
530
<210> 47
<211> 206
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3282941CD1
<400> 47
Met Ser Thr Gly Ser Val Ser Asp Pro Glu Glu Met Glu Leu Arg
1 5 10 15
Gly Leu Gln Arg Glu Tyr Pro Val Pro Ala Ser Lys Arg Pro Pro
20 25 30
Leu Arg Gly Val Glu Arg Ser Tyr Ala Ser Pro Ser Asp Asn Ser
35 40 45
Ser Ala Glu Glu Glu Asp Pro Asp Gly Glu Glu Glu Arg Cys Ala
50 55 60
Leu Gly Thr Ala Gly Ser Ala Glu Gly Cys Lys Arg Lys Arg Pro
65 70 75
Arg Val Ala Gly Gly Gly Gly Ala Gly Gly Ser Ala Gly Gly Gly
80 85 90
Gly Lys Lys Pro Leu Pro Ala Lys Gly Ser Ala Ala Glu Cys Lys
95 100 105
Gln Ser Gln Arg Asn Ala Ala Asn Ala Arg Glu Arg Ala Arg Met
110 115 120
Arg Val Leu Ser Lys Ala Phe Ser Arg Leu Lys Thr Ser Leu Pro
125 130 135
Trp Val Pro Pro Asp Thr Lys Leu Ser Lys Leu Asp Thr Leu Arg
140 145 150
Leu Ala Ser Ser Tyr Ile Ala His Leu Arg Gln Leu Leu Gln Glu
155 160 165
Asp Arg Tyr Glu Asn Gly Tyr Val His Pro Val Asn Leu Thr Trp
170 175 180
Pro Phe Val Val Ser Gly Arg Pro Asp Ser Asp Thr Lys Glu Val
185 190 195
Ser Ala Ala Asn Arg Leu Cys Gly Thr Thr Ala
200 205
<210> 48
<211> 172
<212> PRT
<213> Homo Sapiens
48/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<220>
<221> misc-feature
<223> Incyte ID No.: 3286656CD1
<400> 48
Met Glu Ser Val Thr Phe Glu Asp Val Ala Val Glu Phe Ile Gln
1 5 10 15
Glu Trp Ala Leu Leu Asp Ser Ala Arg Arg Ser Leu Cys Lys Tyr
20 25 30
Arg Met Leu Asp Gln Cys Arg Thr Leu Ala Ser Arg Gly Thr Pro
35 40 45
Pro Cys Lys Pro Ser Cys Val Ser Gln Leu Gly Gln Arg Ala Glu
50 55 60
Pro Lys Ala Thr_Glu Arg Gly Ile Leu Arg Ala Thr Gly Val Ala
65 70 75
Trp Glu Ser Gln Leu Lys Pro Glu Glu Leu Pro Ser Met Gln Asp
80 85 90
Leu Leu Glu Glu Ala Ser Ser Arg Asp Met Gln Met Gly Pro Gly
95 100 105
Leu Phe Leu Arg Met Gln Leu Val Pro Ser Ile Glu Glu Arg Glu
110 115 120
Thr Pro Leu Thr Arg Glu Asp Arg Pro Ala Leu Gln Glu Pro Pro
125 130 135
Trp Ser Leu Gly Cys Thr Gly Leu Lys Ala Ala Met Gln Ile Gln
140 145 150
Arg Val Val Ile Pro Val Pro Thr Leu Gly His Arg Asn Pro Trp
155 160 165
Val Ala Arg Asp Ser Ala Met
170
<210> 49
<211> 275
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3490802CD1
<400> 49
Met Gly Pro Leu Gln Phe Arg Asp Val Ala Ile Glu Phe Ser Leu
1 5 10 15
Glu Glu Trp His Cys Leu Asp Thr Ala Gln Arg Asn Leu Tyr Arg
20 25 30
Asp Val Met Leu Glu Asn Tyr Arg Asn Leu Val Phe Leu Gly Ile
35 40 45
Val Val Ser Lys Pro Asp Leu Val Thr Cys Leu Glu Gln Gly Lys
50 55 60
Lys Pro Leu Thr Met Glu Arg His Glu Met Ile Ala Lys Pro Pro
65 70 75
Val Met Ser Ser His Phe Ala Gln Asp Leu Trp Pro Glu Asn Ile
80 85 90
Gln Asn Ser Phe Gln Ile Gly Met Leu Arg Arg Tyr Glu Glu Cys
95 100 105
Arg His Asp Asn Leu Gln Leu Lys Lys Gly Cys Lys Ser Val Gly
110 115 120
Glu His Lys Val His Lys Gly Gly Tyr Asn Gly Leu Asn Gln Cys
125 13 0 135
Leu Thr Thr Thr Gln Lys Glu Ile Phe Gln Cys Asp Lys Tyr Gly
49/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
140 145 150
Lys Val Phe His Lys Phe Ser Asn Ser Asn Thr Tyr Lys Thr Arg
155 160 165
His Thr Gly Ile Asn Leu Phe Lys Cys Ile Ile Cys Gly Lys Ala
170 175 180
Phe Lys Arg Ser Ser Thr Leu Thr Thr His Lys Lys Ile His Thr
185 190 195
Gly Glu Lys Pro Tyr Lys Cys Glu Glu Cys Gly Lys Ala Phe Asn
200 205 210
Gl.n Ser Ser Asn Leu Thr Thr His Lys Arg Ile His Thr Gly Glu
215 220 225
Lys Pro Tyr Lys Cys Glu Glu Cys Gly Lys Ala Phe Asn Trp Ser
230 235 240
Ser Asp Leu Asn Lys His Lys Lys Ile His Ile Glu Arg Lys Pro
245 250 255
Tyr Ile Val Lys Asn Val Thr Asp Leu Leu Asn Val Pro Pro Leu
260 265 270
Leu Ile Ser Ile Arg
275
<210> 50
<211> 236
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3507366CD1
<400> 50
Met Asp Lys Arg Tyr Leu Gln Phe Asp Ile Lys Ala Phe Val Glu
1 5 10 15
Asn Asn Pro Ala Ile Lys Trp Cys Pro Thr Pro Gly Cys Asp Arg
20 25 30
Ala Val Arg Leu Thr Lys Gln Gly Ser Asn Thr Ser Gly Ser Asp
35 40 45
Thr Leu Ser Phe Pro Leu Leu Arg Ala Pro Ala Val Asp Cys Gly
50 55 60
Lys Gly His Leu Phe Cys Trp Glu Cys Leu Gly Glu Ala His Glu
65 70 75
Pro Cys Asp Cys Gln Thr Trp Lys Asn Trp Leu Gln Lys Ile Thr
80 85 90
Glu Met Lys Pro Glu Glu Leu Val Gly Val Ser Glu Ala Tyr Glu
95 100 105
Asp Ala Ala Asn Cys Leu Trp Leu Leu Thr Asn Ser Lys Pro Cys
110 115 120
Ala Asn Cys Lys Ser Pro Ile Gln Lys Asn Glu Gly Cys Asn His
125 13 0 135
Met Gln Cys Ala Lys Cys Lys Tyr Asp Phe Cys Trp Ile Cys Leu
140 145 150
Glu Glu Trp Lys Lys His Ser Ser Ser Thr Gly Gly Tyr Tyr Arg
155 160 165
Cys Thr Arg Tyr Glu Val Ile Gln His Val Glu Glu Gln Ser Lys
170 175 180
Glu Met Thr Val Glu Ala Glu Lys Lys His Lys Arg Phe Gln Glu
185 190 195
Leu Asp Arg Phe Met His Tyr Tyr Thr Arg Phe Lys Asn His Glu
200 205 210
His Ser Tyr Gln Leu Glu Gln Arg Leu Leu Lys Thr Ala Lys Glu
50/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
215 220 225
Lys Met Glu Gln Met Ser Arg Val Ser Lys Asn
230 235
<210> 51
<211> 214
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3573060CD1
<400> 51
Met Asn Leu Ser Ser Ala Ser Ser Thr Glu Glu Lys Ala Val Thr
1 5 10 15
Thr Val Leu Trp Gly Cys Glu Leu Ser Gln Glu Arg Arg Thr Trp
20 25 30
Thr Phe Arg Pro Gln Leu Glu Gly Lys Gln Ser Cys Arg Leu Leu
35 40 45
Leu His Thr Ile Cys Leu Gly Glu Lys Ala Lys Glu Glu Met His
50 55 60
Arg Val Glu Ile Leu Pro Pro Ala Asn Gln Glu Asp Lys Lys Met
65 70 75
Gln Pro Val Thr Ile Ala Ser Leu Gln Ala Ser Val Leu Pro Met
80 85 90
Val Ser Met Val Gly Val Gln Leu Ser Pro Pro Val Thr Phe Gln
95 100 105
Leu Arg Ala Gly Ser Gly Pro Val Phe Leu Ser Gly Gln Glu Arg
110 115 120
Tyr Glu Ala Ser Asp Leu Thr Trp Glu Glu Glu Glu Glu Glu Glu
125 130 135
Gly Glu Glu Glu Glu Glu Glu Glu Glu Asp Asp Glu Asp Glu Asp
140 145 150
Ala Asp Ile Ser Leu Glu Glu Gln Ser Pro Val Lys Gln Val Lys
155 160 165
Arg Leu Val Pro Gln Lys Gln Ala Ser Val Ala Lys Lys Lys Lys
170 175 180
Leu Glu Lys Glu Glu Glu Glu Ile Arg Ala Ser Val Arg Asp Lys
185 190 195
Ser Pro Val Lys Lys Ala Lys Ala Thr Ala Arg Ala Lys Lys Pro
200 205 210
Gly Phe Lys Lys
<210> 52
<211> 396
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3573661CD1
<400> 52
Met Asn Phe Thr Val Gly Phe Lys Pro Leu Leu Gly Asp Ala His
S 1191
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
1 5 10 15
Ser Met Asp Asn Leu Glu Lys Gln Leu Ile Cys Pro Ile Cys Leu
20 25 30
Glu Met Phe Ser Lys Pro Val Val Ile Leu Pro Cys Gln His Asn
35 40 45
Leu Cys Arg Lys Cys Ala Asn Asp Val Phe Gln Ala Ser Asn Pro
50 55 60
Leu Trp Gln Ser Arg Gly Ser Thr Thr Val Ser Ser Gly Gly Arg
65 70 75
Phe Arg Cys Pro Ser Cys Arg His Glu Val Val Leu Asp Arg His
80 85 90
Gly Val Tyr Gly Leu Gln Arg Asn Val Leu Val Glu Asn Ile Ile
95 100 105
Asp Ile Tyr Lys Gln Glu Ser Ser Lys Pro Leu His Ser Lys Aia
110 115 120
Glu Gln His Leu Met Cys Glu Glu His Glu Glu Glu Lys Ile Asn
125 130 135
Ile Tyr Cys Leu Ser Cys Glu Val Pro Thr Cys Ser Leu Cys Lys
140 145 150
Val Phe Gly Ala His Lys Asp Cys Glu Val Ala Pro Leu Pro Thr
155 160 165
Ile Tyr Lys Arg Gln Lys Ser Glu Leu Ser Asp Gly Ile Ala Met
170 175 180
Leu Val Ala Gly Asn Asp Arg Val Gln Ala Val I1e Thr Gln Met
185 190 195
Glu Glu Val Cys Gln Thr Ile Glu Asp Asn Ser Arg Arg Gln Lys
200 205 210
Gln Leu Leu Asn Gln Arg Phe Glu Ser Leu Cys Ala Val Leu Glu
215 220 225
Glu Arg Lys Gly Glu Leu Leu Gln Ala Leu Ala Arg Glu Gln Glu
230 235 240
Glu Lys Leu Gln Arg Val Arg Gly Leu Ile Arg Gln Tyr Gly Asp
245 250 255
His Leu Glu Ala Ser Ser Lys Leu Val Glu Ser Ala Ile Gln Ser
260 265 270
Met Glu Glu Pro Gln Met Ala Leu Tyr Leu Gln Gln Ala Lys.Glu
275 280 285
Leu Ile Asn Lys Val Gly Ala Met Ser Lys Val Glu Leu Ala Gly
290 295 300
Arg Pro Glu Pro Gly Tyr Glu Ser Met Glu Gln Phe Thr Val Arg
305 310 315
Val Glu His Val Ala Glu Met Leu Arg Thr Ile Asp Phe Gln Pro
320 325 330
Gly Ala Ser Gly Gly Gly Arg Gly Gly Gly Pro Arg Arg Lys Lys
335 340 345
Arg Ala Thr Arg Gly Pro Glu Glu Lys Thr Ala Arg Met Gly Pro
350 355 360
Tyr Arg Pro Leu Arg Pro Asn Pro Asp Pro Leu Leu Arg Lys Ser
365 370 375
Pro Arg Arg Leu Arg Ile Ser Gly Gly Arg Asn Ser Cys Arg Lys
380 385 390
Lys Thr Pro Ala Ser Phe
395
<210> 53
<211> 486
<212> PRT
<213> Homo Sapiens
52/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<220>
<221> misc-feature
<223> Incyte ID No.: 3633422CD1
<400> 53
Met Arg Arg Leu Val His Asp Leu Leu Pro Pro Glu Val Cys Ser
1 5 10 15
Leu Leu Asn Pro Ala Ala Ile Tyr Ala Asn Asn Glu Ile Ser Leu
20 25 30
Arg Asp Val Glu Val Tyr Gly Phe Asp Tyr Asp Tyr Thr Leu Ala
35 40 45
Gln Tyr Ala Asp Ala Leu His Pro Glu Ile Phe Ser Thr Ala Arg
50 55 60
Asp Ile Leu Ile Glu His Tyr Lys Tyr Pro Glu Gly Ile Arg Lys
65 70 75
Tyr Asp Tyr Asn Pro Ser Phe Ala Ile Arg Gly Leu His Tyr Asp
80 85 90
Ile Gln Lys Ser Leu Leu Met Lys Ile Asp Ala Phe His Tyr Val
95 100 105
Gln Leu Gly Thr Ala Tyr Arg Gly Leu Gln Pro Val Pro Asp Glu
110 115 120
Glu Val Ile Glu Leu Tyr Gly Gly Thr Gln His Ile Pro Leu Tyr
125 130 135
Gln Met Ser Gly Phe Tyr Gly Lys Gly Pro Ser Ile Lys Gln Phe
140 145 150
Met Asp Ile Phe Ser Leu Pro Glu Met Ala Leu Leu Ser Cys Val
155 160 165
Val Asp Tyr Phe Leu Gly His Ser Leu Glu Phe Asp Gln Ala His
170 175 180
Leu Tyr Lys Asp Val Thr Asp Ala Ile Arg Asp Val His Val Lys
185 190 195
Gly Leu Met Tyr Gln Trp Ile Glu ~ln Asp Met Glu Lys Tyr Ile
200 ~ 205 210
Leu Arg Gly Asp Glu Thr Phe Ala Val Leu Ser Arg Leu Val Ala
215 220 225
His Gly Lys Gln Leu Phe Leu Ile Thr Asn Ser Pro Phe Ser Phe
230 235 240
Val Asp Lys Gly Met Arg His Met Val Gly Pro Asp Trp Arg Gln
245 250 255
Leu Phe Asp Val Val Ile Val Gln Ala Asp Lys Pro Ser Phe Phe
260 265 270
Thr Asp Arg Arg Lys Pro Phe Arg Lys Leu Asp Glu Lys Gly Ser
275 280 285
Leu Gln Trp Asp Arg Ile Thr Arg Leu Glu Lys Gly Lys Ile Tyr
290 295 300
Arg Gln Gly Asn Leu Phe Asp Phe Leu Arg Leu Thr Glu Trp Arg
305 310 315
Gly Pro Arg Val Leu Tyr Phe Gly Asp His Leu Tyr Ser Asp Leu
320 325 330
Ala Asp Leu Met Leu Arg His Gly Trp Arg Thr Gly Ala Ile Ile
335 340 345
Pro Glu Leu Glu Arg Glu Ile Arg Ile Ile Asn Thr Glu Gln Tyr
350 355 360
Met His Ser Leu Thr Trp Gln Gln Ala Leu Thr Gly Leu Leu Glu
365 370 375
Arg Met Gln Thr Tyr Gln Asp Ala Glu Ser Arg Gln Val Leu Ala
380 385 390
Ala Trp Met Lys Glu Arg Gln Glu Leu Arg Cys Ile Thr Lys Ala
395 400 405
Leu Phe Asn Ala Gln Phe Gly Ser Ile Phe Arg Thr Phe His Asn
410 415 420
Pro Thr Tyr Phe Ser Arg Arg Leu Val Arg Phe Ser Asp Leu Tyr
53/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
425 430 43S
Met Ala Ser Leu Ser Cys Leu Leu Asn Tyr Arg Val Asp Phe Thr
440 445 450
Phe Tyr Pro Arg Arg Thr Pro Leu Gln His Glu Ala Pro Leu Trp
45S 460 465
Met Asp Gln Leu Cys Thr Gly Cys Met Lys Thr Pro Phe Leu Gly
470 475 480
Asp Met Ala His Ile Arg
485 '
<210> 54
<211> 555
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3993377CD1
<400> 54
Met Gly Ala Glu Asp Lys Leu Pro Leu Glu Asp Ser Pro Val Ile
1 S 10 15
Ala Ala Leu Asp Cys Pro Ser Leu Asn Asn Ala Thr Ala Phe Ser
20 25 30
Leu Leu Ala Asp Asp Ser Gln Thr Ser Thr Ser Ile Phe Ala Ser
35 40 45
Pro Thr Ser Pro Pro Val Leu Gly Glu Ser Val Leu Gln Asp Asn
50 55 60
Ser Phe Asp Leu Asn Asn Gly Ser Asp Ala Glu Gln Glu Glu Met
65 70 75
Glu Thr Gln Ser Ser Asp Phe Pro Pro Ser Leu Thr Gln Pro Ala
80 85 90
Pro Asp Gln Ser Ser Thr Ile Gln Leu His Pro Ala Thr Ser Pro
95 100 105
Ala Val Ser Pro Thr Thr Ser Pro Ala Val Ser Leu Val Val Ser
110 115 120
Pro Ala Ala Ser Pro Glu Ile Ser Pro Glu Val Cys Pro Ala Ala
125 130 135
Ser Thr Val Val Ser Pro Ala Val Phe Ser Val Val Ser Pro Ala
140 145 150
Ser Ser Ala Val Leu Pro Ala Val Ser Leu Glu Val Pro Leu Thr
155 160 165
Ala Ser Val Thr Ser Pro Lys Ala Ser Pro Val Thr Ser Pro Ala
170 175 180
Ala Ala Phe Pro Thr Ala Ser Pro Ala Asn Lys Asp Val Ser Ser
185 190 195
Phe Leu Glu Thr Thr Ala Asp Val Glu Glu Ile Thr Gly Glu Gly
200 205 210
Leu Thr Ala Ser Gly Ser Gly Asp Val Met Arg Arg Arg Ile Ala
215 220 225
Thr Pro Glu Glu Val Arg Leu Pro Leu Gln His Gly Trp Arg Arg
230 235 240
Glu Val Arg Ile Lys Asn Ser Ser His Arg Trp Gln Gly Glu Thr
245 250 255
Trp Tyr Tyr Gly Pro Cys Gly Lys Arg Met Lys Gln Phe Pro Glu
260 265 270
Val Ile Lys Tyr Leu Ser Arg Asn Val Val His Ser Val Arg Arg
275 280 285
Glu His Phe Ser Phe Ser Pro Arg Met Pro Val Gly Asp Phe Phe
54/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
290 295 300
Glu Glu Arg Asp Thr Pro Glu Gly Leu Gln Trp Val Gln Leu Ser
305 310 315
Ala Glu Glu Ile Pro Ser Arg Ile Gln Ala Ile Thr Gly Lys Arg
320 325 330
Gly Arg Pro Arg Asn Thr Glu Lys Ala Lys Thr Lys Glu Val Pro
335 340 345
Lys Val Lys Arg Gly Arg Gly Arg Pro Pro Lys Val Lys Ile Thr
350 355 360
Glu Leu Leu Asn Lys Thr Asp Asn Arg Pro Leu Lys Lys Leu Glu
365 370 375
Ala Gln Glu Thr Leu Asn Glu Glu Asp Lys Ala Lys Ile Ala Lys
380 385 390
Ser Lys Lys Lys Met Arg Gln Lys Val Gln Arg Gly Glu Cys Gln
395 400 405
Thr Thr Ile Gln Gly Gln Ala Arg Asn Lys Arg Lys Gln Glu Thr
410 415 420
Lys Ser Leu Lys Gln Lys Glu Ala Lys Lys Lys Ser Lys Ala Glu
425 430 435
Lys Glu Lys Gly Lys Thr Lys Gln Glu Lys Leu Lys Glu Lys Val
440 445 450
Lys Arg Glu Lys Lys Glu Lys Val Lys Met Lys Glu Lys Glu Glu
455 460 465
Val Thr Lys Ala Lys Pro Ala Cys Lys Ala Asp Lys Thr Leu Ala
470 475 480
Thr Gln Arg Arg Leu Glu Glu Arg Gln Arg Gln Gln Met Ile Leu
485 490 495
Glu Asp Met Lys Lys Pro Thr Glu Asp Met Cys Leu Thr Asp His
500 505 510
Gln Pro Leu Pry Asp Phe Ser Arg Val Pro Gly Leu Thr Leu Pro
515 520 525
Ser Gly Ala Phe Ser Asp Cys Leu Thr Ile Val Glu Phe Leu His
530 535 540
Ser Phe Gly Lys Val Leu Gly Leu Asp Pro Ala Gln Gly Cys Ala
545 550 555
<210> 55
<211> 61
<212> PRT
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 4717936CD1
<400> 55
Met Gln Pro Arg Thr Gln Pro Leu Ala Gln Thr Leu Pro Phe Phe
1 5 10 15
Leu Gly Gly Ala Pro Arg Asp Thr Gly Leu Arg Val Pro Val Ile
20 25 30
Lys Met Gly Thr Gly Trp Glu Gly Phe Gln Arg Thr Leu Lys Glu
35 40 45
Val Ala Tyr Ile Leu Leu Cys Cys Trp Cys Ile Lys Glu Leu Leu
50 55 60
Asp
55/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<210> 56
<211> 2781
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 025733CB1
<400> 56
gaagtggggt gcacgcttcg ggttggtgtc atggcagctg cggggagccg caagaggcgc 60
ctggcggagc tgacggtgga cgagttccta gcttcgggct ttgactccga gtccgaatcc 120
gagtccgaaa attctccaca agcggagaca cgggaagcac gcgaggctgc ccggagtccg 180
gataagccgg gcgggagccc ctcggccagc cggcgtaaag gccgtgcctc tgagcacaaa 240
gaccagctct ctcggctgaa ggacagagac cccgagttct acaagttcct gcaggagaat 300
gaccagagcc tgctaaactt cagcgactcg gacagctctg aggaggaaga ggggccgttc 360
cactccctgc cagatgtgct ggaggaagcc agtgaggagg aggatggagc ggaggaagga 420
gaagatgggg acagagtccc cagagggctg aaggggaaga agaattctgt tcctgtgacc 480
gtcgccatgg ttgagagatg gaagcaggca gcaaagcaac gcctcactcc aaagctgttc 540
catgaagtgg tacaggcgtt ccgagcagct gtggccacca cccgagggga ccaggaaagt 600
gctgaggcca acaaattcca ggtcacggac agtgctgcat tcaatgctct ggttaccttc 660
tgcatcagag acctcattgg ctgtctccag aagctgctgt ttggaaaggt ggcaaaggat 720
agcagcagga tgctgcagcc gtccagcagc ccgctctggg ggaagcttcg tgtggacatc 780
aaggcttacc tgggctcggc catacagctg gtgtcctgtc tgtcggagac gacggtgttg 840
gcggccgtgc tgcggcacat cagcgtgctg gtgccctgct tcctgacctt ccccaagcag 900
tgccgcatgc tgctcaagag aatggtggtc gtatggagca ctggggagga gtctctgcgg 960
gtgctggctt tcctggtcct cagcagagtc tgccggcaca agaaggacac tttccttggc 1020
cccgtcctca agcaaatgta catcacgtat gtgaggaact gcaagttcac ctcgcctggt 1080
gccctcccct tcatcagttt catgcagtgg accttgacgg agctgctggc cctggagccg 1140
ggtgtggcct accagcacgc cttcctctac atccgccagc tcgccataca cctgcgcaac 1200
gccatgacca cccgcaagaa ggaaacatac cagtctgtgt acaactggca gtatgtgcac 126
tgcctcttcc tgtggtgccg ggtcctgagc actgcgggcc ccagcgaagc cctccagccc 1320
ttggtctacc cccttgccca agtcatcatt ggctgtatca agctcatccc cactgcccgc 1380
ttctacccgc tgcgaatgca ctgcatccgt gccctgacgc tgctctcggg gagctcgggg 1440
gccttcatcc cggtgctgcc tttcatcctg gagatgttcc agcaggtcga cttcaacagg 1500
aagccagggc gcatgagctc caagcccatc aacttctccg tgatcctgaa gctgtccaat 1560
gtcaacctgc aggagaaggc gtaccgggac ggcctggtgg agcagctgta cgacctcacc 1620
ctggagtacc tgcacagcca ggcacactgc atcggcttcc cggagctggt gctgcctgtg 1680
gtcctgcagc tgaagtcgtt cctccgggag tgcaaggtgg ccaactactg ccggcaggtg 1740
cagcagctgc ttgggaaggt tcaggagaac tcggcataca tctgcagccg ccgccagagg 1800
gtttccttcg gcgtctctga gcagcaggca gtggaagcct gggagaagct gacccgggaa 1860
gaggggacac ccttgacctt gtactacagc cactggcgca agctgcgtga ccgggagatc 1920
cagctggaga tcagtggcaa agagcggctg gaagacctga acttccctga gatcaaacga 1980
aggaagatgg ctgacaggaa ggatgaggac aggaagcaat ttaaagacct ctttgacctg 2040
aacagctctg aagaggacga caccgaggga ttctcggaga gagggatact gaggcccctg 2100
agcactcggc atggggtgga agacgatgaa gaggacgagg aggagggcga ggaggacagc 2160
agcaactcgg agggtgaatg gtcttgggat ggagacccag acgcagaggc ggggctggcc 2220
cctggggagc tgcagcagct ggcccagggg ccggaggacg agctggagga tctgcagctc 2280
tcagaggacg actgaggcag cccatctggg gggcctgtag gggctgccgg gctggtggcc 2340
agtgtttcca cctccctggc agtcaggcct agaggctggc gtctgtgcag ttgggggagg 2400
cagtagacac gggacaggct ttattattta tttttcagca tgaaagacca aacgtatcga 2460
gagctgggct gggctgggct ggtgtggctg ctgaagcccc acagctgtgg gctgctgaag 2520
tcagctccgc gggggagctg accctgacgt cagcagaccg agaccagtcc cagttccagg 2580
gggaggcctg caggcccctg gccccttcca ccacctctgc cctccgtctg cagacctcgt 2640
ccatctgcac caggctctgc cttcactccc ccaagtcttt gaaaatttgt tcctttcctt 2700
tgaagtcaca ttttctttta aaattttttg ttttgcatcc gaaaccgaaa gaaataaagc 2760
ggtgggaggc aaaaaaaaaa a 2781
<210> 57
<211> 2544
<212> DNA
56/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 079702CB1
<400> 57
cgggaaacca aaatggcgag gggctgtatt gaagtgggct gtgtttgagg ccggtgtaag 60
aacgctcatt ctacccccaa cccttgtctc caaggacctc ggtttgtgcg tgcatatgtg 120
ccgggtaccc ggtggggcgg gtgcccagta agtgctcgga ctcgcagggg aagcgcccac 180
ggggacggat tggttgtttt ttcctgtatg aagcggttgg caccactgaa gtgaccgaat 240
gagagactct acaggggcag gtaattcact ggtccacaag cggtctcctt tacgtcgaaa 300
ccaaaagacc ccaacatcct tgaccaagct gtctttacag gatggacata aagccaaaaa 360
gccagcatgt aaatttgaag agggtcagga tgtcctagct agatggtcag atggcttgtt 420
ttatcttggc actatcaaaa agataaacat attgaaacag agctgcttca tcatatttga 480
agacagttct aaatcctggg ttctctggaa ggacattcaa acaggagcca ctggaagtgg 540
ggaaatggtc tgtacaatat gtcaagaaga gtattcagaa gctcccaatg aaatggttat 600
atgtgacaag tgtggccaag gatatcatca gttgtgtcac acacctcata ttgattccag 660
tgtgattgat tcagatgaaa aatggctctg tcggcagtgt gtttttgcaa caacaacaaa 720
gaggggtggt gcacttaaga aaggaccaaa tgccaaagca ttgcaagtca tgaagcagac 780
attaccctat agtgtggcag accttgaatg ggatgcaggt cataaaacca atgtccagca 840
gtgttactgc tattgtggag gccctggaga ctggtatttg aagatgctac agtgctgcaa 900
atgtaagcag tggtttcatg aggcttgtgt gcaatgcctt caaaagccaa tgctatttgg 960
agacagattt tatacgttta tatgctctgt ctgcagttct ggaccagaat acctcaaacg 1020
tctaccatta cagtgggtag atatagcaca cctatgcctt tacaacctaa gtgttattca 1080
taagaagaaa tactttgatt ctgaacttga gcttatgaca tacattaatg aaaactggga 1140
tagattgcac cctggagagc tggcagacac accaaaatct gaaagatatg agcatgttct 1200
ggaggcatta aatgattaca agaccatgtt tatgtctggg aaagaaataa agaagaagaa 1260
gcatttgttt gggttgcgaa ttcgtgttcc tcctgtgcca ccaaatgtgg ctttcaaagc 1320
agagaaagaa cctgaaggaa catctcatga atttaaaatt aaaggcagaa aggcatccaa 138t~
acc'Latatct gattcaaggg aagtaagcaa tggcatagaa aaaaaaaaaa aaaaaaaatc 1440
tgtaggtcgt ccacctggcc catatacaag aaaaatgatt caaaaaactg ctgagccact 1500
tttggataag gaatcaattt cagagaatcc tactttggat ttaccttgtt ctatagggag 1560
aactgaggga actgcacatt catccaatac ctcagatgtg gatttcacgg gtgcttccag 1620
tgcaaaagaa actacctcgt ctagcatttc caggcattat ggattatctg actccagaaa 1680
aagaacgcgt acaggaagat cttggcctgc tgcaatacca catttgcgga gaagaagagg 1740
tcgtcttcca agaagagcac tccagactca gaactcagaa attgtaaaag atgatgaagg 1800
caaagaagat tatcagtttg atgaactcaa cacagagatt ctgaataact tagcagatca 1860
ggagttacaa ctcaatcatc taaagaactc cattaccagt tattttggtg ctgcaggtag 1920
aatagcatgt ggcgaaaaat accgagtttt ggcacgtcgg gtgacacttg atggaaaggt 1980
gcagtatctt gtggaatggg aaggagcaac tgcatcctga ctgtaggact gaacattatg 2040
ttcactgcac tctgattttc tgtaggtaca gttcaaagcc ctaaaggagt ctggctttta 2100
ctatctttct taaaaaaaaa aaaaagtcaa aaaaattcaa aaaaggggat gatactagcc 2160
ttaacatgta cctgtcaatg ttatggatat tgtcataaaa aggtatcttt taaaaatcag 2220
aacagagact taatttttta aatcttaaga tttgtagaat gtttctagga taggatatta 2280
aaaatgattg aaacccatgc atggtgttag acaatttttc taattattcc attgagtcag 2340
ttttttgtga ttagtgatta tcagagcaaa catcatgtag atagcacaag tatttggaga 2400
aacgttgttt gttttgttac caaaatgttg gaaaaattta tttcaatacc ttttagattt 2460
cataaagtgc agtgtatata atgcctactg aaagactgta aaatattgaa attttctttc 2520
aagcaaagtg taaataaata tatc 2544
<210> 58
<211> 1627
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 116208CB1
<400> 58
X7/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/D2237
ctgatgaggg cgctgcattt attgaagagc ggctgcagcc ctgcggttca gattaaaatc 60
cgagaattgt atagacgccg atatccacga ac~cttgaag gactttctga tttatccaca 120
atcaaatcat cggttttcag tttggatggt ggctcatcac ctgtagaacc tgacttggcc 180
gtggctggaa tccactcgtt gccttccact tcagttacac ctcactcacc atcctctcct 240
gttggttctg tgctgcttca agatactaag cccacatttg agatgcagca gccatctccc 300
ccaattcctc ctgtccatcc tgatgtgcag ttaaaaaatc tgccctttta tgatgtcctt 360
gatgttctca tcaagcccac gagtttagtt caaagcagta ttcagcgatt tcaagagaag 420
ttttttattt ttgctttgac acctcaacaa gttagagaga tatgcatatc cagggatttt 480
ttgccaggtg gtaggagaga ttatacagtc caagttcagt tgagactttg cctggcagag 540
acaagttgcc ctcaagaaga taactatcca aatagtctat gtataaaagt aaatgggaag 600
ctatttcctt tgcctggcta tgcaccaccg cctaaaaatg ggattgaaca gaagcgccct 660
ggacgcccct tgaatattac atctttagtt aggttatctt cagctgtgcc aaaccaaatt 720
tccatttctt gggcatcaga aattgggaag aattactcta tgtctgtata tcttgtacgg 780
cagcttacat cagccatgtt attacagaga ttaaaaatga aaggtattag aaaccctgat 840
cattccagag cactaagtaa agaaaaactt actgcagatc ctgatagtga aattgctaca 900
actagccttc gggtatcctt gatgtgccct ttaggaaaaa tgaggctgac aatcccatgc 960
cgtgcagtga cttgtacaca tctgcagtgt tttgatgctg ccctctatct acaaatgaat 1020
gagaaaaagc ccacctggat ttgtcctgtg tgtgacaaaa aagctgccta tgaaagtcta 1080
atattagatg ggctttttat ggaaattctc aatgactgtt ctgatgtaga tgagatcaaa 1140
ttccaagaag atggttcttg gtgtccaatg agaccgaaga aagaagctat gaaagtatcc 1200
agccaaccgt gtacaaaaat agaaagttca agcgtcctca gtaagccttg ttcagtgact 1260
gtagccagtg aggcaagcaa gaagaaagta gatgttattg atcttacaat agaaagctct 1320
tctgacgaag aggaagaccc tcctgccaaa aggaaatgca tctttatgtc agaaacacaa 1380
agcagcccaa ccaaaggggt tctcatgtat cagccatctt ctgtaagggt gcccagtgtg 1440
acttcggttg atcctgctgc tattccgcct tcattaacag actactcagt accattccac 1500
catacgccaa tatcaagcat gtcatcagat ttgccaggag aacaaagaag aaatgatatt 1560
aataatgaac tgaagcttgg aacatcttct gatactgtgc aacagtgaat acaaaataaa 1620
accgata 1627
<210> 59
<211> 1043
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 179261CB1
<400> 59
gtgggatatt tcagtcaaat gaaaatcatc tctgaaaatg tgcccagtta caaaactcat 60
gaatctctta ctttacctcg gagaactcat gacagtgaga agccctatga atacaaggaa 120
tatgagaagg tcttcagttg tgacttagag tttgatgaat atcagaaaat acatactggt 180
ggaaaaaact atgaatgtaa tcaatgttgg'aaaacctttg ggatagataa ctccagtatg 240
ttacaactga atattcatac tggtgtgaaa ccttgtaaat atatggaata tgggaataca 300
tgtagttttt ataaagactt taatgtatac cagaaaattc ataatgagaa gttctataaa 360
tgtaaggaat acagaaggac ctttgaaaga gttggaaaag ttactccact tcaaagagtt 420
catgatggtg agaaacactt tgaatgctca ttctgtggga aatcctttag agtgcatgca 480
caacttactc gacatcagaa aatccatact gatgagaaaa cttacaaatg tatggaatgt 540
ggcaaggact tcagatttca ttcacagctt accgaacatc agagaattca tactggtgag 600
aaaccctaca aatgtatgca ctgtgagaag gtttttagaa ttagttcaca gctcattgaa 660
catcagagaa ttcacactgg tgagaaacct tatgcatgta aggaatgtgg gaaggctttt 720
ggagtatgta gagaacttgc tcgtcatcag agaattcata ctggaaaata ctgtggatgg 780
atttaatagg taatcaaggc aattcagtat ctccctctct taaagtctgt ttttagactt 840
catggtcatt ctgtatgtag acgtagaatt gcttagtcat agctgatata tacttatagc 900
tttgttagat gttgccaaat atttctcctt tttatgttaa aaagtttttt tcatgagttt 960
ctcatcctgg catgttttgt ttacaatagc ttttgatgtt tgtattattg ctcttttgac 1020
taatcagttt tttaattctg gat 1043
<210> 50
<211> 2448
~ 8/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-Leature
<223> Incyte ID No.: 259161CB1
<400> 60
ctggcgggaa gattttactc ccgagtagcg gaaagatctg ctcgaggcct gggtgctttg 60
gtgtcggaga tccgagagtc ggagatcgga gagtcggaca caggacagtc ggacaccgga 120
cagtcaaaca ccggagagtt agactgggct tctcggtggg gagaggctct gggataacta 180
ctgttacagc tttgaagggt caagggagga ttggccacca aagcctgttt attagcagct 240
gccatttgtt gaaagaaatt tggattattt tagaaacaaa tttggaaaga aaaagaatgg 300
cgtccgtttc agctctaact gaggaactgg attctataac cagtgagcta catgcagtag 360
aaattcaaat tcaagaactt acggaaaggc aacaagagct tattcagaaa aaaaaagtcc 420
tgacaaagaa aataaagcag tgtttagagg attctgatgc cggggcaagc aatgaatatg 480
attcttcacc tgccgcttgg aataaagaag attttccatg gtctggtaaa gttaaagata 540
ttctgcaaaa tgtctttaaa ctggaaaagt tcagaccact tcagcttgaa actattaacg 600
taacaatggc tggaaaggag gtatttcttg ttatgcctac aggaggtgga aagagcttat '060
gttaccagtt accagcatta tgttcagatg gttttacact cgtcatttgc ccattgatct 720
ctcttatgga agaccaatta atggttttaa aacaattagg aatttcagca accatgttaa 780
atgcttctag ttctaaggag catgttaaat gggttcatgc tgaaatggta aataaaaact 840
ccgagttaaa gctgatttat gtgactccag agaaaattgc aaaaagcaaa atgtttatgt 900
caagactaga gaaagcctat gaagcaagga gatttactcg aattgctgtg gatgaagttc 960
actgctgtag tcagtgggga catgatttca gacctgatta taaggcactt ggtatcttaa 1020
agcggcagtt ccctaacgca tcactaattg ggctgactgc aactgcaaca aatcacgttt 1080
tgacggatgc tcagaaaatt ttgtgcattg aaaagtgttt tacttttaca gcttctttta 1140
ataagccaga tgtgaggttt gttatccatc attcaatgag taaatccatg gaaaattatt 1200
accaagagag tggacgtgca ggtcgagatg acatgaaagc agactgtatt ttgtactacg 1260
gctttggaga tatattcaga ataagttcaa tggtggtgat ggaaaatgtg ggacagcaga 1320
agctttatga gatggtatca tactgtcaaa acataagcaa atgtcgtcgt gtgttgatgg 1380
ctcaacattt tgatgaagta tggaactcag aagcatgtaa caaaatgtgc gataactgct 1440
gtaaagacag tgcatttgaa agaaagaaca taacagagta ctgcagagat ctaatcaaga 1500
tcctgaagca ggcagaggaa ctgaatgaaa aactcactcc attgaaactg attgattctt 1560
ggatgggaaa gggtgcagca aaactgagag tagcaggtgt tgtggctccc acacttcctc 1620
gtgaagatct ggagaagatt attgcacact ttctaataca gcagtatctt aaagaagact 1680
acagttttac agcttatgct accatttcgt atttgaaaat aggacctaaa gctaatcttc 1740
tgaacaatga ggcacatgct attactatgc aagtgacaaa gtccacgcag aactctttca 1800
gggctgaatc gtctcaaact tgtcattctg aacaaggtga taaaaagatt ggaggaaaaa 1860
aattccaggc aacttccaga agaaggctgc aaacatgctt cagcaatctg gttctaagaa 1920
tacaggagct aagaaaagaa aaatcgatga tgcctgatat gactgttact aaattttcta 1980
attaaagatg gtttatgcat gtatatgcca ttatttttgt agttagacaa tagtttttaa 2040
aagaatttca tagatatttt atatgtatgg atctatattt tcagagctta tctctgaaga 2100
tctaaacttt tgagaatgtt tgaaaattag agatcatgaa ttatataatt ttccagtata 2160
aaacaaggga aaaattttta tgtaaaaccc tttaaatgta aaatatttga gaataagttc 2220
atacaatcgt cttaagtttt ttatgccttt atatacttag ctatattttt tcttttgaca 2280
taactatctt tttgaaagca atattatact gacagaggct cactgagtga tactttaagt 2340
taaatatgta gatcaaggat gtccaatctt ttggcttccc tgagccacac tggaagaaga 2400
attgtcttgg gccgcacata aaatatgcta acactgatga tagctgat 2448
<210> 61
<211> 2255
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-Laature
<223> Incyte ID No.: 320087CB1
X9/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00/02237
<400> 61
ttccggttct gtacccccat cctttctctc gcccctccta cccgcagctc ctggcgctcg 60
gcggggctaa ctgcagcggg gagatctcgg ccgccaagct ccgcctcccg ccccgggctg 120
tgccccgggg ctcgcctgag gccgaccacc cgcaacccac ctctagcggc tttgctcgag 180
gcccaccttc ttcccacccc cggcaaactc cagtaggctc gccc~cgctg actccccgc~ 240
cccgcgtcaa ctgcaagggg cccgcccata gccagttccg gggcggttgc tcacatcgac 300
cggaactccc cgccccctcc cgcggcccct ggggccgtag gaggccgcag cgaggaggta 360
gagggggcgg gggtcgcact agggtgtccc tagagaacga ggactctgaa ggcgggacat 420
ttgggcgacc cccgggcggg gccagccatt aaacagtccc acttctgtgc cagacactga 480
actgggctct tgacgggcat catctcttaa tcctcagaac atcccaggga gctccacagg 540
atccccatat cctgggccat gagtgagttg aaagactgcc ccttgcagtt ccacgacttc 600
aagtctgtgg atcacctgaa ggtctgtccc cgctacacgg cagtgctggc acgctctgag 660
gatgatggca tcggcatcga ggagctggac accctgcagc tggagctgga gaccctgctg 720
tcttctgcca gccggcgcct gcgtgtgctt gaggccgaaa cccagatcct caccgactgg 780
caggataaga aaggtgacag acgattcctg aagctgggtc gagaccatga acttggagct 840
ccccccaaac atgggaagcc caagaagcag aaactggaag ggaaggcagg acatgggccg 900
ggccctggcc caggacggcc caaatccaaa aaccttcagc ccaagatcca ggaatatgaa 960
ttcactgatg accctatcga cgtgccacgg atccccaaaa atgatgcccc caacaggttc 1020
tgggcttcag tggagcccta ctgtgctgac atcaccagcg aggaggtccg cacacttgag 1080
gagttactga agcccccaga agatgaggct gagcattaca agatcccacc cctggggaag 1140
cactactccc agcgctgggc ccaggaggac ctgctggagg agcagaagga tggggcccgg 1200
gcagcggctg tggctgacaa gaagaaaggc ctcatggggc cactgaccga actggacact 1260
aaagatgtgg atgccctgct gaagaagtct gaggcccagc atgaacagcc ggaagatgga 1320
tgcccctttg gtgccctgac gcagcgcctc ctgcaggccc tggtggagga aaatattatt 1380
tcccctatgg aggattctcc tattcctgac atgtctggga aagaatcagg ggctgacggg 1440
gcaagcacct cccctcgcaa tcagaacaag cccttcagtg tgccgcatac taagtccctg 1500
gagagccgca tcaaggagga gctaattgcc cagggccttt tggagtctga ggaccgcccc 1560
gcagaggact ccgaggatga ggtccttgct gagcttcgca aacggcaggc tgagctgaag 1620
gcacttagtg cccacaaccg caccaagaag cacgacctgc tgaggctggc aaaggaggag 1680
gtgagccggc aggagctgag gcagcgggtg cgcatggctg acaacgaggt catggacgcc 1740
tttcgcaaga tcatggctgc ccggcagaag aagcggactc ccaccaagaa agaaaaggac 1800
caggcctgga agactctgaa ggagcgtgag agcatcctga agctgctgga tgggtagccc 1860
tcacccctgc ctcaggctga ttatctggcc taggggaggg gaagggaggc ccacttcctt 1920
ctttgggcac aggaaacatt ggcctgtggc tgtccctcaa atggcggcag tctctagagg 1980
gccgtggccc ttcccctgag gtcttttggc ctagctctgt acaaccagga cacaggaagc 2040
cctgctgggc tagcctgagg cctagtctct gcttggtccc cgagatgggg ttggagggga 2100
cttcgtttct gggtcttcct cttcccctct ttaccatccc ccactcccta atcccctacc 2160
cctgtctccc cttcaaggac ttctcccttg tggttttgta aagtgcaaac ttaagaataa 2220
agtgactgct gtggtttttc aaaaaaaaaa aaaaa 2255
<210> 62
<211> 2982
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 491271CB1
<400> 62
gcgtggggat gtttaccgcc gtttatccgg gatagagact ccatcgtgct gacagcatcc 60
ttttattcac cgcctccgaa tttgcaaaga ggaggaagga gggacttctt ggcttctccc 120
agcatagccc cagttatgcc atctcagaac tatgaccttc cccagaagaa gcaggagaaa 180
atgaccaagt ttcaggaggc tgtgacattc aaggatgtgg ctgtggtctt ctccagggag 240
gaactgcgac tgctcgatct tacccagagg aagctgtacc gagatgtcat ggtggagaac 300
ttcaagaacc tggttgcagt ggggcatctt cccttccaac cagatatggt atcccaattg 360
gaagcagaag aaaagctttg gatgatggaa acagaaaccc aaagaagcag caagcatcaa 420
aataagatgg aaacactcca aaaatttgca ttaaaatacc tttcaaatca agagctgtcc 480
tgctggcaaa tctggaaaca ggttgcaagt gaattaacca ggtgtct_ca ggggaagagt 540
tcccagttat tacaaggtga ctctattcag gtttctgaaa atgagaacaa tataatgaac 500
cctaaaggag atagccctat ttatattgaa aatcaagagt ttccat~rtg gagaacccag 660
60/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
cattcttgcg ggaatacata tctgagtgag tcacagattc agagtagagg taagcaaatt 720
gatgtgaaaa ataacctgca aatacgtgaa gacttcgtga agaaatcacc atttcatgag 780
catattaaaa ctgacacaga accaaaaccc tgcaaaggta atgaatatgg caaaatcatt 840
agtgatggct ccaaccagaa attaccctta ggagagaaac cccatccatg tggtgagtgt 900
ggaaggggct tcagtcatag cccaaggctt ccccttcatc cgaatgttca cacaggagaa 960
aaatgcttca gtcaaagctc acatctgcga actcatcaga gaattcaccc aggagagaaa 1020
ctcaatagat gtcatgaatc tggtgattgc ttcaataaga gctcttttca ttcttatcaa 1080
tctaatcata caggagagaa gtcttataga tgcgacagtt gcggcaaggg attcagtagc 1140
agcacgggtc ttatcattca ttacagaact catactggag agaaacccta taaatgcgag 1200
gaatgtggta aatgctttag tcaaagttca aattttcagt gccatcagag agtccacact 1260
gaagaaaaac catacaaatg cgaagagtgt ggtaagggct tcggttggag tgttaatctc 1320
cgtgttcacc agagggtcca caggggtgag aagccctata aatgtgagga atgtggtaag 1380
ggcttcactc aggctgcaca ttttcacatc catcagagag tccacactgg agagaaaccc 1440
tacaagtgtg atgtgtgtgg taagggcttc agccacaatt caccattaat atgccatcgg 1500
agagtccaca caggagagaa gccatacaag tgtgaggcgt gtgggaaagg ctttacccgt 1560
aatacagatc tgcatattca tttcagagtt cacacgggag agaaacccta taaatgtaag 1620
gagtgtggta agggcttcag tcaggcttca aatcttcaag tccatcagaa tgtccacact 1680
ggggagaaac gattcaagtg tgaaacgtgt gggaagggct tcagtcagtc ctcaaagctt 1740
caaacccatc agcgagtcca cactggagag aaaccatata gatgtgatgt gtgtggtaag 1800
gacttcagtt atagttcaaa tcttaaacta caccaagtaa ttcacactgg agaaaaacca 1860
tataaatgtg aggaatgtgg gaagggcttc agttggagat caaatcttca tgcacatcaa 1920
agagttcact caggagaaaa accctataaa tgtgagcagt gtgataagag cttcagtcag 1980
gccatagatt ttcgggtaca tcagagagtc catactggag agaagccata caaatgtggt 2040
gtctgtggta agggcttcag tcagtcctct ggtcttcaat cccatcagag agtccacacg 2100
ggggaaaagc catacaaatg tgatgtgtgt ggaaagggct ttagatacag ttcgcagttt 2160
atataccatc agagaggcca cactggagaa aaaccttaca aatgtgaaga gtgtgggaaa 2220
ggctttggta ggagcttgaa tcttcgccat catcagaggg tccacacggg agagaaaccc 2280
catatatgtg aggagtgtgg taaggccttc agtctcccct caaatcttcg agtccacctg 2340
ggtgttcaca ccagggaaaa actctttaaa tgtgaagagt gtggtaaagg cttcagtcag 2400
agtgcacgtc ttgaagccca tcagagagtc .cacactggag aaaaaccata caaatgtgac 2460
atatgtgata aggacttccg tcaccgttca cgtcttacat atcatcagaa agtccatact 2520
ggtaaaaagc tttagaaatg agaaatgtgt taccaacttt tgtctgaatg cacatcttca 2580
agtttttggc tagtccatgc tggtggtaaa ccctgtaaaa ctactgagag tggaaggggg 2640
tttgttcaca cttggaatct ttctaacaaa tccatcaaga tgataacaca gaaccatgaa 2700
caggaataga actcgtattt aggggagaaa tagggctggt ggctctcttg gtaagatcta 2760
gttaatataa atgatcacct ttcattgtga atatatgcct gaagataatg tgtggaagga 2820
tatttgccat atgctaactg gttttttggc cagggagagt tttgggttat tatccctttt 2880
ctttaatttt cattttatac ttacagtgat cattattttc ataaaagctg taaagctatg 2940
aaaaatgaat aaaattacta aaaattttct gtaaaaaaaa as 2982
<210> 63
<211> 1185
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 585172CB1
<400> 63
ggagcgtcca gagtcctggc cctgagcggg aatcgcagtg gccgaggctg agcggcaggt 60
agaaggggcg tctccggggc ttcacaggga acacaggggc ttcggcccaa ccacaagtac 120
gcagttgcac atgccctact tttgcccatt ctttgcaaat cccctaagga acgaacgcgc 180
ctcgcgtgcg ggcctttcta atcttcgctt gtcccttcac ttccacagct ggaggtcgaa 240
ttcaccacgt cacgtagaga aaaggggcgg tgtctcgggt ctccccgtgt ggcatcaagg 300
cgggctccct ataggagctg gtgtggacgt ccgggcgtgg ggttagggcg gatgcgggga 360
tcgcggggcg ggtgttgaca ttgtgctctc accaggcgga tcgccccgac cctcactcct 420
ggcgtctgag tctctggcgt agccatgctg agtgggcggc tggtcctggg tctggtctcc 480
atggctggcc gcgtttgttt gtgccagggc agcgcgggat ccggggccat cggtccggtg 540
gaggccgcca ttcgcacgaa gttggaggag gccctgagcc ccgaggtgct agagcttcgc 600
aacgagagcg gtggccacgc ggtcccgcct ggcagtgaga ctcacttccg cgtggctgtg 660
61/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
gtgagctctc gtttcgaggg actgagcccc ctacaacgac accggctggt ccacgcagcg 720
ctggccgagg agctgggagg tccggtccat gcgctggcca tccaggcacg gacccccgcc 780
cagtggagag agaactctca gctggacact agccccccat gcctgggtgg gaacaagaaa 840
actctaggaa ccccctgaac cccaagagag ggaggaccag gatccgaatg ggctgggtga 900
gcacgaatta ccgaggcctt ccctttgata ca4tccagga tttgtaaggg atgaagaccc 960
ctgggcccca ttctgttggg gtccatacat actctccgaa gatagcaact tgcttcaggt 1020
caaagtgaac ccgagaaaag agaagaatca ctcactactg ctcttgccct ggactattca 1080
ggaagggcag cccggatgtt ccatgttaaa tcgtgacaga attgcaccag acctgatgag 1140
ttggaaacaa tcctatacat taaaagaaat tacactaaaa aaaaa 1185
<210> 64
<211> 1191
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 615200CB1
<400> 64
tggacggacg cgtgggcttg atttctgatt tatgactgct ttttgttgta ccccaatagt 60
cgtctaagaa aggtgattat tttgagaggc ctggggagac acacatgctc attctcgagg 120
gtggcggtgg tgcagagggc agagccatgc tcgttcttgc tatcctgaga ttggttgcta 180
tctgtttcct ttgctgctgt gtttttttct gtcagtatta aaggtggaag aaggtccata 240
tctttttctg tgggtgcttc aagtgttgtt ggaagtggag gcagcagtga caaggggaag 300
ctttccctgc aggatgtagc tgagctgatt cgggccagag cctgccagag ggtggtggtc 360
atggtggggg ccggcatcag cacacccagt ggcattccag acttcagatc tccggggagt 420
ggcctgtaca gcaacctcca gcagtacgat ctcccgtacc ccgaggccat ttttgaactc 480
ccattcttct ttcacaaccc ca.agcc~ttt ttcactttgg ccaaggagct gtaccctgga 540
aactacaagc ccaacatcac tcactacttt ctc~ggctgc ttcatgacaa ggggctgctt 600
ctgcggctct acacgcagaa catcgatggg cttgagagag tgtcgggcat ccctgcctca 660
aagctggttg aagctcatgg aacctttgcc tctgccacct gcacagtctg ccaaagaccc 720
ttcccagggg aggacattcg ggctgacgtg atggcagaca gggttccccg ctgcccggtc 780
tgcaccggcg ttgtgaagcc cgacattgtg ttctttgggg agccgctgcc ccagaggttc 840
ttgctgcatg tggttgattt ccccatggca gatctgctgc tcatccttgg gacctccctg 900
gaggtggagc cttttgccag cttgaccgag gccgtgcgga ctcagttccc cgactgctca 960
tcaaccggga cttggtgggg cccttggctt ggcatcctcg cagcagggac gtggcccagc 1020
tgggggacgt ggttcacggc gtggaaagcc tagtggagct tctgggctgg acagaagaga 1080
tgcgggacct tgtgcagcgg gaaactggga agcttgatgg accagacaaa taggatgatg 1140
gctgccccca cacaataaat ggtaacatag gagacatcca catcccaatt c 1191
<210> 65
<211> 2596
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 997067CB1
<400> 65
ccggtgtgtg ggtctgtgac agggtccaac agggcctggt ccgtgtccgg tcccccaaat 60
ctgtcgtccc tgcccccagg cattggcatc aacaaaagtc agaattcccg ggaacttgaa 120
cagaggctgc taaattccca gtaattgctc ctttggcctt ctagggactg acttcaaaga 180
aggaaggaaa gaatcaggca gtgcttcctc attctctttt aaaacccgct tcccgctgag 240
tctgcaccca ggagaccaga gagcaccttg cccttccatg gaaactcagg ctgatctcgt 300
atctcaggaa cctcaggccc tgcttgacag tgctcttcct tcaaaagttc ctgccttttc 360
cgacaaggac agcctggggg atgagatgtt ggcggctgcg ctcctaaagg ccaagtccca 420
ggagctggta acctttgagg atgtagctgt gtacttcatc cggaaggagt ggaagcgttt 480
ggaacctgct cagagggacc tctatagaga tgtgatgctg gagaattacg ggaatgtgtt 540
62/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
ctcactggat cgtgagacca ggactgaaaa tgatcaagaa atttctgaag acacaagatc 600
acatggggtc ctactgggaa gatttcaaaa ggatatttct cagggtctca agtttaaaga 660
agcctatgaa cgagaagtca gtctgaaaag gccgctgggg aactcccctg gagaaagact 720
gaacaggaaa atgccagatt ttggtcaagt gacagttgag gagaagctaa cccccagggg 780
agagagaagc gagaaatata atgattttgg gaacagcttc actgtgaatt ccaaccttat 840
ctcacatcag agactccccg tgggagacag accccataag tgtgatgaat gtagcaagag 900
ctttaatcga acttcagacc ttattcaaca tcagagaatc cacactgggg aaaagcccta 960
tgaatgtaat gagtgtggga aggccttcag ccagagctca caccttattc agcatcagag 1020
aatccacact ggggaaaaac cttatgaatg tagtgattgt gggaaaacct tcagctgtag 1080
ctctgccctc attctgcatc ggaggatcca cacgggggag aaaccctatg aatgtaatga 1140
gtgtgggaag accttcagct ggagctccac cctcacccac catcagagaa tccacactgg 1200
tgagaaaccc tacgcctgca atgaatgtgg gaaggccttc agcaggagct caacccttat 1260
tcaccatcag agaatccaca ctggagaaaa accctatgaa tgtaatgaat gtgggaaagc 1320
cttcagccag agctcacacc tctatcagca ccagagaatc cacactggag agaagcccta 1380
cgaatgtatg gaatgtggag gaaagtttac ctacagttca ggccttattc agcatcaaag 1440
aatccacacc ggggagaacc cctatgaatg tagtgagtgt gggaaagcct tcaggtacag 1500
ctcggctctt gttcgccatc agagaattca cactggagag aagcctttga atgggatcgg 1560
catgagcaaa agctccctca gagttacgac cgagttaaat atcagagagt ccacgtgaaa 1620
gagccacaca cccattttcc tcactttccc tgagtctcaa gagctcttgc cttaccctat 1680
aaatctcaac agcttaggat gtgtcccttt caactcagac ttttcatttt agagaatggg 1740
gcagatgggg caaatcgttg aattttccca gaaatcacac cagccttaga aagcgtcaag 1800
gcaagtggat ggcgtgctgg gaatagaaag cagctctggg accagttacc ccatttagga 1860
aaggagtttg cactaaactg tttttctcac agcagaggaa cctttccaag gtggggatgg 1920
aagcacagtc gggacagaat tcgatggatt cctttagttg gagtccgcgt agtcagcaca 1980
gacagcagtg gaaaggacgc tctgggtcct gttatttgct agggagggta aagggagact 2040
atttcaaagc tactgttcct agtccagctt taagtttcgg taagaaacat gctgttttgt 2100
ttcatgattt cgttaattat ggaaatttgg cattgaggga ttattttatt gagggtagaa 2160
gagattccag aatcatcatc tgtgatgatg gtgtccttta gggctcttgg agcagccaga 2220
ccatgtttcc aagagaaacc tggtgatatt gccagcagac cccctgccat cccccccagt 2280
tgtcctgggg ctgaatgggc aaarctgtcc aaacagctag taaccggctg tgagggagag 2340
ggtcagaagc acttagcgtt ggcctctgat tgctgtcctc tcttgtcctc ttcccactcc 2400
aatgatgaaa atgattttct ctauatgcct gggtaaggat gctttcaagg agctcacttg 2460
gcctgcttgc cctgccctct cacctctgac acccagcccc aggagccaga ccactcctgc 2520
ctccacctct gactcttcag cagctgaaga ttaatgcaga gaaagagcaa agcccaaaag 2580
ggagaaaaaa aaaaaa 2596
<210> 66
<211> 1574
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1443262CB1
<400> 66
cagcccgtga gacgcccgct gctggacgcg ggtagccgtc tgaggtgccg gagctgcggg 60
aggatggagc cgctgaaggt ggaaaagttc gcaaccgcca acaggggaaa cgggctgcgc 120
gccgtgaccc cgctgcgccc cggagagcta ctcttccgct cggatccctt ggcgtacacg 180
gtgtgcaagg ggagtcgtgg cgtcgtctgc gaccgctgcc ttctcgggaa ggaaaagctg 240
atgcgatgct ctcagtgccg cgtcgccaaa tactgtagtg ctaagtgtca gaaaaaagct 300
tggccagacc acaagcggga atgcaaatgc cttaaaagct gcaaacccag atatcctcca 360
gactccgttc gacttcttgg cagagttgtc ttcaaactta tggatggagc accttcagaa 420
tcagagaagc tttactcatt ttatgatctg gagtcaaata ttaacaaact gactgaagat 480
aagaaagagg gcctcaggca actcgtaatg acatttcaac atttcatgag agaagaaata 540
caggatgcct ctcagctgcc acctgccttt gacctttttg aagcctttgc aaaagtgatc 600
tgcaactctt tcaccatctg taatgcggag atgcaggaag ttggtgttgg cctatatccc 660
agtatctctt tgctcaatca cagctgtgac cccaactgtt cgattgtgtt caatgggccc 720
cacctcttac tgcgagcagt ccgagacatc gaggtgggag aggagctcac catctgctac 780
ctggatatgc tgatgaccag tgaggagcgc cggaagcagc tgagggacca gtactgcttt 840
gaatgtgact gtttccgttg ccaaacccag gacaaggatg ctgatatgct aactggtgat 900
63/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
gagcaagtat ggaaggaagt tcaagaatcc ctgaaaaaaa ttgaagaact gaaggcacac 960
tggaagtggg agcaggttct ggccatgtgc caggcgatca taagcagcaa ttctgaacgg 1020
cttcccgata tcaacatcta ccagctgaag gtgctcgact gcgccatgga tgcctgcatc 1080
aacctcggcc tgttggagga agccttgttc tatggtactc ggaccatgga gccatacagg 1140
atttttttcc caggaagcca tcccgtcaga ggggttcaag tgatgaaagt tggcaaactg 1200
cagctacatc aaggcatgtt tccccaagca atgaagaatc tgagactggc ttttgatatt 1260
atgagagtga cacatggcag agaacacagc ctgattgaag atttgattct acttttagaa 1320
gaatgcgacg ccaacatcag agcatcctaa gggaacgcag tcagagggaa atacggcgtg 1380
tgtctttgtt gaatgcctta ttgaggtcac acactctatg ctttgttagc tgtgtgaacc 1440
tctcctattg gaaattctgt tccgtgtttg tgtaggtaaa taaaggcaga catggtttgc 1500
aaaccacaag aatcat.tagt tgtagagaag cacgattata ataaattcaa aacatttggt 1560
tgaaaaaaaa aaaa 1574
<210> 67
<211> 2197
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1521648CB1
<400> 67
cccgacgaac gcgaggaggg cgaggcggga ggtgcaggag ggaccctcgc catgggtcca 60
cgggcctaga gtggcggaag ataccggcct ggtgccaaac tggctactgc tgcttcctgt 120
ggcctccatg gctgaggact ggctggactg cccggccctg ggccctggct ggaagcgccg 180
cgaagtcttt cgcaagtcag gggccacctg tggacgctca gacacctatt accagagccc 240
cacaggagac aggatccgaa gcaaagttga gctgactcga tacctgggcc ctgcgtgtga 300
tctcaccctc ttcgactt_ca aacaaggcat cttgtgctat ccagccccca aggcccatcc 360
cgtggcggtt gccagcaaga agcgaaagaa gccttcaagg ccagccaaga ctcggaaacg 42G
tcaggttgga ccccagagtg gtgaggtcag gaaggaggcc ccgagggatg agaccaaggc 480
tgacactgac acagccccag cttcattccc tgctcctggg tgctgtgaga actgtggaat 540
cagcttctca ggggatggca cccaaaggca gcggctcaaa acgttgtgca aagactgtcg 600
agcacagaga attgccttca accgggaaca gagaatgttt aagcgtgtgg gctgtgggga 660
gtgtgcagcc tgccaggtaa cagaagactg tggggcctgc tccacctgcc tcctgcagct 720
gccccatgat gtggcatcgg ggctgttctg caagtgtgaa cggagacgct gcctccggat 780
tgtggaaagg agccgagggt gtggagtatg ccggggctgt cagacccaag aggattgtgg 840
ccattgcccc atctgccttc gccctccccg ccctggtctc aggcgccagt ggaaatgtgt 900
ccagcgacgt tgcctacggg gtaaacatgc ccgccgcaag ggaggctgtg actccaagat 960
ggctgccagg cggcgccccg gagcccagcc actgcctcca ccacccccat cacagtcccc 1020
agagcccaca gagccgcacc ccagagccct ggccccctcg ccacctgccg agttcatcta 1080
ttactgtgta gacgaggacg agctacagcc ctacacgaac cgccggcaga accgcaagtg 1140
cggggcctgt gcagcctgcc tacggcggat ggactgtggc cgctgcgact tctgctgcga 1200
caagcccaaa ttcgggggca gcaaccagaa gcgccagaag tgtcgttggc gccaatgcct 1260
gcagtttgcc atgaagcggc tgctgcccag tgtctggtca gagtctgagg atggggcagg 1320
atcgccccca ccttaccgtc gtcgaaagag gcccagctct gcccgacggc accatcttgg 1380
ccctaccttg aagcccacct tggctacacg cacagcccaa ccagaccata cccaggctcc 1440
aacgaagcag gaagcaggtg gtggctttgt gctgcccccg cctggcactg accttgtgtt 1500
tttacgggaa ggcgcaagca gtcctgtgca ggtgccgggc cctgttgcag cttccacaga 1560
agccctgttg caggtgaagc aagagaaggc ggatacccag gacgagtgga caccaggcac 1620
agctgtcctg acttctcccg tattggtgcc tggctgccct agcaaggcag tagacccagg 1680
cctgccttct gtgaagcaag agccacctga cccagaggag gacaaggagg agaacaagga 1740
tgattctgcc tccaaattgg ccccagagga agaggcagga ggggctggca cacccgtgat 1800
cacggagatt ttcagcctgg gtggaacccg cttccgagat acagcagtct ggttgccaag 1860
gtccaaagac cttaaaaaac ctggagctag aaagcagtag actggaggct tctacagact 1920
gtaggattca agtctgcagg gcaggcactc gggaagggaa gatggatgta aagtgtggga 1980
gaccgaggac acagtggagc ccacgagcac gagctggaac ccacgaggat ggcctggaac 2040
ccatgtcagt ctctcaccac ctccagcttc gatgatgtgg gtgtcctgca gaagaagctg 2100
gtgcccttcc tcacagagtt aaatatgcat ctggcccagg aattagagaa gctgaaagga 2160
tgatcctggg gaaggcggaa cagctgcagg cctggct 2197
64/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<210> 68
<211> 2081
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1685494CB1
<400> 68
gcatacgcag tccgtgccta agcggcacga ccatcgagcc aaggtcctcc agcgttccta 60
gagcggagaa gaaagcgctc cgaagagcta gagctgacac tcggcgatga gctaagacgc 120
tgtttcagag cgtttgggtc ctctgaggcc ccttgaccag gagtgtctct gaagatacag 180
tccaaagaag gttctccaaa acaaggagag cagtctgaag ctggggatgg caacagcatt 240
ggtgagtgcc cattccctgg ctcccctgag tctgaagaag gaggggcttc gggtagtgag 300
ggaggatcac tactctactt gggaacaggg attcaagctg caaggaaaca gtaaaggcct 360
tggacaggag ccattgtgca aacaattcag gcagttgcgt tatgaagaga ccacaggacc 420
tcgagaagca ctaagtcggc tccgggagct ctgtcaacag tggctacagc ccgagaccca 480
taccaaggag cagatcctgg agctgctggt gctggagcag tttctgatca tcctgcctaa 540
ggagctccag gcccgggtgc aggagcatca cccagagagc agggaggacg tggttgttgt 600
tctggaggat ttgcagctgg atcttggaga aacaggacaa caggtggacc cagaccagcc 660
aaagaaacaa aaaatacttg tggaggagat ggcccctctg aaaggagtac aggaacagca 720
ggttcggcat gagtgtgaag ttacaaagcc tgagaaagag aagggtgagg agacaaggat 780
tgagaatggg aagcttattg tagtaacaga ctcttgtgga agagtagagt catctgggaa 840
aatatctgaa cccatggagg ctcataatga gggctctaac ttggaaaggc atcaggccaa 900
gcccaaagag aagattgagt ataaatgctc agaacgtgag cagagattca tccagcactt 960
ggacctgatt gaacatgcga gtacacacac gggaaagaaa ctctgcgagt ctgatgtgtg 1020
tcagagttcc agtcttacag gacataagaa agtcctctct agagagaaag gtcatcagtg 1080
tcatgagtgt gggaaagcct ttcagaggag ttcacacctc gtcagacatc agaaaatcca 1140
tcttggtgag aagccttatc agtgcaatga gtgtggcaaa gtctttagcc agaatgcagg 1200
ccttttggaa catctcagaa ttcatactgg agagaaacct tatctatgta tccattgtgg 1260
aaaaaatttt aggcgcagct ctcaccttaa tcgacatcag agaattcaca gtcaggagga 1320
gccctgtgag tgcaaggagt gtggaaaaac ctttagtcag gccttactcc tcacccacca 1380
tcagagaatc catagtcact ccaaaagcca tcaatgtaac gagtgtggaa aagctttcag 1440
tttgacctca gaccttattc gacaccacag aattcatact ggagaaaaac ctttcaagtg 1500
taacatatgc cagaaagcct tccgactaaa ctcacacctt gctcagcatg taagaatcca 1560
caatgaagaa aaaccctatc agtgtagtga atgtggagaa gccttcaggc aaaggtcagg 1620
tctttttcaa catcagagat atcaccacaa agacaaactg gcttgatgag gtgttctctc 1680
cttgtagaac atcagagaag gcacattgac tagcaaacag cactttagga aaagtcaccg 1740
tagcccactg tggcatcaga aaattcttgg gggctgagtt ggaggctccc tgcctctatt 1800
ctctctcctt tgctttcctt gaagtcagct ttggaccaca ataatttcac tgtagatgat 1860
atgctaggat caaagttaaa cagcattctt cactgcagga catctcagag catgtaacat 1920
aactgcatga ttatatactc taagcaatag agagcttcat gactgagtaa gagttttgaa 1980
gtcagcagtg aatcaagtgc ccacagattt gcaggcttaa gcagaacaag ggaagattga 2040
tatttttgga tatgctatag cagctttctc ctatgaaata a 2081
<210> 69
<211> 2785
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1730829CB1
<400> 69
gaccgtgcgg cgcccagcgg agtaggggct gcgcttgggg tttgctgaag ctggctgcct 60
ctcccactcc ccttttgggt gcaaagcgcc gctagcggga agacgggggc cgggcgggga 120
caggggcacc tgcgtactgg actgagagcc tgcgcccagc ttacatcgac cccacccggc 180
cccggcccga cccgacgcga cccgatccga tccgaLccca ttccatccgt tcctcg fete 240
ctcccggtct gacccgttgc ccggccgtgg ttcgccacac caggcatcca aagctgaggt 300
65/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
cgctcctacg gcctgggctc gccttcgctt tagagatgtt tggcctcttc cctcccaaac 360
agctcatctt caaaacctgg actcttggac tggcacctgg ccacctttcc ctctaccaag 420
actccacttc cgtcttaccc acttcttcct cagattcttg gtaccccctg ggttggagac 480
tgctcatttt ccttccaaat taatcccaga ccccctaaaa tattgacaac cttgacaacc 540
ccccaaccga ggagccagac tttgttttgg actaacttcc atagccctat catggaggca 600
gtgtacctgg tagtgaatgg gttgggcctg gtgctggacg tgctgacctt ggtgttggac 660
ctcaacttcc tgctggtgtc ctccctcctg gcttccctgg cctggctcct ggccttcgtc 720
tacaacctgc cgcacacggt actgactagt cttctgcact tgggccgcgg agtcttgctt 780
tcattgctgg ccttgatcga agccgtggtc cggttcacat gtgggggctt gcaggccttg 840
tgtactctgc tgtatagctg ctgctctggc ctagagagcc taaagctcct ggggcacctg 900
gcctctcatg gggcactgcg gagcagggag atactgcacc ggggcgtcct caatgtggtc 960
tccagtggcc atgctttgct gcgccaggcc tgtgacatct gtgccattgc catgagcctg 1020
gtggcttatg tgatcaacag cctggtcaac atctgcctca tcggcactca gaacctcttt 1080
tccctggtgc tggccctgtg ggatgcagtg accgggcctc tgtggaggat gacagacgta 1140
gtggctgcct tcctagccca catttccagc agtgctgtgg ccatggccat cctcctttgg 1200
acaccctgcc aactagccct ggagctgctg gcctcagctg cccgcctcct ggccagcttt 1260
gtgcttgtca atctcactgg cttggtgttg ctagcttgtg tgctggcagt gacggtgact 1320
gtgttgcatc cggacttcac cctgaggctg gctacccagg cactcagcca gctccatgcc 1380
cggccatcct accaccgtct tcgagaggat gtcatgcggc tctctcgcct agcactgggc 1440
tcagaggcct ggcgccgagt ctggagccgc agtctgcagc tggcgagttg gccaaaccgg 1500
ggaggggcac ctggagctcc ccagggtgac cctatgaggg tattctcagt taggacccgg 1560
agacaggaca ctcttcctga agcggggcgc agatcagagg cagaagagga ggaggccagg 1620
accatcagag tgacacctgt caggggccga gagaggctca atgaggagga gcctccaggt 1680
gggcaagacc cttggaaatt gctgaaggag caagaggagc ggaagaagtg tgtcatctgc 1740
caggaccaga gcaagacagt gttgctcctg ccctgccggc atctgtgcct gtgccaggcc 1800
tgcactgaaa tcctgatgcg ccaccccgtc taccaccgca attgcccgct ctgccgccgg 1860
ggcatcctgc agaccctcaa tgtctacctc tgaagcctcc ttccctgcct gcccacccct 1920
ccatgctcca cgcaggcact cacgctagga cagcattaac acctcatctc cgggtcctgg 1980
tctgaatccc ctcctacccc tgtggccatc ctgccataca tccaggacat tgagttggaa 2040
gactatgatc tgggtggggg caggataaca tggcttctct ttacccagtg ggtcccttcg 2'._70
atgctgaggg tggtgagtat gtcactatgc aagggccctg agactatttg ctgtgggctc 2160
tcctccagcc tgcccagggc ccacccagat gcctctgggg ttacccctgt ctgc~tctgg 2220
tttttctgtt ggagatctat aggtcctttt cctgcctcct tcacatttcc tccccagctt 2280
ttgcggccac aacacatcag tgtcatttgg gtgttttggc aactcagggg ccttcggatg 2340
atcttaaacc tttgtgttca gccagagccc ctgtgccctg gtaggcgttg gggttagtat 2400
ctctcgggtg ccctcagagc cacctctgcc tgtgatcgtc tgatgaggct ccctcccaac 2460
ctgatccaaa agccagtctc aggagtttac ccctgggatg ggggatgcat ctgcacctga 2520
ctttggggcc acgtgccctg tggcacccca gctcactggg agtctcagga gggataaccg 2580
gatttctgct ctttcccctg tcactcccac atcacacaga aaaatggcat tcctctctgt 2640
ctctccctgg catggagagg gcagactgtg cacatttcac tagggttcaa atacagaagg 2700
cccagggccc aggggttgca gcttcgtgag gggtctctgg cccagtttcc aatgaataaa 2760
gttctcttga cagctaaaaa aaaaa 2785
<210> 70
<211> 1231
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1864641CB1
<400> 70
tcccgtccta tgacgtcagc cgtaaggcgc tgctgtcgta aaaggacgtc cggtccgtct 60
cctagtgtcc ggaatcggct gtcagcctcc ctggctgtta gtaccttctt tcccggagtc 120
ctggtccacg agttggattt actgctgtcg cgggtgggcc tcacgccatt ccctgtccct 180
cggccccctg agtgagtccg gtctcccggc gaaagtgagc gaggtttgcc cggagcgcgc 240
acgaggggaa aatgcctaaa aaaaagactg gtgcgaggaa gaaggctgag aaccgccgag 300
aacgtgaaaa acaactaaga gcatcaagaa gcactataga tttagctaaa catccatgta 360
atgcctcaat ggaatgtgac aagtgtcaga ggcggcagaa gaatagagca ttttgctact 420
66/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00/02237
tttgtaattc tgtacagaag ttaccaattt gtgcacagtg tgggaaaaca aagtgcatga 480
tgaagtcttc agactgtgtc ataaagcatg ctggtgtata cagtactggc cttgcaatgg 540
tgggtgcaat atgtgacttc tgtgaagctt gggtttgcca tggtaggaaa tgtctcagta 600
cacatgcttg tgcctgccct cttaccgatg ctgagtgtgt tgaatgtgaa cgaggcgtgt 660
gggaccatgg aggcagaata ttcagttgtt ctttttgcca taactttctc tgtgaagatg 720
atcaatttga gcatcaagcc agctgccagg ttttagaggc agaaacattt aaatgtgttt 780
catgcaatcg gcttggtcag cactcatgtc tccgttgtaa ggcttgtttc tgtgatgatc 840
atacaaggag caaagtgttt aagcaagaaa aaggaaaaca gcctccttgt cctaaatgtg 900
ggcatgaaac tcaggagact aaggacctta gcatgtcaac acgctccctg aaatttggca 960
ggcagactgg aggtgaagag ggagatggag cttctgggta tgatgcttat tggaagaacc 1020
tttcatctga taagtatggt gataccagct accacgatga ggaggaggat gagtatgaag 1080
cagaggatga tgaagaggaa gaagatgaag gcagaaagga ttcagatact gagtcatcag 1140
atttgtttac taatttgaat ttaggaagga cctatgctag tggctatgct cactatgagg 1200
aacaagagaa ctaggggagc tgctctggtg g 1231
<210> 71
<211> 700
<212> DNA
<213> Homo sapiens
<220> -
<221> misc-feature
<223> Incyte ID No.: 2444604CB1
<400> 71
gccccaggtg acacaatggc cgcagtccat ggcggctggc ttcttccagc ccttcatgtc 60
accgcgcttc ccagggggcc cccggcccac cctgcggatg ccgagtcagc ctcccgcatg 120
cctccctggc tcccagcccc tcctccctgg cgccatggag ccctccccac gagcccaggg 180
gcatccgagc atgggcggcc caatgcagag ggtgacgcct cctcc~tggca tggccagcgt 240
ggggccccag agctatggag gtggcatgcg acccccaccc aactccctcg ccggcccagg 300
cctgcctgcc atgaacatgg gcccaggagt tcgtggcccg tgggecagcc ccagtggaaa 360
ctcgatcccc tactcctcct catcccccgg cagctacacc ggacccccag gaggaggtgg 420
gccccctgga acacccatca tgcctagccc tggagattcc accaactcca gcgaaaacat 480
gtacactatc atgaacccca tcgggcaggg cgccggcagg gctaatttcc cgctcggccc 540
tggcccggag ggcccatggc cgccatgagc gcgatggagc ctcaccacgt gaacggatcc 600
ctgggctcgg gcgacatgga cgggttgccg aagagttccc ccggcgccgt ggccggcctg 660
agcaacgccc cggggcaccc cgcgggacga cggcgagatg 700
<210> 72
<211> 2332
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2445008CB1
<400> 72
aggcggacgg ggaacgaggc cgtcggccat tttgtgtctg cttcctgtgg gacgtggtgg 60
tagccgttgg gttgggaaag tgagggattt ttggcctcgt ttctcctgct tcttttctcc 120
tcccttttac tttgccggta gaacacagtt atgggtcgca agaagaagaa gcagctgaag 180
ccgtggtgct ggtattgtaa tagagatttt gatgatgaga agatccttat tcagcaccaa 240
aaagcaaagc attttaaatg ccatatatgt cacaagaaat tgtatacagg acctggctta 300
gctattcatt gcatgcaggt acataaagaa acaatagatg ccgtaccaaa tgcaatacct 360
ggaagaacag acatagagtt ggaaatatat ggtatggaag gtattccaga aaaagacatg 420
gatgaaagac gacgacttct tgaacagaaa acacaagaaa gtcaaaaaaa gaagcaacaa 480
gatgattctg atgaatatga tgatgacgac tctgcagcct caacttcatt tcagccacag 540
cctgttcaac ctcagcaagg ttatattcct ccaatggcac agccaggact gccaccagta 600
ccaggagcac caggaatgcc tccaggcata cctccattaa tgccaggtgt tcctcctctg 660
atgccaggaa tgccaccagt tatgccaggc atgccacctg gattgcatca tcagagaaaa 720
67/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
tacacccagt cattttgcgg tgaaaacata atgatgccaa tgggtggaat gatgccacct 780
ggaccaggaa taccacctct gatgcctgga atgccaccag gtatgccccc acctgttcca 840
cgtcctggaa ttcctccaat gactcaagca caggctgttt cagcgccagg tattcttaat 900
agaccacctg caccaacagc aactgtacct gccccacagc ctccagttac taagcctctt 960
ttccccagtg ctggacagat ggggacacct gtcacaagct caagtacagc ttcatccaat 1020
tcagaaagtc tgtctgcatc ttctaaagct ctgtttccta gcacagcaca agctcaggca 1080
gctgtccaag gacctgttgg tacagatttc aaacccttaa atagtacccc tgcaacaact 1140
acagaacccc caaagcctac attccctgct tatacacagt ctacagcttc aacaactagt 1200
acaacaaata gtactgcagc taaaccagcg gcttcaataa caagtaagcc tgctacactt 1260
acaacaacta gtgcaaccag taagttgatc catccagatg aggatatatc cctggaagag 1320
agaagggcac agttacctaa gtatcaacgt aatcttcctc ggccaggaca ggcccccatc 1380
ggtaatccac cagttggacc aattggaggt atgatgccac cacagccagg catcccacag 1440
caacaaggaa tgagaccccc aatgccacct catggtcagt atggtggtca tcatcaaggc 1500
atgccaggat accttcctgg tgctatgccc ccgtatgggc agggaccgcc aatggtgccc 1560
ccttaccagg gtgggcctcc tcgacctccg atgggaatga gacctcctgt aatgtcgcaa 1620
ggtggccgtt actgatctta cttcatccag tctaataggt ttggagatta aaccttttct 1680
caacttgtgc tgtttatata gccaagcttc cgtcaataag gcttcattgt gactttaaca 1740
aacattatct tcccacatac caggaactat tggacattta ttttacatgg gaaaaattat 1800
ttggaataat aaagcaggaa cttttcctga agttgcaatt tatactgtat ggcttctttt 1860
tcatgtttca tctaggtttt tagaagtgaa gtatagtaaa tttggttcgt taaattgtga 1920
aggcgctgga attacatgaa cataccaccc tagtaaaggc aagttctgta agcttacatt 1980
gctatttgta aagtttgcct tcacagcatt tcagatgctg ttggacttca tgtccccaac 2040
ctagcttggt gagggctgta actgtttcca agtacttgta cattggaagt ctgaatgtgt 2100
aacaatattt aatgtattta gagttcctca tgttgcaggg tttaagaaat ctgacccacc 2160
aaggtcatgt gacttttctg tactgttaaa cttcattgta ataaaatgag agaaaaattt 2220
atgccttttt attcataacc cagctgtgga ccactgcctg aaaggtttgt acagatgcat 2280
gccacagtag atgtccacat aataaaattc atagttacca aaaaaaaaaa as 2332
<210> 73
<211> 1936
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2572462CB1
<400> 73
ttggttctat attactgttt tatagctgag gagaaagact cacatcattt actaagatca 60
tatagctagc tagtaaatgt ttgagtgaaa atacaaacaa aggttttctg actttaagag 120
cttgagtttt ttccactata ccatattgca tctgttgtaa ttgttaacta atgtgcattt 180
taaaattctc atttgtctta tgtactgagc ccttatacca gtgctaattt atgtgactcc 240
tttctcctgc agctaagaga aaaatacctt tttaattcat ttatagtacc cagtttttaa 300
agaagattta ttttgtaaaa ttttgcttat ggtacatgtc atcttagcct gtaaataaat 360
taaagcatta atttttatcc ctccctggtc ttttcctcct tctgacttta.tacgtctttc 420
tagagagctt atcttctata ataacaattc tttgttttaa agtgagaaag atcagtctaa 480
agaaaaggag aagaaagtga aaaaaacaat tccttcctgg gctacccttt ctgccagcca 540
gctagccagg gcccagaaac aaacaccgat ggcttcttcc ccacgtccca agatggatgc 600
aatcttaact gaggccatta aggcatgctt ccagaagagt ggtgcatcag tggttgctat 660
tcgaaaatac atcatccata agtatccttc tctggagctg gagagaaggg gttatctcct 720
taaacaagca ctgaaaagag aattaaatag aggagtcatc aaacaggtta aaggaaaagg 780
tgcttctgga agttttgttg tggttcagaa atcaagaaaa acacctcaga aatccagaaa 840
cagaaagaat aggagctctg cagtggatcc agaaccacaa gtaaaattgg aggatgtcct 900
cccactggcc tttactcgcc tttgtgaacc taaagaagct tcctacagtc tcatcaggaa 960
atatgtgtct cagtattatc ctaagcttag agtggacatc aggcctcagc tgttgaagaa 1020
cgctctgcag agagcagtag agaggggcca gttagaacag ataactggca aaggtgcttc 1080
ggggacattc cagctgaaga aatcagggga gaaacccctg cttggtggaa gcctgatgga 1140
atatgcaatc ttgtctgcca ttgctgccat gaatgagccg aagacctgct ctaccactgc 1200
tctgaagaag tatgtcctag agaatcaccc aggaaccaat tctaactatc aaatgcattt 1260
gctgaaaaaa accctgcaga aatgcgaaaa gaatgggtgg atggaacaga tctctgggaa 1320
agggttcagt ggcaccttcc agctctgttt tccctattat cccagcccag gagttctgtt 1380
68/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
tccgaagaaa gagccagatg attctagaga tgaggatgaa gatgaagatg agtcatcaga 1440
agaagactct gaggatgaag agccgccacc taagagaagg ttgcagaaga aaaccccagc 1500
caagtcccca gggaaggccg catctgtgaa gcagagaggg tccaaacctg cacctaaagt 1560
ctcagctgcc cagcggggga aagctaggcc cttgcctaag aaagcacctc ctaaggccaa 1620
aacgcctgcc aagaagacca gaccctcatc cacagtcatc aagaaaccta gtggtggctc 1680
ctcaaagaag cctgcaacca gtgcaagaaa ggaagtaaaa ttgccgggca agggcaaatc 1740
caccatgaag aagtctttca gagtgaaaaa gtaaatttta taggaaaaaa gggtatcatg 1800
atgaaattca aaatcttatt ttctaaggtc agtgtgcatt tgtttagttt tgatgctttt 1860
caaattacat tattttcctc ccctatgaac attgtgggga gggactctaa ataaaccagt 1920
ttaggcaaaa aaaaaa 1936
<210> 74
<211> 1667
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2572892CB1
<400> 74
cgcgaatcgg cgaccccagt gcctcgacca ctatgccgcg ctctttcctc gtcaggaagc 60
cctccgaccc caatcggaag cctaactaca gcgagctgca ggactctaat ccagagttta 120
ccttccagca gccctacgac caggcccacc tgctggcagc catcccacct ccggagatcc 180
tcaaccccac cgcctcgctg ccaatgctca tctgggactc tgtcctggcg ccccaagccc 240
agccaattgc ctgggcctcc cttcggctcc aggagagtcc cagggtggca gagctgacct 300
ccctgtcaga cgaggacagt gggaaaggct cccagccccc cagcccaccc tcaccggctc 360
cttcgtcctt ctcctctact tcagcctctt ccttggaggc cgaggcctat gctgccttcc 420
caggcttggg ccaagtgccc aagcagctgg cccagctctc tgaggccaag gatctccagg 480
ctcgaaaggc cttcaactgc aaatactgca acaaggaata cctcagcctg ggtgccctca 540
agatgcacat ccgaagccac acgctgccct gcgtctgcgg aacctgcggg aaggccttct 600
ctaggccctg gctgctacaa ggccatgtcc ggacccacac tggcgagaag cccttctcct 660
gtccccactg cagccgtgcc ttcgctgacc gctccaacct gcgggcccac ctccagaccc 720
actcagatgt caagaagtac cagtgccagg cgtgtgctcg gaccttctcc cgaatgtccc 780
tgctccacaa gcaccaagag tccggctgct caggatgtcc ccgctgaccc tcgaggctcc 840
ctcttcctct ccatacctgc ccctgcctga cagccttccc cagctccagc aggaaggacc 900
ccacatcctt ctcactgcca tggaattccc tcctgagtgc cccacttctg gccacatcag 960
ccccacagga ctttgatgaa gaccattttc tggttctgtg tcctctgcct gggctctgga 1020
agaggccttc ccgtggccat ttctgtggag ggagggcagc tggcccccag ccctggggga 1080
ttcctgagct ggcctgtctg cgtgggtttt tgtatccaga gctgtttgga tacagctgct 1140
ttgagctaca ggacaaaggc tgacagactc actgggaagc tcccacccca ctcaggggac 1200
cccactcccc tcacacacac ccccccacaa ggaaccctca ggccaccctc cacgaggtgt 1260
gactaactat gcaataatcc acccccaggt gcagccccag ggcctgcgga ggcggtggca 1320
gactagagtc tgagatgccc cgagcccagg cagctatttc agcctcctgt ttggtggggt 1380
ggcacctgtt tcccgggcaa tttaacaatg tctgaaaagg gactgtgagt aatggctgtc 1440
acttgtcggg ggcccaagtg gggtgctctg gtctgaccga tgtgtctccc agaactattc 1500
tgggggcccg acaggtgggc ctgggaggaa gatgtttaca tttttaaagg tacactggta 1560
tttatatttc aaacattttg tatcaaggaa acgttttgta tagttatatg tacagtttat 1620
tgatattcaa taaagcagtt aatttatata ttaaaaaaaa aaaaaaa 1667
<210> 75
<211> 759
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2785674CB1
<400> 75
69/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
tgggctcgcc tccctgggac taggtttcag cggccgctgc gatgaccaaa ataaaggcag 60
atcccgacgg gcccgaggct caggcggagg cgtgttccgg ggagcgcacc taccaggagc 120
tgctggtcaa ccagaacccc atcgcgcagc ccctggcttc tcgccgcctc acgcggaagc 180
tctacaaatg catcaagaaa gcggtgaagc agaagcagat tcggcgcggg gtgaaagagg 240
ttcagaaatt tgtcaacaaa ggagaaaaag ggatcatggt tttggcagga gacacactgc 300
ccattgaggt atactgccat ctcccagtca tgtgtgagga ccgaaatttg ccctatgtct 360
atatcccctc taagacggac ctgggtgcag ccgcaggctc caagcgcccc acctgtgtga 420
taatggtcaa gccccatgag gagtaccagg aggcttacga tgagtgcctg gaggaggtgc 480
agtccctgcc cctaccccta tgaggggctc cggtagcacc tgggcacctg ccgctggaag 540
ctattgggct ggcagcagga cgactggctg tcctcctgcc cacccacact gacggcatct 600
tcccagttcc ccaaggcacg ccttcttccc aggcagctct aacagccctt tcatgaaggt 660
aatgctagtc ttctgtccat cagtgccatt tcctgtagaa ctaaaggctg ttccaagaat 720
gtggggtggg gaaagtaaat gctaagacta aaaaaaaaa 759
<210> 76
<211> 1421
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2797479CB1
<400> 76
ccccagtcac tgttcctgcc cgttgcctgt cagcctcact gcctttaatc cgcttccagg 60
gctcattcac ctgaatatat tggttgccat gtcgagatat ggtgaggata ctgcgcaagg 120
catcccggat ccgaaccttc tcaagtagct gttgatagtg ctggagctcc acggtgacat 180
gagctaacag gcgctgatca tcatgggtga tgacatatcg acgcacatag cccccaaaga 240
acttagacac aaacatccca gctctgttga ~gaagttgcc caggttgtta agcagctcag 300
aattattctt cagcagcagg tccgtccagg agaaagcact gtcctggccc tcaggccgaa 360
tgtacagcag atagaagcgc cagatgtcag cagggatccc cgtgtcctgg gctttgattt 420
tcctggttca gcacgaattc atgaaggaac tcacactcta gagaaaccct atgaatgtaa 480
gcaatgtggg aaattgttat ctcatcgctc aagctttcga agacacatga tggcacacac 540
tggagatggc cctcataaat gcacagtatg tgggaaagcc tttgactctc ctagtgtatt 600
tcaaagacat gaaaggactc acactggaga gaaaccctat gaatgcaagc aatgtgggaa 660
agccttccgt acttccagtt cccttcgaaa acatgaaaca acacacactg gagagcaacc 720
ctataaatgt aaatgtggaa aagcttttag tgatttattt tcctttcaaa gtcatgaaac 780
aacacacagt gaagaggagc cttatgaatg taaggagtgt gggaaagcat ttagttcttt 840
taaatacttt tgtcgccatg aacggactca cagtgaagaa aaatcttatg agtgtcaaat 900
ttgtggcaaa ctttcagtcg tttcagttac ttaaaaactc atgaaaggac tcacacggca 960
gagaagccat atgaatgtaa gcaatgcagg aaagcattct tttggccctc tttccttcta 1020
agacatgaaa ggactcacac tggagaaaga ccctatgaat gtaaacactg tggtaaagcc 1080
ttcagtcgtt ccagtttctg tcgagaacat gaaagaactc acgctggaga gaagccctat 1140
gaatgtaagg aatgtgggaa agccttcagt tctctcagtt cctttaatag acataaaagg 1200
acacactgga aggatattct ataagtgtat ggaatgtggg aaagcattca ttggttttat 1260
cacattcaga tacttgaaag aaataaatcc tgtgaatgta aacgtggtaa agccttaaga 1320
agtttccagg ctgggcgcag cggctcacac ctgtaatccc agcactttga gaggccgagg 1380
agggcatatc acgaggccag gagatcgaga ccagcctggg g 1421
<210> 77
<211> 2386
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2960640CB1
<400> 77
gacttttaag ggatcacaga gctcacacca aagaccaggg gaacagtcag aagcctggct 60
70/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
tgctcctcag gctcccagga acctgcctca aaacacaggt ctccacgacc aggagacagg 120
tgctgtggtc tggacagctg ggtcccaggg accagccatg cgtgacaaca gagctgtatc 180
cctctgtcag caagaatgga tgtgcccagg ccctgcacaa agggccctct acaggggtgc 240
cacccagagg aaggacagtc acgtctcgct ggcaacaggt gtgccctggg gctatgaaga 300
gaccaagacg ctcctggcta ttcttagtag ttctcaattt tatggaaaac tccagacctg 360
tcagcagaac agccagatct acagggccat ggcggaagga ctctgggagc agggttttct 420
gcggacccca gaacagtgtc gcaccaagtt caaaagccta cagttgagtt accgcaaagt 480
gaggagaggc cgtgtgcctg agccttgtat cttttatgag gaaatgaatg ctctttcagg 540
ctcctgggcc tctgcacctc ctatggcaag cgatgctgtt cctggccaag aaggaagtga 600
tattgaggct ggagagctga atcaccagaa tggggaaccc acggaggtag aagatggcac 660
tgtggatggt gcagacaggg atgaaaagga cttcaggaat cctggccagg aagtcaggaa 720
actagacctg ccagtgctgt tcccaaacag acttggtttt gagttcaaga acgagattaa 780
aaaagaaaat ctaaaatggg atgattcaga ggaagtagaa ataaacaagg ctttacagag 840
aaagtccaga ggagtttatt ggcactctga gctacaaaaa ggcttggaga gtgagccaac 900
atcaagaagg caatgtagaa attctccagg ggagagtgag gagaaaaccc catcccagga 960
gaagatgagt caccagagtt tttgtgccag ggacaaagcc tgtacacata tcctctgtgg 1020
gaaaaactgc tctcagagtg tgcactctcc ccacaagcca gcgctcaaac tggaaaaagt 1080
atctcaatgt cctgaatgtg ggaaaacctt tagccgaagt tcttatcttg ttcggcatca 1140
aagaatccac acaggcgaga agcctcacaa gtgcagtgag tgcgggaagg gctttagtga 1200
gcgctccaac ctcactgccc acctacgaac tcacacaggg gagaggccct atcagtgtgg 1260
gcaatgtggg aaaagcttca accagagttc cagcctcatt gtccaccaga ggacccatac 1320
cggggaaaag ccttaccagt gcattgtctg tggaaagaga ttcaacaaca gttcccagtt 1380
cagtgctcac cggcgcatcc acactgggga gagcccatac aagtgtgcag tgtgtgggaa 1440
aatcttcaac aatagctccc acttcagtgc ccaccgaaaa acccacactg gtgaaaagcc 1500
ttacaggtgt tctcactgtg agagaggctt cactaagaac tctgccctca cccgtcatca 1560
gacagtacac atgaaagcag tactctcatc acaggaagga agagatgcgt tatgagtgtg 1620
tcggtaaact gtcagattaa gttcctcagg tcagcatgta tgagctttct tctgctgtgg 1680
agagatctag ccagtccctg actttgcaac agacctactg actactggat cttaagaccc 1740
atgtctagga ccaggagtca gcataaggac gctgacctct cctggctgtg cctgtgactc 1800
cagagtccta tcttactgtg acttaaagtt tga::ggagag aaagctgtag gatccataaa 1860
ttctaccagg aatccagggt cttcctgttc ctagcactga gaatgggcac ccagtggtcc 1920
aagaacactt tctgggctaa catagtcctc acacagggct gagaaagaaa gtgtctcctt 1980
tcctggaaag cacatgtaaa agttaagggc ctgaatctct tctaaaccaa taattgacct 2040
ctaggcaccc accgtaatac tgctaccttc agagcagaag acactgctct ttgtaaccca 2100
gccaccacca aaaagcaaac agaaagaagg aaggatggtt aagccattgg ataatactga 2160
atctgtttcc ctaagtgact taaccttaga gcaagcacaa catccaggtt aattaattgt 2220
aagatttctc ctctcattat tgccctcatc atagttcctg attgtctctt aaagtaagtg 2280
gtttatagac attactattt ctgataataa tttacaaact actataaaca aatttataaa 2340
cattactaat ttctgatgaa aataaagttg tttctccctc caccac 2386
<210> 78
<211> 1432
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3454051CB1
<400> 78
agtatgagct ggacctgtcc gcgttgccag caacctgttt tcttcgctga gaaggtgagc 60
tccctgggca agaactggca ccgcttctgc ctgaaatgtg agcgctgcca cagcatcctg 120
tcccctggcg ggcatgcaga gcacaatggg aggccatact gccacaagcc atgctatggg 180
gctctctttg gacccagggg ccctccccat atgaagacat tcactgggga gacctcgctg 240
tgccctggct gtggggagcc cgtctatttt gctgagaagg tgatgtcatt aggcagaaat 300
tggcaccgac cgtgtctgag gtgccagcgt tgccacaaga ccctgactgc tgggagtcat 360
gctgagcatg atggagtccc ctactgccac gtcccctgct acggctacct gtttggcccc 420
aaaggtgtga acattggcga tgtgggctgc tacatctatg acccagtgaa gataaaattc 480
aaatgagacg ctcacaaaaa aggtcaccct aactcaggcc tcccatcatg cccctcatgg 540
tccaatggaa gctacaaaaa tctccagtcc catgggggtt ggggaaggtg ggatcttggg 600
ggcctgggcc taggctccat ggtaggccag agagtctaga ctttctctgc caattttttc 660
71/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
cctttcccat ttctatctgg ttagggaaca gcccgttttg aagggtatcc tcctcctggc 720
catcacaacc cctttcccca gcacattctg gagcttcaag gtactcataa aacttgtgtt 780
tattgaattt cagcctctgt ggcttcttca ataaaatgtt ggctcccatg ccttcaactc 840
ttctttgggc atgagaccag tgggttggag gatggggagt gtgggggttg ggatgacatg 900
cattgccctg cagggtgcct cggaggtagc agggccagcc atgagaacaa aaagctctgt 960
tctttttgtc ccttgggcct ggcattggca gtcctagcac cacacagtgg acagcatgcc 1020
caccagcccc attggtacca gaagtctcat atgctagtcc tttctttagc accatctcta 1080
gaagaagcag aagcacctta ttcagtaact catttgagca tggcaacaga tcctatggta 1140
gggcctccca agaggcttca ttatccattt gggagatgaa cagactgagg cccagagagg 1200
gaaagccaca tgcccaaggt cacacagcaa gttaatggtg aaggttttat cagagcccag 1260
ggcagactca gtggcttcct atccagggct cttctcacag ctcgtcacca ctgccccaac 1320
ccaaggggca cctttattta cagaatctcc ccaaccgtga gacgggtgcc agcagaccac 1380
tgcattctgg gaagtcaact gttcctagaa gcaaataatc aaggatggat ga 1432
<210> 79
<211> 1816
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3510640CB1
<400> 79
cactgatgca ggaactgtat agcacaccag cctccaggct ggactccttc gtggctcagt 60
ggctgcagcc ccaccgggag tggaaggaag aggtgctaga cgctgtgcgg accgtggagg 120
agtttctgag gcaggagcat ttccagggga agcgtgggct ggaccaggat gtgcgggtgc 180
tgaaggtagt caaggtgggc tccttcggga atggcacggt tctcaggagc accagagagg 240
tggagctggt ggcgtttctg agctgtttcc acagcttcca ggaggcagcc aagcatcaca 300
aagatgttct gaggctgata tggaaaacca tgtggcaaag ccaggacctg ctggacctcg 360
ggctcgagga cctgaggatg gagcagagag tccccgatgc tctcgtcttc accatccaga 420
ccagggggac tgcggagccc atcacggtca ccattgtgcc tgcctacaga gccctggggc 480
cttctcttcc caactcccag ccaccccctg aggtctatgt gagcctgatc aaggcctgcg 540
gtggtcctgg aaatttctgc ccattcttca gcgagctgca gagaaatttc gtgaaacatc 600
ggccaactaa gctgaagagc ctcctgcgcc tggtgaaaca ctggtaccag cagtatgtga 660
aagccaggtc ccccagagcc aatctgcccc ctctctatgc tcttgaactt ctaaccatct 720
atgcctggga aatgggtact gaagaagacg agaatttcat gttggacgaa ggcttcacca 780
ctgtgatgga cctgctcctg gagtatgaag tcatctgtat ctactggacc aagtactaca 840
cactccacaa tgcaatcatt gaggattgtg tcagaaaaca gctcaaaaaa gagaggccca 900
tcatcctgga tccggccgac cccaccctca acgtggcaga agggtacaga tgggacatcg 960
ttgctcagag ggcctcccag tgcctgaaac aggactgttg ctatgacaac agggagaacc 1020
ccatctccag ctggaacgtg aagagggcac gagacatcca cttgacagtg gagcagaggg 1080
gttacccaga tttcaacctc atcgtgaacc cttatgagcc cataaggaag gttaaagaga 1140
aaatccggag gaccaggggc tactctggcc tgcagcgtct gtccttccag gttcctggca 1200
gtgagaggca gcttctcagc agcaggtgct ccttagccaa atatgggatc ttctcccaca 1260
ctcacatcta tctgctggag accatcccct ccgagatcca ggtcttcgtg aagaatcctg 1320
atggtgggag ctacgcctat gccatcaacc ccaacagctt catcctgggt ctgaagcagc 1380
agattgaaga ccagcagggg cttcctaaaa agcagcagca gctggaattc caaggccaag 1440
tcctgcagga ctggttgggt ctggggatct atggcatcca agacagtgac actctcatcc 1500
tctcgaagaa gaaaggagag gctctgtttc cagccagtta gttttctctg ggagacttct 1560
ctgtacattt ctgccatgta ctccagaact catcctgtca atcactctgt cccattgtct 1620
actgggaagg tcccaggtct tcaccagttt tacaatgagt tatcccaggc cagacgtggt 1680
agctcacacc tgtaatccca gaactttggg aggccgaggt gggaggagcg cttgagccga 1740
ggagttcaag accagcctgg gtatcatagg gagaccccgt ctctacaaaa taaaaaaata 1800
attcactggg aaaaaa
1816
<210> 80
<211> 1556
<212> DNA
<213> Homo sapiens
72/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
<220>
<221> misc-feature
<223> Incyte ID No.: 3815083CB1
<400> 80
ctcaggtccg gagcgcggtc gggacacagc gcctctagga gaaagcctgg aaggcgctcc 60
gggggtatcc agagctctta gcgggccggc agcatgtgcg gggccccagt aaatggaaat 120
gttttctaac atataaaaac ctacagaaga agaaaataat tttctggatc aaattagaag 180
tctgtattat attgatgtct ccagattcaa atatattaga aagcagccgt ggagacaacc 240
atcttcattt tgggagaaat aactaaagcc cgcctcaagc attagaacta cagacaaacc 300
ctgatgcgac ctctccagat tgtcccaagt cgattgattt cccagctata ttgtggcctg 360
aagcctccag cgtccacacg aaaccagatt tgcctgaaaa tggctcggcc aagttcaagt 420
atggcagatt ttcgaaagtt ttttgcaaaa gcaaagcaca tagtcatcat ctcaggagct 480
ggtgttagtg cagaaagtgg tgttccgacc ttcagaggag ctggaggtta ttggagaaaa 540
tggcaagccc aggacctggc gactcccctg gcctttgccc acaacccgtc ccgggtgtgg 600
gagttctacc actaccggcg ggaggtcatg gggagcaagg agcccaacgc cgggcaccgc 660
gccatagccg agtgtgagac ccggctgggc aagcagggcc ggcgagtcgt ggtcatcacc 720
cagaacatcg atgagctgca ccgcaaggct ggcaccaaga accttctgga gatccatggt 780
agcttattta aaactcgatg tacctcttgt ggagttgtgg ctgagaatta caagagtcca 840
atttgtccag ctttatcagg aaaaggtgct ccagaacctg gaactcaaga tgccagcatc 900
ccagttgaga aacttccccg gtgtgaagag gcaggctgcg ggggcttgct gcgacctcac 960
gtcgtgtggt ttggagaaaa cctggatcct gccattctgg aggaggttga cagagagctc 1020
gcccactgtg atttatgtct agtggtgggc acttcctctg tggtgtaccc agcagccatg 1080
tttgcccccc aggtggctgc caggggcgtg ccagtggctg aatttaacac ggagaccacc 1140
ccagctacga acagattcag gtttcatttc cagggaccct gtggaacgac tcttcctgaa 1200
gcccttgcct gtcatgaaaa tgaaactgtt tcttaagtgt cctggggaag aaagaaatta 1260
cagtatatct aagaactagg ccacacgcag aggagaaatg gtcttatggg tggtgagctg 1320
agtactgaac aatctaaaaa tagcctctga ttccctcgct ggaatccaac ctgttgataa 1380
gtgatggggg tttagaagta gcaaagagca cccacattca aaagtcacag aactggaaag 1440
ttaattcata ttatttggtt tgaactgaaa cgtgaggtat ctttgatgtg tatggttggt 1500
tattgggagg gaaaaatttt gtaaattaga ttgtctaaaa aaaataaaaa aaaaaa 1556
<210> 81
<211> 1951
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3988457CB1
<400> 81
ctccgattat gggataggag aagtgcccgt ggagcccctg gatgtcccct taccctccac 60
gatcaggcca gcttcccccg tggccgggtc tccaaagcag ccggtgcgtg gctactaccg 120
tggcgctgtc ggtggcacgt ttgaccgcct gcacaacgcc cacaaggtgt tgctcagtgt 180
cgcgtgcatc ctggcccagg agcagcttgt ggtgggagta gcagacaaag atctgttgaa 240
gagcaagttg ctccctgagc tgctccaacc ttatacagaa cgtgtggaac atctgagtga 300
attcctggtg gacatcaagc cctccttgac ttttgatgtc atccccctgc tggaccccta 360
tgggcccgct ggctctgacc cctccctgga gttcctggtg gtcagcgagg agacctatcg 420
tggggggatg gccatcaacc gcttccgcct tgagaatgac ctggaggaac ttgctttgta 480
ccagatccag ctgctgaagg acctcagaca tacagagaat gaagaggaca aagtcagctc 540
ctccagcttc cgccagcgaa tgttggggaa cctgcttcgg cctccatatg aaaggccaga 600
gctccccaca tgtctctatg taattgggct gactggcatc agtggctctg ggaagagctc 660
aatagctcag cgactgaagg gcctgggggc gtttgtcatt gacagtgacc acctgggtca 720
tcgggcctat gccccaggtg gccctgccta ccagcctgtg gtggaggcct ttggaacaga 780
tattctccat aaagatggca tcatcaacag gaaggtccta ggcagccggg tgtttgggaa 840
taagaagcag ctgaagatac tcacggacat tatgtggcca attatcgcaa agctggcccg 900
agaggagatg gatcgggctg tggctgaggg aaagcgtgtg tgtgtgattg atgccgctgt 960
gttgcttgaa gccggctggc agaacctggt ccatgaggtg tggactgctg tcatcccaga 1020
gactgaggct gtaagacgca ttgtggagag ggatggcctc agtgaagccg cggctcaaag 1080
ccggctgcag agccagatga gcgggcagca gcttgtggaa cagagccacg tggtgctcag 1140
73/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
cagcccttgt gggagccgca tatcacccaa cgccaggtgg agaaagcctg ggccctcttg 1200
cagaagcgca ttcccaagac tcatcaggcc ctcgactgaa aagttctcag tggggccaga 1260
ctggctcctg gagctgacaa gcgaccccgt ggtgaggaga aatgggggcc ttgatgctca 1320
ccctggttca ggcccagagg tccaagctat actgtgcagg acatggccag gcctggtgga 1380
cacaggaagc ctacccaaca cgctggtatt tggccaacac tgaggatgtg gttcatgggg 1440
gagcagtccc ctccccactc ttgcccatgg gtgactctta cccacagctg actagggcca 1500
gcgcaaatac tggaacctgt aacagaatta aaggtgaatg ttctgaaaaa aaaatagaat 1560
tttggacatc tacaactaac tcgatttaca cttacgaaca taatggactc ttaaaaaatg 1620
gaaagggata acagggaccc cccgggttct gcatccttcc tcccggggat ttttttccgg 1680
ccgggtcctt gcgggtgaac tgattttcct tacactgcgc ctatttaaac gttggggtaa 1740
ccagggtcgg accttttccc ttggaacttt ttttacccgt cacgatttcc actgcaactt 1800
agactcggga aacttagggt ggaatccctg gggggcctaa ggcgggaact ccctcccttt 1860
atctgctttg ggtcaaagag cccgtttctc catctggcaa ctctgtccat ccaaggggtt 1920
ttcgggttct cgggccaagg cccggggtgg g 1951
<210> 82
<211> 1313
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 131890CB1
<400> 82
cgtcgggagg gcctaagtcc gtgtgcggtg cccttcggcc ggcctgagcc ccagagtcag 60
ctcccctttc tcgcccagcg cccccaggcc gctcccgggg ctcacggaat agtaaagaaa 120
cacatcataa aacctcccag gacataaagg tgagcacaga ccctgtttgg atcaagtcag 180
ttcctggagc ctgaatgatg actgctgaat cacgggaagc cacgggtctg tccccacagg 240
ctgcacagga gaaggatggt atcgttatag tgaaggtgga agaggaagat gaggaagacc. 300
acatgtgggg gcaggattcc accctacagg acacgcctcc tccagaccca gagatattcc 360
gccaacgctt caggcgcttc tgttaccaga acacttttgg gccccgagag gctctcagtc 420
ggctgaagga actttgtcat cagtggctgc ggccagaaat aaacaccaag gaacagatcc 480
tggagcttct ggtgctagag cagtttcttt ccatcctgcc caaggagctc caggtctggc 540
tgcaggaata ccgccccgat agtggagagg aggccgtgac ccttctagaa gacttggagc 600
ttgatttatc aggacaacag gtcccaggtc aagttcatgg acctgagatg ctcgcaaggg 660
ggatggtgcc tctggatcca gttcaggagt cctcgagctt tgaccttcat cacgaggcca 720
cccagtccca cttcaaacat tcgtctcgga aaccccgcct cttacagtca cgaggtaaga 780
agcaaggttt catttagggg aagggaaatg attcaggacg agagtctttg tgctgctgag 840
tgcctgtgat gaagaagcat gttagtcctg ggcaacgtag cgagacccca tctctacaaa 900
aaatagaaaa attagccagg tatagtggcg cacacctgtg attccagcta cgcaggaggc 960
tgaggtggga ggattgcttg agcccaggag gttgaggctg cagtgagctg taatcatgcc 1020
actactccaa cctgggcaac acagcaagga ccctgtctca aaagctactt acagaaaaga 1080
attaggctcg gcacggtagc tcacacctgt aatcccagca ctttgggagg ctgaggcggg 1140
cagatcactt gaggtcagga gtttgagacc agcctggcca acatggtgaa accttgtctc 1200
tactaaaaat atgaaaatta gccaggcatg gtggcacatt cctgtaatcc cagctactcg 1260
ggaggctgag gcaggagaat cacttgaacc caggaggtgg aggttgcagt aag 1313
<210> 83
<211> 1197
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 238642CB1
<400> 83
cggctcgagc gtgaaccgaa gtccttatat tcccgggctt ctttctcctc tgggtaccag 60
ctccttactg ccctgcagac aagcgtgccg tgcgtgcttg tggccaaggg aaggaagagc 120
tggttgatcc acagatagct ccttcctccc cgccccttcc tttttgtttg gaggtcccag 180
74/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
gatctgtgtt cacagacatc tgggggaaga aaaggagcag gaaactaccc cgcacagagt 240
taagcaggaa acaacaacaa catcatgcaa aaaccctgca aagaaaacga aggaaagcca 300
aagtgcagcg tgccaaagag ggaggaaaaa cgcccgtatg gagaatttga acgccagcaa 360
acagaaggga attttagaca gaggctgctt cagtctctcg aagaatttaa agaggacata 420
gactataggc attttaaaga tgaagaaatg acaagggagg gagatgagat ggaaaggtgt 480
ttggaagaga taaggggtct gagaaagaaa tttagggctc tgcattctaa ccataggcat 540
tctcgggacc gtccttatcc catttaatta atttctctga caattcaatt attttctgtt 600
attaatgttg ccactgcttt ctgtttgtct gcactttctt gataaatatt tgctatcgtt 660
ttactccagt cattcgatgt tgctgagatt tacatatgac tcttgtcaac atctcatctt 720
ttgacccaat cttattcatt taataagagg tctcattcat ttgcatggaa aaatgctcat 780
tgtatattgc aaagtgaaaa taacgagttg caaaacagtg tatacatata tgtgtgtata 840
tatgtacact ttatttgtac atttctatgt gacataatgc aaaggaaagt gtctgatttt 900
attatacacc aaaggttaac agtgaatctc tgtgtgatct cttttttttt ctttttgcct 960
atctgcatct tctcacttgc caaaaaatga atatatgttt atgtgtgtat attacttgtg 1020
tcacaaaaaa ccctaaagta gacagtaaaa gaacttgtca atcgcctttg gaaggcaatg 1080
aaacacttaa taaactctca ataacagaag cgtaaaaatg aaatgtaaac ctccaattac 1140
ctctggatct cttagccaga gtaataaact ggtaattatt acagataaaa aaaaaaa 1197
<210> 84
<211> 2170
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 669862CB1
<400> 84
agcgtgcgcg ataggacagg gccttaaatt catggttatg tgtttggttt tca~,:tctaag 60
ataaagccga accactgaca aaattatata gagagcaatg tgataatgtt aggaatagag 120
atattcagga catactcctg tgcattctga tccactcagt ctgagtggat atctaaaaga 180
tagtgtatgt aaaatgctcc tatggtaatt ctgatttgca actaaatatg agaactagtg 240
actttgtctt tgcctactca taaatcttac atcctcctgt gcactttcat aattttctgt 300
gcccttcttg ccttttatat attgcttggc agtactttag aattttctaa actctttgat 360
tactaacaga tacacttttt agttgatcac tatttttaat atagatgtcc tctccctacc 420
cgctattatt ggaaaatagc atttgtttgt tttttcattt tcttccagac tttaatttca 480
caactgaaag caacaagtta tcttcagaaa aaagaaatta tgaagtaaat gcgtaccatc 540
aggagacatg gaaaagaaat aaaaccttca accttatgag gtttattttc agaactgacc 600
cacagtacac aattgaattt gggagacaac agagacctaa agtgggatgt tttagtcaaa 660
tgatattcaa aaaacataaa tcccttcctc tacataagag aaataacaca agagagaaat 720
catatgagtg taaggaatat aagaagggct ttagaaaata tttgcacctt actgaacatc 780
tgagagacca tactggtgtg ataccctatg aatgtaatga atgtggaaaa gcatttgtag 840
ttttccagca ttttattaga catcgaaaaa tccacactga tttgaaaccc tatgaatgca 900
atggatgtga gaaggccttt aggttttatt cacagcttat tcagcatcag ataattcata 960
ctggtatgaa accctatgaa tgtaagcaat gcgggaaggc ttttagacgt cattctcacc 1020
ttacagaaca tcagaaaatt catgttggct tgaaaccctt tgaatgtaag gaatgtgggg 1080
aaacgtttag attatatcga catatgtgtc tgcatcagaa aattcatcat ggtgtgaaac 1140
cctacaaatg taaagaatgt ggaaaggctt ttggtcatcg ttcaagtctt taccaacata 1200
agaaaattca ttctggtgag aaaccatata aatgtgaaca atgtgaaaag gcctttgttc 1260
gcagctatct acttgttgaa catcaaagaa gtcatactgg tgagaaacct catgaatgca 1320
tggaatgtgg aaaggctttt agtaagggct caagccttct taaacataag agaattcata 1380
gtagtgagaa actctatgat tgtaaggatt gtggaaaggc cttttgtaga ggctctcaac 1440
ttacacagca tcagagaatt catactggtg agaagccaca tgaatgtaaa gaatgtggga 1500
agacttttaa gcttcattca tatcttattc aacatcagat aattcatact gatttgaagc 1560
catatgaatg taagcaatgt gggaaagcct tcagtcgtgt tggagacctt aagacacatc 1620
aatcaattca tgctggggag aaaccctatg aatgtaagga atgtggaaaa acctttagac 1680
ttaattctca actaatttat catcagacaa ttcatactgg tttgaaaccc tatgtatgta 1740
aagaatgtaa gaaggccttt cgttctatct caggtctttc tcaacataag agaattcata 1800
ctggtgaaaa accctatgaa tgtaaagaat gtgataaggc ctttaatcgc agtgatcgac 1860
ttactcaaca tgagacaatt catactggtg tgaaaccaca gaaatgcaaa gaatgtggta 1920
aggcctttag tcattgctat caacttagtc aacatcaaag atttcaccat ggtgagagac 1980
75/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
tcttaatgta atgagaggga aagcctttag ccatggcaca tttttactgt tgtcactatt 2040
atgatgctat agtgaagatt aaactagtta atatagaata taaatacttg gaaaggcatc 2100
tggcacatcg tatttgctta ctaaatacat tatttttatg ataattgtta gaattactaa 2160
gaataaatga 2170
<210> 85
<211> 1904
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1003663CB1
<400> 85
cagctctcag gtccgacacc cgctggaagc cggcgcgggc gcaggcgcgc acgcaaaggc 60
ggccgggagt aaggcggact gaaggaggag cttgatggaa gcgtgcgaga aggggcgtaa 120
ctgatttgga aaccagagga aaggcgctgt tttcaccgaa ttagaatcgc gggaaaatag 180
agaagagttt gtttgaaggt ctcgcgagat cgagaccgga agtccttcat ctcaagcatc 240
caatgctgaa agcggcctga ttttctctac cggaagccct tttccagagg ctgggaacac 300
ggcccaccta gcaggaagtc ccacctcctt gagctccgcc acccttcccg aagtttttct 360
gtcacctgtg ttaggctccg tcccctttcc gcgttttatc cccgtaccag aaaaggatac 420
atttagtgcc tcccacccag ctccactaaa cgggttggat atctcattct ttgagttggt 480
gttccttccc cggcgccccc atgtagctgg gaagtgggac ctgggggtgg ttggacccct 540
gggatcctaa aggaggggca gggagggcgc agaactccgc ttctgctcct tgctaccagg 600
acgcgcggcc tcctcagcct ctttcctccc gctgccatgc accctgcagc cttcccgctt 660
cctgtggttg tggccgctgt gctgtgggga gcggccccga cccgggggct cattcgagcg 720
acctcggacc acaatgccag catggacttt gcagaccttc cagctctgtt tggggctacc 780
ttgagccagg agggcctcca ggggttcctt gtggaggctc acccagacaa tgcctgcagc 840
cccattgccc caccaccccc agccccggtc aatgggtcag tctttattgc gctgcttcga 900
agattcgact gcaactttga cctcaaggtc ctaaatgccc agaaggctgg atatggtgcc 960
gctgtagtac acaatgtgaa ttccaatgaa cttctgaaca tggtgtggaa tagtgaggaa 1020
atccagcagc agatctggat cccgtctgta tttattgggg agagaagctc cgagtacctg 1080
cgtgccctct ttgtctacga gaagggggct cgggtgcttc tggttccaga caataccttc 1140
cccttgggct attacctcat ccctttcaca gggattgtgg gactgctggt tttggccatg 1200
ggagcagtaa tgatagctcg ttgtatccag caccggaaac ggctccagcg gaatcgactt 1260
accaaagagc aactgaaaca gattcctaca catgactatc agaagggaga ccagtatgat 1320
gtctgtgcca tttgcctgga tgaatatgag gatggggaca agctgcgggt actcccctgt 1380
gctcatgcct accacagccg ctgcgtggac ccctggctca ctcagacccg gaagacctgc 1440
cccatttgca agcagcctgt tcatcggggt cctggggacg aagaccaaga ggaagaaact 1500
caagggcaag aggagggtga tgaaggggag ccaagggacc accctgcctc agaaaggacc 1560
ccacttttgg gttctagccc cactcttccc acctcctttg gttccttagc cccagctccc 1620
cttgtttttc ctgggccttc aacagatccc ccactgtccc ctccctcttc ccctgttatc 1680
ctggtctaat aaccccccac acatacacct ctggtgacct atttgcacag accgtcgtct 1740
tccctccagt cttctgaggg ataggggaca ttccatccca agcttctccc ttacccacac 1800
ctatcctttt gaggggcttt ggggtggggc tggggcaagc agagggactg ggtcttcact 1860
tcttgggcta ataaaattgt ttctttgtgg actaaaaaaa aaaa 1904
<210> 86
<211> 1249
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1432557CB1
<400> 86
cgtttatcct gttgggggcg gaagtgagag agcccttatt cgtattggct tagatttgca 60
agcggcagtt gtctatcaaa tctatcaagt cgcccttagc gctcaggaag tacgacaccg 120
76/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
gaaggggtgg gctttgcgaa gatggcggcg ctgggggtgc tggagtccga cctgccaagt 180
gccgtgacac ttctgaaaaa tctccaggag caagtgatgg ctgtaactgc acaagtgaaa 240
tcactgacac aaaaagttca agctggtgcc tatcctacag aaaagggtct cagcttcttg 300
gaagtgaaag accagctgct gctcatgtac cttatggatt tgacccacct cattctggac 360
aaagcctcag gaggatctct tcagggacat gatgcagttt tgagactggt agagattcga 420
acggttttgg aaaagcttcg tcccttggac caaaagctga agtatcaaat tgacaagctg 480
atcaagactg cagtgacagg cagccttagt gagaatgacc cacttcgttt taagcctcat 540
cccagcaata tgatgagcaa gttgagctct gaggatgagg aggaagatga agcagaagat 600
gaccagtctg aggcttcagg gaagaaatct gtgaagggag tgtctaagaa atatgttcct 660
ccacgcttgg ttccagtaca ttatgatgaa acagaagctg agcgggagaa gaagcgtcta 720
gaacgagcca agagacgggc attgagcagc tctgtcattc gtgaacttaa ggagcagtac 780
tcagatgctc cagaggaaat ccgtgatgct cggcatcccc atgttacccg ccagagtcag 840
gaggaccaac acaggattaa ctatgaggag agcatgatgg tgcgtttgag cgtcagtaag 900
cgagagaaag gacggcgaaa acgagcaaat gtcatgagct cacaacttca ttcccttaca 960
cacttcagtg acatcagtgc tttgacaggg ggaactgttc atcttgatga ggatcagaat 1020
cctattaaga agcggaagaa gatacctcag aaaggtcgga agaaaaaagg ttttcggagg 1080
cggcggtgat tatgggtgta catatttgta tattttttgt catcctgaga tacttctaat 1140
ttcattgtat ataggtggtt ttccctggaa ttcattaatt gtttgctttg gacatgtgga 1200
aagagcctta ctaataaaat tgattttact tatgaaaaaa aaaaaaaaa 1249
<210> 87
<211> 1064
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1441770CB1
<400> 87
cggctctcca gagcgtctgt aaacacccag agactgtcat ggagggggag gaggaggcgg 60
cggcggcgaa gggaggcgtt tggggccgcc tccagggtcc gctctgccat tcctgaactg 120
gtccctcgtc cccgtgactc tggcatcagg gaagcgaact gttaggcgag aggaggaggc 180
agccagaacc atatcccctt cttcctcggg gcgggggccg ggccaggccg gctgagccgg 240
gggagggctc cgggagggag tgcctggcca ggccggcctg tctgccgcga tggatgacag 300
taaggtggtt ggaggcaaag taaagaagcc cggtaaacgt ggtcggaagc cagccaaaat 360
tgacttgaaa gcaaaacttg agaggagccg gcagagtgca agagaatgcc gagcccgaaa 420
aaagctgaga tatcagtatt tggaagagtt ggtatccagt cgagaaagag ctatatgtgc 480
cctcagagag gaactggaaa tgtacaagca gtggtgcatg gcaatggacc aaggaaaaat 540
cccttctgaa ataaaggccc tactcactgg agaagagcag aacaaatctc agcagaactc 600
aagcaggcat accaaggctg ggaagacaga tgctaatagc aattcctggt gaagattata 660
taaagatgag tcagtgattg aagccaatat tctgattccc atggaagatg gatgggcaag 720
agtgtacttc ttggctccat ttactaccta ctgctcagta gtcatctctg taaatctgca 780
atttctacca aaatgtgtga tcgtagatct caaaggatct tgctttaact ttcaacactt 840
agaaaatcta caaacattca gacctgtctg ggttggtatt gccacccatg acatttaaca 900
tgttgtgatg cttgaaaaca caggagtaga gaaaatcgat gaagattgta tttttgcacc 960
ttaactccac attgctttat tggttaattt atattctttc catgtaattc atgtaattgt 1020
atgtctgtgt gtgttttatg tgtcaccacc tttcatgttt ttga 1064
<210> 88
<211> 1398
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1456684CB1
<400> 88
agacccaaaa gcattaagga gaaaaagaaa actacatcac ataccagggg agaaataccg 60
77/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
gaggagtcaa actatgttgc tgatcctgga ggatcactga gcaaaaccac aaatattgct 120
gaagaaacca gcaaaattga aacctacatt gcaaaacctg ctctgccggg aacctccaca 180
aatagtaatg ttgcacccct ttgccaaata acagtgaaaa ttggaaacga agccattgtg 240
aaaaggcaca ttctaggatc taaattgttt tataaaagag ggagaagacc caagtatcag 300
atgcaggagg agcctttgcc acaggggaat gacccagaac ccagtggaga cagcccactc 360
gggctttgcc aatccgagtg catggagatg agtgaagtgt tcgatgacgc aagtgaccag 420
gattccactg acaaaccgtg gcgcccttac tacaactaca aacccaaaaa gaaatccaga 480
cagttgaaaa aaatgaggaa agtcaactgg aggaaggagc acggaaacag gagcccgagc 540
cataaatgta aatacccagc agaactggat tgcgccgtgg ggaaggctcc tcaggataaa 600
ccctttgagg aagaagaaac taaagagatg cccaagctgc agtgtgaact ctgtgatgga 660
gacaaagcag tgggggctgg aaaccaagga aggccccacc gacatcttac ttctcggcca 720
tatgcctgcg agctctgcgc caagcagttc cagagccctt ccacactcaa aatgcacatg 780
agatgtcaca ccggggagaa gccataccag tgcaagacct gcggacggtg cttttcggtg 840
caaggaaact tacagaaaca tgaacgcatc cacctgggct tgaaggagtt cgtctgtcag 900
tattgcaaca aggcattcac cttgaatgag accctcaaaa tccatgaaag aatccatact 960
ggagaaaagc gttaccactg tcagttctgc tttcagagat ttttgtatct ctccaccaaa 1020
aggaatcacg agcagaggca tattcgggag cataatggga agggctatgc ctgcttccag 1080
tgccccaaaa tttgcaaaac agctgctgcc cttggaatgc accaaaagaa acacttattc 1140
aaaagcc.caa gtcagcagga gaaaataggt gacgtgtgcc acgaaaactc aaatcccttg 1200
gagaatcaac atttcattgg ttcagaagac aatgaccaaa aggataacat acaaaccggt 1260
gtggaaaatg ttgtcctttg agtggcaaga attagaaaaa tcttcaaaaa tatagttggt 1320
ggttttttta gttatgattt aagtttagtt tcattttgtc catgtgacag tcatgaagga 1380
gtgaaaaaaa aaaaaaaa 1398
<210> 89
<211> 746
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1602916CB1
<400> 89
cggctcgagg cgtctttatg ggcccccttt aaggccggcg gaggcatctc gggccgggcg 60
cggcgctccg tccgtcggcc gtagcgactg aactgcgcgc ggatccctcc gcggggctcc 120
tcgtccccgt cacgctgact ttccgtgcag tgccgtggtg cgaaaatgcc tcgccggtgc 180
gcaccggaga cagccgattt ttacgaccca gcaagaggcc gagctggtac aatatcctga 240
ctgtaaatcg tccagtggta atattggcga ggacccagac cacttaaatc agagctcgtc 300
tccttctcaa atgtttccgt ggatgagacc acaagcagct cctggtagac gaagaggaag 360
acaaacctac agtcgcttcc aaactctaga gttggaaaag gaatttcttt ttaaccccta 420
tctgaccagg aaaagaagaa tcgaggtttc ccacgcccta gccctcaccg agagacaggt 480
aaaaatctgg ttccagaaca ggagaatgaa atggaaaaag gaaaacaaca aggacaaatt 540
tcccgtttcc cggcaggagg tgaaggacgg ggaaacgaaa aaggaagccc aagagctgga 600
ggaagacaga gccgaacgct tgacaaatta acttctacct ttaaaattta ccacagacta 660
ttaaaactaa taatcaccat atgctgtgga caccacctat tttctttgtt ggaaaagacc 720
ttactgtgtt tcaagctacc ttcatg 746
<210> 90
<211> 1270
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1692816CB1
<400> 90
gttggtcacg tggttgttcg gagcgggcga gcggagttag cagggcttta ctgcagagcg 60
cgccgggcac tccagcgacc gtggggatca gcgtaggtga gctgtggcct tttgcgaggt 120
78/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
gctgcagcca tagctacgtg cgttcgctac gaggattgag cgtctccacc cagtaagtgg 180
gcaagaggcg gcaggaagtg ggtacgcagg ggcgcaaggc gcacagcctc tagacgactc 240
gctttccctc cggccaacct ctgaagccgc gtcctacttt gacagctgca gggccgcggc 300
ctggtcttct gtgcttcacc atctacataa tgaatcccag tatgaagcag aaacaagaag 360
aaatcaaaga gaatataaag aatagttctg tcccaagaag aactctgaag atgattcagc 420
cttctgcatc tggatctctt gttggaagag aaaatgagct gtccgcaggc ttgtccaaaa 480
ggaaacatcg gaatgaccac ttaacatcta caacttccag ccctggggtt attgtcccag 540
aatctagtga aaataaaaat cttggaggag tcacccagga gtcatttgat cttatgatta 600
aagaaaatcc atcctctcag tattggaagg aagtggcaga aaaacggaga aaggcgctgt 660
atgaagcact taaggaaaat gagaaacttc ataaagaaat tgaacaaaag gacaatgaaa 720
ttgcccgcct gaaaaaggag aataaagaac tggcagaagt agcagaacat gtacagtata 780
tggcagagct aatagagaga ctgaatggtg aacctctgga taattttgaa tcactggata 840
atcaggaatt tgattctgaa gaagaaactg ttgaggattc tctagtggaa gactcagaaa 900
ttggcacgtg tgctgaagga actgtatctt cctctacgga tgcaaagcca tgtatatgaa 960
atgcattaat atttgactgt tgagaatttt actgccgaag tttacctcca ctagttcttt 1020
gtagcagagt acataactac ataatgccaa ctctggaatc aaatttcctt gtttgaatcc 1080
tgggacccta ttgcattaaa gtacaaatac tatgtatttt taatctatga tggtttatgt 1140
gaataggatt ttctcagttg tcagccatga cttatgttta ttactaaata aacttcaaac 1200
tcctgttgaa cattgtgtat aacttagaat aatgaaatat aaggagtatg tgtagaaaaa 1260
aaaaaaaaaa 1270
<210> 91
<211> 943
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 1968191CB1
<400> 91
gtcccatttc cagaaatcac aaggatgtta ggcaatgaat ggagtaaact gcctcctgag 60
gaaaaacagc gctaccttga tgaagcagac agagataagg agcgttacat gaaggaactg 120
gaacagtatc agaaaacaga ggcctacaag gtcttcagta ggaaaaccca ggaccgtcag 180
aaaggcaaat ctcataggca agatgcagcc cggcaggcca ctcatgatca tgagaaagaa 240
acagaggtaa aggaacggtc tgtttttgac atccctatat ttacagagga attcttgaac 300
catagcaaag ctcgggaagc agagctccgc cagcttcgca aatccaacat ggagtttgag 360
gagaggaatg cagccctgca aaagcacgtg gagagcatgc gcacagcagt ggagaagctg 420
gaggtggatg tgatccagga gcggagccgc aacacagtct tacagcagca cctggagacc 480
ctgcggcagg tgctgaccag cagctttgcc agcatgccct tgcctggaag tggagagaca 540
cctacagtgg acaccattga ctcatatatg aacagactgc acagtattat tttagctaat 600
ccccaagaca atgaaaactt catagctaca gttcgagaag ttgtgaacag actcgatcgt 660
tagggaatgg tgagtgctca ctgataaata tttatatgcc agcacatcat caaaaataag 720
atgtcatcag actttatcaa tactactaaa accctgggat tacattggat gaacaagttg 780
gagacttggt taagattcct gttgcatggt tgttaaatgt agtaaataat attagaaaag 840
agaatcactg tagtcccagc tacttgggag gctgaggtgg gaggattgct tgagcccagc 900
agttcaagtc cagagagatc ctgtctctaa aaataaaaga aaa 943
<210> 92
<211> 1997
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2052061CB1
<400> 92
cgaccacgcg tccgctcgcg tggggcgcga ggtaccccgt ggggcagcta ggtgcctcca o0
agaaaccccg ccccagagga cccgcacgag ttgttgccat ttttcgctga agcccctgcc 120
79/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
ctgggggtgg tgttcttctc tatgattcta ccaatcgtcg gaattttttt cctcccttct 180
ttctttttag gaaggcgctg gggtgtgcgg cggaaacggc ggcggtgaag ggatcctctt 240
gtggtatctc ctccccggag aaatagggga gtgggggccc.aagaacgaga agacgagaac 300
gcgtcgccct gcgctatgtc agaatggggc gggtgtgagg ggaacagctc tcttgcgatc 360
agatcaggag tatgagcctc ccggaggacg gcatgagttc tggacacttc aggagtcctc 420
agctagtgac atggtcgata tggataaact cataaacaac ttggaggtcc aacttaattc 480
agaaggtggc tcaatgcagg tattcaagca ggtcactgct tctgttcgga acagagatcc 540
ccctgagata gaatacacaa gtaatatgac ttctccaaca ctcctggatg ccaaccccat 600
ggagaaccca gcactgttta atgacatcaa gattgagccc ccagaagaac ttttggctag 660
tgatttcagc ctgccccaag tggaaccagt tgacctctcc tttcacaagc ccaaggctcc 720
tctccagcct gctagcatgc tacaagctcc aatacgtccc cccaagccac agtcttctcc 780
ccagaccctt gtggtgtcca cgtcaacatc tgacatgagc acttcagcaa acattcctac 840
tgttctgacc ccaggctctg tcctgacctc ctctcagagc actggtagcc agcagatctt 900
acatgtcatt cacactatcc cctcagtcag tctgccaaat aagatgggtg ggctgaagac 960
catcccagtg gtagtgcagt ctctgcccat ggtgtatact actttgcctg cagatggggg 1020
gcctgcagcc attacagtcc cactcattgg gggagatggt aaaaatgctg gatcagtgaa 1080
agttgacccc acctccatgt ctccactgga aattccaagt gacagtgagg agagtacaat 1140
tgagagtgga tcctcagcct tgcagagtct gcagggacta cagcaagaac cagcagcaat 1200
ggcccaaatg cagggagaag agtcgcttga cttgaagaga agacggattc accaatgtga 1260
ctttgcagga tgcagcaaag tgtacaccaa aagctctcac ctgaaagctc accgcagaat 1320
ccatacagga gagaagcctt ataaatgcac ctgggatggc tgctcctgga aatttgctcg 1380
ctcagatgag ctcactcgcc atttccgcaa gcacacaggc atcaagcctt ttcggtgcac 1440
agactgcaac cgcagctttt ctcgttctga ccacctgtcc ctgcatcgcc gtcgccatga 1500
caccatgtga gccgcacagg tcacactaga gaagctgcgc tggtatcttt cctggtcgtg 1560
tgctgaggtt gggacaattt tttcctcttt gacttcagct tgcatatggg gttgaagcag 1620
cccactgagc caagttgagg agactggagg aaaagagagc tggtctcccg tggggctctt 1680
catattctac ctccacttct ccactgtcca gacccgtttt tttcaacccc cacatgggtt 1740
gacttccagc gtggcaccca tgggtgcctt cccatccccc cctgttctga aatagggaat 1800
ttttccccca gcaacaccac aggaatcaaa ctcaaggctg gcaaccacat ccgctgtttc 1860
ttcctcccac ttccctcttg tctctagaac tcttatccaa tgtcttaaca tcctaccaaa 1920
agggctcgat gcgttccaca gatttttcac ttcttattgc agggatacat tcgtggtcgc 1980
cacataaggg ttgcttc
1997
<210> 93
<211> 4334
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2056207CB1
<400> 93
cggtggtggt ggcgggccgg ggcatgagca ggaggaggat taccgctacg aggtgctcac 60
ggccgagcag attctacaac acatggtgga atgtatccgg gaggtcaacg aggtcatcca 120
gaatccagca actatcacaa gaatactcct tagccacttc aattgggata aagagaagct 180
aatggaaagg tactttgatg gaaacctgga gaagctcttt gctgagtgtc atgtaattaa 240
tccaagtaaa aagtctcgaa cacgccagat gaatacaagg tcatcagcac aggatatgcc 300
ttgtcagatc tgctacttga actaccctaa ctcgtatttc actggccttg aatgtggaca 360
taagttttgt atgcagtgct ggagtgaata tttaactacc aaaataatgg aagaaggcat 420
gggtcagact atttcgtgtc ctgctcatgg ttgtgatatc ttagtggatg acaacacagt 480
tatgcgcctg atcacagatt caaaagttaa attaaagtat cagcatttaa taacaaatag 540
ctttgtagag tgcaatcgac tgttaaagtg gtgtcctgcc ccagattgcc accatgttgt 600
taaagtccaa tatcctgatg ctaaacctgt tcgctgcaaa tgtgggcgcc aattttgctt 660
taactgtgga gaaaattggc atgatcctgt taaatgtaag tggttaaaga aatggattaa ?20
aaagtgtgat gatgacagtg aaacctccaa ttggattgca gccaacacaa aggaatgtcc 780
caaatgccat gtcacaattg agaaggatgg tggttgtaat cacatggtct gtcgtaacca 840
gaattgtaaa gcagagtttt gctgggtgtg tcttggccca tgggaaccac atggatctgc 900
ctggtacaac tgtaaccgct ataatgaaga tgatgcaaag gcagcaagag atgcacagga 960
gcgatctagg gcagccctgc agaggtacct gttctactgt aatcgctata tgaaccacat 1020
gcagagcctg cgctttgagc acaaactata tgctcaggtg aaacagaaaa tggaggagat 1080
gcagcagcac aacatgtcct ggattgaggt gcagttcctg aagaaggcag ttgatgtcct 1140
80/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
ctgccagtgt cgtgccacac tcatgtacac ttatgtcttc gctttctacc tcaaaaagaa 1200
taaccagtcc attatctttg agaataacca agcagatcta gagaatgcca cagaggtgct 1260
ctcgggctac cttgaacgag atatttccca agattctctg caggatataa agcagaaagt 1320
acaagacaag tacagatact gtgagagtcg acgaagggtt ttgttacagc atgtgcatga 1380
aggctatgaa aaagatctgt gggagtacat tgaggactga gaatggccct gcataaaatg 1440
aactctgaaa actttaccat ctagagtgct catgcaatta aaacaaaaca aacacaaaca 1500
aggaggcact aagcctattc tgacaccact ggtctgtagt accagaattg ttttgttaat 1560
ggaaagttta agtaaattat attgtaataa aaaggtagat aaaccattgt acaacagtat 1620
tctaggccgc caacaaaagt gtgacagaca cactaaaagc cctccaactt taacttgtaa 1680
cgtagcttca ttctcaaagc tgactccttt tttttctttt tccttttcct gagtgtagta 1740
cagttaaaat ttcaaacagc tccttgacac tgcttttcat gttcaaacca gccattttgt 1800
tgtactttgg taaaggacct cttccccttc ctcccctaca catacagata cacccacaca 1860
cagactgact ctctttctct cataccccaa ggtcatgagt gaatgatgct tagttccttg 1920
taaagaaaat cttgggatgg ggaaaggggt aggcagcaag aggattcaac aaacgaaaaa 1980
cataaaaact ttgtatatga cttttaaaac aagaggacaa cacagtattt ttcaaaattg 2040
tatatagcgc atatgcatgg acaaagcaag cgtggcacgt gtttgcataa tgtttaatta 2100
caaaaaaata tttattcttt aaaaatcttc aagattatgt ctatttgctg tgcattttct 2160
ttcagtttgc ttatctttcc cgggttgggg ttgggataaa ggtgtgtcgg tttagcacct 2220
ctggaagacc tatctagagc tctttcactt tcctgaggtt attttgccct ttctggtgtt 2280
ggtatgtctg ttgccggcca tgggcctcat gccttgaatt cctgctcttg atcagggaca 2340
agggaggtca agctctgact aatgccatga cctgattaag gggtacagca gggagttttg 2400
ttgctacagc tcatgaatta acctgtccca acctaatccc cctccatggc atcatgcctc 2460
tacccaagcc tttgtgtgcc catgttatgc acacagctgc aggcattctt aagtcccctg 2520
tcgcatccag tggaagcatt ttaaaatttc ttttactttt tggttttccc ttaattgctg 2580
cttttcagat tttagttatg gctcgtctgc tcaccccttc tctacattag ggtgtcaaag 2640
agaatgtttt gctttaaata taaatagcca ttcatttagt ctcagattgt gaatttaaaa 2700
tggtggatac cgaaattgct tgtgtgtgtt gctgtgggtt tggtttgaag gcaaacaccc 2760
ctagaacatg atattcccat ctagtgcatt taaatagaaa tcactgagtt tgctgctttt 2820
ttattgtcag cagataggag aattaataat gcattttagc tgtgatgtcc atttttatga 2880
aattcctact aagagctatg ttaaaagtaa aggatggtgg tggttgtatt aactatatac 2940
ctgtttaggc cattctggct gtggtatttt tcaataggtc agcatctgta aatctgtcag 3000
ttttat~.cag gagtgcagag tgaactaggc aactagatta agaggtctaa atatgaaata 3060
ccagttgagg ctgaggacct cttcgtcttc ctttagatgt cttttgccta gggagtgttt 3120
accatttgtg aggcagcttt gtctgctctt acactgtaca tcctattact ccattgggaa 3180
gtaggttcac tttcctctgg ccttttgcct aagttaggct ttgctgaatc aaccctactt 3240
ttccttttag aaaaggttgt tacaggagat ttactggcaa ctgttctttt cccatcaaaa 3300
atcagtgaat gtttgctgag tataaatgct gcttccttaa accacttgtc gctttaggat 3360
caactttacc tgtacctttt ctcctttcct cccttgccac ctcaggtgca aatctgaact 3420
cagtgtctgc ttcttccatt ttctcgtctc tctcccctct tcccccatta tccatatgac 3480
attattttac ttcaaatgac agcatcaatc ttaaaaagat atacattaaa actaaggagt 3540
ttttttaaag aaagcctgaa taagttcctt tccctggtaa ctttgaaaag cagtcagagt 3600
tgctatatag atatatgtgg ctcctttaaa atgctttgtg tatgtgtggt gtttaaaaaa 3660
aaaaatctta ccagttaact ttgcagtgtc taggtttgag tgtcataaat ccacgtgttc 3720
ctgttgcaac aaatacccaa aaattgtgtg tgcacttcct aataccagtc ttcacccatg 3780
gaggaacagt gctttttaga gatgctttct atttcaatgt tggcatactg cctgagggta 3840
ttgcagttgt gggtgcattc cctaatttgt atgatcaaga tgaactggcc cttttctact 3900
tccaagcttt taacagatac caccatattt gacagaattc ccagagtgaa ttgcttgtgt 3960
tattagtaga ttcagtgccc ccagctggga taggcaagcc atgacagctt ccctgtttca 4020
cctacagaag tcttatctga gggatctatt cacagtaagc accaaggtct ccatgtcttg 4080
aggtcagttt cattgtcttt tgaaaagtgc atgcttcatt tgaacaattc attcagcagc 4140
agatggactt tcagtgattt aaaataaaat tttgatccaa agctcaggac acaaaccaca 4200
gtggtaaaat tgagtagcat ataatatcag actaaattat ctgtaatttt ccacaaccca 4260
gattgtatgt gttttatgtg tgtttaaata aatatgttag atacacgtgt atacatacac 4320
ccatatacag caga 4334
<210> 94
<211> 1706
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
81/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
<223> Incyte ID No.: 2101803CB1
<400> 94
ccgcgccccg ccgccaccat gagggccgag ggcctcggcg gcctggagcg cttctgcagc 60
ccgggcaaag gccgggggct gcgggctctg cagcccttcc aggtggggga cttgctgttc 120
tcctgcccgg cctatgccta cgtgctcacg gtcaacgagc ggggcaacca ctgcgagtac 180
tgcttcacca ggaaagaagg attgtccaaa tgtggaagat gcaagcaggc attttactgc 240
aatgtggagt gtcagaaaga agattggccc atgcacaagc tggaatgttc tcccatggtt 300
gtttttgggg aaaactggaa tccctcggag actgtaagac taacagcaag gattctggcc 360
aaacagaaaa tccacccaga gagaacacct tcggaaaaat tgttagctgt gaaggagttt 420
gaatcacatc tggataagtt agacaatgag aagaaggatt tgattcagag tgacatagct 480
gctctccatc acttttactc caagcatctc gaattccctg acaatgatag cctcgtagta 540
ctctttgcac aggttaactg taatggcttc acaattgaag atgaagaact ttctcatttg 600
ggatcagcga tatttcctga tgttgcattg atgaatcata gctgttgccc caatgtcatt 660
gtgacctaca aagggaccct ggcagaagtc agagctgtac aggaaatcaa gccgggagag 720
gaggttttta ccagctatat tgatctcctg tacccaacgg aagatagaaa tgaccggtta 780
agagattctt atttctttac ctgtgagtgc caggagtgta ccaccaagga caaggataag 840
gccaaggtgg aaatccggaa gctcagcgat cccccaaagg cagaagccat ccgagacatg 900
gtcagatatg cacgcaacgt cattgaagag ttccggaggg ccaagcacta taaatcccct 960
agtgagctgc tggagatctg cgagctcagc caggagaaga tgagctctgt gtttgaggac 1020
agtaacgtgt acatgttgca catgatgtac caggccatgg gtgtctgctt gtacatgcag 1080
gactgggaag gagccctgca atatggacag aaaatcatta agccctacag taagcactat 1140
cctttgtact ccctcaacgt ggcctccatg tggttgaagc tagggagact ctacatgggc 1200
ctggaacaca aagccgcagg ggagaaagcc ctgaagaagg ccattgcaat catggaagta 1260
gctcacggca aagatcatcc atatatttct gagatcaaac aggaaattga aagccactga 1320
aactatgcag catttcagtt ttcatttaaa cacttagttc agaaacctta aaggatttga 1380
atatttcaaa ttgcacacgt cactccagca tctctgtaaa ataattggaa tgaaaatact 1440
tcttgcactt aaacactgca catgccgtac tttgaggtta gtctgaatct tgaactttaa 1500
taccaaatta attttgaatg cttttgtttc ctaagagata atggcatggt ttcatatgtt 1560
atactttgga cagacagagt tttaaaaatg gaattatttt ttctttcatg cctcttgtaa 1620
tgttctgaac aaacttgaat gatgaaagta ttaaagagat atcagtaaaa agaacaaaaa 1680
ataaagatcc agaaagaaaa aaaggg 1706
<210> 95
<211> 1602
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2112362CB1
<400> 95
ccgtggggca gtcgaggatg tcggtgaatt acgcggcggg gctgtcgccg tacgcggaca 60
agggcaagtg cggcctcccg gagatcttcg accccccgga ggagctggag cggaaggtgt 120
gggaactggc gaggctggtc tggcagtctt ccaatgtggt gttccacacg ggtgccggca 180
tcagcactgc ctctggcatc cccgacttca ggggtcccca cggagtctgg accatggagg 240
agcgaggtct ggcccccaag ttcgacacca cctttgagag cgcgcggccc acgcagaccc 300
acatggcgct ggtgcagctg gagcgcgtgg gcctcctccg cttcctggtc agccagaacg 360
tggacgggct ccatgtgcgc tcaggcttcc ccagggacaa actggcagag ctccacggga 420
acatgtttgt ggaagaatgt gccaagtgta agacgcagta cgtccgagac acagtcgtgg 480
gcaccatggg cctgaaggcc acgggccggc tctgcaccgt ggctaaggca agggggctgc 540
gagcctgcag gggagagctg agggacacca tcctagactg ggaggactcc ctgcccgacc 600
gggacctggc actcgccgat gaggccagca ggaacgccga cctgtccatc acgctgggta 660
catcgctgca gatccggccc agcgggaacc tgccgctggc taccaagcgc cggggaggcc 720
gcctggtcat cgtcaacctg cagcccacca agcacgaccg ccatgctgac ctccgcatcc 780
atggctacgt tgacgaggtc atgacccggc tcatgaagca cctggggctg gagatccccg 840
cctgggacgg cccccgtgtg ctggagaggg cgctgccacc cctgccccgc ccgcccaccc 900
ccaagctgga gcccaaggag gaatctccca cccggatcaa cggctctatc cccgccggcc 960
ccaagcagga gccctgcgcc cagcacaacg gctcagagcc cgccagcccc aaacgggagc 1020
ggcccaccag ccctgccccc cacagacccc ccaaaagggt gaaggccaag gcggtcccca 1080
gctgaccagg gtgcttgggg agggtggggc tttttgtaga aactgtggat tctttttctc 1140
82/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
tcgtggtctc actttgttac ttgtttctgt ccccgggagc ctcagggctc tgagagctgt 1200
gctccaggcc aggggttaca cctgccctcc gtggtccctc cctgggctcc aggggcctct 1260
ggtgcggttc cgggaagaag ccacacccca gaggtgacag ctgagcccct gccacacccc 1320
agcctctgac ttgctgtgtt gtccagaggt gaggctgggc cctccctggt ctccagctta 1380
aacaggagtg aactccctct gtccccaggg cctcccttct gggcccccta cagcccaccc 1440
tacccctcct ccatgggccc tgcaggaggg gagacccacc ttgaagtggg ggatcagtag 1500
aggcttgcac tgcctttggg gctggaggga gacgtgggtc caccaggctt ctggaaaagt 1560
cctcaatgca ataaaaacaa tttctttctt gcaaaaaaaa as 1602
<210> 96
<211> 1951
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2117346CB1
<400> 96
gaggcgcgcg cgaccggcgg ctctttggcg cggattaggg ggtctcggcg agggagtcat 60
caagctttgg tgtatgtgtt ggccggttct gaagtcttga agaagctctg ctgaggaaga 120
ccaaagcagc actcgttgcc aattagggaa tggaccgttt gggttccttt agcaatgatc 180
cctctgataa gccaccttgc cgaggctgct cctcctacct catggagcct tatatcaagt 240
gtgctgaatg tgggccacct ccttttttcc tctgcttgca gtgtttcact cgaggctttg 300
agtacaagaa acatcaaagc gatcatactt atgaaataat gacttcagat tttcctgtcc 360
ttgatcccag ctggactgct caagaagaaa tggccctttt agaagctgtg atggactgtg 420
gctttggaaa ttggcaggat gtagccaatc aaatgtgcac caagaccaag gaggagtgtg 480
agaagcacta tatgaagcat ttcatcaata accctctgtt tgcatctacc ctgctgaacc 540
tgaaacaagc agaggaagca aaaactgctg acacagccat tccatttcac tctacagatg 600
accctccccg acctaccttt gactccttgc tttctcggga catggccggg tacatgccag 660
ctcgagcaga tttcattgag gaatttgaca attatgcaga atgggacttg agagacattg 720
attttgttga agatgactcg gacattttac atgctctgaa gatggctgtg gtagatatct 780
atcattccag gttaaaggag agacaaagac gaaaaaaaat tataagagac catggattaa 840
tcaaccttag aaagtttcaa ttaatggaac ggcggtatcc caaggaggtc caggacctgt 900
atgaaacaat gaggcgattt gcaagaattg tggggccagt ggaacatgac aaattcattg 960
aaagccatgc attggaattt gaactccgaa gggaaatcaa gaggctccaa gaatacagga 1020
cagcaggcat taccaatttt tgtagtgcca gaacctacga tcacctcaag aagacacggg 1080
aggaagagcg ccttaaacgc actatgctct cagaagttct ccagtatatc caggacagta 1140
gtgcttgcca gcagtggctc cgccggcaag ctgacattga ttccggcctg agtccttcca 1200
ttccaatggc ttcgaattca ggtagacgga gtgcaccacc cttgaacctc actggcctcc 1260
ctggcacaga gaagctgaat gaaaaagaaa aggagctctg tcagatggtg aggttggtcc 1320
ctggagccta tttagaatac aaatctgctc tattgaacga atgtaacaag caaggaggct 1380
taagactggc gcaggcaaga gcactcatca agatagatgt gaacaaaacc cggaaaatct 1440
atgatttcct catcagagaa ggatacatca ctaaaggcta aggctccaag agcttgggat 1500
cagaagtcag aagtttggaa tgtggtgggt caaaggacaa tatgggtggg cattctggag 1560
agttgttttt cagctgaatt ctcatggtga aaacagggga aaggacaaag gaaaccttaa 1620
gttgtattgt ctactttctt ctccatcctg ctttaaaaca ctcctgttgt tggtattatg 1680
ctgcagagtt gtgtgctaca taagctatta ttaaatgtga gtgggcattc attcctaaca 1740
cctcttgtaa ctaaaagacc catagtaccc tcacatcaca gtgcctggga gaaattggac 1800
ctaaacccac agtctgtaaa tcccaggagt tcaagcctag aatccttaat attgtccggg 1860
gaaaggtttt tctgaataaa acacggcttt ggcctttaaa aaaactttgg ggaaacgaat 1920
tttaaaaatt aaaagggaaa agggtttttt a 1951
<210> 97
<211> 854
<212> DNA
<213> Homo sapiens
<220>
83/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCTNS00/02237
<221> misc-feature
<223> Incyte ID No.: 2119917CB1
<400> 97
cccacgcgtc cgcggacggt gggcgcgcgc tatgacggcc agcgcacagc cgcgcgggcg 60
gcggccagga gtcggagtcg gagtcgtggt gaccagctgc aagcatccgc gttgcgtcct 120
cctggggaag aggaaaggct cggttggagc tggcagtttc caactccctg gaggtcatct 180
ggagttcggt gaaacctggg aagaatgtgc tcaaagggaa acctgggaag aagcagctct 240
tcacctgaaa aatgttcact ttgcctcagt tgtgaattct ttcattgaga aggagaatta 300
ccattatgtt actatattaa tgaaaggaga agtggatgtg actcatgatt cagaaccaaa 360
gaatgtagag cctgaaaaaa atgaaagttg ggagtgggtt ccttgggaag aactacctcc 420
cctggaccag cttttctggg gactgcgttg tttaaaagaa caaggctatg atccatttaa 480
agaagatctg aaccatctgg tgggatacaa aggaaatcat ctctaggtgg ccgagaagat 540
ttgattttct ttaaaaagac aagaataagg tctggttagg gaatgaaaaa tgtatacatt 600
tcggaacaac tccattttat ctaaaaaagt tcttgtgatt gccagtttat ttgcagtctc 660
ttaatgtatc ccccactctt tcagccagta cttgagaaaa tttttctgaa atatgtcatt 720
gaattgtatt ccagacacag aatacatgat aaatactgat attatgggta atctgctttc 780
catatttacc tatggatatg tacgtgcaat gtgccataac tagttgagag ggtgggtgag 840
gcagattttc cttt 854
<210> 98
<211> 1581
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2123456CB1
<400> 98
tccgggaaag tttctttgga ggtccggccc ggagcggcca tgtcccacgg ccccaagcag 60
cccggcgcgg ccgccgtgcc ggcgggcggc aaggctccgg gccagcatgg gggcttcgtg 120
gtgactgtca agcaagagcg cggcgagggt ccacgcgcgg gcgagaaggg gtcccacgag 180
gaggagcccg gttctgcagc cggtgaagaa acgcggctgg cccaagggca agaagcggaa 240
gaagattctg ccgaatgggc ccaaggcacc ggtcacgggc tacgtgcgct tcctgaacga 300
gcggcgcgag cagatccgca cgcgccaccc ggatctgccc tttcccgaga tcaccaagat 360
gctgggcgcc gagtggagca agctgcagcc aacggaaaag cagcggtacc tggatgaggc 420
cgagagagag aagcagcagt acatgaagga gctgcgggcg taccagcagt ctgaagccta 480
taagatgtgc acggagaaga tccaggagaa gaagatcaag aaagaagact cgagctctgg 540
gctcatgaac actctcctga atggacacaa gggtggggac tgcgatggct tctccacctt 600
cgatgttccc atcttcactg aagagttctt ggaccaaaac aaagcgcgtg aggcggagct 660
tcggcgcttg cggaagatga atgtggcctt cgaggagcag aacgcggtac tgcagaggca 720
cacgcagagc atgagcagcg cgcgcgagcg tctggagcag gagctggcgc tggaggagcg 780
gaggacgctg gcgctgcagc agcagctcca ggccgtgcgc caggcgctca ccgccagctt 840
cgcctcactg ccggtgccgg gcacgggcga aacgcccacg ctgggcactc tggacttcta 900
catggcccgg cttcacggag ccatcgagcg cgaccccgcc cagcacgaga agctcatcgt 960
ccgcatcaag gaaatcctgg cccaggtcgc cagcgagcac ctgtgaggag tgggcgggcc 1020
cacgatgcag aggagaagct gtgggcgcgg ccctgccaca ccccaccccg tggacgagag 1080
gctgggggtc caccctttgg ggcctggtcc catcctgcac cttgggggct ccagcccccc 1140
taaaattaaa tttctgcagc atccctttag ctttcaatct ccccagcccc ctgaacccgg 1200
aaaaagcact cgctgcgcga tacacccaga agaacctcac agccgagggt gcccctcctc 1260
ggaggacagc cacgcgctac actggctctc cgggccaccc ccaggacaca gggcagacga 1320
aacccacccc cagcacacgg caggaccccc caaattactc actacggggg gctgtgccat 1380
aggccacaca ggaagctgcc ttgtggggac ttacctgggg tgtcccccgc atgcctgtac 1440
cccagatggg tgggggccgg ctttgcccat cctgctctcc tccagccgag ggaccctggt 1500
gggggtggct ccttctcact gctggatccg gactttttaa ataaaaacaa gtaaaatttg 1560
tgttttaaaa aaaaaaaaaa a 1581
<210> 99
<211> 2150
84/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00144900 PCT/US00/02237
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2148792CB1
<400> 99
gtctcgatct cctgacctcg ccatccaccc gcctcagcca cccgaagtgt tgggatttca 60
ggggccaaat agttgcatca catgtatcta atccgagagt ctcatgcttc tggtagctcc 120
tcagtgacca gctcctgctc actgccctca gaaagcccaa ccctcaggca atggcggcct 180
tgttcctgtc tgccccaccc caggccgagg tgaccttcga ggacgtggct gtgtacctct 240
cccgggagga atggggccgc ctgggccctg ctcagagggg cctctacagg gacgtgatgc 300
tggagaccta cgggaaccta gtctcactgg gagtaggacc tgcaggcccc aagcctggag 360
tgatctcgca gttggagcga ggggatgagc cctgggtcct ggatgttcag ggcacctctg 420
ggaaagagca cctgagagtc aacagcccag ctcttgggac cagaactgag tacaaggagt 480
tgacttcaca ggagacattt ggtgaggaag atccccaggg atctgagcca gtagaagcct 540
gtgaccacat cagtaagtca gaggggagcc tggaaaagct agtggagcag agaggcccca 600
gggcagtcac actgaccaac ggggagagca gcagggagtc tgggggaaac ctcaggttgc 660
tgtcaagacc tgttcctgat cagagacctc acaaatgtga tatatgtgag caaagttttg 720
aacagagatc atatctcaac aaccataagc gtgtacacag gtcaaaaaaa acaaatacag 780
ttcgtaactc tggggaaatc ttcagtgcaa acttagttgt taaagaagat cagaaaattc 840
ctactgggaa aaaattgcat tattgcagtt actgtgggaa aacattcagg tacagtgcca 900
accttgtcaa gcatcagcgg cttcacactg aagagaagcc ctacaaatgt gatgagtgtg 960
ggaaagcctt cagccagagc tgcgagttca tcaatcaccg aaggatgcac tcaggagaga 1020
ttccctaccg gtgtgacgag tgtgggaaga cattcacccg gaggcccaac ctcatgaagc 1080
accagaggat tcacactggg gagaaaccct acaagtgtgg ggagtgtggg aagcacttta 1140
gcgcctactc ttccctgatt tatcaccaga gaatccacac cggagagaaa ccctataaat 1200
gtaatgactg cgggaaagcc ttcagtgatg gctcaatcct tatccgacat cgtcggactc 1260
acaccggaga gaagccattt gagtgcaagg aatgtggcaa aggctttaca caaagttcta 1320
accttatcca acatcagaga attcacactg gagagaaacc ctataaatgt aatgaatgtg 1380
agaaagcttt cattcaaaaa accaaactcg tggaacatca gagaagccac actggagaga 1440
agccctatga atgcaatgac tgtggcaaag ttttcagcca aagcacacac ctcatccagc 1500
accagagaat ccacacagga gagaagccct acaagtgcag cgagtgtggg aaagccttcc 1560
acaacagttc cagactcatc caccaccaga ggctgcacca cggagagaaa ccctacagat 1620
gcagcgattg caagaaagcc ttcagccaga gcacgtactt gattcagcac cggaggatcc 1680
acaccgggga gaagccctac aagtgcagcg agtgtgggaa ggccttccgg cacagttcca 1740
acatgtgtca gcatcagcgg attcacctcc gggaggactt ctccatgtaa cagtggcgcg 1800
gtgtccgagg gcagagtcca gctgagcact tcctgcatgc gcccccggca cctgactctg 1860
ccctttatgt attatccaca cgatgttttc acagagtgaa aggacgtttc tcattaaaca 1920
aacctctttt cttaaatcaa aaaaaaaaaa agggggggcc gctttagggg tcccaggggt 1980
tcccaacccc taatcctaaa caatgtaata gctgttcccg gtgtaaaatt gttagcggcc 2040
caaaattccc tggcaaatta tcgaaccggg aatccttaaa tgtttaaaac ccccggggtg 2100
gcccccaaaa agggttgact cgaaacttcc acattaaaat tcgggggggg 2150
<210> 100
<211> 691
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 2751943CB1
<400> 100
cggcgccgga gcgggcgtca tggcgcggct cctctggttg ctccggggcc tgaccctcgg 60
aactgcgcct cggcgggcgg tgcggggcca agcgggcggc ggcgggcccg gcaccgggcc 120
gggactgggg gaggcagggt ctcttgcaac gtgtgagctg cctcttgcca agagtgagtg 180
gcaaaagaaa ctaaccccgg agcagttcta cgtcacaaga gaaaagggaa cggaaccgcc 240
tttcagtggg atctacctga ataacaagga agcaggaatg tatcattgcg tgtgctgcga 300
cagtccactc ttcagttctg agaaaaagta ctgctctggc actgggtggc cttcgttttc 360
cgaggctcat ggtacgtctg gctctgatga aagccacaca gggatcctga gacgtctgga 420
85/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
tacctcgtta ggatcagctc gcacagaggt tgtctgcaag cagtgtgaag ctcatctagg 480
tcacgtgttt cctgatggac ctgggcccaa tggtcagagg ttttgcatca acagtgtggc 540
tttgaagttc aaaccaagga aacactgacc atcttcaaga gtcccgttcc cttgccaccc 600
cttcacgtgc accctcaatt tccacaattc acttgaatga cttgttttat ttgcaataaa 660
actgggctga atttgcaaaa aaaaaaaaaa a 691
<210> 101
<211> 2101
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3128913CB1
<400> 101
gtggcttgca gctcggggtg ggtggctcat ttcctggccg ctcctgggct tcgcggaaag 60
aagagattac tcacactcct tctcaagcac agaaccagtt gtactgagct ttttgctaag 120
ctgtttcagc caagaatggc tgtggaatct ggagtgattt caaccctgat acctcaggat 180
cctccggaac aagaactaat actagtgaaa gtagaagata acttttcctg ggatgagaaa 240
tttaagcaga atgggagtac tcaatcctgc caagaattgt ttcgtcagca attcagaaaa 300
ttttgctacc aggagacacc tgggccccgg gaggctctga gccgactcca ggaactttgc 360
tatcagtggc taatgccaga gttgcacaca aaggagcaga tcttagaact gctggtactg 420
gagcagttcc tgagcattct gcctgaggag ctgcagatct gggttcagca acataatcca 480
gaaagcggcg aggaagctgt gaccctgttg gaggatttag agagggagtt tgatgaccca 540
gggcagcagg tcccagctag tccacaggga ccagcagtgc catggaagga tttaacatgt 600
ctcagagcat cccaagagtc aacagacatc cacctccagc ccttaaagac acagctgaaa 660
tcctggaaac catgcctttc ccctaaaagt gattgtgaga acagtgaaac agcaacaaaa 720
gagggcatct cagaagaaaa atcacaggga ctccctcagg aaccttcatt tcgaggaatt 780
agtgagcatg aaagcaattt agtgtggaag caaggaagtg ctacagggga gaaactaaga 840
tctccttccc aagggggcag ttttagtcaa gtgatcttca caaacaaatc tctaggaaag 900
agagaccttt atgatgaggc tgaaagatgc ttgattctaa ctacagactc tataatgtgt 960
cagaaagttc ctccagaaga gagaccttat agatgtgatg tatgtgggca cagcttcaag 1020
cagcattcct ctctaacaca acatcagaga atccatactg gagaaaagcc ctataaatgt 1080
aaccagtgtg ggaaggcctt tagtttgagg tcctatctta ttattcatca gagaattcat 1140
agtggtgaga aagcatatga atgtagtgaa tgtgggaaag ctttcaatca gagctcagcc 1200
ctcattagac atcggaaaat ccatactggt gagaaagctt gtaaatgtaa tgagtgtggc 1260
aaagcattca gtcaaagttc atatctcatt atacatcaaa gaattcacac tggtgagaaa 1320
ccttatgagt gtaatgaatg tgggaaaacc tttagccaga gctcaaaact cattagacat 1380
cagcgaattc acacaggaga gagaccctat gaatgtaatg aatgtggaaa agctttcagg 1440
cagagctcag agctgattac tcatcagaga atacatagtg gagagaaacc ctatgaatgt 1500
agtgaatgtg gaaaagcttt cagtttgagc tcaaacctta tcagacatca gagaattcat 1560
agtggggagg aaccttatca gtgtaatgaa tgtggcaaaa ctttcaaaag gagctcagcc 1620
cttgttcagc atcagagaat tcattctggg gatgaagctt atatatgtaa tgaatgtggg 1680
aaggctttca ggcacagatc ggtccttatg cgccatcaaa gagtccacac tataaagtaa 1740
tttgtgaata ctgtgaatag tgtaaatact tcagtcagat ttttaagttt gttagtcaaa 1800
agagtttact ttggagcaaa actccataaa ggttataaaa tactaggtct tgagtctagc 1860
ttgctttgtg cagcatttcc cagtgctaat gtaaagtgtc ccttgaaagc ttttcctgtg 1920
actaatcaga acagaataca gaagaatcat tacttccagc tcttctctta ttaggaatac 1980
tcaggaaata cgaaaagtgg gaatgtaaca ttgaaacctc attttgtatg aaagtgtcat 2040
gaatatagca acccaggctc tgtcactgca tctgattgtt agtgtgccag gttatggggg 2100
g 2101
<210> 102
<211> 2196
<212> DNA
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3282941CB1
86/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02Z37
<400> 102
cctactttct ctagaccaga aaattcccaa aattgtgcac attagaatca cgtgggtagc 60
ccacaaaatt cccagtgcca aattataacc tgcctttcct gtggcccagt ggtttccaac 120
gacattgggc cctcggtctg agaagtgcct ataatactgg cttacatggc cctcaggctg 180
aaccttggac gtggcaggta ttgcaaatat tttccgcggt gcgcgcggat tctggacttg 240
ggcgccaact cgtagtccac gctccccggg gtcagcagag gggcgtcacg ctctcgccac 300
ccacctcgct ttctcacccc gcgcttcccg gcctgggttt ttagtcttcc ttggagcgct 360
ctctggcctc cgcctccgcc agggagcgga aggcggagac agcgagactg gccagggggg 420
aggaaagagg acgcgtgtgg gcaaggggga caacgggatg tccacgggct cggtgagtga 480
tccggaggag atggagcttc gggggctgca gcgggagtac ccggtccccg cctccaagag 540
gccgcccctc cgcggcgtag agcgcagcta cgcctcgccc agtgacaact cgtcggcaga 600
ggaggaggac cccgacggcg aggaggagcg ctgcgctctg ggcacagccg gcagcgcgga 660
aggctgcaag aggaagcggc cccgtgtggc tgggggcggc ggcgcaggtg gtagcgcggg 720
cggtggtggc aagaagcccc tcccggccaa gggctcagcc gcagagtgca agcagtcgca 780
gcggaacgcg gccaacgccc gtgagcgtgc ccggatgcgc gtgctgagca aagccttctc 840
caggctcaag accagcctgc cctgggtgcc ccccgacact aagctctcca agctggacac 900
gctccggctg gcttccagtt acatcgctca cctgcggcag ctgttgcagg aggaccgcta 960
tgagaacggc tacgtgcacc cagtgaacct gacatggcca ttcgtggtct cgggaagacc 1020
ggactctgac accaaagaag tttccgcagc caacagacta tgtggaacca ccgcttaaat 1080
cggactggaa ctcacttgat gggattattc gttaaatgcg agtgtttggg ggccacggag 1140
agaagggaga gctcgtgaga tgggaagaag tttccgctgg attctccttg acccttcccc 1200
tttccctgga actgtgatcg tgacaggtgg cgggtgtggc tgtcactgca cagcgcccac 1260
ggctacagct gcgccggatc tgggcgacca cgttttgcct ctccaaaaag agcttccttt 1320
cgtgacgaga cgcggacgca ggtccaccct cgggccctag ctctgtagac taactctcgg 1380
ctgctgcccc agcccgcgcc agacagccca cggatccgtt ctcagcggac gcagattcat 1440
cgcacacgtg cgggacggtt ccacacagcc ccggcctttc gcggtgacac aatggttagg 1500
gaacggttag aacgcgctct acatccgctt taaagacaga ggtctagacg tgagatccgc 1560
gtcgggacag ggttttaagt gacaaagaag ggcgagtggc ttctctgggc cgggttcgta 1620
ctccagcaca gcgcccttct aacgggcggg aggaaggccg ctgctcgcag ggctaggtgg 1680
agacacactt cccagatcac cgcaggcggg ttttacccgg agagctctgg gccgttcggc 1740
ctccctgccg ggtggcttct tcaatcccgt ctccttccca agctcccggc tttttctaat 1800
caggcaggcg tctgtcaacc ctctccactt ctgggctgaa gcctccccaa gccccgctgc 1860
gccaacctgt gtggggtctt cttcgggcct ccctctccgc cccgctcctg ctcctacctg 1920
cagcaccccc agctccgact ccagactctc tgcatcaggt ctccccactc cacgctccgg 1980
gcgccccaac tccaacacca cgtcctgccg cgcaggttct tccccgcgcg gaggagcgcg 2040
cagggtgggc ggcttaccat agcaagtgat cctgcgatag ggaacgcgcc cttgccccga 2100
ggctgcacta ccacaggaaa taacatatgt aaataaattt atttttttat gaataataaa 2160
acgcgctgta aaaaccgtga aaaaaaaaaa aaaagg 2196
<210> 103
<211> 749
<212> DNA
<213> Homo sapiens
<220>
<221> unsure
<222> 735, 736, 741
<223> a or g or c or t, unknown, or other
<223> Incyte ID No.: 3286656CB1
<400> 103
gctgagctgt gctgcgcggc gcggcgcggc gcggtgcggc acggcacggt gggagtgtct 60
ccggctggct tgcagggaga acaccgactg agacctcaaa ccctggctcc agtgtcatgg 120
aatccgtcac ctttgaggat gtggccgtgg agttcatcca ggagtgggca ttgctggaca 180
gcgcacggag gagcctgtgc aaatacagga tgcttgacca gtgcaggacc ctggcctcca 240
ggggaactcc accatgcaaa cccagttgtg tctcccagct ggggcaaaga gcagagccaa 300
aggcaacaga acgagggatt ctccgtgcca caggtgttgc ctgggaatct caacttaaac 360
ccgaagagtt gccttctatg caggatcttt tggaagaagc atcctccagg gacatgcaaa 420
tggggccggg gctgttcctg aggatgcagc tggtgccctc catagaagag agggagacac 480
cattgactcg agaggaccgg ccagctctcc aggagccgcc ttggtctctg ggatgcacgg 540
gactgaaggc cgctatgcag attcagaggg tggtgatacc agtgcctact ctgggccacc 600
gcaacccatg ggtggccagg gattctgcca tgtagcacgt gcctgcttcc cctttgcctt 660
87/91
SUBSTITUTE SHEET (RULE Z6)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
ccgccatgat tgtaagtttc tcgagtcctc cccagccatg cgtcctgtac aacctgtgga 720
accaggcagc caaanncagt natagttgt 749
<210> 104
<211> 1311
<212> DNA
<213> Homo sapiens
<220>
<221> unsure
<222> 1294
<223> a or g or c or t, unknown, or other
<223> Incyte ID No.: 3490802CB1
<400> 104
gggcctttgt ttctcgctgc agcgggagct ccaggtttat cctctgtgtt ctgtgtcctg 60
tgcttataga ggcccgtcct ctgtggccgt gtgacctgca agtattggga gagccacagc 120
taaaccccgg gacccctgga agcctagaaa tgggaccatt gcaatttaga gatgtggcca 180
tagaattctc tctggaggag tggcattgcc tggacactgc acagcggaat ttatataggg 240
atgtgatgtt agagaactac agaaacttgg tcttccttgg tattgttgtc tctaagccag 300
acctggttac ctgtctggag caaggaaaaa aacctttaac tatggaaaga catgagatga 360
ttgccaaacc cccagttatg agttctcatt ttgcccaaga cctttggcca gagaacatac 420
aaaattcttt ccaaataggg atgctgagaa gatatgaaga atgcagacat gacaatttac 480
agttaaaaaa aggctgtaaa agcgtgggtg agcataaggt gcacaaagga ggttataatg 540
gacttaacca atgtttgaca actacccaga aagaaatatt tcaatgtgat aaatatggaa 600
aagtctttca taagttttca aattcaaaca catataagac aagacatact ggaataaatc 660
ttttcaaatg tataatatgt ggcaaagctt ttaaacggtc ctcaaccctt actacacata 720
agaaaattca tactggagag aaaccttaca aatgtgaaga atgtggcaaa gcttttaacc 780
aatcctcaaa ccttactaca cataagagaa ttcatactgg agagaaacct tacaaatgtg 840
aagaatgtgg caaagctttt aactggtcct cagaccttaa taaacataag aaaattcata 900
ttgaacgaaa accctacata gtgaagaatg tgacagatct tttaaatgtt cctccacttt 960
taattagcat aagataattc atactggaga gaaaccctat gaatgtgatg aatgtgggaa 1020
agcctttaac cagccctcga ctcttagtaa atttgagagt ttatatggaa cacaaaccct 1080
acaaatataa agaatgtgac aaagcttttt aaggaagttc tcaaccctta ttacacataa 1140
ttcataccaa acagaagccc tacaagtgtg aagaatgtgg caaaacctat aaacctataa 1200
caagttctca attccttttt ttttgagatg gagtttcact cttgtcaccg aggcagaggt 1260
tgcagtgagc actccagtct aggcgacaga gtangccttg tcgcgatccc a 1311
<210> 105
<211> 990
<212> DNA
<213> Homo Sapiens
<220>
<221>
<223> Incyte ID No.: 3507366CB1
<400> 105
caaaaaggaa agaataaggc aaattcttag aatgtatgca caacttaata tccttgctcg 60
tttgatgtgc attgatctca tttaataggt ttttgaatct gaaaattcaa gaaggtgaag 120
ctcacaacat tttttgccct gcatatgatt gcttccaact tgtacctgtg gatatcatag 180
aaagtgtagt ttcaaaggag atggacaaac gatacctaca gtttgatatt aaggcctttg 240
ttgaaaataa tcctgccatt aaatggtgtc ctactccagg ctgtgacaga gcagtaagac 300
taacgaaaca agggtcaaat acatctggat ctgatacact cagcttccca ttgctgagag 360
ctcctgctgt tgattgtgga aaaggacacc tcttctgctg ggagtgcctt ggtgaagcac 420
atgagccttg tgactgccaa acatggaaga attggctgca aaaaataacc gaaatgaaac 480
cagaagaact tgtgggagtt agtgaagcct acgaggatgc cgccaattgt ctctggttat 540
taactaactc caagccttgt gccaactgta agtctccaat acagaagaat gaaggctgca 600
atcacatgca gtgtgctaag tgcaagtatg acttttgctg gatttgcctt gaagagtgga 660
aaaaacatag ttcgtccact ggaggttatt acagatgtac tcgctatgaa gtcattcaac 720
acgtggagga gcaatccaag gaaatgactg tggaggctga gaaaaaacac aaacgatttc 780
8 8/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
aggaacttga cagatttatg cactattata caagatttaa aaaccatgag catagttatc 840
agctagaaca acgccttctt aaaacagcca aagaaaagat ggagcaaatg agcagagtct 900
caaagaactg aaggaggctg tccagatacc actttcattg gagatgagtt catgtgctct 960
aaaaatcggc gcatctcaag tgtcttatca 990
<210> 106
<211> 1048
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3573060CB1
<400> 106
ccgctgcagc tctccgcggg acatctcacc gttctggaga cagggctcgc tcgctctcac 60
ggcttcttag gccggggttg gacagccgcc ttccggccag aggggatgag gttgcgctgc 120
gctccgggag cgccgatggc gtgactggcc ccgcgcggag cagcgacact gcccggccag 180
cccgcttctc tgcccggagc catgaatctc agtagcgcca gtagcacgga ggaaaaggca 240
gtgacgaccg tgctctgggg ctgcgagctc agtcaggaga ggcggacttg gaccttcaga 300
ccccagctgg aggggaagca gagctgcagg ctgttgcttc atacgatttg cttgggggag 360
aaagccaaag aggagatgca tcgcgtggag atcctgcccc cagcaaacca ggaggacaag 420
aagatgcagc cggtcaccat tgcctcactc caggcctcag tcctccccat ggtctccatg 480
gtaggagtgc agctttctcc cccagttact ttccagctcc gggctggctc aggacccgtg 540
ttcctcagtg gccaggaacg ttatgaagca tcagacctaa cctgggagga ggaggaggaa 600
gaagaagggg aggaggagga agaggaagag gaagatgatg aggatgagga tgcagatata 660
tctctggagg agcaaagccc tgtcaaacaa gtcaaaaggc tggtgcccca gaagcaggcg 720
agcgtggcta agaaaaaaaa gctggaaaaa gaagaagagg aaataagagc cagcgttaga 780
gacaagagcc ctgtgaaaaa ggccaaagcc acagccagag ccaagaagcc aggattcaag 840
aaatgaggag ccacgccttg gggggcacgg tgcaaagtgg gccttccctg ggctgtgctg 900
caggcacagg gtgcccctgt ccagcccctc cacctgtgtc tgaatgcaac aggggtgttg 960
cgggggcaac atgagagccc ctcaccccca actctccact ttcaggaggc ccccagtgaa 1020
gagccccacc tcgggtcaca ataagtgt 1048
<210> 107
<211> 1349
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3573661CB1
<400> 107
gagaaagcag agctatttca agagtgagcc acagaaggga atccagaggc catctaagcg 60
aggaagggtc tacaggcagt gagtgaaggc caggagcagg gcccaggcca ggcacgacca 120
ccgaggggat gaacttcaca gtgggtttca agccgctgct aggggatgca cacagcatgg 180
acaacctgga gaagcagctc atctgcccca tctgcctgga gatgttctcc aaaccagtgg 240
tgatcctgcc ctgccaacac aacctgtgcc gcaaatgtgc caacgacgtc ttccaggcct 300
cgaatcctct atggcagtcc cggggctcca ccactgtgtc ttcaggaggc cgtttccgct 360
gcccatcgtg caggcatgag gttgtcctgg acagacacgg tgtctacggc ctgcagcgaa 420
acgtgctagt ggagaacatt atcgacattt acaagcagga gtcatccaag ccgctgcact 480
cgaaggctga gcagcacctc atgtgcgagg agcatgaaga agagaagatc aatatttact 540
gcctgagctg tgaggtgccc acctgctctc tctgcaaggt cttcggtgcc cacaaggact 600
gtgaggtggc cccactgccc accatttaca aacgccagaa gagtgagctc agcgatggca 660
tcgcgatgct ggtggcaggc aatgaccgcg tgcaagcagt gatcacacag atggaggagg 720
tgtgccagac tatcgaggac aatagccgga ggcagaagca gttgttaaac cagaggtttg 780
agagcctgtg cgcagtgctg gaggagcgca agggtgagct gctgcaggcg ctggcccggg 840
agcaagagga gaagctgcag cgcgtccgcg gcctcatccg tcagtatggc gaccacctgg 900
aggcctcctc taagctggtg gagtctgcca tccagtccat ggaagagcca caaatggcgc 960
89/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900 PCT/US00/02237
tgtatctcca gcaggccaag gagctgatca ataaggtcgg ggccatgtcg aaggtggagc 1020
tggcagggcg gccggagcca ggctatgaga gcatggagca attcaccgta agggtggagc 1080
acgtggccga aatgctgcgg accatcgact tccagccagg cgcttccggg ggaggaagag 1140
gaggtggccc cagacggaag aagagggcaa cccgggggcc ggaagaaaaa acggcccgga 1200
tggggcctta taggcctttg cgcccgaacc ccgaccccct gcttcgaaaa agcccccggc 1260
gcttaagaat ttccggggga aggaattctt gccgcaaaaa aaccccggca agcttttaac 1320
cccccaaaat tccggggcgc ccggggccc 1349
<210> 108
<211> 1642
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3633422CB1
<400> 108
ctagttctag atcgcgagcg cccgcccagg cacccaccag cggcgccgac ctcagcgcgc 60
acctatgggc tcgctaccag gacatgcgga gactggtgca cgacctcctg ccccccgagg 120
tctgcagtct cctgaaccca gcagccatct acgccaacaa cgagatcagc ctgcgtgacg 180
ttgaggtcta cggctttgac tacgactaca ccctggccca gtatgcagac gcactgcacc 240
ccgagatctt cagtaccgcc cgtgacatcc tgatcgagca ctacaagtac ccagaaggga 300
ttcggaagta tgactacaac cccagctttg ccatccgtgg cctccactat gacattcaga 360
agagccttct gatgaagatt gacgccttcc actacgtgca gctggggaca gcctacaggg 420
gcctccagcc tgtgccagac gaggaggtga ttgagctgta tgggggtacc cagcacatcc 480
cactatacca gatgagtggc ttctatggca agggtccctc cattaagcag ttcatggaca 540
tcttctcgct accggagatg gctctgctgt cctgtgtggt ggactacttt ctgggccaca 600
gcctggagtt tgaccaagca catctctaca aggacgtgac ggacgccatc cgagacgtgc 660
atgtgaaggg cctcatgtac cagtggatcg agcaggacat ggagaagtac atcctgagag 720
gggatgagac gtttgctgtc ctgagccgcc tggtggccca tgggaaacag ctgttcctca 780
tcaccaacag tcctttcagc ttcgtagaca aggggatgcg gcacatggtg ggtcccgatt 840
ggcgccagct cttcgatgtg gtcattgtcc aggcagacaa gcccagcttc ttcactgacc 900
ggcgcaagcc tttcagaaaa ctcgatgaga agggctcact tcagtgggac cggatcaccc 960
gcttggaaaa gggcaagatc tatcggcagg gaaacctgtt tgacttctta cgcttgacgg 1020
aatggcgtgg cccccgcgtg ctctacttcg gggaccacct ctatagtgat ctggcggatc 1080
tcatgctgcg gcacggctgg cgcacaggcg ccatcatccc cgagctggag cgtgagatcc 1140
gcatcatcaa cacggagcag tacatgcact cgctgacgtg gcagcaggcg ctcacggggc 1200
tgctggagcg catgcagacc tatcaggacg cggagtcgag gcaggtgctg gctgcctgga 1260
tgaaagagcg gcaggagctg aggtgcatca ccaaggccct gttcaatgcg cagttcggca 1320
gcatcttccg caccttccac aaccccacct acttctcaag gcgcctcgtg cgcttctctg 1380
acctctacat ggcctccctc agctgcctgc tcaactaccg cgtggacttc accttctacc 1440
cacgccgtac gccgctgcag cacgaggcac ccctctggat ggaccagctc tgcaccggct 1500
gcatgaagac ccccttcctt ggtgacatgg cccacatccg ctgagggcac ctttattgtc 1560
tgggacaggc cctcagcccc tcctgcccca tccacccaga caagcaataa aagtggtctc 1620
1642
ctccctgaaa aaaaaaaaaa as
<210> 109
<211> 1818
<212> DNA
<213> Homo Sapiens
<220>
<221> misc-feature
<223> Incyte ID No.: 3993377CB1
<400> 109
gaagactctc tggagccctt caactctctg gcaccagagc cagtgagtgg aggactatat 60
ggtattgatg acacggagct gatgggtgca gaggacaagc tgcctcttga ggacagccct 120
gtgattgctg cccttgattg cccttccctc aataatgcta ctgccttcag tctcctggca 180
gatgatagtc aaacatcaac ctctatcttt gccagtccca cctctccacc tgtcctaggg 240
90/91
SUBSTITUTE SHEET (RULE 26)
CA 02359701 2001-07-17
WO 00/44900
PCTNS00/02237
gagtctgtcc tgcaagataa cagctttgac ctgaataatg gtagtgacgc tgaacaggaa 300
gaaatggaaa ctcaatcttc agacttccca ccatccctga cccagccagc tcctgatcag 360
tcatccacta ttcagctaca tccagcaacc tcaccagcag tctcgccaac aacctcccca 420
gcagtctccc tagtggtttc tccagcagcc tccccagaaa tctctccaga agtttgtccc 480
gcagcttcta cagttgtctc tccagcagtc ttctcagtgg tctctccagc ttcctcagca 540
gtcctcccag cagtctcctt agaagtcccg ttgacggctt cagtgacatc cccaaaagcc 600
tctcccgtaa cttccccagc agctgccttt ccaacagcct ccccagcaaa taaggatgtc 660
agcagctttc tagaaaccac tgctgacgtg gaagagatca ctggagaagg actcactgct 720
tctggtagtg gtgatgtcat gaggagacgt attgctaccc cagaagaagt tcgtcttccc 780
ctccaacatg ggtggcggag agaggtgcgc atcaagaaca gcagccaccg atggcagggg 840
gagacctggt attatggccc ctgtgggaag aggatgaagc aatttccaga agtgatcaag 900
tacctgagcc gcaacgtggt acacagtgtc cgccgagagc acttcagctt cagtccccgt 960
atgcctgttg gagatttctt tgaagaaaga gacacgccag agggcttgca gtgggtgcag 1020
ctctcagcag aggagatccc gtcgaggatt caggcaatta ctggcaaacg gggtcgacct 1080
cgaaacactg agaaggctaa gactaaggaa gtccccaagg tgaaacgggg tcgaggtcgg 1140
ccacctaagg tcaaaatcac tgagctattg aacaagacag acaaccgccc cctaaagaaa 1200
ctggaggccc aagaaacatt gaatgaggag gataaagcaa agattgctaa aagcaagaag 1260
aagatgaggc agaaggttca acggggagag tgtcagacta ctatccaagg gcaggccaga 1320
aataagcgga aacaagagac caagagctta aagcagaagg aagctaagaa gaaatccaag 1380
gctgagaaag aaaaaggaaa gacaaagcag gaaaaactga aggaaaaagt caagagggaa 1440
aagaaggaga aggtaaaaat gaaggaaaag gaggaggtga ccaaagccaa gccagcctgt 1500
aaagcagata agaccctggc cacacagagg cgcttggagg aacggcagag gcagcagatg 1560
atcttggagg acatgaagaa gccgacagag gatatgtgtc tgactgacca ccagcccctg 1620
cctgacttct cacgagtccc tggtctgaca ttgcccagtg gagccttctc agactgcttg 1680
accattgtgg agttcctgca tagctttggc aaggtgctgg gccttgatcc tgcccaaggt 1740
tgtgcctagc ctggggggtc ctgcaggaag gggctcctgt gttcaaggtg accactctgg 1800
1818
gtgaaggtgc aaaacccg
<210> 110
<211> 785
<212> DNA
<213> Homo Sapiens
<220>
<221> unsure
<222> 738
<223> a or g or c or t, unknown, or other
<223> Incyte ID No.: 4717936CB1
<400> 110
gtctctgtag tcatgaggct gaagggggtg gggacagtgt tgataaaagg cactagaggc 60
agctcccaca cccttcctcg gaactgttgc ccacatgcag ccccggacac agcccctagc 120
ccaaacccta cccttcttcc tcggaggggc ccctcgagac actgggctgc gggtgcctgt 180
cattaagatg ggcacagggt gggagggctt ccagcggacc ctgaaggaag tcgcctacat 240
cctcctctgc tgctggtgta tcaaggaact gctggattaa tggtagcagg gaactgcctc 300
ctctccccac cagcaccatg gctggcatcg ctcaggtggg cagggtagag taaacaggag 360
gcatagctgc agcttctgtg gcagagcttg ccttagcttc tcattctctt ctttagcccc 420
cagcccaatt gccatcaaga ctcctgaagc cagctgtgct tgaccaagga tgggccataa 480
acaatgagta aacagtaaag tgtggatcct gctttgagct gtgtcatcta gcagacctgc 540
ctcatctctg agcctccttc attcccaacc cctgcctctg gtggacctct ggtgggcagg 600
agcttggact gctctggcta ggaccccagt aagattgtgg caagacctgg cactcctcca 660
agcttggcac agtgagccca ccagctcaga tggttgatct taccataccc tcatagtacc 720
aagaatggac tgcccccnta agaaacctgt ttgagaatca ctgaattata aatataaacc 780
785
cagat
91/91
SUBSTITUTE SHEET (RULE 26)
