Note: Descriptions are shown in the official language in which they were submitted.
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Regulatory DNA seQUences of the gene for the human catalytic tetomerase
subunit, and their dia nostic and therapeutic use
Structure and function of the chromosome ends
The genetic material of eukaryotic cells is distributed on linear chromosomes.
The
ends of hereditary units are termed telomeres, derived from the Greek words
telos
(end) and meros (part, segment). Most telomeres consist of repeats of short
sequences
which are mainly composed of thymine and guanine (Zakian, 1995). In all the
vertebrates which have so far been investigated, the telomeres consist of the
sequence
TTAGGG (Meyne er al., 1989).
The telomeres have a variety of important functions. They prevent the fusion
of
chromosomes (McClintock, 1941) and thus the formation of dicentric hereditary
1 ~ units. Such chromosomes having two centromeres can lead to the development
of
cancer due to loss of heterozygosis or duplication, or loss of genes.
In addition, telomeres serve the purpose of distinguishing intact hereditary
units from
damaged hereditary units. Thus, yeast cells ceased their cell division when
they
contained a chromosome without a telomere (Sandell and Zakian. 1993).
Telomeres fulfil another important task in association with the replication of
eukaryotic cell DNA. In contrast to the circular genomes of prokaryotes, the
linear
chromosomes of eukaryotes cannot be completely replicated by the DNA
polymerase
complex. RNA primers are required to initiate DNA replication. After
elimination of
the RNA primers, extension of the Okazaki fragments and subsequent ligation,
the
newly synthesized DNA strand lacks the ~' end since the R\A primer cannot be
replaced by DNA at that point. Without special protective mechanisms, the
chromosomes would therefur~;: shrink with each cell division ("end-replication
problem"; Harley Et al.. l~'~t)). The non-coding telomere sequences presumably
constitute a buffer-zone for preventin~l the loss of genes (Sandell and
Zakian, 1993).
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In addition to this, telomeres also play an import role in regulating cell
ageing
(Olovnikov, 1973). Human somatic cells exhibit a limited capacity for
replication in
culture; after a certain period of time, they become senescent. In this state,
the cells
no longer divide even after having been stimulated with growth factors;
however,
S they do not die and remain metabolically active (Goldstein, 1990). Various
observations support the hypothesis that a cell determines how many more times
it
can divide on the basis of the length of its telomeres (Allsopp et al., 1992).
In summary, the telomeres consequently possess key functions in the ageing of
cells,
and in stabilizing the genetic material and preventing cancer.
The enzyme telomerase synthesizes the telomeres
As described above, organisms which possess linear chromosomes can only
replicate
1 ~ their genome incompletely in the absence of a special protective
mechanism. Most
eukaryotes use a special enzyme, i.e. telomerase, for regenerating the
telomere
sequences. Telomerase is expressed constitutively in the single-cell organisms
which
have so far been investigated. On the other hand, telomerase activity has only
been
measured in humans in germ cells and tumour cells, whereas neighbouring
somatic
tissue did not contain any telomerase (Kim et al., 1994).
Telomerase can also be designated functionally as terminal telomere
transferase,
which is located in the cell nucleus as a multiprotein complex. While the RNA
moiety of human telomerase has been known for a relatively long period of time
(Feng et al., 1995), the catalytic subunit of this enzyme group was recently
identified
in a variety of orylanisms (Lingmer et al., 1997; cf. our application PCT
EP/98/03468
which is likewise pending). These catalytic subunits of telomerase are
strikingly
homolo~~ous both among themselves and in relation to all previously known
reverse
transcnptases.
WO 98; 1459? also describes nucleic acid and amino acid sequences of the
catalytic
telomeras~ subunit
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Activation of telomerase in human tumours
It was originally only possible to demonstrate telomerase activity in humans
in germ
line cells and not in normal, somatic cells (Hastie et al., 1990; Kim et al.,
1994).
Following the development of a more sensitive detection method (Kim et al.,
1994),
a low telomerase activity was also detected in hematopoietic cells (Broccoli
et al.,
1995; Counter et al., 1995; Hiyama et al., 1995). It is true, however, that
these cells
nevertheless exhibited a reduction in the telomeres (Vaziri et al., 1994;
Counter et
al., 1995). It has still not been resolved whether the quantity of enzyme in
these cells
is not sufficient for compensating the telomere loss or whether the telomerase
activity
which is measured stems from a subpopulation, e.g. incompletely differentiated
CD34+38+ precursor cells (Hiyama et al., 1995). In order to resolve this, it
would be
necessary to detect telomerase activity in a single cell.
Interestingly, however, significant telomerase activity was detected in a
large number
of the tumour tissues which had thus far been tested (1734/2031, 85%; Shay,
1997),
whereas no activity was found in normal somatic tissue ( 1 / 196, < 1 %, Shay,
1997). In
addition various investigations have shown that the telomeres still shrank in
senescent cells which were transformed with viral oncoproteins and it was only
possible to detect telomerase in the subpopulation which survived the growth
crisis
(Counter et al., 1992). The telomeres were also stable in these immortalized
cells.
(Counter et al., 1992). Similar findings from investigations in mice (Blasco
et al.,
1996) support the assumption that reactivation of the telomerase is a late
event in
tumorigenesis.
Based on these results, a "telomerase hypothesis" was developed which links
the loss
of telomere sequences and cell ageing with telomerase activity and the
development
of cancer. In long-lived species such as humans, the shrinkin~T of the
telomeres can be
regarded as being a mechanism for suppressing tumours. Differentiated cells
which
do not contain any telomerase cease their cell division at a particular
telomere length.
If such n cell mutates, it can curly form a tumour if the cell can extend its
telomeres.
~
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Otherwise, the cell would continue to lose telomere sequences until its
chromosomes
became unstable and it was finally destroyed. Telomerase reactivation is
presumably
the main mechanism used by tumour cells to stabilize their telomeres.
S It follows from these observations and considerations that it should be
possible to
treat tumours by inhibiting the telomerase. Conventional cancer therapies
using
cytostatic agents or short-wave radiation damage all the dividing cells in the
body in
addition to the tumour cells. However, since only germ line cells, apart from
tumour
cells, contain significant telomerase activity, telomerase inhibitors would
attack the
tumour cells more specifically and consequently elicit fewer undesirable side
effects.
Telomerase activity has been detected in all the tumour tissues which have so
far
been tested, which means that these therapeutic agents could be employed
against all
types of cancer. The effect of telomerase inhibitors would then set in when
the
telomeres of the cells had shortened to such an extent that the genome became
unstable. Since tumour cells usually possess telomeres which are shorter than
those
of normal somatic cells, cancer cells would be the first to be eliminated by
the
telomerase inhibitors. By contrast, cells possessing long telomeres, such as
the germ
cells, would only be damaged at a much later date. Telomerase inhibitors
consequently represent a potential way forward in the treatment of cancer.
It becomes possible to obtain unambiguous answers to the question of the
nature and
points of attack of physiological telomerase inhibitors once the manner in
which
expression of the telomerase gene is regulated has also been identified.
Regulation of gene expression in eukaryotes
There are a large number of points in eukaryotic gene expression, i.e. the
cellular
flow of information from the DNA to the protein by way of the RNA, at which
regulatory mechanisms can exert an effect. Examples of individual control
;reps are
gene amplification, the recombination of gene loci, chromatin structure, DNA
methylation, transcription, post-transcriptional modifications of mRNA. mRNA
transport, translation and post-translational modifications of proteins.
Studio; which
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have been earned out to date indicate that control at the level of
transcription
initiation is of the greatest importance (Latchman, 1991 ).
A region which is responsible for regulating transcription, and which is
designated
S the promoter region, is located directly upstream of the transcription start
of a gene
which is transcribed by RNA polymerise II. Comparison of the nucleotide
sequences
of promoter regions from a large number of known genes shows that particular
sequence motifs occur regularly in this region. These elements include, inter
alia, the
TATA box, the CCAAT box and the GC box, which elements are recognized by
specific proteins. The TATA box, which is located about 30 nucleotides
upstream of
the transcription start, is, for example, recognized by the TFIID subunit TBP
("TATA
box-binding protein"), whereas particular GC-rich sequence segments are
specifically
bound by the transcription factor Sp 1 ("specificity protein 1 ").
1 S The promoter can be functionally subdivided into a regulatory segment and
a
constitutive segment (Latchman, 1991 ). The constitutive control region
comprises the
so-called core promoter which enables transcription to be initiated correctly.
This
promoter contains the sequence elements which are described as UPE's (upstream
promoter elements) which are necessary for efficient transcription. The
regulatory
control segments, which can be interlaced with the UPE's, possess sequence
elements
which can be involved in the signal-dependent regulation of transcription by
hormones, growth factors, etc. They impart tissue-specific or cell-specific
promoter
properties.
DNA segments which are able to exert an influence on gene expression over
relatively large distances are a characteristic feature of eukaryotic genes.
These
elements can be located upstream or downstream of a transcription unit, or
within the
unit, and can perform their tunction independently of their orientation. These
sequence segments may reinforce (enhancers) or attenuate (silencers) promoter
activity. In a similar way to the pronu>ter regions, enhancers and silencers
also
accommodate several binding sites for transcription factors.
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The invention relates to the DNA sequences from the 5'-flanking region of the
gene
for the catalytically active human telomerase subunit and intron sequences for
this
gene.
The invention particularly relates to the 5'-flanking regulatory DNA sequence
which
contains the promoter DNA sequence for the gene for the human catalytic
telomerase
subunit, as depicted in Fig. 10 (SEQ ID NO 3).
The invention furthermore relates to part regions of the 5'-flanking
regulatory DNA
sequence, as depicted in Fig. 4 (SEQ ID NO 1 ), which has a regulatory effect.
Intron sequences for the gene for the human catalytic telomerase subunit, in
particular those sequences which have a regulatory effect, are also part of
the subject-
matter of the present invention. The intron sequences according to the
invention are
described in detail in the context of Example 5 (cf. SEQ ID NO 4, 5, 6, 7, 8,
9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19 and 20).
The invention furthermore relates to a recombinant construct which comprises
the
DNA sequences according to the invention, in particular the 5'-flanking DNA
sequence of the gene for the human catalytic telomerase subunit, or part
regions
thereof.
Preference is given to recombinant constructs which, in addition to the DNA
sequences according to the invention, in particular the 5'-flanking DNA
sequence of
the gene for the human catalytic telomerase subunit, or part regions thereof,
also
contain one or more additional DNA sequences which encode polypeptides or
proteins.
According to a particularly preferred embodiment, these additional DNA
sequences
encode antineoplastic proteins_
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Particular preference is given to those antineoplastic proteins which inhibit
angiogenesis directly or indirectly. Examples of these proteins are:
Plasminogen activator inhibitor (PAI-1 ), PAI-2, PAI-3, angiostatin,
endostatin,
platelet factor 4, TIMP-1, TIMP-2, TIMP-3 and leukaemia inhibitory factor
(LIF).
Antineoplastic proteins which have a direct or indirect cytostatic effect on
tumours
are likewise particularly preferred. These proteins include, in particular:
perform, granzyme, IL-2, IL-4, IL-12, interferons, such as IFN-a, IFN-13 and
IFN-y, TNF, TNF-a, TNF-13, oncostatin M; tumour suppressor genes, such as p53,
retinoblastoma.
Particular preference is furthermore given to antineoplastic proteins which,
where
appropriate in addition to their antineoplastic effect, stimulate
inflammations and
thereby contribute to the elimination of tumour cells. Examples of these
proteins are:
RANTES, monocyte chemotactic and activating factor (MCAF), IL-8, macrophage
inflammatory protein (MIP-la,-f3), neutrophil activating protein-2 (NAP-2), IL-
3, IL-
5, human leukaemia inhibitory factor (LIF), IL-7, IL-11, IL-13, GM-CSF, G-CSF
and
M-CSF.
Particular preference is furthermore given to antineoplastic proteins which,
due to
their action as enzymes, are able to convert precursors of an antineoplastic
active
2~ compound into an antineoplastic active compound. Examples of these enzymes
are:
herpes simplex virus thymidine kinase, varicella zoster virus thymidine
kinase,
bacterial nitroreductase, bacterial f3-glucuronidase, plant f~-glucuronidase
from Secale
cer-eale, human glucuronidase, human carboxypeptidase, bacterial
carboxypeptidase,
s0 bacterial fl-lactamase, bacteria( cytosine deaminidase, human catalase
and/or
phosphatase, human alkaline phosphatas~, type ~ acid phosphatase, human
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lysooxidase, human acid D-aminooxidase, human glutathione peroxidase, human
eosinophil peroxidase and human thyroid peroxidase.
The abovementioned recombinant constructs can also contain DNA sequences which
encode factor VIII or factor IX, or part fragments thereof. These DNA
sequences also
include other blood clotting factors.
The abovementioned recombinant constructs can also contain DNA sequences which
encode a reporter protein. Examples of these reporter proteins are:
Chloramphenicol acetyl transferase (CAT), glow-worm luciferase (LUC), 13-galac-
tosidase (f3-Gal), secreted alkaline phosphatase (SEAP), human growth hormone
(hGH), 13-glucuronidase (GUS), green-fluorescing protein (GFP), and all the
variants
derived therefrom, aquarin and obelin.
Recombinant constructs according to the invention can also contain DNA which
encodes the human catalytic telomerase subunit and its variants and fragments
in the
antisense orientation. Where appropriate, these constructs can also contain
other
protein subunits of the human telomerase and the telomerase RNA component in
the
antisense orientation.
The recombinant constructs can, in addition to the DNA which encodes the human
catalytic telomerase subunit, and its variants and fragments, also contain
other
protein subunits of the human telomerase and the telomerase RNA component.
2~
The invention furthermore relates to a vector which contains the
abovementioned
DNA sequences according to the invention, in particular the 5'-Clanking DNA
sequences and also one or more of the other DNA sequences mentioned above.
The preferred vector for these constructs is a virus, for example a
retrovirus, an
adenovirus, an adeno-associated virus, a herpes simplex virus, a vaccina
virus, a
lentiviral virus, a Sindbis virus and a Semliki forest virus.
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Preference is also given to using plasmids as vectors.
The invention furthermore relates to pharmaceutical preparations which
comprise
recombinant constructs or vectors according to the invention; for example a
preparation in a colloidal dispersion system.
Examples of suitable colloidal dispersion systems are liposomes or polylysine
ligands.
The preparations of the constructs or vectors according to the invention in
colloidal
dispersion systems can be supplemented with a ligand which binds to the
membrane
structures of tumour cells. Such a ligand can, for example, be attached to the
construct or the vector or else be a component of the liposome structure.
l~
Suitable ligands are, in particular, polyclonal or monoclonal antibodies, or
antibody
fragments thereof, which bind, by their variable domains, to the membrane
structures
of tumour cells, or substances carrying mannose terminally, cytokines or
growth
factors, or fragments or part sequences thereof, which bind to receptors on
tumour
cells.
Examples of corresponding membrane structures are receptors for a cytokine or
a
growth factor, such as IL-l, EGF, PDGF, VEGF, TGF 13, insulin or insulin-like
growth factor (ILGF), or adhesion molecules, such as SLeX, LFA-1, MAC-I,
2> LECAM-1 or VLA-4, or the mannose-6-phosphate receptor.
The present invention includes pharmaceutical preparations which, in addition
to the
vector constructs according to the invention, can also comprise non-toxic,
inert,
pharmaceutically suitable excipients. It is possible to conceive of
administering (e.g.
intravenously, intraarterially, intramuscularly, subcutaneously,
intradermally, anally,
vaginally, nasally, transdernlally, intraperitoneally, as an aerosol or
orally) these
preparations at the site of a tumour or administering them systemically.
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The vector constructs according to the invention can be employed in gene
therapy.
The invention furthermore relates to a recombinant host cell, in particular a
recombinant eukaryotic host cell, which harbours the above-described
constructs or
vectors.
The invention furthermore relates to a process for identifying substances
which affect
the promoter activity, silencer activity or enhancer activity of the catalytic
telomerase
subunit, with this process comprising the following steps:
A. adding a candidate substance to a host cell which harbours the regulatory
DNA sequence according to the invention, in particular the 5'-flanking
regulatory DNA sequence for the gene for the human catalytic telomerase
subunit, or a part region thereof which has a regulatory effect, which
sequence
or part region is functionally linked to a reporter gene, and
B. measuring the effect of the substance on expression of the reporter gene.
The process can be employed for identifying substances which increase the
promoter
activity, silencer activity or enhancer activity of the catalytic telomerase
subunit.
The process can furthermore be employed for identifying substances which
inhibit
the promoter activity, silencer activity or enhancer activator of the
catalytic
telomerase subunit.
The invention furthermore relates to a process for identifying factors which
bind
specifically to fragments of the DNA fragments according to the invention, in
particular the 5'-flanking re~Tulatory DNA sequence of the catalytic
telomerase
subunit. This method comprises screening an expression cDNA library using the
above-described DNA sequence, or subfragments of widely differing length, as
the
probe.
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The above-described constructs or vectors can also be used for preparing
transgenic
animals.
The invention furthermore relates to a process for detecting telomerase-
associated
conditions in a patient, which process comprises the following steps:
A. incubating a construct or vector, which contains the DNA sequence according
to the invention, in particular the 5'-flanking regulatory DNA sequence for
the
gene for the human catalytic telomerase subunit, or a part region thereof
having a regulatory effect, and a reporter gene, with body fluids or cell
samples,
B. detecting the activity of the reporter gene in order to obtain a diagnostic
value;
I5 and
C. comparing the diagnosic value with standard values for the reporter gene
construct in standardized normal cells or body fluids of the same type as the
test sample;
The detection of diagnostic values which are higher or lower than the standard
comparative values indicates a telomerase-associated condition, which in turn
indicates a pathogenic condition.
Explanation of the figures:
Fig. 1: Southern blot analysis using genomic DNA from various species
A: Photograph of an ethidium bromide-stained 0.7",a> agarose gel
containing approximately 4 pg of Eco RI-cut genomic DNA. Track 1
contains Hind III-cut a~ DNA as size markers (23.5, 9.4, 6.7, 4.4, 2.3, 2.0
and 0.6 kb). Tracks 2 to 10 contain human, rhesus monkey. Sprague
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Dawley rat, BALB/c mouse, dog, bovine, rabbit, chicken and yeast
(Saccharomyces cerevisiae) genomic DNA.
B: Autoradiogram, corresponding to Fig.l A, of a Southern blot analysis
in which radioactively labelled hTC-cDNA probe of about 720 by in
length is used for the hybridization.
Fig. 2: Restriction analysis of the recombinant 7~ DNA of the phage clone P
12,
which hybridizes with a probe from the 5' region of the hTC cDNA.
The figure shows a photograph of an ethidium bromide-stained 0.4%
agarose gel. Tracks 1 and 2 contain Eco RI/Hind III-cut ~. DNA and a
1 kb ladder from Gibco as size markers. Tracks 3 - 7 each contain 250 ng
of the DNA from the recombinant phage which has been cut with Bam
HI (track 3), Eco RI (track 4), Sal I (track 5), Xho I (track 5) and Sac I
(track 7). The arrows mark the two ~, arms of the vector EMBL3 Sp6/T7.
Fig.3: Restriction analysis and Southern blot analysis of the recombinant
~, DNA of the phage clone which hybridizes with a probe from the 5'
region of the hTC cDNA.
A: The figure shows a photograph of an ethidium bromide-stained 0.8%
agarose gel. Tracks 1 and 15 contain a 1 kb ladder from Gibco as size
markers. Tracks 2 to 14 each contain 2~0 ng of cut ~, DNA from the
recombinant phage clone. The followin~~ enzymes were employed: track
2: Sac I, track 3: Xho I, track 4: Xho I, Xba I, track ~: Sac I, Xho I, track
6: Sal I, Xho I, Xba I, track 7: Sac I, Xho I, Xba I, track 8: Sac I, Sal I,
Xba I, track 9: Sac I, Sal I, BamH I, track 10: Sac I, Sal I, Xho I, track I
1:
Not I, track 12: Sma I. track 13: empty, track 14: not digested.
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B: Autoradiogram, corresponding to Fig. 3 A, of a Southern blot analysis.
A 5'-hTC cDNA fragment of about 420 by in length was used as the
probe for the hybridization.
Fig. 4: Partial DNA sequence of the 5'-flanking region and of the promoter of
the gene for the human catalytic telomerase subunit. The ATG start
codon in the sequence is printed in bold. The depicted sequence
corresponds to SEQ ID NO 1.
Fig. S: Use of primer extension analysis to identify the transcription start.
The figure shows an autoradiogram of a denaturing polyacrylamide gel
which was selected for depicting a primer extension analysis. An
oligonucleotide having the sequence
S~GTTAAGTTGTAGCTTACACTGGTTCTC 3' was used as the primer.
The primer extension reaction was loaded in track 1. Tracks G, A, T and
C constitute the sequence reactions using the same primer and the
corresponding dideoxynucleotides. The thick arrow marks the main
transcription start while the thin arrows point to three subsidiary
transcription start points.
Fig. 6: cDNA sequence of the human catalytic telomerase subunit (hTC; cf. our
pending application PCT/EP/98/03468). The depicted sequence
corresponds to SEQ ID NO 2.
Fig. 7: Structural organization and restriction map of the human hTC gene and
its > ~-flanking and 3'-flanking regions.
Exons are shown as consecutively numbered rectan~Tlia which are filled-
in in black, and introns are shown as regions which are not filled in.
Untransl<ited sequence segments in the exons are hatched. Translation
starts in exon I and ends in exon 16. Restriction enzyme cleavage sits
The figure shows a photograp
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are marked as follows: S, SacI; X, XhoI. The relative arrangement of the
five phage clones (P2, P3, P5, P 12, P 17), and of the product from the
genome walking, are shown by thin lines. As the dots indicate, the
sequence of intron 16 has only been partly deciphered.
Fig. 8: HTL splice variants.
A: Diagrammatic structure of the hTC mRNA splice variants. The
complete hTC mRNA is depicted as a rectangle with a grey background
in the upper region of the figure. The 16 exons are depicted in accordance
with their size. The translation start (ATG) and the stop codon, and also
the telomerase-specific T motif, and the seven RT motifs, are all shown.
The hTC variants are subdivided into deletion and insertion variants. The
missing exon sequences are marked in the deletions. The insertions are
shown by additional white rectangles. The sizes and origins of the
inserted sequences are given. Newly formed stop codons are marked. The
size of the insertion in variant INS2 is unknown.
B: Exon-intron transitions in the hTC splice variants. Unspliced 5 ~-
flanking and 3 ~-flanking sequences are shown as white rectangles. The
origins of the exon and intron sequences are given. Intron and exon
sequences are shown in small letters and large letters, respectively. The
donor and acceptor sequences in the splice sites are underlaid as grey
rectangles, and their exon and intron origins are also given.
Fig- 9: Identification of the transcription start by means of R-r-PCR
analysis.
The RT-PCR was carried out using a cDNA library prepared from HL 60
cells and genomic DNA as the positive control- A common 3' primer
hybridizes to a region of the exon 1 sequence. -I~i~~ positions of the
different 5' primers in the codin~~ region or the ~'-tlanking region are
given. In the negative control, no template DNA w as added to the PCR
reaction. M: DNA size marker.
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Fig. 10: Nucleotide sequence and structural features of the hTC promoter.
The figure depicts 11273 by of the 5'-flanking hTC gene sequence,
beginning with the translation start codon ATG (+1). The putative region
S of the translation start is underlined. Possible regulatory sequence
segments within the 4000 by upstream of the translation start are ringed.
The depicted sequence corresponds to SEQ ID NO 3.
Fig. 11: Activity of the hTC promoter in HEK-293 cells.
The first 5000 by of the 5'-flanking hTC gene region are shown
diagrammatically in the upper part of the figure. The ATG start codon is
picked out. CpG-rich islands are marked by grey rectangles. The sizes of
the hTC promoter-luciferase construct are shown on the left-hand side of
the figure. The promoterless pGL2 basic construct and the SV40
promoter construct pGL2-Pro were used as controls in each transfection.
The relative luciferase activities of the different promoter constructs in
HEK cells are shown as continuous bars on the right-hand side of the
figure. The standard deviation is indicated. The numerical values
represent the average of two independent experiments which were earned
out in duplicate.
Tab. 1: Exon-intron transitions in the hTC gene
The table lists the nucleotide sequences at the 3 ~ and S ~ splice transitions
of the hTC gene. The consensus sequences for donor and acceptor
sequences (.AG and GT) are underlaid with grey rectangles. The table
shows the intron sequences (small letters) and exon sequences (large
letters) which dank the splice acceptor and donor sites. The sizes of the
exons and introns are given in bp.
Tab. ?: Potential bindin~~ sites for DNA-binding factors in the nucleotide
sequence of intros 2
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The search for possible DNA-binding factors (e.g. transcription factors)
was carried out using the "find pattern" algorithm from the Genetics
Computer Group (Madison, USA) GCG sequence analysis program
package. The table lists the abbreviations of the DNA-binding factors
which were identified and their location in intron 2.
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CA 02316282 2000-06-21
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Tab. 2
Factors Location in intron 2
C/EBP 2925
CRE.2 2749
S 1 2378, 4094, 4526, 4787, 4835, 4995
AP-2 CS3 5099
AP-2 CS4 2213, 3699, 4667, 5878, 5938, 6059, 6180,
6496
AP-2 CS5 5350, 5798, 5880, 5940, 6061, 6182, 6375,
6498
PEA3 934, 2505
P53 2125
GR utero lobin 848, 1487, 2956
PR utero lobin 3331
Zeste-white 1577, 1619, 1703, 1745, 1787, 1829, 1871,
1913, 1955,
1997, 2039, 2081, 3518, 3709, 4765, 5014,
5055
GRE 846
MyoD-MCK right 447, 509, 558, 1370, 1595, 1900, 2028,
site/rev 2099, 4557
MyoD-MCK left 108, 118, 453, 1566, 1608, 1692, 1734,
site 1818, 1902,
1986, 2372, 2460, 2720, 3491, 5030
Ets-1 CS 6408
AP1 3784, 4406
CREB 2801
GATA-1 839, 1390, 3154
c-Myc 108, 118, 453, 1566, 1608, 1692, 1734,
1818, 1902,
1986, 2372, 2460, 2720, 3491, 5030
CACCC site 991
CCAAT site 1224
CCAC box 992
CAAT site 463, 2395
Rb site 992, 4663
TATA 3650
CDEI 106, 1564, 1606, 1690, 1732, 1816, 1900,
1984
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Examples
The human gene for the catalytic telomerase subunit (ghTC), and the regions of
this
gene located 5' and 3', were cloned, while the start point for transcription
was
determined, potential binding sites for DNA-binding proteins were identified
and
active promoter fragments were highlighted. The sequence of the hTC cDNA (Fig.
6)
has already been reported in our application PCT/EP/98/03468, which is also
pending. Unless otherwise mentioned, all the data refer to the position of the
cDNA
in this sequence.
Example 1
A genomic Southern blot analysis was used to determine whether ghTC
constitutes a
single gene in the human genome or whether there exist several loci for the
hTC gene
and possibly also ghTC pseudogenes.
In order to do this, a commercially available zoo blot from Clontech was
subjected to
Southern blot analysis. This blot contains 4 pg of Eco RI-cut genomic DNA from
nine different species (human, monkey, rat, mouse, dog, bovine, rabbit,
chicken and
yeast). With the exception of yeast, chicken and human, the DNA was isolated
from
kidney tissue. The human genomic DNA was isolated from placenta and the
chicken
genomic DNA was purified from liver tissue. An hTC cDNA fragment of about 720
by in length, which was isolated from hTC cDNA, variant Del2 (position 1685 to
2349 plus 2531 to 2590 in Fig. 6 [deletion 2; cf. Example 5 in Fig. 8]), was
used as
the radioactively labelled probe in the autoradiogram in Fig. 1. The
experimental
conditions for the blot hybridization and washing steps were taken from
Ausubel et
al. ( 1987).
In the case of the human DNA, the probe recognizes two specific DNA fragments.
The smaller Eco RI fragment, of from about 1.~ to 1.8 kb in length, probably
ori~~inates from two Eco RI cleavage sites in an intron in the ghTC DNA. On
the
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basis of this result, it is to be assumed that only one single ghTC gene is
present in
the human genome.
Example 2
In order to isolate the 5' flanking hTC gene sequence, approx. 1.5 x 106
phages from
a human genomic placenta gene library (EMBL 3 SP6/T7 from Clontech, order
number HL1067j) were hybridized on nitrocellulose filters (0.45 um; from
Schleicher and Schuell), in accordance with the manufacturer's instructions,
with a
radioactively labelled 5'-hTC cDNA fragment of about 500 by in length
(position
839 to 1345 in Fig. 6). The nitrocellulose filters were firstly incubated, at
42°C for
two hours, in 2 x SSC (0.3 M NaCI; 0.5 M Tris-HC1, pH 8.0) and then in a
20
prehybridization solution (50% formamide; 5 x SSPE, pH 7.4; 5 x Denhard's
solution; 0.25% SDS; 100 pg of herring sperm DNA/ml). For the overnight
hybridization, the prehybridization solution was supplemented with 1.5 x 106
cpm of
denatured, radioactively labelled probe/ml of solution. Nonspecifically bound
radioactive DNA was removed under stringent conditions, i.e. by means of three
five-
minute steps of washing with 2 x SSC; 0.1% SDS at from 55 to 65°C. The
filters
were evaluated by autoradiography.
The phage clones which were identified in this primary investigation were
purified
(Ausubel et al. ( 1987)). In subsequent analyses, one phage clone, i.e. P 12
turned out
to be potentially positive. A i~ DNA preparation carried out on this phage
(Ausubel et
al. ( 1987)), and the subsequent restriction digestion with enzymes which
release the
genomic insert in fragments. showed that this phage clone contains an insert
of
approx. 15 kb in the vector (Fia. 2).
In order to isolate the complete hTC gene sequence, in each case from 1 to 1.5
x 106
pha~~es were screened, in independent experiments, with in each case different
radioactively labelled probes. as described above.
~
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The phage clones which were identified in these primary investigations, and
which
were positive for the corresponding probes, were purified. The phage clone P17
was
found to contain an hTC cDNA fragment of about 250 by in length (position 1787
to
2040 in Fig. 6). The phage clone P2 was identified as containing an hTC cDNA
S fragment of about 740 by in length (position 1685 to 2349 plus 2531 to 2607
in Fig.
6 [deletion 2; cf. Example 5]). The phage clones P3 and PS were found to
contain a
3' hTC cDNA fragment of 420 by in length (position 3047 to 3470 in Fig. 6).
After
the ~, DNA had been prepared from these phages, and subsequently subjected to
restriction digestion with enzymes which release the genomic insert in
fragments, the
inserts were subcloned into plasmids (Example 4).
Example 3
In order to investigate whether the 5' end of the hTC cDNA was also present in
the
insert in the recombinant phage clone P 12, the ~, DNA from this clone was
hybridized, in a Southern blot analysis, with a radiactively labelled hTC cDNA
fragment of about 440 by in length (position 1 to 440 in Fig. 6) from the
extreme 5'
region (Fig.3).
Since the isolated ~, DNA from the positive clone also hybridizes with the
extreme 5'
end of the hTC cDNA, this phage probably also contains the 5' sequence region
flanking the ATG start codon.
Example 4
In order to subclone the entire 15 kb insert in the positive phase clone P 12
in the
form of subfra'~ments, and subsequently to sequence these fra~~ments,
restriction
endonucleases which, on the one hand. release the entire insert from EMBL3
Sp6/T7
(cf. Example 2) and, in addition, cut within the insert, were selected for
digesting the
DN.~.
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In all, two Xho I subfragments, of about 8.3 and about 6.5 kb in length;
respectively,
and three Sac I subfragments, of about 8.5, about 3.5 and about 3 kb in
length,
respectively, were subeloned into the pBluescript KS(+) vector (from
Stratagene).
The 5123 by 5'-flanking nucleotide sequence of the ghTC gene region, starting
from
the ATG start codon, was determined by analysing the sequences of these
fragments
(Fig. 4; corresponding to SEQ ID NO 1). Fig. 4 depicts the first 5123 by
(starting
from the ATG start codon). Fig. 10 depicts the entire cloned 5' sequence
(corresponding to SEQ ID NO 3).
In order to subclone the entire insert, of approx. 14.6 kb in size, in phage
clone P 17
in the form of subfragments, restriction endonucleases which, on the one hand,
release the entire insert from EMLB3 Sp6/T7 and, in addition, cut a few times
within
the insert, were selected for digesting the DNA. Three XhoI/BamHI fragments,
of 7.1
kb, 4.2 kb and 1.5 kb in size, respectively, and one BamHI fragment, of 1.8 kb
in
1 ~ size, were subcloned by means of using a combination digestion with the
enzymes
XhoI and BamHI. Combination restriction digestion with the enzymes XhoI and
XbaI
resulted in a XhoI/XbaI fragment of 6.~ kb in size, and two XhoI fragments, of
6.5 kb
and 1.5 kb in size, respectively, being cloned.
Digestion with the restriction enzyme Xhol was used to subclone the insert, of
approx. 17.9 kb in size, in phage clone P2 in the form of subfragments. In
all, three
XhoI subfragments, of 7.5 kb, 6.4 kb and 1.6 kb in length, respectively, were
cloned.
Four SacI fragments, of 4.8 kb, 3 kb, 2 kb and 1.8 kb in size, respectively,
were
additionally subcloned by digesting with the restriction enzyme SacI.
The insert, of approx. 13.s kb in size. in phav~e clone P3 was subcloned by
digesting
with the restriction enzymes Sacl anc~, or Xhol. Six SacI subfragments, of 3.2
kb,
2 kb, 0.9 kb, 0.8 kb, 0.6~ kb and (). ~ kb in length, respectively, and two
XhoI
subfragments, of 6.~ kb and 4.3 kb io l~n'~th, respectively, were obtained in
this
connection.
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The insert, of approx. 13.2 kb in size, in phage clone PS was subcloned by
digesting
with the restriction enzymes SacI and/or XhoI. In all, SacI fragments of 6.5
kb, 3.3
kb, 3.2 kb, 0.8 kb and 0.3 kb in size, and XhoI fragmente of 7 kb and 3.2 kb
in size,
were subcloned.
In order to clone the hTC genomic sequence region located 3 ' of phage clone P
17
and 5' of phage clone P2, 3 genomic walkings were earned out using the
Clontech
GenomeWalkerTM kits (catalogue number K1803-1) and various combinations of
primers. In a final volume of 50 ~l, 1 U pmol of dNTP mix were added to 1 ul
of
human GenomeWalker Library HDL (from Clontech), and a PCR reaction was
carried out in 1 xKlen Taq PCR reaction buffer and 1 xAdvantage Klen Taq
polymerase mix (from Clontech). 10 pmol of an internal gene-specific primer,
and 10
pmol of the adaptor primer AP 1 (S'-GTAATACGACTCACTATAGGGC-3 '; from
Clontech) were added as primers. The PCR was carried out in 3 steps as a
touchdown
PCR. First of all, denaturation was carried out at 94°C for 20 sec, and
the primers
were then annealed, and the DNA chain extended, at 72°C for 4 min, over
7 cycles.
There then followed 37 cycles in which the DNA was denaturated at 94°C
for 20 sec
but the subsequent primer extension took place at 67°C for 4 min. In
conclusion,
there followed a chain extension at 67°C for 4 min. After this first
PCR, the PCR
product was diluted 1:50. One ~1 of this dilution was used in a second nested
PCR
together with 10 pmol of dNTP mix in lxKlen Taq PCR reaction buffer and
1 xAdvantage Klen Taq polymerase mix and also 10 pmol of a nested gene-
specific
primer and 10 pmol of the nested Marathon Adaptor primers AP2 (5'-
ACTATAGGGCACGCGTGGT-3'; from Clontech). The PCR conditions
corresponded to the parameters which were selected in the first PCR. As the
sole
exception, only 5 cycles rather than 7 cycles were selected in the first PCR
step and
only 24 cycles, instead of 37 cycles, were run in the second PCR step. The
products
of this nested genomic walking PCR were cloned into the TA Cloning Vector
pCRII
from InVitrogen.
3 (>
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In the first genomic walking, the gene-specific primer C3K2-GSP1 (5'-
GACGTGGCTCTTGAAGGCCTTG-3') and the nested gene-specific primer C3K2-
GSP2 (5'-GCCTTCTGGACCACGGCATACC-3') were used, together with the
HDL library 4, and a PCR fragment of 1639 by in length was obtained. In the
second
genomic walking, a PCR fragment of 685 by in length was amplified from the HDL
library 4 using the gene-specific primer C3F2 (5'-
CGTAGTTGAGCACGCTGAACAGTG-3') and the nested gene-specific primer
C3F (5'-CCTTCACCCTCGAGGTGAGACGCT-3. The third genomic walking
mixture, using the gene-specific primer DELS-GSP 1 (5 '-
GGTGGATGTGACGGGCGCGTACG-3 ') and the nested gene-specific primer
CSK-GSPI (5'-GGTATGCCGTGGTCCAGAAGGC-3'), led to a 924 by PCR
fragments being cloned from the HDL library 1. In all, 2100 by of the genomic
hTC
region located 3 ' of phage clone P 17 were identified using this genomic
walking
method (see Fig. 7).
The subcloned fragments, and the genomic walking products, were sequenced in
single-stranded form. The Lasergene Biocomputing Software (DNASTAR Inc.
Madison, Wisconsin, USA) was used to identify overlapping regions and form
contigs. In all, 2 large contigs were assembled from the sequences collected
from
phage clones P 12, P 17, P2, P3 and P5, and also the sequence data from the
genomic
walking. Contig 1 consists of sequence data from phage clones P 12 and P 17
and the
sequence data from the genomic walking. Contig 2 was put together from the
sequences from phage clones P2, P3 and P5. Overlapping phage clone regions are
shown diagrammaticaly in Fig. 7. The sequence data from the 2 contigs are
shown
below. The ATG start codon in contig 1 is underlined. The TGA stop codon is
underlined in contig 2.
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Contigl:
ACTTGAGCCC AGCCATGATTGCAACACCAC TGGTGACAGA70
AAGAGTTCAA ACGCCAGCCT
GGCTACGGTG
ATGAGACCCTGTCTCAAAAA AATTGAAATAATATAAAGCA CCACAGTGGA140
AAAAAAAAAA TCTTCTCTGG
S ACAAAACCAGAAATCAACAA TTTGAAAACTATACAAACAC AACAATATAC210
CAAGAGGAAT ATGAAAATTA
TTCTGAATGACCAGTGAGTC TTAAAAAGGAAATTGAAAAA CAAATGATAA280
AATGAAGAAA TTTATTTAAG
CGGAAACATAACCTCTCAAA TACAGCAAAAGCAGTGCTAA TATAGCTATA350
ACCCACGGTA GAAGGAAGTT
AGCAGCTACATCAAAAAAGT GGCGCAGTGGCTCATGCCTG ACTTTGGGAG920
AGAAAAGCCA TAATCCCAGC
GCCAAGGCGGGCAGATCGCC AGTTCGAGACCAGCCTGACC AACCTTGTCG990
TGAGGTCAGG AACACAGAGA
IO CTACTAAAAATACAAAATTA GTGGCACATGCCTGTAATCC GGAGGCTGAG560
GCTGGGCATG CAGCTACTCG
GCAGGATAACCGCTTGAACC AGGTTGCGGTGAGCCGGGAT GACTCCAGCC630
CAGGAGGTGG TGCGCCATTG
TGGGTAACAAGAGTGAAACC AAAAAAAAAAAAGTAGAAAA ACAACCTAAT700
CTGTCTCAAG ACTTAAAAAT
GATGCACCTTAAAGAACTAG GCAAACTAAACCTAAAATTG AGAAATAATA770
AAAAGCAAGA GTAAAAGAAA
AAGATCAGAGCAGAAATAAA AGATAACAATACAAAAGATC AAAGTTGGTT890
TGAAACTGAA AACAAAATTA
IS TTTTGAAAAGATAAACAAAA TTTGCCCAGACTAAGAAAAA ACCTAAATAA910
TTGACAAACC AGGAAAGAAG
ATAAAGTCAGAGATGAAAAA CAACTGATACCACAGAAATT .CTAGAGGCTA980
AGAGACATTA CAAAGGATCA
CTATGAGCAACTGTACACTA AAACCTAGAAAAAATAGATA TGCATACAAC1050
ATAAATTGAA AATTCCTAGA
CTACCAAGATTGAACCATGA AGCCCAAACAGACCAATAAC TTAAAGCCAT1120
AGAAATCCAA AATAATGGGA
AATAAAAAGTCTCCTAGCAA AGGACCCAATGGCTTCCCTG CCAATCATTT1190
AGAGAAGCCC CTGGATTTTA
2O AAAGAAGAATGAATTCCAAT CTATTCTGAAAAATAGAGGA CCAAACTCAT1260
CCTACTCAAA AAGAATACTT
TCTACATGGCCAGTATTACC AACCAGACAAAAACACATCA AACAAAAAAA1330
CTGATTCCAA AAAACAAACA
CAGAAAGAAAGAAAACTACA CCTGATGAATACTGATACAA CAAAACACTA1400
GGCCAATATC AAATCCTCAA
GCAAACCAAATTAAACAACA ATCATTCATTGTGATCAAGT CCAGGGATGG1970
CCTTCGAAAG GGGATTTATT
AAGGATGGTTCAACATATGC ATGTGATACATCATCCCAAC ACAAAAACTA1590
AAATCAATCA AAAATGAAGT
ZS TATGATTATTTCACTTTATG ATTTGATAAAATTCTGCACC AAAACCCTCA1610
CAGAAAAAGC CTTCATGATA
AAAAACCAGGTATACAAGAA CAGGCACAGTGGCTCACACC GCACTCTGGG1680
ACATACAGGC TGCGATCCCA
AGGCCAAGGTGGGATGATTG GGAGTTTGAGACTAGCCTGG GAGACCTGGT1750
CTTGGGCCCA GCAACAAAAT
CTACAAAAAACTTTTTTAAA GGCATGATGGCATATGCCTG TAGTCTGGAG1820
AAATTAGCCA TAGTCCCAGC
GCTGAGGTGGGAGAATCACT AGGTCGAGGCTGCAGTGAGC TCACTGTACT1890
TAAGCCTAGG CATGAACATG
3 CCAGCCTAGACAACAGAACA GAATAAGAAGAAGGAGAAGG AGGGAGGGAG1960
O AGACCCCACT AGAAGGGAGA
AAGGGAGGAGGAGGAGAAGG GGAGAAGTGGAAGGGGAAGG GAGGAAGAAG2030
AGGAGGTGGA GGAAGGGAAA
F~GAAACATATTTCAACATA TATATGACAGACCGAGGTAG AAAAACTGAA2100
ATAAAAGCCC TATTATGAGG
AGCCTTTCCTCTAAGATCTG AGGGCCCACTTTCACCACTG TAGTACTAGA2170
GAAAATGACA TGAT'rCAACA
AGTCCTAGCTAGAGCAATCA AGAAATAAAAGGCATCCAAA AGAAGTCAAA2240
GATAAGAGAA CTGGAAAGGA
3 TTATCCTGTTTGCAGATGAT ATCTGGAAAAGACTTAAGAC AACTATTAGA2310
S ATGATCTTAT ACCACTAAAA
GCTGAAATTTGGTACAGCAG CAATGTACAAAAATCAGTAG TTCCAACAGC2380
GATACAAAAT TATTTCTATA
SAACAATCTGAAAAAGAAAC GCTACAAATAAAATTAAACA AACCAAAGAA2950
CAAAAAAGCA GCTAGGAATT
GTGAAAGATCTCTACAATGA ATGTTGATAAAAGAAATTGA AAAAAAGAAA2520
AAACTATAAA AGAGGGCACA
AGATATTCCATGTTCATAGA AAATACTGTTAAAATGTCCA AGCAATTTAC2590
TTGGAAGAAT TACTACCCAA
4O AAATTCAATGCAATCCCTAT ATGACGTTCTTCACAGAAAT ATTCTAAGAT2660
TAAAATACTA AGAAGAAACA
TTGTACAGAACCACAAAAGA CCAAAGCTATCCTGACCAAA CTGGAAGCAT2%30
CCCAGAATAG AAGAACAAAA
CACATTACCTGACTTCAAAT AGCTATAGTAACCCAAACTA GCATAAAAAC2800
TATACTACAA CATGGTACTG
AGATGAGACATGGACCAGAG GAGAATCCAGAAACAAATCC AGTGAACTCA2870
GAACAGAATA ATGCATCTAC
TTTTTGACAAAGGTGCCAAG GGGGAAAAGATAATCTCTTC GCTGGAGGAA2940
AACATACTTT AATAAATGGT
4 CTGGATATCCATATGCAAAA AGAACTCTGTCTCTCACCAT AAATCAAAAT3010
S TAACAATACT ATACAAAAGC
GGATGAAAGGCTTAAATCTA CTTTGCAACTACTAAAAGAA AAACTCTCCA3080
AAACCTCAAA AACACCGGAG
GGACATTGGAGTGGGCAAAG TAATTCCCTGCAGGCACAGG AAAAACAGAC3150
ACTTCTTGAG CAACCAAAGC
AAATGGGATCATATCAAGTT TGCCCAGCAAAGGAAACAAT AAGAGACAAC3220
AAAAAGCTTC CAACAAAGAG
CCACAGAATGGGAGAATATA ATTCATCTRACAAGGAATTA TATATAAGGA3290
TTTGCAAACT ATAACCAGTA
S GCTCAAACTACTCTATAAGA ATAAGCTGATTTTCAAAAAT TCTGGGTAGA3360
O AAAACACCTA AAGCAAAAGA
CATTTCTCAAAATAAGTCAT AACAGGCATCTGAAAATGTG CTGATCATCA3430
ACAAATGGCA CTCAACACCA
GAGAAATGCAAATCAAAACT ATCATCTCATCCCAGTTAAA TTCAAAAGAC3500
ACTATGAGAG ATGGCTTTTA
AGGCAATAACAAATGCCAGT ATAAAAGGAAACCCTTGGAC GGAATGGAAA3570
GAGGATGTGG ACTGTTGGTG
TTGCTACCACTATGGAGAAC TTCCTCAAAAAACTAAAAAT TACAGCAATC3690
AGTTTGAAAG AAAGCTACCA
S CCATTGCTAGGTATATACTC AATCAGTGTATCAACAAGCT CCACATTTAC3710
S CAAAAAAGGG ATCTCCACTC
TGCAGCACTGTTCATAGCAG GAAGCAACCTCAGTGTCCAT ATGGAAAAAG3780
CCAAGGTTTG CAACAGACGA
AAAATGTGGTGCACATACAC TACGCAGCCATAAAAAAGAA TCAGTTGCAA3850
AATGGAGTAC TGAGATCCTG
CAGCATGGGGGGCACTGGTC GTGAAATAAGCCAGGCACAG TTTTCATGTT3920
AGTATGTTAA AAAGACAAAC
CTCCCTTACTTGTGGGAGCA CRATTGACATAGAAATAGAG GTTCTAGAGG3990
AAAATTAAAA GAGAATGGTG
E)O GGTGGGGGACAGGGTGACTA TAATTTATTGTATGTTTTAA AGAGTATAAT4060
GAGT.CAACAA AATAACTAAA
TGGGTTGTTTGTAACACAAA ATGCTTGAAGGTGACAGATA CCTGATGTGA4130
GAAAGGATAA CCCCATTTAC
TTATTACACATTGTATGCCT ATCTCATGTATGCTATAGAT CTATATTAAA4200
GTATCAAAAT ATAAACCCTA
AATTAAAATTTTAATGGCCA CTCATGTCCGTAATCCCAGC GCCGAGGCGG4270
GGCACGGTGG ACTTTGGGAG
GTGGATCACCTGAGGTCAGG CAGTCTGGCCACCATGATGA ~TACTAAAGA4390
AGTTTGAAAC AACCCTGTCT
6J TACAAAAATTAGCCAGGCGT ACCTGTAGTCCCAACTACTC GACAGGAGAA4410
GGTGGCACAT AGGAGGCTGA
TTGCTTGAACCTGGGAGGCG TGAGCCGAGATCATGCCACT CTGGGTGACA4980
GAGGTTGCAG GCACTGCAGC
GAGCAAGACTCCATCTCAAA AAAAAAGAAGATTAAAATTG GTACCGTATA4550
ACAAAAACAA TAATTTTTAT
AATATATACTCTACTATATT AATTAAAACAATTATAAAAG ACTTAATCTA4620
AGAAGTTAAA GTAATTAACC
AAATAAGAACAATGTATGTG CTTCTGAAGAAGTAAAAGTT TGGCAGAAAT4690
GGGTTTCTAG ATGGCCACGA
IO GTGAGGAGGGAACAGTGGAA TTAGACGCTCATACTCTCTG AATTTTAACC4760
GTTACTGTTG TAAGTGACTT
AAAGACAGGCTGGGAGAAGT TTCTATAAGCCCTAAAACAA TGGTGAAAGG4830
TAAAGAGGCA CTGCTAATA.~
TAATCTCTATTAATTACCAA TATCTCTAAAATCGAGCTGC ~GTCTGATCA9900
TAATTACAG:. AGAATTGGC=,
CACCGTCCTCTCATTCACGG CTTGTGTGCTTGGAGATTTT TTCGTGTTTG4970
TGCTTTTTTT CGATTGTGTG
GTTAAACTTAATCTGTATGA GAAAAATGGTGGTGATTTCC TTAGAGTACC5040
ATCCTGAAAC TCCAGAAGA
=.
75 TGGCAGGAAGCAGGTGGCTC AGCCACTTCA. 1AGACCCAGG5110
TGTGGACCTG ATCTTCAAGG
GTCTCTGGC~
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-26-
TGCAAGGCAGAGGCCTGATGACCCGAGGACAGGAAAGCTCGGATGGGAAGGGGCGATGAG 5180
AAGCCTGCCT
CGTTGGTGAGCAGCGCATGAAGTGCCCTTATTTACGCTTTGCAAAGATTGCTCTGGATACCATCTGGAAA5250
AGGCGGCCAGCGGGAATGCAAGGAGTCAGAAGCCTCCTGCTCAAACCCAGGCCAGCAGCTATGGCGCCCA5320
CCCGGGCGTGTGCCAGAGGGAGAGGAGTCAAGGCACCTCGAAGTATGGCTTAAATCTTTTTTTCACCTGA5390
S AGCAGTGACCAAGGTGTATTCTGAGGGAAGCTTGAGTTAGGTGCCTTCTTTAAAACAGAAAGTCATGGAA5960
GCACCCTTCTCAAGGGAAAACCAGACGCCCGCTCTGCGGTCATTTACCTCTTTCCTCTCTCCCTCTCTTG5530
CCCTCGCGGTTTCTGATCGGGACAGAGTGACCCCCGTGGAGCTTCTCCGAGCCCGTGCTGAGGACCCTCT5600
TGCAAAGGGCTCCACAGACCCCCGCCCTGGAGAGAGGAGTCTGAGCCTGGCTTAATAACAAACTGGGATG5670
TGGCT'GGGGGCGGACAGCGACGGCGGGATTCAAAGACTTAATTCCATGAGTAAATTCAACCTTTCCACAT5740
IO CCGAATGGATTTGGATTTTATCTTAATATTTTCTTAAATTTCATCAAATAACATTCAGGACTGCAGAAAT5810
CCAAAGGCGTAAAACAGGAACTGAGCTATGTTTGCCAAGGTCCAAGGACTTAATAACCATGTTCAGAGGG5880
ATTTTTCGCCCTAAGTACTTTTTATTGGTTTTCATAAGGTGGCTTAGGGTGCAAGGGAAAGTACACGAGG5950
AGAGGCCTGGGCGGCAGGGCTATGAGCACGGCAGGGCCACCGGGGAGAGAGTCCCCGGCCTGGGAGGCTG6020
ACAGCAGGACCACTGACCGTCCTCCCTGGGAGCTGCCACATTGGGCAACGCGAAGGCGGCCACGCTGCGT6090
IS GTGACTCAGGACCCCATACCGGCTTCCTGGGCCCACCCACACTAACCCAGGAAGTCACGGAGCTCTGAAC6160
CCGTGGAAACGAACATGACCCTTGCCTGCCTGCTTCCCTGGGTGGGTCAAGGGTAATGAAGTGGTGTGCA6230
GGAAATGGCCATGTAAATTACACGACTCTGCTGATGGGGACCGTTCCTTCCATCATTATTCATCTTCACC6300
CCCAAGGACTGAATGATTCCAGCAACTTCTTCGGGTGTGACAAGCCATGACAAAACTCAGTACAAACACC6370
ACTCTTTTACTAGGCCCACAGAGCACGGSCCACACCCCTGATATATTAAGAGTCCAGGAGAGATGAGGCT6940
2O GCTTTCAGCCACCAGGCTGGGGTGACAACAGCGGCTGAACAGTCTGTTCCTCTAGACTAGTAGACCCTGG6510
CAGGCACTCCCCCAGATTCTAGGGCCTGGTTGCTGCTTCCCGAGGGCGCCATCTGCCCTGGAGACTCAGC6580
CTGGGGTGCCACACTGAGGCCAGCCCTGTCTCCACACCCTCCGCCTCCAGGCCTCAGCTTCTCCAGCAGC6650
TTCCTAAACCCTGGGTGGGCCGTGTTCCAGCGCTACTGTCTCACCTGTCCCACTGTGTCTTGTCTCAGCG6720
ACGTAGCTCGCACGGTTCCTCCTCACATGG'GGTGTCTGTCTCCTTCCCCAACACTCACATGCGTTGAAGG6790
2S GAGGAGATTCTGCGCCTCCCAGACTGGCTCCTCTGAGCCTGAACCTGGCTCGTGGCCCCCGATGCAGGTT6860
CCTGGCGTCCGGCTGCACGCTGACCTCCATTTCCAGGCGCTCCCCGTCTCCTGTCATCTGCCGGGGCCTG6930
CCGGTGTGTTCTTCTGTTTCTGTGCTCCTTTCCACGTCCAGCTGCGTGTGTCTCTGCCCGCTAGGGTCTC7000
GGGGTTTTTATAGGCATAGGACGGGGGCGTGGTGGGCCAGGGCGCTCTTGGGAAATGCAACATTTGGGTG7070
TGAAAGTAGGAGTGCCTGTCCTCACCTAGGTCCACGGGCACAGGCCTGGGGATGGAGCCCCCGCCAGGGA7190
)O CCCGCCCTTCTCTGCCCAGCACTTTCCTGCCCCCCTCCCTCTGGAACACAGAGTGGCAGTTTCCACAAGC7210
ACTAAGCATCCTCTTCCCAAAAGACCCAGCATTGGCACCCCTGGACATTTGCCCCACAGCCCTGGGAATT7280
CACGTGACTACGCACATCATGTACACACTCCCGTCCACGACCGACCCCCGCTGTTTTATTTTA~1TAGCTA7350
CAAAGCAGGGAAATCCCTGCTAAAATGTCCTTTAACAAACTGGTTAAACAAACGGGTCCATCCGCACGGT7420
GGACAGTTCCTCACAGTGAAGAGGAACATGCCGTTTATAAAGCCTGCAGGCATCTCAAGGGAATTACGCT7990
.~S GAGTCAAAACTGCCACCTCCATGGGATACGTACGCAACATGCTCAAAAAGAAAGAATTTCACCCCATGGC7560
AGGGGAGTGGTTAGGGGGGTTAAGGACGGTGGGGGCGGCAGCTGGGGGCTACTGCACGCACCTTTTACTA7630
AAGCCAGTTTCCTGGTTCTGATGGTATTGGCTCAGTTATGGGAGACT_AACCATAGGGGAGTGGGGATGGG7700
GGAACCCGGAGGCTGTGCCATCTTTGCCATGCCCGAGTGTCCTGGGCAGGATAATGCTCTAGAGATGCCC7770
ACGTCCTGATTCCCCCAAACCTGTGGACAGAACCCGCCCGGCCCCAGGGCCTTTGCAGGTGTGATCTCCG7890
4 TGAGGACCCTGAGGTCTGGGATCCTTCGGGACTACCTGCAGGCCCGAAAAGTAATCCAGGGGTTCTGGGA7910
O
AGAGGCGGGCAGGAGGGTCAGAGGGGGGCAGCCTCAGGACGATGGAGGCAGTCAGTCTGAGGCTGAAAAG7980
GGAGGGAGGGCCTCGAGCCCAGGCCTGCAAGCGCCTCCAGAAGCTGGAAAAAGCGGGGAAGGGACCCTCC8050
ACGGAGCCTGCAGCAGGAAGGCACGGCTGGCCCTTAGCCCACCAGGGCCCATCGTGGACCTCCGGCCTCC8120
GTGCCATAGGAGGGCACTCGCGCTGCCCTTCTAGCATGAAGTGTGTGGGGATTTGCAGAAGCAACAGGAA8190
4S ACCCATGCACTGTGAATCTAGGATTATTTCAAAACAAAGGTTTACAGAAACATCCAAGGACAGGGCTGAA8260
GTGCCTCCGGGCAAGGGCAGGGCAGGCACGAGTGATTTTATTTAGCTATTTTATTTTATTTACTTACTTT8330
CTGAGACAGAGTTATGCTCTTGTTGCCCAGGCTGGAGTGCAGCGGCATGATCTTGGCTCACTGCAACCTC8900
CGTCTCCTGGGTTCAAGCAATTCTCGTGCCTCAGCCTCCCAAGTAGCTGGGATTTCAGGCGTGCACCACC8470
ACACCCGGCTAATTTTGTATTTTTAGTAGAGATGGGCTTTCACCATGTTGGTCAAGCTGATCTCAAAATC8540
S CTGACCTCAGGTGATCCGCCCACCTCAGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGCACCT8610
O
GGCCTATTTAACCATTTTAAAACTTCCCTGGGCTCAAGTCACACCCACTGGTAAGGAGTTCATGGAGTTC8680
AATTTCCCCTTTACTCAGGAGTTACCCTCCTTTGATATTTTCTGTAATTCTTCGTAGACTGGGGATACAC8750
CGTCTCTTGACATATTCACAGTTTCTGTGACCACCTGTTATCCCATGGGACCCACTGCAGGGGCAGCTGG8820
GAGGCTGCAGGCTTCAGGTCCCAGTGGGGTTGCCATCTGCCAGTAGAAACCTGATGTAGAATCAGGGCGC8890
S AAGTGTGGACACTGTCCTGAATCTCAATGTCTCAGTGTGTGCTGAAACATGTAGAAATTAAAGTCCATCC8960
S
CTCCTACTCTACTGGGATTGAGCCCCTTCCCTATCCCCCCCCAGGGGCAGAGGAGTTCCTCTCACTCCTG9030
TGGAGGAAGGAATGATACTTTGTTATTTTTCACTGCTGGTACTGAATCCACTGTTTCATTTGTTGGTTTG9100
TTTGTTTTGTTTTGAGAGGCGGTTTCACTCTTGTTGCTCAGGCTGGAGGGAGTGCAATGGCGCGATCTTG9170
GCTTACTGCAGCCTCTGCCTCCCAGGTTCAAGTGATTCTCCTGCTTCCGCCTCCCATT'rGGCTGGGATTA9290
6O CAGGCACCCGCCACCATGCCCAGCTAATTTTTTGTATTTTTAGTAGAGACGGGGGTGGGTGGGGTTCACC9310
ATGTTGGCCAGGCTGGTCTCGAACTTCTGACCTCAGATGATCCACCTGCCTCTGCCTCCTAAAGTGCTGG9380
GATTACAGGTGTGAGCCACCATGCCCAGCTCAG~.ATTTACTCTGTTTAGAAACATCTGGGTCTGAGGTAG9950
GAAGCTCACCCCACTCAAGTGTTGTGGTGTTTT:.nGCCAATGATAGAATTTTTTTATTGTTGTTAGAACA9520
CTCTTGATGTTTTACACTGTGATGACTAAGACATCATCAGCTTTTCAAAGACACACTAACTGCACCCATA9590
6S ATACTGGGGTGTCTTCTGGGTATCAGCAATCTTCATTGAATGCCGGGAGGCGTTTCCTCGCCATGCACAT9660
GGTGTTAATTACTCCAGCATAATCTTCTGCTTCCi:TTTCTTCTCTTCCCTCTTTTAAA.ATTGTGTTTTCT9730
ATGTTGGCTTCTCTGCAGAGAACCAGTGTAAGCTACAACTTAACTTTTGTTGGAACAAATTTTCCAAACC9800
GCCCCTTTGCCCTAGTGGCAGAGACi-
~ATTCACT;?.i:CACAGCCCTTTAAAAAGGCTTAGGGATCACTAAGG9870
GGATTTCTAGAAGAGCGACCTGTAATCCTAAGTATTTACAAGACGAGGCTAACCTCCAGCGAGCGTGACA9990
7O
GCCCAGGGAGGGTGCGAGGCCTGTTCAAATGCT=.GCTCCATAAATAAAGCAATTTCCTCCGGCAGTTTCT10010
GAAAGTAGGAAAGGTTACATTTAAGGTTGCGTT'_GTTAGCATTTCAGTGT.TTGCCGACCTCAGCTACAGC10080
ATCCCTGCAAGGCCTCGGGAGACCCAGAAGTTTCTCGCCCCCTTAGATCCAAACTTGAGCAACCCGGAGT10150
CTGGATTCCTGGGAAGTCCTCAGCTGTCCTGCGC-TTGTGCCGGGGCCCCAGGTCTGGAGGGGACCAGTGG10220
CCGTGTGGCTTCTACTGCTGGGCTGGAAGTCGGGCCTCCTAGCTCTGCAGTCCGAGGCTTGGAGCCAGGT10290
7S
GCCTGGACCCCGAGGCTGCCCTCCACCCTGTGCGGGCGGGATGTGACCAGATGTTGGCCTCATCTGCCAG10360
ACAGAGTGCCGGGGCCCAGGGTCA.yGG'CCGTTGTGGCTGGTGTGAGGCGCCCGGTGCGCGGCCAGCAGGA10430
GCGCCTGGCTCCATTTCCCACCCTT'"CTCGACGGGACCGCCCCGGTGGGTGATTAACAGATTTGGGGTGG10500
TTTGCTCATGGTGGGGACCCCTCGCCGCCTGAGAACCTG::AAAGAGAAATGACGGGCCTGTGTCAAGGAG10570
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-27-
CCCAAGTCGCGGGGAAGTGTTGCAGGGAGGCACTCCGGGAGGTCCCGCGTGCCCGTCCAGGGAGCAATGC10640
GTCCTCGGGTTCGTCCCCAGCCGCGTCTACGCGCCTCCGTCCTCCCCTTCACGTCCGGCATTCGTGGTGC10710
CCGGAGCCCGACGCCCCGCGTCCGGACCTGGAGGCAGCCCTGGGTCTCCGGATCAGGCCAGCGGCCAAAG10780
GGTCGCCGCACGCACCTGTTCCCAGGGCCTCCACATCATGGCCCCTCCCTCGGGTTACCCCACAGCCTAG10850
S
GCCGATTCGACCTCTCTCCGCTGGGGCCCTCGCTGGCGTCCCTGCACCCTGGGAGCGCGAGCGGCGCGCG10920
GGCGGGGAAGCGCGGCCCAGACCCCCGGGTCCGCCCGGAGCAGCTGCGCTGTCGGGGCCAGGCCGGGCTC10990
CCAGTGGATTCGCGGGCACAGACGCCCAGGACCGCGCTCCCCACGTGGCGGAGGGACTGGGGACCCGGGC11060
ACCCGTCCTGCCCCTTCACCTTCCAGCTCCGCCTCCTCCGCGCGGACCCCGCCCCGTCCCGACCCCTCCC11130
GGGTCCCCGGCCCAGCCCCCTCCGGGCCCTCCCAGCCCCTCCCCTTCCTTTCCGCGGCCCCGCCCTCTCC11200
IO
TCGCGGCGCGAGTTTCAGGCAGCGCTGCGTCCTGCTGCGCACGTGGGAAGCCCTGGCCCCGGCCACCCCC11270
GCG_ATGCCGCGCGCTCCCCGCTGCCGAGCCGTGCGCTCCCTGCTGCGCAGCCACTACCGCGAGGTGCTGC11390
CGCTGGCCACGTTCGTGCGGCGCCTGGGGCCCCAGGGCTGGCGGCTGGTGCAGCGCGGGGACCCGGCGGC11410
TTTCCGCGCGCTGGTGGCCCAGTGCCTGGTGTGCGTGCCCTGGGACGCACGGCCGCCCCCCGCCGCCCCC11480
TCCTTCCGCCAGGTGGGCCTCCCCGGGGTCGGCGTCCGGCTGGGGTTGAGGGCGGCCGGGGGGAACCAGC11550
IS
GACATGCGGAGAGCAGCGCAGGCGACTCAGGGCGCTTCCCCCGCAGGTGTCCTGCCTGAAGGAGCTGGTG11620
GCCCGAGTGCTGCAGAGGCTGTGCGAGCGCGGCGCGAAGAACGTGCTGGCCTTCGGCTTCGCGCTGCTGG11690
ACGGGGCCCGCGGGGGCCCCCCCGAGGCCTTCACCACCAGCGTGCGCAGCTACCTGCCCAACACGGTGAC11760
CGACGCACTGCGGGGGAGCGGGGCGTGGGGGCTGCTGCTGCGCCGCGTGGGCGACGACGTGCTGGTTCAC11830
CTGCTGGCACGCTGCGCGCTCTTTGTGCTGGTGGCTCCCAGCTGCGCCTACCAGGTGTGCGGGCCGCCGC11900
2O
TGTACCAGCTCGGCGCTGCCACTCAGGCCCGGCCCCCGCCACACGCTAGTGGACCCCGAAGGCGTCTGGG11970
ATGCGAACGGGCCTGGAACCATAGCGTCAGGGAGGCCGGGGTCCCCCTGGGCCTGCCAGCCCCGGGTGCG12090
AGGAGGCGCGGGGGCAGTGCCAGCCGAAGTCTGCCGTTGCCCAAGAGGCCCAGGCGTGGCGCTGCCCCTG12110
AGCCGGAGCGGACGCCCGTTGGGCAGGGGTCCTGGGCCCACCCGGGCAGGACGCGTGGACCGAGTGACCG12180
TGGTTTCTGTGTGGTGTCACCTGCCAGACCCGCCGAAGAAGCCACCTCTTTGGAGGGTGCGCTCTCTGGC12250
S
ACGCGCCACTCCCACCCATCCGTGGGCCGCCAGCACCACGCAGGCCCCCCATCCACATCGCGGCCACCAC12320
GTCCCTGGGACACGCCTTGTCCCCCGGTGTACGCCGAGACCAAGCACTTCCTCTACTCCTCAGGCGACAA12390
GGAGCAGCTGCGGCCCTCCTTCCTACTCAGCTCTCTGAGGCCCAGCCTGACTGGCGCTCGGAGGCTCGTG12960
GAGACCATCTTTCTGGGTTCCAGGCCCTGGATGCCAGGGACTCCCCGCAGGTTGCCCCGCCTGCCCCAGC12530
GCTACTGGCAAATGCGGCCCCTGTTTCTGGAGCTGCTTGGGAACCACGCGCAGTGCCCCTACGGGGTGCT12600
3
CCTCAAGACGCACTGCCCGCTGCGAGCTGCGGTCACCCCAGCAGCCGGTGTCTGTGCCCGGGAGAAGCCC12670
O
CAGGGCTCTGTGGCGGCCCCCGAGGAGGAGGACACAGACCCCCGTCGCCTGGTGCAGCTGCTCCGCCAGC12790
ACAGCAGCCCCTGGCAGGTGTACGGCTTCGTGCGGGCCTGCCTGCGCCGGCTGGTGCCCCCAGGCCTCTG12810
GGGCTCCAGGCACAACGAACGCCGCTTCCTCAGGAACACCAAGAAGTTCATCTCCCTGGGGAAGCATGCC12880
AAGCTCTCGCTGCAGGAGCTGACGTGGAAGATGAGCGTGCGGGACTGCGCTTGGCTGCGCAGGAGCCCAG12950
3
GTGAGGAGGTGGTGGCCGTCGAGGGCCCAGGCCCCAGAGCTGAATGCAGTAGGGGCTCAGAAAAGGGGGC13020
S
AGGCAGAGCCCTGGTCCTCCTGTCTCCATCGTCACGTGGGCACACGTGGCTTTTCGCTCAGGACGTCGAG13090
TGGACACGGTGATCTCTGCCTCTGCTCTCCCTCCTGTCCAGTTTGCATAAACTTACGAGGTTCACCTTCA13160
CGTTTTGATGGACACGCGGTTTCCAGGCGCCGAGGCCAGAGCAGTGAACAGAGGAGGCTGGGCGCGGCAG13230
TGGAGCCGGGTTGCCGGCAATGGGGAGAAGTGTCTGGAAGCACAGACGCTCTGGCGAGGGTGCCTGCAGG13300
4O
TTACCTATAATCCTCTTCGCAATTTCAAGGGTGGGAATGAGAGGTGGGGACGAGAACCCCCTCTTCCTGG13370
GGGTGGGAGGTAAGGGTTTTGCAGGTGCACGTGGTCAGCCAATATGCAGGTTTGTGTTTAAGATTTAATT13940
GTGTGTTGACGGCCAGGTGCGGTGGCTCACGCCGGTAATCCCAGCACTTTGGGAAGCTGAGGCAGGTGGA13510
TCACCTGAGGTCAGGAGTTTGAGACCAGCCTGACCAACATGGTGAAACCCTATCTGTACTAAAAATACAA13580
AAATTAGCTGGGCATGGTGGTGTGTGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCACT13650
'~S
TGAACCCAGGAGGCGGAGGCTGCAGTGAGCTGAGATTGTGCCATTGTACTCCAGCCTGGGCGACAAGAGT13720
GAAACTCTGTCTTTAAAAAAAAAAAGTGTTCGTTGATTGTGCCAGGACAGGGTAGAGGGAGGGAGATAAG13790
ACTGTTCTCCAGCACAGATCCTGGTCCCATCTTTAGGTATGAAGAGGGCCACATGGGAGCAGAGGACAGC13860
AGATGGCTCCACCTGCTGAGGAAGGGACAGTGTTTGTGGGTGTTCAGGGGATGGTGCTGCTGGGCCCTGC13930
CGTGTCCCCACCCTGTTTTTCTGGATTTGATGTTGAGGAACCTCCGCTCCAGCCCCCTTTTGGCTCCCAG14000
S
TGCTCCCAGGCCCTACCGTGGCAGCTAGAAGAAGTCCCGATTTCACCCCCTCCCCACAAACTCCCAAGAC14070
O
ATGTAAGACTTCCGGCCATGCAGACAAGGAGGGTGACCTTCTTGGGGCTCTTTTTTTTCTTTTTTTCTTT19190
TTATGGTGGCAAAAGTCATATAACATGAGATTGGCACTCCTAACACCGTTTTCTGTGTACAGTGCAGAAT19210
TGCTAACTCGGCGGTGTTTACAGCAGGTTGCTTGAAATGCTGCGTCTTGCGTGACTGGAAGTCCCTACCC19280
ATCGAACGGCAGCTGCCTCACACCTGCTGCGGCTCAGGTGGACCACGCCGAGTCAGATAAGCGTCATGCA19350
JS
ACCCAGTTTTGCTTTTTGTGCTCCAGCTTCCTTCGTTGAGGAGAGTTTGAGTTCTCTGATCAGGACTCTG19920
CCTGTCATTGCTGTTCTCTGACTTCAGATGAGGTCACAATCTGCCCCTGGCTTATGCAGGGAGTGAGGCG19490
TGGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGTTGCCCCCAGGTGTCCCTGTCACGTGTA14560
GGGTGAGTGAGGCGCGGCCCCCGGGTGTCCCTGTCCCGTGCAGCGTGATTGAGGTGTGGCCCCCGGGTGT14630
CCCTGTCACGTGTAGGGTGAGTGAGGCGCCATCCCCGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCG14700
GO
TGGTCCCCGGGTGTCCCTGTCCCGTGCAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCA14770
GGGTGAGTGAGGCGCGGTCCCCGGGTGTCCCTCTCAGGTGTAGGGTGAGTGAGGCGCGGCCCCAGGGTGT19840
CCCTGTCACGTGTAGGGTGAGTGAGGCACCGTCCCTGGGTGTCCCTCCCAGGTATAGGGTGAGTGAGGCA19910
CTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGCGGCCCCCGGGTGTCCCTCTCAGGTGCA19980
GGGTGAGTGAGGCGCTGTCCCTGGGTGTCCCTGTCTCGTGTAGGGTGAGTGAGGCTCTGTCCCCAGGTGT15050
E)S
CCTTGGCGTTTGCTCACTTGAGCTTGCTCCTGAATGTTTGCTCTTTCTATAGCCACAGCTGCGCCGGTTG15120
CCCATTGCCTGGGTAGATGGTGCAGGCGCAGTGCTGGTCCCCAAGCCTATCTTTTCTGATGCTCGGCTCT15190
TCTTGGTCACCTCTC~GTTCCATTTTGCT;CGGGGACACGGGACTGCAGGCTCTCGCCTCCCGCGTGCCA15260
GGCACTGCAGCCACAGCTTCAGGTCCGCTTGCCTCTGTTGGGCCTGGCTTGCTCACCACGTGCCCGCCAC15330
ATGCATGCTGCCAATACTCCTCTCCCAGCTTGTCTCATGCCGAGGCTGGACTCTGGGCTGCCTGTGTCTG15400
7O
CTGCCACGTGTTGCTGGAGACATCCCAGA."1AGGGTTCTCTGTGCCCTGAAGGAAAGCAAGTCACCCCAGC15970
CCCCTCACTTGTCCTGTTTTCTCCCAAGCTGCCCCTCTGCTTGGCCCCCTTGGGTGGGTGGCAACGCTTG15540
TCACCTTATTCTGGGCACCTGCCGCTCATTGCTTAGGCTGGGCTCTGCCTCCAGTCGCCCC~TCACATGG'5610
ATTGACGTCCAGCCACAGGTTGGAGTGTCTCTGTCTGTCTCCTGCTCTGAGACCCACGTGGAGGGCCGGT15680
GTCTCCGCCAGCCTTCGTCAGACTTCCCT~TTGGGTCTTAGTTTTGAATTTCACTGATTTACCTCTGACG15750
7J
TTTCTATCTCTCCATTGTATGCTTTTTCT"GGTTTATTCTTTCATTCCTTTTCTAGCTTC':'TAGTTTAGT.5820
CATGCCTTTCCCTCT.-",AGTGCTGCCTTAC~TGCPCCCTGTGTTTTGATGTGAAGTAATCTCAACATCAGC15890
CACTTTCAAGTGTTC'~TAAAATACTTCAAAGTGTTAATACTTCTTTTAAGTATTCTTATTCTGTGATTTT'_590'0
TTTCTTTGTGCACGCTGTGTTTTGACGTG:1AATCATTTTGATATCAGTGACTTTTAAGTAT;CTTTAG~".'10030
CA 02316282 2000-06-21
Le A 32 808-Foreign Countries
-28-
TATTCTGTGATTTCTTTGAGCAGTGAGTTATTTGAACACTGTTTATGTTC GAGTATCAAG16100
AAGATATGTA
ATACGTAGAGTATTTTAAGTTATCATTTTATTATTGATTTCTAACTCAGTTGTGTAGTGGTCTGTATAAT16170
ACCAATTATTTGAAGTTTGCGGAGCCTTGCTTTGTGATCTAGTGTGTGCATGGTTTCCAGAACTGTCCAT16290
TGTAAATTTGACATCCTGTCAATAGTGGGCATGCATGTTCACTATATCCAGCTTATTAAGGTCCAGTGCA16310
S
AAGCTTCTGTCTCCTTCTAGATGCATGAAATTCCAAGAAGGAGGCCATAGTCCCTCACCTGGGGGATGGG16380
TCTGTTCATTTCTTCTCGTTTGGTAGCATTTATGTGAGGCATTGTTAGGTGCATGCACGTGGTAGAATTT16450
TTATCTTCCTGATGAGTGAATCTTTTGGAGACTTCTATGTCTCTAGTAATCTAGTAATTCTTTTTTTAAA16520
TTGCTCTTAGTACTGCCACACTGGGCTTCTTTTGATTAGTATTTTCCTGCTGTGTCTGTTTTCTGCCTTT16590
AATTTATATATATATATATATTTTTTTTTTTTTTGAGACAGAGTCTTGGTCTGTCGCCCAGGGTGAGTGC16660
IO
AGTGGTGTGATCACAGGTCAGTGTAACTTTTACCTTCTGGCCTGAGCCGTCCTCTCACCTCAGCCTCCTG16730
AGTAGCTGGAACTGCAGACACGCACCGCTACACCTGGCTAATTTTTAAATTTTTTCTGGAGACAGGGTCT16800
TGCTGTGTTGCCCAGGCTGGTCTCAAACTCTTGGACTCAAGGGATCCATCTACCTCGGCTTCCCAAAGTG16870
CTGAATTACAGGCATGAGCCACCATGTCTGGCCTAATTTTCAACACTTTTATATTCTTATAGTGTGGGTA16990
TGTCCTGTTAACAGCATGTAGGTGAATTTCCAATCCAGTCTGACAGTCGTTGTTTAACTGGATAACCTGA17010
IS
TTTATTTTCATTTTTTTGTCACTAGAGACCCGCCTGGTGCACTCTGATTCTCCACTTGCCTGTTGCATGT17080
CCTCGTTCCCTTGTTTCTCACCACCTCTTGGGTTGCCATGTGCGTTTCCTGCCGAGTGTGTGTTGATCCT17150
CTCGTTGCCTCCTGGTCACTGGGCATTTGCTTTTATTTCTCTTTGCTTAGTGTTACCCCCTGATCTTTTT17220
ATTGTCGTTGTTTGCTTTTGTTTATTGAGACAGTCTCACTCTGTCACCCAGGCTGGAGTGTAATGGCACA17290
ATCTCGGCTCACTGCAACCTCTGCCTCCTCGGTTCAAGCAGTTCTCATTCCTCAACCTCATGAGTAGCTG17360
2O
GGATTACAGGCGCCCACCACCACGCCTGGCTAATTTTTGTATTTTTAGTAGAGATAGGCTTTCACCATGT17930
TGGCCAGGCTGGTCTCAAACTCCTGACCTCAAGTGATCTGCCCGCCTTGGCCTCCCACAGTGCTGGGATT17500
ACAGGTGCAAGCCACCGTGCCCGGCATACCTTGATCTTTTAAAATGAAGTCTGAAACATTGCTACCCTTG17570
TCCTGAGCAATAAGACCCTTAGTGTATTTTAGCTCTGGCCACCCCCCAGCCTGTGTGCTGTTTTCCCTGC17690
TGACTTAGTTCTATCTCAGGCATCTTGACA'CCCCCACAAGCTAAGCATTATTAATATTGTTTTCCGTGTT17710
2S G
G
A GTAGCTTTGCCCCCGCCCTGCTTTTCCTCCTTTGTTCCCCGTCTGTCTTCTGTCTCAGGC17780
TGTTTCT
CCGCCGTCTGGGGTCCCCTTCCTTGTCCTTTGCGTGGTTCTTCTGTCTTGTTATTGCTGGTAAACCCCAG17850
CTTTACCTGTGCTGGCCTCCATGGCATCTAGCGACGTCCGGGGACCTCTGCTTATGATGCACAGATGAAG17920
ATGTGGAGACTCACGAGGAGGGCGGTCATCTTGGCCCGTGAGTGTCTGGAGCACCACGTGGCCAGCGTTC17990
CTTAGCCAGTGAGTGACAGCAACGTCCGCTCGGCCTGGGTTCAGCCTGGAAAACCCCAGGCATGTCGGGG18060
3
O
TCTGGTGGCTCCGCGGTGTCGAGTTTGAAATCGCGCAAACCTGCGGTGTGGCGCCAGCTCTGACGGTGCT18130
GCCTGGCGGGGGAGTGTCTGCTTCCTCCCTTCTGCTTGGGAACCAGGACAAAGGATGAGGCTCCGAGCCG18200
TTGTCGCCCAACAGGAGCATGACGTGAGCCATGTGGATAATTTTAAAATTTCTAGGCTGGGCGCGGTGGC18270
TCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCGGGTGGATCACGAGGTCAGGAGGTCGAGACCAT18390
CCTGGCCAACATGATGAAACCCCATCTGTACTAAAAACACAAAAATTAGCTGGGCGTGGTGGCGGGTGCC18910
JS
TGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATTGCTTGAACC'TGGGAGTTGGAAGTTGCAGTGA18980
GCCGACATTGCACCACTGCACTCCAGCCTGGCAACACAGCGAGACTCTGTCTCAAAAAAAAAAAAAAAAA18550
AAAAAAAAAAAATTCTAGTAGCCACATTAAAAAAGTAAAAAAGAAAAGGTGAAATTAATGTAATAATAGA18620
TTTTACTGAAGCCCAGCATGTCCACACCTCATCATTTTAGGGTGTTATTGGTGGGAGCATCACTCACAGG18690
ACATTTGACATTTTTTGAGCTTTGTCTGCGGGATCCCGTGTGTAGGTCCCGTGCGTGGCCATCTCGGCCT18760
GGACCTGCTGGGCTTCCCATGGCCATGGCTGTTGTACCAGATGGTGCAGGTCCGGGATGAGGTCGCCAGG18830
CCCTCAGTGAGCTGGATGTGCAGTGTCCGGATGGTGCACGTCTGGGATGAGGTCGCCAGGCCCTGCTGTG18900
AGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTGAGCTGGAGGT18970
ATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCT19090
GGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTAAGCTGGAGGTATGGAGTCCGGATGATGCA19110
4S
GGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGGG19180
TGAGGTCACCAGGCCCTGCGGTGAGCTGGGTGTGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGC19250
CAGACGGTGCCAGACCATGCGGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTTG19320
CCAGGCCCTGCTGTGAGTTGGATGTGGGGTGTCCGGATGCTGCAGGTCCGGTGTGAGGTCACCAGGCCCT19390
GCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGGGTGAAGGTCGCCAGGCCCCTGCTTGTG19960
S
O
AGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGGCCCTCGGTGAGCTGGATGT19530
GCAGTGTCCAGATGGTGCAGGTCCGGGGTGAGGTCGCCAGACCCTGCGGTGAGCTGGATGTGCGGTGTCT19600
GGATGGTGCAGGTCTGGAGTGAGGTCGCCAGGCCCTCGGTGAGCTGGATGTATGGAGTCCGGATGGTGCC19670
GGTCCGGGGTGAGGTCGCCAGACCCTGCTGTGAGCTGGATGTGCGGTGTCTGGATGGTACAGGTCTGGAG19740
TGAGGTCGCCAGACCCTGCTGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCAGGGGTGAGGTCTC19810
SS
CAGGCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGC19880
TGTGAACTGGATGTGCGGCGTCTGGATGGTGCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCTGG19950
AGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCGGC20020
GTCTGGATGGTGCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGA20090
TGCAGGTCCGGGGTGAGGTTGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGTCCG20160
GO
GGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCTGGGGTGAGGT20230
CACCAGGCCCTGCGGTGAGCTGGTTGTGCGGTGTCCGGTTGCTGCAGGTCCGGGGTGAGTTCGCCAGGCC20300
CTCGGTGAGCTGGATGTGCGGTGTCCCCGTGTCCGGATGGTGCAGGTCCAGGGTGAGGTCGCTAGGCCCT20370
TGGTGGGCTGGATGTGCCGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCTTTGGTGAGCTG20990
GATGTGCGGTGTCTGCATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCCTTGGTGGGCTGGATGTGTGGT20510
C)S
GTCCGGATGGTGCAGGTCCGGCGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCGGTGTCTGGATG20580
GTGCAGGTCCGGGGTGAGGTAGCCAAGGCCTTCGGTGAGCTGGATGTGGGGTGTCCGGA"'GGTGCAGGTC20650
CGGGGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCCGGGGTGAG20720
GTCACCAGGCCCTGCGGTTAGCTGGATGTGCGGTGTCTGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGG20790
CCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCAGT20860
GAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCTGGCGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGAT20930
ATGCGGTGTCGGATGGTGCAGGTCCGGGGTGAGGTCACCAGGCCCTGCGGTTAGCTGG..-.TGTG~GGTGTC21000
CGGATGGTG:~AGGTCTGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCTGT.'-
.T~CGGAT.GGTG21070
CAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTGAGCTGGATGTGCTGTATCCGGATG;~TGCAGGTCTGG21190
CGTGAGGTCGCCAGGCCCTGCGGTGAGCTGGATGTGCAGTGTACGGATGGTGCAGGTC:~GGGTGAGGTC21210
7S '
GCCAGGCCCGCGGTGGGCTGTATGTGTGTTGTCTGGATGGTGCAGGTCCGGGGTGAG:':'CGC,P.GGCCC21280
TGCGGTGAGCTGGATGTGTGGTGTCTGG~ITGCTGCAGGTCCGGGGTGAGT.T~GCCAGG~:CTCGGTGAGC21350
TGGATA'rGCGGTGTCCCCGTGTCCGAATGGTGCAGGTCCAG:~GTGAGGTCGCCAGGCC::"TGG"'GGGCTG21420
GATGTGCCG'."GTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCC:T GGTGi,GC,AT'~: 21990
':~ GCGGT
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-29-
GTCCGGATGGTGCAGGTCCG ACCAGGCCCT GATGTGGCATGTCCTTCTCG21560
GGGTGAGGTC CGGTGATCTG
TTTAAGGGGTTGGCTGTGTTCCGGCCGCAGAGCACCGTCTGCGTGAGGAGATCCTGGCCAAGTTCCTGCA21630
CTGGCTGATGAGTGTGTACGTCGTCGAGCTGCTCAGGTCTTTCTTTTATGTCACGGAGACCACGTTTCAA21700
AAGAACAGGCTCTTTTTCTACCGGAAGAGTGTCTGGAGCAAGTTGCAAAGCATTGGAATCAGGTACTGTA21770
S
TCCCCACGCCAGGCCTCTGCTTCTCGAAGTCCTGGAACACCAGCCCGGCCTCAGCATGCGCCTGTCTCCA21890
CTTGCCTGTGCTTCCCTGGCTGTGCAGCTCTGGGCTGGGAGCCAGGGGCCCCGTCACAGGCCTGGTCCAA21910
GTGGATTCTGTGCAAGGCTCTGACTGCCTGGAGCTCACGTTCTCTTACTTGTAAAATCAGGAGTTTGTGC21980
CAAGTGGTCTCTAGGGTTTGTAAAGCAGAAGGGATTTAAATTAGATGGAAACACTACCACTAGCCTCCTT22050
GCCTTTCCCTGGGATGTGGGTCTGATTCTCTCTCTCTTTTTTTTTTCTTTTTTGAGATGGAGTCTCACTC22120
IO
TGTTGCCCAGGCTGGAGTGCAGTGGCATAATCTTGGCTCACTGCAACCTCCACCTCCTGGGTTTAAGCGA22190
TTCACCAGCCTCAGCCTCCTAAGTAGCTGGGATTACAGGCACCTGCCACCACGCCTGGCTAATTTTTGTA22260
CTTTTAGGAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACTCATGACCTCAGGTGATCCAC22330
CCACCTTGGCCTCCCAAAGTGCTGGGTTTACAGGCTAAGCCACCGTGCCCAGCCCCCGATTCTCTTTTAA22900
TTCATGCTGTTCTGTATGAATCTTCAATCTATTGGATTTAGGTCATGAGAGGATAAAATCCCACCCACTT22470
IS
GGCGACTCACTGCAGGGAGCACCTGTGCAGGGAGCACCTGGGGATAGGAGAGTTCCACCATGAGCTAACT22590
TCTAGGTGGCTGCATTTGAATGGCTGTGAGATTTTGTCTGCAATGTTCGGCTGATGAGAGTGTGAGATTG22610
TGACAGATTCAAGCTGGATTTGCATCAGTGAGGGACGGGAGCGCTGGTCTGGGAGATGCCAGCCTGGCTG22680
AGCCCAGGCCATGGTATTAGCTTCTCCGTGTCCCGCCCAGGCTGACTGTGGAGGGCTTTAGTCAGAAGAT22750
CAGGGCTTCCCCAGCTCCCCTGCACACTCGAGTCCCTGGGGGGCCTTGTGACACCCCATGCCCCAAATCA22820
2O
GGATGTCTGCAGAGGGAGCTGGCAGCAGACCTCGTCAGAGGTAACACAGCCTCTGGGCTGGGGACCCCGA22890
CGTGGTGCTGGGGCCATTTCCTTGCATCTGGGGGAGGGTCAGGGCTTTCCCTGTGGGAACAAGTTAATAC22960
ACAATGCACCTTACTTAGACTTTACACGTATTTAATGGTGTGCGACCCAACATGGTCATTTGACCAGTAT23030
TTTGGAAAGAATTTAATTGGGGTGACCGGAAGGAGCAGACAGACGTGGTGGTCCCCAAGATGCTCCTTGT23100
CACTACTGGGACTGTTGTTCTGCCTGGGGGGCCTTGGAGGCCCCTCCTCCCTGGACAGGGTACCGTGCCT23170
2S
TTTCTACTCTGCTGGGCCTGCGGCCTGCGGTCAGGGCACCAGCTCCGGAGCACCCGCGGCCCCAGTGTCC23290
ACGGAGTGCCAGGCTGTCAGCCACAGATGCCCAGGTCCAGGTGTGGCCGCTCCAGCCCCCGTGCCCCCAT23310
GGGTGGTTTTGGGGGAAAAGGCCAAGGGCAGAGGTGTCAGGAGACTGGTGGGCTCATGAGAGCTGATTCT23380
GCTCCTTGGCTGAGCTGCCCTGAGCAGCCTCTCCCGCCCTCTCCATCTGAAGGGATGTGGCTCTTTCTAC23450
CTGGGGGTCCTGCCTGGGGCCAGCCTTGGGCTACCCCAGTGGCTGTACCAGAGGGACAGGCATCCTGTGT23520
3 G
O
GAGGGGCAT GGGTTCACGTGGCCCCAGATGCAGCCTGGGACCAGGCTCCCTGGTGCTGATGGTGGGACA23590
GTCACCCTGGGGGTTGACCGCCGGACTGGGCGTCCCCAGGGTTGACTATAGGACCAGGTGTCCAGGTGCC23660
CTGCAAGTAGAGGGGCTCTCAGAGGCGTCTGGCTGGCATGGGTGGACGTGGCCCCGGGCATGGCCTTCAG23730
CGTGTGCTGCCGTGGGTGCCCTGAGCCCTCACTGAGTCGGTGGGGGCTTGTGGCTTCCCGTGAGCTTCCC23800
CCTAGTCTGTTGTCTGGCTGAGCAAGCCTCCTGAGGGGCTCTCTATTGCAGACAGCACTTGAAGAGGGTG23870
3 C
S
AGCTGCGGG AGCTGTCGGAAGCAGAGGTCAGGCAGCATCGGGAAGCCAGGCCCGCCCTGCTGACGTCCA23990
GACTCCGCTTCATCCCCAAGCCTGACGGGCTGCGGCCGATTGTGAACATGGACTACGTCGTGGGAGCCAG29010
AACGTTCCGCAGAGAAAAGAGGGTGGCTGTGCTTTGGTTTAACTTCCTTTTTAAACAGAAGTGCGTTTGA29090
GCCCCACATTTGGTATCAGCTTAGATGAAGGGCCCGGAGGAGGGGCCACGGGACACAGCCAGGGCCATGG29150
CACGGCGCCAACCCATTTGTGCGCACAGTGAGGTGGCCGAGGTGCCGGTGCCTCCAGAAAAGCAGCGTGG29220
4O
GGGTGTAGGGGGAGCTCCTGGGGCAGGGACAGGCTCTGAGGACCACAAGAAGCAGCCGGGCCAGGGCCTG29290
GATGCAGCACGGCCCGAGGTCCTGGATCCGTGTCCTGCTGTGGTGCGCAGCCTCCGTGCGCTTCCGCTTA29360
CGGGGCCCGGGGACCAGGCCACGACTGCCAGGAGCCCACCGGGCTCTGAGGATCCTGGACCTTGCCCCAC24930
GGCTCCTGCACCCCACCCCTGTGGCTGCGGTGGCTGCGGTGACCCCGTCATCTGAGGAGAGTGTGGGGTG29500
AGGTGGACAGAGGTGTGGCATGAGGATCCCGTGTGCAACACACATGCGGCCAGGAACCCGTTTCAAACAG29570
4S
GGTCTGAGGAAGCTGGGAGGGGTTCTAGGTCCCGGGTCTGGGTGGCTGGGGACACTGGGGAGGGGCTGCT24690
TCTCCCCTGGGTCCCTATGGTGGGGTGGGCACTTGGCCGGATCCACTTTCCTGACTGTCTCCCATGCTGT29710
CCCCGCCAGGCCGAGCGTCTCACCTCGAGGGTGAAGGCACTGTTCAGCGTGCTCAACTACGAGCGGGCGC29780
GGCGCCCCGGCCTCCTGGGCGCCTCTGTGCTGGGCCTGGACGATATCCACAGGGCCTGGCGCACCTTCGT29850
GCTGCGTGTGCGGGCCCAGGACCCGCCGCCTGAGCTGTACTTTGTCAAGGTGGGTGCCGGGGACCCCCGT29920
S
O
GAGCAGCCCTGCTGGACCTTGGGAGTGGCTGCCTGATTGGCACCTCATGTTGGGTGGAGGAGGTACTCCT24990
GGGTGGGCCGCAGGGAGTGCAGGTGACCCTGTCACTGTTGAGGACACACCTGGCACCTAGGGTGGAGGCC25060
TTCAGCCTTTCCTGCAGCACATGGGGCCGACTGTGCACCCTGACTGCCCGGGCTCCTATTCCCAAGGAGG25130
GTCCCACTGGATTCCAGTTTCCGTCAGAGAAGGAACCGCAACGGCTCAGCCACCAGGCCCCGGTGCCTTG25200
CACCCCAGTCCTGAGCCAGGGGTCTCCTGTCCTGAGGCTCAGAGAGGGGACACAGCCCGCCCTGCCCTTG25270
SS
GGGTCTGGAGTGGTGGGGGTCAGAGAGAGAGTGGGGGACACCGCCAGGCCAGGCCCTGAGGGCAGAGGTG25390
ATGTCTGAGTTTCTGCGTGGCCACTGTCAGTCTCCTCGCCTCCACTCACACAGGTGGATGTGACGGGCGC25910
GTACGACACCATCCCCCAGGACAGGCTCACGGAGGTCATCGCCAGCATCATCAAACCCCAGAACACGTAC25980
TGCGTGCGTCGGTATGCCGTGGTCCAGAAGGCCGCCCATGGGCACGTCCGCAAGGCCTTCAAGAGCCACG25550
TAAGGTTCACGTGTGATAGTCGTGTCCAGGATGTGTGTCTCTGGGATATGAATGTGTCTAGAATGCAGTC25620
6O
GTGTCTGTGATGCGTTTCTGTGGTGGAGGTACTTCCATGATTTACACATCTGTGATATGCGTGTGTGGCA25690
CGTGTGTGTCGTGGTGCATGTATCTGTGGCGTGCATATTTGTGGTGTGTGTGTGTGTGGCACGTGTGTGT25760
CCATGGTGTGTGTGCCTGTGGTGTGCATGTGTGTGTGTCTGTGACACGTGCATGTTCATGCTGTGTGCTG25830
CATGTCTGTGATGTGCCTATTTGTGGTGTGTGTGTGCATGTGTCCGTGACATATGCGTGTCTATGGCATG25900
GGTGTGTGTGGCCCCTTGGCCTTr~CTCCTTCCTCCTCCAGGCATGGTCCGCACCATTGTCCTCACGCTCT25970
C)S
CGGGTGCTGGTTTGGGGAGCTCCACATTCAGGGTCCTCACTTCTAGCATGGGTGCCCCTGTCCTGTCACA26040
GGGCTGGGCCTTGGAGACTGTA.;~CC.aGGTTTGAGAGGAGAGTAGGGATGCTGGTGGTACCTTCCTGGAC26110
CCCTGGCACCCCCAGGACCCC~~TCTGG~CTATGCCGGCTCCATGAGATATAGGAAGGCTGATTCAGGCC26180
TCGCTCCCCGGGACACACTCCTCCCAGAGCGGCCGGGGGCCTTGGGGCTCGGCAGGGGTGAAAGGGGCCC26250
TGGGCTTGGGTTCCCACCCAGTGGTCATGAGCACGCTGGAGGGGTAAGCCCTCAAAGTCGTGCCAGGCCG26320
7O
GGGTGCAGAGGTGAAGAAGTAT~~CCT~Ga,GCTTCGGTCTGGGGAGAGGCACATGTGGAAACCCACAAGGA26390
CCTCTTTCTCTGACTTCTTGA.~__ 26419
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-30-
Contig 2:
TGTGGGATTGGTTTTCATGTGTGGGATAGG TGGGATTGGT GGGGTAACAC70
TGGGGATCTG TTTTATGAGT
AGAGTTCAAGGCGAGCTTTCTTCCTGTAGTGGGTCTGCAGGTGCTCCAACAGCTTTATTGAGGAGACCAT190
ATCTTCCTTTGAACTATGGTCGGGTTTATAGTAAGTCAGGGGTGTGGAGGCCTCCCCTGGGCTCCCTGTT210
S
CTGTTTCTTCCACTCTGGGGTCGTGTGGTGCCTGCTGTGGTGTGTGGCCGGTGGGCAGGGCTTCCAGGCC280
TCCTTGTGTTCATTGGCCTGGATGTGGCCCTGGCTACGCTCCGTCCTTGG CGAGTTGGAG350
AATTCCCCTG
GCTTTCTTTCTTTCTTTTTTTCTTTCTTTTTTTTTTTTTTTGATAACAGAGTCTCGCTCTTTTTTGCCCA920
GGCTGGAGTGGTTTGGCGTGATCTTGGCTCACTGCAACCTGTGCTTCCTGAGTTCAAGCAATTCTCTTGC990
CTCAGCCTCCCAAGTAGCTGGAATTATAGGCGCCCACCACCATGCTGACTAATTTTTGTAATTTTAGTAG560
IO
AGACGAGGTTTCTCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCTCCCACCTCGGC630
CTCCCAAAGTGCTGGGATGACAGGTGTGAACCGCCGCGCCCGGCCGAGACTCGCTTCCTGCAGCTTCCGT700
GAGATCTGCAGCGATAGCTGCCTGCAGCCTTGGTGCTGACAACCTCCGTTTTCCTTCTCCAGGTCTCGCT770
AGGGGTCTTTCCATTTCATGACTCTCTTCACAGAAGAGTTTCACGTGTGCTGATTTCCCGGCTGTTTCCT890
GCGTAATTGGTGTCTGCTGTTTATCGATGGCCTCCTTCCATTTCCTTTAGGCTTTGTTTATTGTTGTTTT910
IS
TCCGGCTCCTTGAAGGAAAAGTTTCGATTATGGATGTTTGAACTTTCTTTTCTAAACAAGCATCTGAAGT980
TGCCGTTTTCCCTCTAAAGCAGGGATCCCGAGGCCCCTGGCTGTGGAGTGGCACCGGTCTGGGGCCTGTT1050
AGGAACCCGGCGCACAGCGGGAGGCTAGGTGGGGTGTGGGGAGCCAGCGTTCCCGCCTGAGCCCCGCCCC1120
TCTCAGATCAGCAGTGGCATGCi;GTGCTCAGAGGCGCACACACCCTACTGAGAACTGTGCGTGAGAGGGG1190
TCTAGATTCTGTGCTCCTTATGGGAATCTAATGCCTGATGATCTGAGGTGGAACCGTTTGCTCCCAAAAC1260
2
O
CATCCCCTTCCCCACTGCTGTCCTGTGGAAAAATCGTCTTCCACGAAACCAGTCCCTGGTACCACAATGG1330
TTGGGGACCCTGTGCTAAAGACCTGCTTCAGCAGCCTCTCGTCAGTGTTGATATATTGGCTTTTCTGTGT1900
TGAGTCCAGAATAATTACGGATTTCTGTGA.TGCTTTCCGCCGACCTCAGACCCATGGGCTATTTGTGGGC1470
GTGTTGCCTGCTCCTGGGTTGGGAAGGGTGCAGGCCCCATGTACCTTCCTGTTACTGCCTTCCAGGTTGG1540
TTCTCAGGGTTGAATCGTACTCGATGTGGTTTTAGCCCACGGCCCTGCCGCCAGCTCCTGGGGGCTGGGG1610
2S
AACATGCTGAAGCACAGAGTCACCGTGCGCGTCTTTTGATGCCTCACAAGCTCGAGGCCTCCTGTGTCCG1680
TGTTAGTGTGTGTCACGTGCCTGCTCACATCCTGTCTTGGGGACGCAGGGGCTTAGCAGGTCCCGTAGTA1750
AATGACAAGCGTCCTGGGGGAGTCTGCAGAATAGGAGGTGGGGGTGCCGGTCTCTCTCCCGCGTCTTCAG1820
ACTCTTCTCCTGCCTGTGCTGTGGCTGCACCTGCATCCCTGCAATCCCTCCAGCACTGGGCTGGAGAGGC1890
CCGGGAGCTCGAGTGCCACTTGTGCCACGTGACTGTGGATGGCAGTCGGTCACGGGGGTCTGATGTGTGG1960
3
O
TGACTGTGGATGGCGGTTGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2030
TGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2100
TGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG2170
TGGTGAC'TGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG2290
TGGTGACTGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG2310
3
S
TGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2380
TGTGTGG'PGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2450
TGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGG2520
GGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCG2590
GTCGivGv'GTCTGATGTGTGGTGACTGTGGATGGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTG2660
4O
GATGGCGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGT2730
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGT2800
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGT2870
GACTGTGGATGGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGAT2990
GTGGTGACTGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGAT3010
4
S
GTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTG3080
ATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTG3150
ATGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTG3220
GGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTG3290
GGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTAGGGTCTGATGTGTGGTGACTGTGGATGGCAGTCG3360
S
O
GTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATG3930
GCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGA3500
TGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTAGCT3570
GCAGGTGGAGTCCCAGGTGTGTCTGTAGCTACTTTGCGTCCTCGGCCCCCCGGCCCCCGTTTCCCAAACA3690
GAAGCTTCCCAGGCGCTCTCTGGGCTTCATCCCGCCATCGGGCTTGGCCGCAGGTCCACACGTCCTGATC3710
SS
GGAAGAAACAAGTGCCCAGCTCTGGCCGGGGCAGGCCACATTTGTGGCTCATGCCCTCTCCTCTGCCGGC3780
AGGTCTCTACCTTGACAGACCTCCAGCCGTACATGCGACAGTTCGTGGCTCACCTGCAGGAGACCAGCCC3850
GCTGAGGGATGCCGTCGTCATCGAGCAGGTCTGGGCACTGCCCTGCAGGGTTGGGCACGGACTCCCAGCA3920
GTGGGTCCTCCCCTGGGCAATCACTGGGCTCATGACCGGACAGACTGTTGGCCCTGGGGGGCAGTGGGGG3990
GAATGAGCTGTGATGGGGGCATGATGAGCTGTGTGCCTTGGCGAAATCTGAGCTGGGCCATGCCAGGCTG9060
6O
CGACAGCTGCTGCATTCAGGCACCTGCTCACGTT.TGACTGCGCGGCCTCTCTCCAGTTCCGCAGTGCCTT913J
TGTTCATGATTTGCTAAATGTCTTCTCTGCCAGTTTTGATCTTGAGGCCAAAGGAAAGGTGTCCCCCTCC92CJ
TTTAGGAGGGCAGGCCATGTTTGAGCCGTGTCCTGCCCAGCTGGCCCCTCAGTGCTGGGTCTGAGGCCAA4270
AGGAAACGTGTCCCCCTTCTTAGGAGGACGGGCCGTGTTTGAGCCACGCCCCGCTGAGCGGGCCTCTCAG934J
TGCTGGGTCTGTCCACGTGGCCCTGTGGCCCTTTGCAGATGTGGTCTGTCCACGTGGCCCTGTGGCTCTT941J
C
J
TGCAGATGCCTGTTAGCACTTGCTCGGCTCTAGGGGACAGTCGTGTCCACCGCATGAGGCTCAGAGACCT448:7
CTGGGCGAATTTCCTTGGCTCCCAGGGTGGGGGTGGAGGTGGCCTGGGCTGCTGGGACCCAGACCCTGTG455)
CCCGGCAGCTGGGCAGCAACTCCTGGATCACATATGCCATCCGGGCCACGGTGGGCTGTGTGGGTGTGAG46~J
CCCAGCTGGACCCACAGGTGGCCCAGAGGAGACGTTCTGTGTCACACACTCTGCCTAAGCCCATGTGTGT969J
CTGCAGAGACTCGGCCCGGCCAGCCCACGATGGCCCTGCATTCCAGCCCAGCCCCGCACTTCATCACi-_i,A970
7O
CACTGACCCC GAGGGTCTTGGCCACGTGGTCCTGCCTGTCTCAGCACCCACCGGCTCACT983;
AAAAGGGACG
CCCATGTGTC TTTCGCAGAGCTCC':CCCTG GCAGTGGCCTCTTCGACGTC49CJ
TCCCGTCTGC AATGAGGCCA
TTCCTACGCT CCACGCCGTGCGCATCAGGGGCAAGTGAGTCAGGTGGCCAGGTGCCATTG99,7
TCATGTGCCA
CCCTGCGGGT
GCTGGCAGGGCT.TC'_"GC':CACCTCTCTCCTGCCCC:'TCCCCACTGtICC'.".'S04J
GGCTGGGCGG
CTGCCCGGGG CTCCTTTTCTG CCTGGGCTGCAGGCTCCCGA511
7J CCACCAGe'~GT v CCCCCGCC
CCCTCCGGCT
GGCCCCGGAA GCTTGCGGCAGCCGGAGCGG ACACGAGGCCTGGAAAT~~~C518J
ACATGGCTCG AGCAGGTGCC
P.AGCGGGGTG CCTGCGTGGAGGACGA~GGG GTCTGGGTCA~GTGTGC;~~~-.5:'
TGGAGTTGCT CGGGGGGTGT
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-31 -
GAGCGTTTGAGCCTGCAGCTTGTCAGCTCC TGACGCTGGACACCCGGCTCTCACACGCTT5320
AAGTTACTAC
GTATCTCTCTCTCCCGATAC TATCCGATTCTCATTCCTGTCCCTGTCGTGTGACCCCCGC5390
AAAAGGATTT
GAGGGCGCGGGCTCTTCTCTCTGTGACTAGATTTCCCATCTGGAAAGTGCGGGGTTGACCGTGTAGTTTG5960
CTCCTCTCGGGGGGCCTGTGGTGGCCATGGGGCAGGCGGCCTGGGAGAGCTGCCGTCACACAGCCACTGG5530
S
GTGAGCCACACTCACGGTGGTAGAGCCACAGTGCCTGGTGCCACATCACGTCCTCTGGATTTTAAGTAAA5600
ACCACACACCTCCCGGCAGGCATCTGCCTGCGACCCTGTGTGTGCCTGGGGAGAGTGGTAGCACGGAGGA5670
AATTCGTGCACACTCAAGGTCATCAGCAAGGTCATCCGCAGTCAGGTGGAACGTGGAGGCCTCTCTCTGG5790
GATCGTCTCCAGCGGATAAAGGACTGTGCACAGCTTCGGAAGCTTTTATTTAAAAATATAACTATTAATT5810
ATTGCATTATAAGTAATCACTAATGGTATCAGCAATTATAATATTTATTAAAGTATAATTAGAAATATTA5880
IO
AGTAGTACACACGTTCTGGAAAAACACAAATTGCACATGGCAGCAGAGTGAATTTTGGCCGAGGGACACG5950
TGTGCACATGTGTGTAAGCGGCCCCCAGGCCCACAGAATTCGCTGACAAAGTCACCTCCCCAGAGAAGCC6020
ACCACGGGCCTCCTTCGTGGTCGTGAATTTTATTAAGATGGATCAAGTCACGTACCGTCCACGTGTGGCA6090
GGGCTTTGGGGAATGTGAGGTGATGACTGCGTCCTCATGCCCTGACAGACAGGAGGTGACTGTGTCTGTC6160
CTGTCCCTAGGACACGGACAGGCCCGAAGCTCTAGTCCCCATCGTGGTCCAGTTTGGCCTCTGAATAAAA6230
IS A
CGTCTTCAAAACCTGTTGCCCCAAAAACTAAGAACAGAGAGAGTTTCCCATCCCATGTGCTCACAGGGG6300
CGTATCTGCTTGCGTTGACTCGCTGGGCTGGCCGGACTCCTAGAGTTGGTGCGTGTGCTTCTGTGCAAAA6370
AGTGCAGTCCTCTTGCCCATCACTGTGATATCTGCACCAGCAAGGAAAGCCTCTTTTCTTTTCTTTCTTT6990
TTTTTTTTTTGAGACGGAACGTCACTGTTGTCTGCCTGGGCTTGAGTGCAGTGGCGCGATCTCAACTCAC6510
TGCAACCTCCGCCTCCCGGGTTCCAGCATTTCTCCTGCCTCAGCCTCCCGAGCAGCTGAGATTACAGGCA6580
2O
CCCACCCCCTGCGCCTGGCTAATTTTTGTATTTTTAGTAGAGAGGGGTTTTTGCCATGTTGGCCAGGCTG6650
GTCTCGAACTCCTGACCTCAGGTGATCCACCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAG6720
CCATCACGCCCAGCCGGAAAGCCTCTTTTTAAGGTGACCACCTATAGCGCTTCCCGAAAATAACAGGTCT6790
TGTTTTTGCAGTAGGCTGCAAGCGTCTCTTAGCAACAGGAGTGGCGTCCTGTGGGCTCTGGGGATGGCTG6860
AGGGTCGCGTGGCAGCCATGCCTTCTGTG'I'GCACCTTTAGGTTCCACGGGGCTATTCTGCTCTCACTGTT6930
2S
TGTCTGAAAACGCACCCTTGGCATCCTTGTTTGGAGAGTTTCTGCTTCTCGTTGGTCATGCTGAAACTAG7000
GGGCAAGGTTGTATCCGTTGGCGCGCAGCGGCTACATGTAGGGTCATGAGTCTTTCACCGTGGACAAATT7070
CCTTGAAAAAAAAAAAAGGAGTCCGGTTAAGCATTCATTCCGGGTCAAGTGTCTGGTTCTGTGAATAAAC7190
TCTAAGATTTAAGAAACCTTAATGAAAGAAAACCTTGATGATTCAGAGCAAGGATGTGGTCACACCTGTG7210
GCTGGATCTGTTTCAGCCGCCCCAGTGCATGGTGAGAGTGGGGAGCAGGGATTGTTTGTTCAGAGGTCTC7280
3
O
ATCTGGTATGTTTCTGAGGTGTTTGCCGGCTGAATGGTAGACGTGTCGTTTGTGTGTATGAGGTTCTGTG7350
TCTGTGTGTGGCTCGGTTTGAGTGTACGCATGTCCAGCACATGCCCTGCCCGTCTCTCACCTGTGTCTTC7420
CCGCCCCAGGTCCTACGTCCAGTGCCAGGGGATCCCGCAGGGCTCCATCCTCTCCACGCTGCTCTGCAGC7490
CTGTGCTACGGCGACATGGAGAACAAGCTGTTTGCGGGGATTCGGCGGGACGGGTGAGGCCTCCTCTTCC7560
CCAGGGGGGCTTGGGTGGGGGTTGATTTGCTTTTGATGCATTCAGTGTTAATATTCCTGGTGCTCTGGAG7630
3
S
ACCATGACTGCTCTGTCTTGAGGAACCAGACAACGTTGCAGCCCCTTCTTGGTATGAAGCCGCACGGGAG7700
GGGTTGCACAGCCTGAGGACTGCGGGCTCCACGCAGGCTCTGTCCAGCGGCCATGTCCAGAGGCCTCAGG7770
GCTCAGCAGGCGGGAGGGCCGCTGCCCTGCATGATGAGCATGTGAATTCAACACCGAGGAAGCACACCAG7840
CTTCTGTCACGTCACCCAGGTTCCGTTAGGGTCCTTGGGGAGATGGGGCTGGTGCAGCCTGAGGCCCCAC7910
ATCTCCCAGCAGGCCCTCGACAGGTGGCCTGGACTGGGCGCCTCTTCAGCCCATTGCCCATCCCACTTGC7980
ATGGGGTCTACACCCAAGGACGCACACACCTAAATATCGTGCCAACCTAATGTGGTTCAACTCAGCTGGC8050
TTTTATTGACAGCAGTTACTTTTTTTTTTTTAATACTTTAAGTTCTAGGGTACATGTGCACGACGTGCAG8120
~TTAGTTACATATGTATACATGTGCCATGTTGGTGTGCTGCACCCATTAACTCATCATTTACATTAGGTA8190
TATC.TCCTAATGCTATCCCTCCCCACTCCCCCCATCCCATGACAGGCCCTGGTGTGTGATGTTCCCCACC8260
CTGTGTCCAAGTGTTCTCATTGTTCAGTTCCCACCTGTGAGTGAGAACATGTGGTGTTTGGTTTTCTTTC8330
4S '
CT TTTGCTCAGAGTGATGGTTTCCAGCTTCGTCCATGTCCCTACAAAGGACATGAACTCATC8900
TGCAATAG
CTTTTTTATGACTGCATAGTATTCCGTGGTGTATATGTGCCACATTTTCTTAATCCAGTCTATCATCGAT8970
GGACATTTGGGTTGGTTGCAAGTCTTTGCTACTGTGAATAGTGCCGCAATAAACATACGTGTGCATGTGT8540
CTTTATAGCAGCATGATTTATAATCCTTTGGGTATATACCCAGTAATGGGATGGCTGGGTCAAATGGTAT8610
T'rCTAGTTCTAGATCCTTGAGGAATCACCACACTGTCTTCCACAATGGTTGAACTAGTTTACACTCCCAC8680
S
O
CAACAGTGTAAAAGTGTTCTGGTGCTGGAGAGGATGTGGACAGCAGTTATTTTTTTATGAAAATAGTATC8750
ACTGAACAAGCAGACAGTTAGTGAAGGATGCGTCAGGAAGCCTGCAGGCCACACAGCCATTTCTCTCGAA8820
GACTCCGGGTTTTTCCTGTGCATCTTTTGAAACTCTAGCTCCAATTATAGCATGTACAGTGGATCAAGGT8890
TCTTCTTCATTAAGGTTCAAGTTCTAGATTGAAATAAGTTTATGTAACAGAAACAAAAATTTCTTGTACA8960
CACAACTTGCTCTGGGATTTGGAGGAAAGTGTCCTCGAGCTGGCGGCACACTGGTCAGCCCTCTGGGACA903C
S
S
GGATACCTCTGGCCCATGGTCATGGGGCGCTGGGCTTGGGCCTGAGGGTCACACAGTGCACCATGCCCAG9100
CTTCCTGTGGATAGGATCTGGGTCTCGGATCATGCTGAGGACCACAGCTGCCATGCTGGTAAAGGGCACC91'70
ACGTGGCTCAGAGGGGGCGAGGTTCCCAGCCCCAGCTTTCTTACCGTCTTCAGTTATTTTTCCCTAAGAG9290
TCTGAGAAGTGGGGCCGCGCCTGATGGCCTTCGTTCGTCTTCAGCTGGCACAGAATTGCACAAGCTGATG9310
GTAAACACTGAGTACTTATAATGAATGAGGAATTGCTGTAGCAGTTAACTGTAGAGAGCTCGTCTGTTGG9380
AA
AGAAATTT AAGTTTTTCATTTAACCGCTTTGGAGAATGTTACTTTATTTATGGCTGTGTAAATTGTTT9950
GACATTCAGTCCCTCGTAGACAGATACTACGTA.a.AAAGTGTAAAGTTAACCTTGCTGTGTATTTTCCCTT9520
ATTTTAGGCTGCTCCTGCGTTTGGTGGATGATTTCTTGTTGGTGACACCTCACCTCACCCACGCGAAAAC9590
CTTCCTCAGGTGAGGCCCGTGCCGTGTGTCTGTGGGGACCTCCACAGCCTGTGGGCTTTGCAGTTGAGCC9660
CCCCGTGTCCTGCCCCTGGCACCGCAGCGTTGTCTCTGCCAAGTCCTCTCTCTCTGCCGGTGCTGGATCC9730
GS
GCAAGAGCAGAGGCGCTTGGCCGTGCACCCAGGCCTGGGGGCGCAGGGGCACCTTCGGGAGGGAGTGGGT9800
ACCGTGCAGGCCCTGGTCCTG~AGAGACGCACCC.=,GGTTACACACGTGGTGAGTGCA~GGCGGTGACCTGG9370
CTCCTGCTGCTCTTTGGAAAG'."CAAG-
~,GT_GGCGGCT~CTGGGGCCCCAGTGAGACCC:CAGGAGCTGTGC9940
ACAGGGCCTGCAGGGCCGAGGCGGCAGCCTCCTCCCCAGGGTGCACCTGAGCCTGCGGAGAGCAGGAGCT10010
GCTGAGTGAGCTGGCCCACAGCGTTCGCTGCGGT~~ACGT'"CCTGCGTGGGGTTGTTT.GGGATCGGTGGGA10080
7O
GAATTTGGATTTGCTGAGTGCTGCTGTCTTGAS-
.~_.=~CGGi,GATGGCTAGGAGTGGGTT.TCAGAGTTGATT10150
TTTGTGAATCAAACTAAAATC~GGC=,~=;GGGGA~~TGGC~TCAGCACAGGGGATTGTC~AATGTGGTCCC1220
CCTCAAGGGCGCCCCACAGAG;CGGT;>GGCTTGTT:'TAA~"-
,GTGCGATTTGACGAGGGACGAGAAACCTTG1;7290
AAAGCTGTAAAGGGAACCCTCAGAAAATGTGGCCGCCAGGGGTGGTTTCAGGTGCTTTGCTGGGCTGTGT10360
TTGTGAAAACCCATTTGGACC:GCCC:CCAAGTC~ACCCTCCAGGTCCACCCTCCAGGGCCGCCCTGGGC'0430
7J TG '
"
GGGGTATG CCTGGCGTTCC AGC~~GGAG:.ACAGCAGGCTGTGCACATTTAAATCCACTA'x')500
_
TGTG'CGC
AGATTCACTCGGGGGGA~CCCAGGTCCCAAGCAr.~TGAGGGCTCAGGAGTCCTGAGGCTGCTGAGGGGAC10570
AGAGCAGACGGGGAACGCTGCTTCTGTGTGGCr.AGTTCCTGAGGGTGCTGGCCAGGGAGGTGGCTCAGAG'0640
TGTATGTTGGGGTCCCACCGG ~GGCA TCTG~'~ATGAGTCGGCAGCCATGTAACAGGAAGGGG_~i710
~.=;.,C "~T~~
CA 02316282 2000-06-21
Le A 32 805-Forei~~n Countries
-32-
TGGCCACAGG GAGCTGGGAA TGCACCAGGG GAGCTGCGCA GCTGGCCGAG
GTCCCAGGGC CAGGCCACAG 10780
GAAGGGCAGG GGGACGCCCG GGGCCACAGC AGAGGCCGCA GGAAGGGAAG
GGGATGCCCA GGCCAGAGCA 10850
GAGGCTACCG GGCACAGGGG GGCTCCCTGA GCTGGGTGAG CGAGGCTCAT10920
GACTCGGCGA GGGAACCTCC
TTGACGTGAA GCTGACGACT GGTGTTGCCC AGCTCACAGC CCAGCCAGGT10990
S CCCGCGCCTG AGCAGGAACT
CAGAACCCTC CCCTTTGTCT AAAGCACAGC AGATGCCTTC AGGGCATCTA11060
GGAGAAAACA GGCAAAGTCG
TTGAGAAACG TCTTAAAAGA AGGTGGGATG GTGGCAATTT CTTGTCCAGA11130
TTTTAGTCTG CCCCGGACCA
CAGATGAGTC TATAACGGGA TTGTGGTGTT GCCATGGGGA CACATGAGAT11200
GGACCATCAC AGAGGCCACT
GGGGCTGCAC CTCCCATCTG AGTCCTGGCT GTCCCGGGTC CAGGCCAGGT11270
TCTTGCATGC TCACCTACCT
GTCCTGCCCG GGAGACAGGG AAAGCACCCC GAAGTCTGGA GCAGGGCTGG11340
IO GTCCAGGCTC CTCAGAGCTC
CTGCCAGGCC CAGCACCCTG CTCCAAATCA CCACTTCTCT GGGGTTTTCC11910
AAAGCATTTA ACAAGGGTGT
CAGGTTACCT CCTGGGTGAC GGCCCCGCAT CCTGGGGCTG ACATTGCCCC11980
TCTGCCTTAG GACCCTGGTC
CGAGGTGTCC CTGAGTATGG CTGCGTGGTG AACTTGCGGA AGACAGTGGT11550
GAACTTCCCT GTAGAAGACG
AGGCCCTGGG TGGCACGGCT TTTGTTCAGA TGCCGGCCCA CGGCCTATTC11620
CCCTGGTGCG GCCTGCTGCT
IS GGATACCCGG ACCCTGGAGG TGCAGAGCGA CTACTCCAGG TGAGCGCACC11690
TGGCCGGAAG TGGAGCCTGT
GCCCGGCTGG GGCAGGTGCT GCTGCAGGGC CGTTGCGTCC ACCTCTGCTT11760
CCGTGTGGGG CAGGCGACTG
CCAATCCCAA AGGGTCAGAG GCCACAGGGT GCCCCTCGTC CCATCTGGGG11830
CTGAGCAGAA ATGCATCTTT
CTGTGGGAGT GAGGGTGCTC ACAACGGGAG CAGTTTTCTG TGCTATTTTG11900
GTAAAAGGAA ATGGTGCACC
AGACCTGGGT GCACTGAGGT GTCTTCAGAA AGCAGTCTGG ATCCGAACCC11970
AAGACGCCCG GGCCCTGCTG
GGCGTGAGTC TCTCAAACCC GAACACAGGG GCCCTGCTGG GCATGAGTCC12090
2O CTCTGAACCC GAGACCCTGG
GGCCCTGCTG GGCGTGAGTC TCTCCGAACC CAGAGACTTC AGGGCCCTTT12110
TGGGCGTGAG TCTCTCCGCT
GTGAGCCCCA CACTCCAAGG CTCATCCACA GTCTACAGGA TGCCATGAGT12180
TCATGATCAC GTGTGACCCA
TCAGGGGACA GGGCCATGGT GTGGGGGGGG TCTCTACAAA ATTCTGGGGT12250
CTTGTTTCCC CAGAGCCCGA
GAGCTCAAGG CCCCGTCTCA GGCTCAGACA CAAATGAATT GAAGATGGAC12320
ACAGATGCAG AAATCTGTGC
TGTTTCTTTT ATGAATAAAA AGTATCAACA-TTCCAGGCAG GGCAAGGTGG12390
2 CTCACACCTA TAATCCCAGC
S
ACTTTGGGAG GCCGAGGTGG GTGGATCACT TGAGGCCAGG AGTTTGAGGC12960
CAACCTAACC AACATAGTGA
AATTCCATTT CTACTTAAAA AATACAAAAA TTAGCCTGGC CTGGTGGCAC12530
ACGCCTGTAG TCCCCGCTAT
GCGGGAGGCT GAGGCAGGAG AATCATTTGA ACCCAGGAGG CAGAGGTTGC12600
AGTGAGCCGA GATCACACCA
CTGCACTCCA GCCTGGGCAA CAGAGTGAGA CTTCATCTTA AAAAAAAAAA12670
AAAAAGTATC AGCATTCCAA
AACCATAGTG GACAGGTGTT TTTTTATTCT GTCCTTCGAT AATATTTACT12740
3 GGTGCTGTGC TAGAGGCCGG
O
AACTGGGGGT GCCTTCCTCT GAAAGGCACA CCTTCATGGG AAGAGAAATA12810
AGTGGTGAAT GGTTGTTAAA
CCAGAGGTTT AAACTGGGGT CCTGTCGTTC TGAGTTAACA GTCCAGATCT12880
GGACTTTGCC TCTTTCCAGA
ATGCTCCCTG GGGTTTGCTT CATGGGGGAG CAGCAGGTGT GGACACCCTC12950
GTGATGGGGG AGCAGCAGGT
GCAGACGCCC TCATGATGGG GGAGTGGCAG GTGCAGACAC CCTTGTGCAT13020
GGTGCCCAGC ATGTCCCTGT
TGCAGCTCCC TCCCCACAAG GATGCCGGTC TCCTGTGCTC CCCACAGTCC13090
3 CTGCTTCCCT CTCACAGCCT
S
TACCTGGTCC TGGCCTCCAC TGGCTTTGTC TGCATGATTT CCACATTTCC13160
TGGGCTCCCA GCACCTCTTC
GCCTCTCCCA GGCACCTCTG CAGTGCTGGC CATACCAGTC AGCTGTGAAC13230
TGTCCACTGC TTATTTTGCT
CCCCATGAAA TGTATTTTTT AGGACAGGCA CCCCTGGTTC CAGCCTCTGG13300
CACAGCATCA GTGAATGTTA
TTGAAGGACA AAGGACAGAC AAACAAATCA GGAAAATGGG TTCTCTCTAA13370
ACACATTGCA AAGCCACAGA
GGCTAGTGCA GGATGGGTGG GCATCAGGTC ATCAGATGTG GGTCCAATGC13990
CAGAATATTC TGTGCTCCCA
AAGGCCACTT GGTCAGAGTG TGTGCTTGCA GAGGTGGCTC TAAAAGCTCA13510
GCAGTGGAGG CAGTGGTTCG
CCATACTCAG GGTGAACTCA CATCCTCTGT GTCTGAAGTA TACAGCAGAG13580
GCTTGAAGGG CATCTGGGAG
A.AGAAAACAG GCAAAATGAT TAAGAAAAGT GAAAAAGGAA AAGTGGTAAG13650
ATGGGAATTT TCTTGTCCAG
ATTTTAGTCT CCCAAACCAC AGCTCAGATG GTAGAATGTG GTCAGAACTG13720
ATGGACAGAA CAATAGAACA
AAACGGAAGC CCTATCTCTC AGAAACGTGT GTTAATGTGG TATGTGGCAC13790
4S AGCTGATGGA AAAGAGAGTG
TGTGTGTAAT TTTTTTTTCT GAGAAAACTG ACTGGAAGCA AATAAGTTGT13860
GTCTTTACAG CATATACCAG
AGCAGATTCT AGGTAGAAGA GGAGACACAT GCAAACAACA CCAGCAACAG13930
AAATAAAACA AAAGACTCAA
AGGGAAGGGA GGTGAACGTT CCCTGGTTTG GTGTTGGGGA AGGACACACA19000
GGGAGGCGGA TGAAACCAGT
GAGGCAACGG GCATTGCTTT CACTGCAGAG AAACTCAGCT TGCCTGAGCC14070
ACAGTGAAAA TGGCCATTCC
CTGGAGCGTT TGTGCACGTG ATTTATTTAA GGCGCCCTGT GAGGTCCTGC14190
S ACATTCATCC TCTCACTTTG
O
TTCTCCTAAC CACCTGAGAG GTAGAGGAGG AAAGGCTCCA GGGGAGCAGC14210
CGCCCTTGGT CACCCAGCTG
GCAAAGGGCA TGCATGATTG CAGCCTGGCC TCCTGCTCCG GGGCCCTTGC19280
TCTGCCCGAG GACCCCACAC
AAGTCAGACC CATAGGCTCA GGGTGAGCCG GAGCCCAAGG TCGTGTTGGG19350
GATGGCTGTG AAAGAAGAAA
TGGACGTCTG ATGCACACTT GGGAAGGTCC TACCAGCAGC GTCAAAGAAA19420
TGCATGTGAA ACTGACAGCG
AGACCCATCC CTCAAAGAAA CGCACGTGAA ACTGATGGCG AGACCTGTCC14990
SS CCATCCCTCA TGCTGG~:.''::C
TTTTCTGGGC TTGCCAAGAG CCAGCATCAG GTTGAGGCAA GCTGGAAAGA19560
CTTTTCTGGA AAGCAGCTTG
TTTGCATGGA AGTCCTCACA ATGTCCTGTG TCTTCCCAGT AATTCCACTT19630
CTGAAGTGAC CAGACATTAT
CACGGGTCTT ATTTACCATT TCCAGTGTTC CAGGCAGGGG GACTTGCCAC14700
AGCAAGTCAC GAACCTGCCC
AAATACAGGG CTAAGGAGAT ATTATGCATC ACAAAACTTG CTCTGCCATT19770
AAACATTTTT CAAAGAATTT
TTGAAGAATG TTTAATGGCA CAAAACGTTT ATTTCAATGT AGCAGTGTTC19890
AAAGCTGGAT GTAAAAGAAC
ACACCCCAGG AGCCTGCCGT GAATGTCATG TGTGTTCATC TTTGGACATG19910
GACATAC~~-.TG GGCAGTGAGT
GGTGGTGAGG CCCTGGAGGA CATCGGTGGG ATGCCTCCAT CCTGCCCCTC19980
TGGAGACACC ATGTGTGCCA
CGTGCACTCA CTGGAGCCCT GTTTAGCTGG TGCCACCTGG CTCTTCCATC15050
CCTGAGAT'.".~ AAACACAGTG
AGATTCCCCA CGCCCAACTC AGTGTTCTCC CACAAAAAAC CTGAGTCACA15120
CCTGTGTTCA CTCGAGGG-iC
GCCCGGGAGC CAGGGCTCCA CAGTTTATTA TGTGTTTTTG GCTGAGTTAT15190
6S GTGCAGATCT CATCAGG~CA
GATGATGAGT GCACAAACAC GGCCGTGCGA GGTTTGGATA CACTCAACAT15260
CACTAGCCAG GTCCTGG'G
AGTTTGGTCA TGCAGAGTCT GGATGGCATG TAGCATTTGG AGTC~ATGGA15330
GTGAGCAC~C AGCCCC~~;G
GGCTGCAGCG CATGCCCCAG G::AGGAC.=u'aG GAAGCGGGAG GAAG 15400
~CAGGA GGCTCTT T "G AGCAAG~ _' _'T
GCAGGAGGGG GCTGGGTGTG GGGCAGGCAC CTGTGTCTGA CATTCCCCCC15970
TGTGTCTCAG CTATGC~~~G
ACCTCCATCA GAGCCAGTCT CACCTTCAAC CGCGGCTTCA AGGCTGGGAG15540
GAACATGC~'f CGCAAACT,:T
'
TTGGGGTCT: 15610
GCGGCTGAAG TGTCACAGCC TGTTTCTGGA TTTG~AGGTG AGCAGGCTv:,
TGGTCAGC.',C
AGAGTTCAGA GTTCAGGAGG T~TGTG~~GCA AGTATGTGTG TGTGTGTGTG15680
CGCGCGT~':~ TGCAAGG'::'G
ATGGTGACTG GCTGCACGTA AGAGTGC=.CA TGTACGCATA TACA~GTGAG15750
CACATACATG TGTGCAT~:'G
TGTACATGAA GGCATGGCAG TGTGTGC-',CA GGTGTGCAAG GGCA:AAGTG15820
TGTGCACAI'G CGAATGC-",'.A
CCTGACATGC ATGTGTGTTC GTGCACAGTC GTGTGGGCAT TCAC~TGAGG15890
7S TGCATGCGTG TGGGTGT~~:A
GTGTGAGTAG CATGTGTGCA CATP.AC=;"GT ATTGAGGGGT CCTC~TGTTC15960
ACCCCGCT:~.G G'rCCTC=,:,':A
CCAGTGCCAC TCCTTACAGG ATGAGACGGG GTCCCAGGCC TTGGTGGGCT16030
GAGGCTCTW, AGCTGC,:;;C
CTGAGGGCAT TGT~CCATCT GGGCATCCGC GTCCACTCCC TCTC~TGTGG16100
GCTTCTG'."_~." CCACT~'::"~
TCTCCTGTGG GCATT"'ACAT Ci:~CTCU yCT CCCTCTCTCC TGTG~;;CATC16170
CGCGTCCa,::' CCCCC:'~.":'."
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-33-
GTGGGCATCTGCGTCCACCTCCCCTCTCTG CTCTCCTGGT
TGGGCATTTG TCCTTCCTGT
CGTCCACTCC 16290
CTTGGCCGAGCCTCGGGGGCAGGCAGATGA TGACTCGCCCAGGGTGGTTC
CACAGAGTCT GCAGCTGCCG
16310
GGTGAGGGCCAGGCCGGATTTCACTGGGAA TTCTTGTCAAAATGTTCCTC
GAGGGATAGT TTTCTTGTTC
16380
CATCTGAATGGATGATAAAGCAAAAAGTAA GTTTCTACCG 16450
S AAACTTAAAA TTTCTCACTC
TCCCAGAGAG
TTTCTTGGCGACTCTAGGTGAACAGCCTCC CACCAACATCTACAAGATCCTCCTGCTGCA
AGACGGTGTG 16520
GGCGTACAGGTGAGCCGCCACCAAGGGGTG CTCCAGGGACCCTCCGCGCTCTGCTCACCT16590
CAGGCCCAGC
CTGACCCGGGGCTTCACCTTGGAACTCCTG GCAAGGAATGTCTTACGTTTTCAGTGGTGC16660
GGTTTTAGGG
TGCTGCCTGTGCACAGTTCTGTTCGCGTGGCTCTGTGCAAAGCACCTGTTCTCCATCTCTGGGTAGTGGT16730
AGGAGCCGGTGTGGCCCCAGGTGTCCCCACTGTGCCTGTGCACTGGCCGTGGGACGTCATGGAGGCCATC16800
IO
CCAGGGCAGCAGGGGCATGGGGTAAAGAGATGTTTATGGGGAGTCTTAGCAGAGGAGGCTGGGAAGGTGT16870
CTGAACAGTAGATGGGAGATCAGATGCCCGGAGGATTTGGGGTCTCAGCAAAGAGGGCCGAGGTGGGTGC16990
AGGTGAGGGTCGCTGGCCCCACCCCCGGGAAGGTGCAGCAGAGCTGTGGCTCCCCACACAGCCCGGCCAG17010
CACCTGTGCTCTGGGCATGGCTGTGCTCCTGGAACGTTCCCTGTCCTGGCTGGTCAGGGGGTGCCCCTGC17080
CAAGAATCGACAACTTTATCACAGAGGGAAGGGCCAATCTGTGGAGGCCACAGGGCCAGCTTCTGCCTGG17150
IS
AGTCAGGGCAGGTGGTGGCACAAGCCTCGGGGCTGTACCAAAGGGCAGTCGGGCACCACAGGCCCGGGCC17220
TCCACCTCAACAGGCCTCCCGAGCCACTGGGAGCTGAATGCCAGGAGGCCGAAGCCCTCGCCCCATGAGG17290
GCTGAGAAGGAGTGTGAGCATTTGTGTTACCCAGGGCCGAGGCTGCGCGAATTACCGTGCACACTTGATG17360
TGAAATGAGGTCGTCGTCTATCGTGGAAACCCAGCAAGGGCTCACGGGAGAGTTTTCCATTACAAGGTCG17930
TACCATGAAAATGGTTTTTAACCCGAGTGCTTGCGCCTTCATGCTCTGGCAGGGAGGGCAGAGCCACAGC17500
2O
TGCATGTTACCGCCTTTGCACCAGCTCCAGAGGCTTGGGACCAGGCTGTCTCAGTTCCAGGGTGCGTCCG17570
GCTCAGACCGCCCTCCTCTCTGCCTTCTCTCTCTGCCTCAAATCTTCCCTCGTTTGCATCTCCCTGACGC17690
GTGCCTGGGCCCTCGTGCAAGCTGCTTGACTCCTTTCCGGAAACCCTTGGGGTGTGCTGGATACAGGTGC17710
CACTGAGGACTGGAGGTGTCTGACACTGTGGTTGACCCCAGGGTCCAGCTGGCGTGCTTGGGGCCTCCTT17780
GGGCCATGATGAGGTCAGAGGAGTTTTCCCAGGTGAAAACTCCTGGGAAACTCCCAGGGCCATGTGACCT17850
2S
GCCACCTGCTCCTCCCATATTCAGCTCAGTCTTGTCCTCATTTCCCCACCAGGGTCTCTAGCTCCGAGGA17920
GCTCCCGTAGAGGGCCTGGGCTCAGGGCAGGGCGGCTGAGTTTCCCCACCCATGTGGGGACCCTTGGGTA17990
GTCGCTTGATTGGGTAGCCCTGAGGAGGCCGAGATGCGATGGGCCACGGGCCGTTTCCAAACACAGAGTC18060
AGGCACGTGGAAGGCCCAGGAATCCCCTTCCCTCGAGGCAGGAGTGGGAGAACGGAGAGCTGGGCCCCGA18130
TTTCACGGCAGCCAGGCTGCAGTGGGCGAGGCTGTGGTGGTCCACGTGGCGCTGGGGGCGGGGTCTGATT18200
CAAATCCGCTGGGGCTCGGCCTTCCTGGCCCGTGCTGGCCGCGCCTCCACACGGGCTTGGGGTGGACGCC18270
CCGACCTCTAGCAGGTGGCTATTTCTCCCTTTGGAAGAGAGCCCCTCACCCATGCTAGGTGTTTCCCTCC18340
TGGGTCAGGAGCGTGGCCGTGTGGCAACCCCGGGACCTTAGGCTTATTTATTTGTTTAAAAACATTCTGG18910
GCCTGGCTTCCGTTGTTGCTAAATGGGGAAAAGACATCCCACCTCAGCAGAGTTACTGAGAGGCTGAAAC16980
CGGGGTGCTGGCTTGACTGGTGTGATCTCAGGTCATTCCAGAAGTGGCTCAGGAAGTCAGTGAGACCAGG18550
3J
TACATGGGGGGCTCAGGCAGTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGTGGGTGAGGCCAGGTA18620
CATGGGGGGCTCAGGCACTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGAGGGTCAGACCAGGTACA18690
CGGGGGCTCTGATCACACGCACATATGAGCACATGTGCACATGTGCTGTTTCATGGTAGCCAGGTCTGTG18760
CACACCTGCCCCAAAGTCCCAGGAAGCTGAGAGGCCAAAGATGGAGGCTGACAGGGCTGGCGCGGTGGCT18830
CACACCTGTAGTCCCAGCACTTTGGGAGGCCGAGGCGAGAGGATCCCTTGAGCCCAGGAGTTTAAGACCA18900
GCCTGAGCAACATAGTAGAACCCCATCTCTATGAAAAATAAAAACAAAAATTAGCTGAACATGGTGGTGT18970
GCGCCTGTAGTTCCAATACTTGGGAGGCTGAAGTGGGAGGATCACTTGAGCCCAGGAGGTGGAAGCTGCA19090
GTGAGC'rGAGATTGCACCACTGTACTGCAGCCTGGGTGACAGAGTGAGAGCCCATCTCAACAACAACAAA19110
GAAGACTGACAAATGCAGTTTCTTGGAAAGAAACATTTAGTAGGAACTTAACCTACACArAGAAGCCAAG19180
TCGGTGTCTCGGTGTCAGTGAGATGAGATGATGGGTCCTCACACCATCACCCCAGACCCAGGGTTTATGC19250
4S
ACCACAGGGGCGGGTGGCTCAGAAGGGATGCGCAGGACGTTGATATACGATGACATCAAGGTTGTCTGAC19320
GA.~1GGGCAGGATTCATGATAAGTACCTGCTGGTACACAAGGAACAATGGATAAACTGGAAACCTTAGAGG19390
CCTTCCCGGAACAGGGGCTAATCAGAAGCCAGCATGGGGGGCTGGCATCCAGGATGGAGCTGCTTCAGCC19960
TCCACATGCGTGTTCATACAGATGGTGCACAGAAACGCAGTGTACCTGTGCACACACAGACACGCAGCTA19530
CTCGCACACACAAGCACACACACAGACATGCATGCATGCATCCGTGTGTGTGCACCTGTGCCCATGAGGA19600
SO
AACCCATGCATGTGCATTCATGCACGCACACAGGCACCGGTGGGCCCATGCCCACACCCACGAGCACCGT19670
CTGATTAGGAGGCCTTTCCTCTGACGCTGTCCGCCATCCTCTCAGGTTTCACGCATGTGTGCTGCAGCTC19740
CCATTTCATCAGCAAGTTTGGAAGAACCCCACATTTTTCCTGCGCGTCATCTCTGACACGGCCTCCCTCT19810
GCTACTCCATCCTGAAAGCCAAGAACGCAGGTATGTGCAGGTGCCTGGCCTCAGTGGCAGCAGTGCCTGC19880
CTGCTGGTGTTAGTGTGTCAGGAGACTGAGTGAATCTGGGCTTAGGAAGTTCTTACCCCTTTTCGCATCA19950
SS
GGAAGTGGTTTAACCCAACCACTGTCAGGCTCGTCTGCCCGCCCTCTCGTGGGGTGAGCAGAGCACCTGA20020
TGGAAGGGACAGGAGCTGTCTGGGAGCTGCCATCCTTCCCACCTTGCTCTGCCTGGGGAAGCGCTGGGGG20090
GCCTGGTCTCTCCTGTTTGCCCCATGGTGGGATTTGGGGGGCCTGGCCTCTCCTGTTTGCCCTGTGGTGG20160
GATTGGGCTGTCTCCCGTCCATGGCACTTAGGGCCCTTGTGCAAACCCAGGCCAAGGGCTTAGGAGGAGG20230
CCAGGCCCAGGCTACCCCACCCCTCTCAGGAGCAGAGGCCGCGTATCACCACGACAGAGCCCCGCGCCGT20300
GO
CCTCTGCTTCCCAGTCACCGTCCTCTGCCCCTGGACACTTTGTCCAGCATCAGGGAGGTTTCTGATCCGT20370
CTGAAATTCAAGCCATGTCGAACCTGCGGTCCTGAGCTTAACAGCTTCTACTTTCTGTTCTTTCTGTGTT20490
GTGGAAATTTCACCTGGAGAAGCCGAAGAAAACATTTCTGTCGTGACTCCTGCGGTGCTTGGGTCGGGAC20510
AGCCAGAGATGGAGCCACCCCGCAGACCGTCGGGTGTGGGCAGCTTTCCGGTGTCTCCTGGGAGGGGAGC20580
TGGGCTGGGCCTGTGACTCCTCAGCCTCTGTTTTCCCCCAGGGATGTCGCTGGGGGCCAAGGGCGCCGCC20650
GS
GGCCCTCTGCCCTCCGAGGCCGTGCAGTGGCTGTGCCACCAAGCATTCCTGCTCAAGCTGACTCGACACC20720
GTGTCACCTACGTGCCACTCCTGGGGTCACTCAGGACA~~CAAGTGTGGGTGGAGGCCAGTGCGGGCCCC20790
ACCTGCCCAGGGGTCATCCTTGAACGCCCTGTGTGGGG(';AGCAGCCTC~-.GATGCTGCTGAAGTGCAGAC20860
GCCCCCGGGCCTGACCCTGGGGGCCTGGAGCCACGCTG,~AGCCCTATGTGATTAAACGCTGGTGTCCCC20930
AGGCCACGGAGCCTGGCAGGGTCCCCAACTTCTTGAACCCCTGCTTCCCTCTCAGGGGCGATGGCTCCC21000
7O A
CACGCTTGGGAGCCTTCTGACCCCTGACCTGTGTCCTCT;.ACAGCC CCCTGGCTGCTGCCCTGAGC21070
TCTT
TCCTGGGGTCCTGAGCAAGTTCTCTCCCCGCCCC~CCG'i'CCAGCGTC:1:;TGGGCTGCCTGTCTGCTCGC21190
CCCGGTGGAGGGGTGTCTGT AGGTTCCC~CCAGCCAGGGCCACGAGGTGCAGGCCCTGCC21210
CCCTTCACTG
TGCCCGGCCACCCACACGTC TGGAGGATGCCACCTCTG;~CTCTTCTGGAACGGAGTCTG21280
CTAGGAGGGT
ATTTTGGCCCCGCAGCCCAG GTCGGAAG:TCCCGGGGA:,~,ACGCTGACTGCCCTGGAGGC21350
ACGCAGCTGA
CGCAGCCAACCCGGCACTGC CAAG~=.CCAT;CTGGAC GGCCACCCGCCCACAGCCAG21920
CCTCAGACTT TG.~"
GCCGAGAGCAGACACCAGCA GCCGGGCT:~.'_ GAGGGAGGGGCGGCCCACAC21490
GCCCTGTCAC ACGTCCCA~,~
CCAGGCCCGC TGAGTGAG'~TTTGGCCG.,G~~CTGCATGTCCGGCTGAAG21560
.-ICCGCTGGGA
GTCTGAGGCC
GCTGAGTGTC GTCCAGCC?."~.G~GCTGAG.":;:'.CAG~~ACACCTGCCGTCTT21630
~~GGCTGAGGC
CTGAGCGAGT
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-34-
CACTTCCCCACAGGCTGGCGCTCGGCTCCACCCCAGGGCCAGCTTTTCCTCACCAGGAGCCCGGCTTCCA21700
CTCCCCACATAGGAATAGTCCATCCCCAGATTCGCCATTGTTCACCCCTCGCCCTGCCCTCCTTTGCCTT21770
CCACCCCCACCATCCAGGTGGAGACCCTGAGAAGGACCCTGGGAGCTCTGGGAATTTGGAGTGACCAAAG21890
GTGTGCCCTGTACACAGGCGAGGACCCTGCACCTGGATGGGGGTCCCTGTGGGTCAAATTGGGGGGAGGT21910
S
GCTGTGGGAGTAAAATACTGAATATATGAGTTTTTCAGTTTTGAAAAAAATCTCATGTTTGAATCCTAAT21980
GTGCACTGCATAGACACCACTGTATGCAATTACAGAAGCCTGTGAGTGAACGGGGTGGTGGTCAGTGCGG22050
GCCCATGGCCTGGCTGTGCATTTACGGAAGTCTATGAGTGAATGGGGTTGTGGTCAGTGCGGGCCCATGG22120
CCTGGCTGGGCCTGGGAGGTTTCTGATGCTGTGAGGCAGGAGGGGAAGGAGGGTAGGGGATAGACAGTGG22190
GAGCCCCCACCCTGGAAGACATAACAGTAAGTCCAGGCCCGAAGGGCAGCAGGGATGCTGGGGGCCCAGC22260
lO
TTGGGCGGCGGGGATGATGGAGGGCCTGGCCAGGGTGGCAGGGATGATGGGGGCCCCAGCTGGGGTGGCA22330
GGGGTGATGGGGGGGGCTGGTCTGGGTGGCGGGGAAGATGGGGAAGCCTGGCTGGGCCCCCTCCTCCCCT22400
GCCTCCCACCTGCAGCCGTGGATCCGGATGTGCTTCCCTGGTGCACATCCTCTGGGCCATCAGCTTTCAT22470
GGAGGTGGGGGGCAGGGGCATGACACCATCCTGTATAAAATCCAGGATTCCTCCTCCTGAACGCCCCAAC22590
TCAGGTTGAAAGTCACATTCCGCCTCTGGCCATTCTCTTAAGAGTAGACCAGGATTCTGATCTCTGAAGG22610
IS
GTGGGTAGGGTGGGGCAGTGGAGGGTGTGGACACAGGAGGCTTCAGGGTGGGGCTGGTGATGCTCTCTCA22680
TCCTCTTATCATCTCCCAGTCTCATCTCTCATCCTCTTATCATCTCCCAGTCTCATCTGTCTTCCTCTTA22750
TCTCCCAGTCTCATCTGTCATCCTCTTACCATCTCCCAGTCTCATCTCTTATCCTCTTATCTCCTAGTCT22820
CATCCAGACTTACCTCCCAGGGCGGGTGCCAGGCTCGCAGTGGAGCTGGACATACGTCCTTCCTCAGGCA22890
GAAGGAACTGGAAGGATTGCAGAGAACAGGAGGGGCGGCTCAGAGGGACGCAGTCTTGGGGTGAAGAAAC22960
2O
AGCCCCTCCTCAGAAGTTGGCTTGGGCCACACGAAACCGAGGGCCCTGCGTGAGTGGCTCCAGAGCCTTC23030
CAGCAGGTCCCTGGTGGGGCCTTATGGTATGGCCGGGTCCTACTGAGTGCACCTTGGACAGGGCTTCTGG23100
TTTGAGTGCAGCCCGGACGTGCCTGGTGTCGGGGTGGGGGCTTATGGCCACTGGATATGGCGTCATTTAT23170
TGCTGCTGCTTCAGAGAATGTCTGAGTGACCGAGCCTAATGTGTATGGTGGGCCCAAGTCCACAGACTGT23240
GTCGTAAATGCACTCTGGTGCCTGGAGCCCCCGTATAGGAGCTGTGAGGAAGGAGGGGCTCTTGGCAGCC23310
2
S
GGCCTGGGGGCGCCTTTGCCCTGCAAACTGGAAGGGAGCGGCCCCGGGCGCCGTGGGCGGACGACCTCAA23380
GTGAGAGGTTGGACAGAACAGGGCGGGGACTTCCCAGGAGCAGAGGCCGCTGCTCAGGCACACCTGGGTT23950
TGAATCACAGACCAACaGGTCAGGCCATTGTTCAGCTATCCATCTTCTACAAAGCTCCAGATTCCTGTTT23520
CTCCGGGTGTTTTTTGTTGAAATTTTACTCAGGATTACTTATATTTTTTGCTAAAGTATTAGACCCTTAA23590
AAAAGGTATTTGCTTTGATATGGCTTAACTCACTAAGCACCTACTTTATTTGTCTGTTTTTATTTATTAT23660
3
O
TATTATTATTATTAGAGATGGTGTCTACTCTGTCACCCAGGTTGTTAGTGCAGTGGCACAGTCATGGCTC23730
GCTGTAGCCGCAAACCCCCAGGCTCAAGTGATCCTCCGGCCTCAGCTTCCCAGAGTGCTGGGATTACAGG23800
TGTGAGCCACTGCCCTTGCCTGGCACTTTTAAAAACCACTATGTAAGGTCAGGTCCAGTGGCTTCCACAC23870
CTGTCATCCCAGTAGTTTGGGAAGCCGAGGCAGAAGGATTGTCTGAGGCCAGGAGTTTGAGACCAGCATG23940
GGTAACATAGGGAGACCCCATCTCTACAAAAAATGCAAAAAGTTATCCGGGCGTGGGGTCCAGCATCTGT29010
~
S
AGTCCCAGCTGCTCGGGAGGCTGAGTGGGAGGATCGCTTGAGCCCGGGAGGTCPTGGCTGCAGTGAGCTG29080
TGATTGTACCATCGCACTCCAGCCTGGGCAACAGAGTGAGACCCTGTCTCAAAAAAAAAAAAAAAAAAAG29150
AAGGAGAAGGAGAAGAGAAGAAGAAGGAAGAAGGAAAGAGAAGAAGAAGGAAGAAGGAAGAAAGAAGGAG24220
AAGGAGGCCTGCTAGGTGCTAGGTAGACTGTCAAATCTCAGAGCAAAATGAAAATAACAAAGTTTTAAAG24290
GGAAAGAAAAACCCCAGCTCTTTGGACTTCCTTAGGCCTGAACTTCATCTCAAGCAGCTTCCTTCCACAG24360
4O
ACAAGCGTGTATGGAGCGAGTGAGTTCAAAGCAGAAAGGGAGGAGAAGCAGGCAAGGGTGGAGGCTGTGG'9930
GTGACACCAGCCAGGACCCCTGAAAGGGAGTGGTTGTTTTCCTGCCTCAGCCCCACGCTCCTGCCGGTCC24500
TGCACCTGCTGTAACCGTCGATGTTGGTGCCAGGTGCCCACCTGGGAAGGATGCTGTGCAGGGGGCTTGC24570
CAAACTTTGGTGGGTTTCAGAAGCCCCAGGCACTTGTGGCAGGCACAATTACAGCCCCTCCCCAAAGATG29640
CCCACGTCCTTCTCCTGGAACCTGTGAATGTGTCACCCGCAAGGCAGAGGCTGGTGAAGGCTGCAGGTGG24710
4S
AATCACGGCTGCCAGTCAGCCGATCTTAAGGTCATCCTGGATTATCTGGTGGGCCTGATATGGCCACAAG24780
GGTCCCTAGAAGTGAGAGAGGGAGGCAGGGGAGAGTCAGAGAGGGGACGTGAGAAGGACCACTGGCCACT29850
GCTGGCTTTGAGATGGAGGAGGGGGTCCCCAGCCAAGGAATGGGGGCAGCCGCTCCATGCTGGAAAAGCA29920
AGCAATCCTCCCCGGTCCTGAGGGCACACGGCCCTGCCCACGCCTCGATTTCAGGCCAGTGGGACCTGTT24990
_
TCAGCTTTCCGGCCTCCAGAGCTGTAAGATGATGCGTTTGTGTTCAGCCACTAAGCTGCAGTGATTCGTC25060
JO
ACAGCAGCAAATGGAATAGCAGTACAGGGAAATGAATACAGGGACAGTTCTCAGAGTGACTCTCAGCCCA25130
CCCCTGGG 25138
Example S
SS Comparison of the above-described genomic hTC sequence and the sequence of
the
hTC cDNA (Fig. 6; corresponding to SEQ ID NO 2) made it possible to elucidate
the
exon-mtron structure of the hTC gene. The genomic organization of the hTC gene
is
illustrated diagrammatically in Fig. 7. The coding region of the hTC gene is
composed of 16 exons which vary in size between 62 by and 1354 by (see Table 1
).
60 Exon l contains the translation start codon ATG. The translation stop codon
TGA
and the 3'-untranslated region lie on exon 16 (Fig. 8). No possible
polyadenylation
signal (AATAAA) was found either in exon l6 or in the 3195 by of the following
- CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-35-
3 '-flanking region. The exon-intron transitions were determined on the basis
of the
consensus sequence
S '-Exon Intron 3 '-Exon
Pre-mRNA A/C A G ~ G T A/G A ... N C A G ~ G
Frequency (%) ~o so so ioo ioo 95 ~o eo ioo ioo so
and listed in Table 1. With the exception of the 5' splice site between exon
15 and
intron 1 S, all the exon-intron transitions are in accord with the published
(Shapiro
and Senapathy, 1987) splice consensus sequence. The sizes of the introns are
between 104 by and 8616 bp. Since only part of intron 6 was isolated, it is
not
possible to determine the precise length of the hTC gene. Based on the part
sequence
of 4660 bp, which was obtained from intron 6, the minimum size of the hTERT
gene is 37 kb.
- CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-36-
Introns 1-5 and the 5' region of intron 6, are contained in contig 1:
Intron 1: by 11493-11596 (SEQ ID NO 4);
lntron 2: by 12951-21566 (SEQ ID NO S);
Intron 3: by 21763-23851 (SEQ ID NO 6);
Intron 4: by 24033-24719 (SEQ ID NO 7);
Intron 5: by 24900-25393 (SEQ ID NO 8);
5' region of intron 6: by 25550-26414 (SEQ ID NO 9).
The 3' region of intron 6, and introns 7-15, are located in contig 2 at the
following
positions:
3' region of intron 6: by I-3782 (SEQ ID NO 10);
Intron 7: by 3879-4858 (SEQ ID NO 11 );
Intron 8: by 4945-7429 (SEQ ID NO 12);
Intron 9: by 744-9527 (SEQ ID NO 13);
i5 Intron 10: by 9600-11470 (SEQ ID NO 14);
Intron I 1: by 11660-15460 (SEQ ID NO 15;
Intron 12: by 15588-16467 (SEQ ID NO 16);
Intron 13: by 16530-19715 (SEQ ID NO 17);
Intron 14: 19841-20621 (SEQ ID NO 18);
Intron 15: 20760-21295 (SEQ ID NO 19).
The 3'-untranscribed region is also located in contig 2 at position 21960-
25138 (SEQ
ID NO 20).
The individual sequences of the abovernentioned introns are as follows:
CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
-37-
Intron 1 (SEQ ID NO 4)
GTGGGCCTCCCCGGGGTCGGCGTCCGGCTGGGGTTGAGGGCGGCCGGGGGGAACCAGCGACATGCGGAGAGCAGCGCAG
G
CGACTCAGGGCGCTTCCCCCGCAG
Intron 2 (SEQ ID NO 5)
GTGAGGAGGTGGTGGCCGTCGAGGGCCCAGGCCCCAGAGCTGAATGCAGTAGGGGCTCAGAAAAGGGGGCAGGCAGAGC
C
CTGGTCCTCCTGTCTCCATCGTCACGTGGGCACACGTGGCTTTTCGCTCAGGACGTCGAGTGGACACGGTGATCTCTGC
C
TCTGCTCTCCCTCCTGTCCAGTTTGCATAAACTTACGAGGTTCACCTTCACGTTTTGATGGACACGCGGTTTCCAGGCG
C
CGAGGCCAGAGCAGTGAACAGAGGAGGCTGGGCGCGGCAGTGGAGCCGGGTTGCCGGCAATGGGGAGAAGTGTCTGGAA
G
IO
CACAGACGCTCTGGCGAGGGTGCCTGCAGGTTACCTATAATCCTCTTCGCAATTTCAAGGGTGGGAATGAGAGGTGGGG
A
CGAGP.ACCCCCTCTTCCTGGGGGTGGGAGGTAAGGGTTTTGCAGGTGCACGTGGTCAGCCAATATGCAGGTTTGTGTT
TA
AGATTT.AATTGTGTGTTGACGGCCAGGTGCGGTGGCTCACGCCGGTAATCCCAGCACTTTGGGAAGCTGAGGCAGGTG
GA
TCACCTGAGGTCAGGAGTTTGAGACCAGCCTGACCAACATGGTGAAACCCTATCTGTACTAAAAATACAAAAATTAGCT
G
GGCATGGTGGTGTGTGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCACTTGAACCCAGGAGGCGGAGG
C
IS
TGCAGTGAGCTGAGATTGTGCCATTGTACTCCAGCCTGGGCGACAAGAGTGAAACTCTGTCTTTAAP,AAAAAAAAGTG
TT
CGTTGA1'TGTGCCAGGACAGGGTAGAGGGAGGGAGATAAGACTGTTCTCCAGCACAGATCCTGGTCCCATCTTTAGGT
AT
GAAGAGGGCCACATGGGAGCAGAGGACAGCAGATGGCTCCACCTGCTGAGGAAGGGACAGTGTTTGTGGGTGTTCAGGG
G
ATGGTGCTGCTGGGCCCTGCCGTGTCCCCACCCTGTTTTTCTGGATTTGATGTTGAGGAACCTCCGCTCCAGCCCCCTT
T
TGGCTCCCAGTGCTCCCAGGCCCTACCGTGGCAGCTAGAAGAAGTCCCGATTTCACCCCCTCCCCACAAACTCCCAAGA
C
2O
ATGTAAGACTTCCGGCCATGCAGACAAGGAGGGTGACCTTCTTGGGGCTCTTTTTTTTCTTTTTTTCTTTTTATGGTGG
C
AAAAGTCATATAACATGAGATTGGCACTCCTAACACCGTTTTCTGTGTACAGTGCAGAATTGCTAACTCGGCGGTGTTT
A
CAGCAGGTTGCTTGAAATGCTGCGTCTTGCGTGAC'iGGAAGTCCCTACCCATCGAACGGCAGCTGCCTCACACCTGCT
GC
GGCTCAGGTGGACCACGCCGAGTCAGATAAGCGTCATGCAACCCAGTTTTGC'TTTTTGTGCTCCAGCTTCCTTCGTTG
AG
GAGAGTTTGAGTTCTCTGATCAGGACTCTGCCTGTCATTGCTGTTCTCTGACTTCAGATGAGGTCACAATCTGCCCCTG
G
2S
CTTATGCAGGGAGTGAGGCGTGGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGTTGCCCCCAGGTGTCCC
T
GTCACGTGTAGGGTGAGTGAGGCGCGGCCCCCGGGTGTCCCTGTCCCGTGCAGCGTGATTGAGGTGTGGCCCCCGGGTG
T
CCCTGTCACGTGTAGGGTGAGTGAGGCGCCATCCCCGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCGTGGTCCCCG
G
GTGTCCCTGTCCCGTGCAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGCGGTC
C
CCGGGTGTCCCTCTCAGGTGTAGGGTGAGTGAGGCGCGGCCCCAGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCAC
C
3O
GTCCCTGGGTGTCCCTCCCAGGTATAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAG
G
CGCGGCCCCCGGGTGTCCCTCTCAGGTGCAGGGTGAGTGAGGCGCTGTCCCTGGGTGTCCCTGTCTCGTGTAGGGTGAG
T
GAGGCTCTGTCCCCAGGTGTCCTTGGCGTTTGCTCACTTGAGCTTGCTCCTGAATGTTTGCTCTTTCTATAGCCACAGC
T
GCGCCGGTTGCCCATTGCCTGGGTAGATGGTGCAGGCGCAGTGCTGGTCCCCAAGCCTATCTTTTCTGATGCTCGGCTC
T
TCTTGGTCACCTCTCCGTTCCATTTTGCTACGGGGACACGGGACTGCAGGCTCTCGCCTCCCGCGTGCCAGGCACTGCA
G
3S
CCACAGCTTCAGGTCCGCTTGCCTCTGTTGGGCCTGGCTTGCTCACCACGTGCCCGCCACATGCATGCTGCCAATACTC
C
TCTCCCAGCTTGTCTCATGCCGAGGCTGGACTCTGGGCTGCCTGTGTCTGCTGCCACGTGTTGCTGGAGACATCCCAGA
A
AGGGTTCTCTGTGCCCTGAAGGAAAGCAAGTCACCCCAGCCCCCTCACTTGTCCTGTTTTCTCCCAAGCTGCCCCTCTG
C
TTGGCCCCCTTGGGTGGGTGGCAACGCTTGTCACCTTATTCTGGGCACCTGCCGCTCATTGCTTAGGCTGGGCTCTGCC
T
CCAGTCGCCCCCTCACATGGATTGACGTCCAGCCACAGGTTGGAGTGTCTCTGTCTGTCTCCTGCTCTGAGACCCACGT
G
4O
GAGGGCCGGTGTCTCCGCCAGCCTTCGTCAGACTTCCCTCTTGGGTCTTAGTTTTGAATTTCACTGATTTACCTCTGAC
G
TTTCTATCTCTCCATTGTATGCTTTTTCTTGGTTTATTCTTTCATTCCTTTTCTAGC'TTCTTAGTTTAGTCATGCCTT
TC
CCTCTAAGTGCTGCCTTACCTGCACCCTGTGTTTTGATGTGAAGTAATCTCAACATCAGCCACTTTCAAGTGTTCTTAA
A
ATACTTCAAAGTGTTAATACTTCTTTTAAGTATTCTTATTCTGTGATTTTTTTCTTTGTGCACGCTGTGTTTTGACGTG
A
AATCATTTTGATATCAGTGACTTTTAAGTATTCTTTAGCTTATTCTGTGATTTCTTTGAGCAGTGAGTTATTTGAACAC
T
4S
GTTTATGTTCAAGATATGTAGAGTATCAAGATACGTAGAGTATTTTAAGTTATCATTTTATTATTGATTTCTAACTCAG
T
TGTGTAGTGGTCTGTATAATACCAATTATTTGAAGTTTGCGGAGCCTTGCTTTGTGATCTAGTGTGTGCATGGTTTCCA
G
AACTGTCCATTGTAAATTTGACATCCTGTCAATAGTGGGCATGCATGTTCACTATATCCAGCTTATTAAGGTCCAGTGC
A
- CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
-38-
AAGCTTCTGTCTCCTTCTAGATGCATGAAATTCCAAGAAGGAGGCCATAGTCCCTCACCTGGGGGATGGGTCTGTTCAT
T
TCTTCTCGTTTGGTAGCATTTATGTGAGGCATTGTTAGGTGCATGCACGTGGTAGAATTTTTATCTTCCTGATGAGTGA
A
TCTTTTGGAGACTTCTATGTCTCTAGTAATCTAGTAATTCTTTTTTTAAATTGCTCTTAGTACTGCCACACTGGGCTTC
T
TTTGATTAGTATTTTCCTGCTGTGTCTGTTTTCTGCCTTTAATTTATATATATATATATATTTTTTTTTTTTTTGAGAC
A
S
GAGTCTTGGTCTGTCGCCCAGGGTGAGTGCAGTGGTGTGATCACAGGTCAGTGTAACTTTTACCTTCTGGCCTGAGCCG
T
CCTCTCACCTCAGCCTCCTGAGTAGCTGGAACTGCAGACACGCACCGCTACACCTGGCTAATTTTTAAATTTTTTCTGG
A
GACAGGGTCTTGCTGTGTTGCCCAGGCTGGTCTCAAACTCTTGGACTCAAGGGATCCATCTACCTCGGCTTCCCAAAGT
G
CTGAATTACAGGCATGAGCCACCATGTCTGGCCTAATTTTCAACACTTTTATATTCTTATAGTGTGGGTATGTCCTGTT
A
ACAGCATGTAGGTGAATTTCCAATCCAGTCTGACAGTCGTTGTTTAACTGGATAACCTGATTTATTTTCATTTTTTTGT
C
IO
ACTAGAGACCCGCCTGGTGCACTCTGATTCTCCACTTGCCTGTTGCATGTCCTCGTTCCCTTGTTTCTCACCACCTCTT
G
GrT~rGCCATGTGCGTTTCCTGCCGAGTGTGTGTTGATCCTCTCGTTGCCTCCTGGTCACTGGGCATTTGCTTTTATTT
CT
CTTTGCTTAGTGTTACCCCCTGATCTTTTTATTGTCGTTGTTTGCTTTTGTTTATTGAGACAGTCTCACTCTGTCACCC
A
GGCTGGAGTGTAATGGCACAATCTCGGCTCACTGCAACCTCTGCCTCCTCGGTTCAAGCAGTTCTCATTCCTCAACCTC
A
TGAGTACCTGGGATTACAGGCGCCCACCACCACGCCTGGCTAATTTTTGTATTTTTAGTAGAGATAGGCTTTCACCATG
T
1S
TGGCCAGGCTGGTCTCAAACTCCTGACCTCAAGTGATCTGCCCGCCTTGGCCTCCCACAGTGCTGGGATTACAGGTGCA
A
GCCACCGTGCCCGGCATACCTTGATCTTTTAAAATGAAGTCTGAAACATTGCTACCCTTGTCCTGAGCAATAAGACCCT
T
AGTGTATTTTAGCTCTGGCCACCCCCCAGCCTGTGTGCTGTTTTCCCTGCTGACTTAGTTCTATCTCAGGCATCTTGAC
A
CCCCCACAAGCTAAGCATTATTAATATTGTTTTCCGTGTTGAGTGTTTCTGTAGCTTTGCCCCCGCCCTGCTTTTCCTC
C
T'_TTGTTCCCCGTCTGTCTTCTGTCTCAGGCCCGCCGTCTGGGGTCCCCTTCCTTGTCCTTTGCGTGGTTCTTCTGTC
TTG
20
TTATTGCTGGTAAACCCCAGCTTTACCTGTGCTGGCCTCCATGGCA'rCTAGCGACGTCCGGGGACCTCTGCTTATGAT
GC
.?CAGATGAAGATGTGGAGACTCACGAGGAGGGCGGTCATCTTGGCCCGTGAGTGTCTGGAGCACCACGTGGCCAGCGT
TC
CTTAGCCAGTGAGTGACAGCAACGTCCGC'TCGGCCTGGGTTCAGCCTGG.~AAACCCCAGGCATGTCGGGGTCTGGTG
GCT
CCGCGGTGTCGAGTTTGAAATCGCGCAAACCTGCGGTGTGGCGCCAGCTCTGACGGTGCTGCCTGGCGGGGGAGTGTCT
G
CTTCCTCCCTTCTGCTTGGGAACCAGGACAAAGGATGAGGCTCCGAGCCGTTGTCGCCCAACAGGAGCATGACGTGAGC
C
2S
ATGTGGATAATTTTAAAATTTCTAGGCTGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCGG
G
TGGATCACGAGGTCAGGAGGTCGAGACCATCCTGGCCAACATGATGAAACCCCATCTGTACTAAAAACACAAAAATTAG
C
TGGGCGTGGTGGCGGGTGCCTGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATTGCTTGAACCTGGGAGTTGGA
A
GTTGCAGTGAGCCGACATTGCACCACTGCACTCCAGCCTGGCAACACAGCGAGACTCTGTCTCP~~4AAAAAAAAAApA
AA
AAAAAAAAAAAATTCTAGTAGCCACATTAAAAAAGTAAAAAAGAAAAGGTGAAATTAATGTAATAATAGATTTTACTGA
A
3O
GCCCAGCATGTCCACACCTCATCATTTTAGGGTGTTATTGGTGGGAGCATCACTCACAGGACATTTGACATTTTTTGAG
C
TTTGTCTGCGGGATCCCGTGTGTAGGTCCCGTGCGTGGCCATCTCGGCCTGGACCTGCTGGGCTTCCCATGGCCATGGC
T
GTTGTACCAGATGGTGCAGGTCCGGGATGAGGTCGCCAGGCCCTCAGTGAGCTGGATGTGCAGTGTCCGGATGGTGCAC
G
TCTGGGATGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCA
G
GCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGAT
G
3S
TGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTAAGCTGGAGGTATGGAGTCCGGATGATGC
A
GGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGGGTGAGGTCAC
C
AGGCCCTGCGGTGAGCTGGGTGTGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGACGGTGCCAGACCATG
C
GGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTTGCCAGGCCCTGCTGTGAGTTGGATGTGGGG
T
GTCCGGATGCTGCAGGTCCGGTGTGAGGTCACCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTC
T
4O
GGGGTGAAGGTCGCCAGGCCCCTGCTTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCA
G
GCCCTCGGTGAGCTGGATGTGCAGTGTCCAGATGGTGCAGGTCCGGGGTGAGGTCGCCAGACCCTGCGGTGAGCTGGAT
G
TGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGGCCCTCGGTGAGCTGGATGTATGGAGTCCGGATGGTGC
C
GGTCCGGGGTGAGGTCGCCAGACCCTGCTGTGAGCTGGATGTGCGGTGTCTGGATGGTACAGGTCTGGAGTGAGGTCGC
C
AGACCCTGCTGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTGAGCTGG
A
4S
GGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAACTGGATGTGCGGCGTCTGGATGG
T
GCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTC
G
CCAGGCCCTGCTGTGAGCTGGATGTGCGGCGTCTGGATGGTGCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCT
G
CA 02316282 2000-06-21
Le A 32 $OS-Foreien Countries
-39-
GAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTTGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGAT
G
GTGCAGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCTGGGGTGAGG
T
CACCAGGCCCTGCGGTGAGCTGGTTGTGCGGTGTCCGGTTGCTGCAGGTCCGGGGTGAGTTCGCCAGGCCCTCGGTGAG
C
TGGATGTGCGGTGTCCCCGTGTCCGGATGGTGCAGGTCCAGGGTGAGGTCGCTAGGCCCTTGGTGGGCTGGATGTGCCG
T
S
GTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCTTTGGTGAGCTGGATGTGCGGTGTCTGCATGGTGCAGGTCT
G
GGGTGAGGTCGCCAGGCCCTTGGTGGGCTGGATGTGTGGTGTCCGGATGGTGCAGGTCCGGCGTGAGGTCGCCAGGCCC
T
GCTGTGAGCTGGATGTGCGGTGTCTGGATGGTGCAGGTCCGGGGTGAGGTAGCCAAGGCCTTCGGTGAGCTGGATGTGG
G
GTGTCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGATATGCGGTGTCCGGATGGTGCAGG
T
CCGGGGTGAGGTCACCAGGCCCTGCGGTTAGCTGGATGTGCGGTGTCTGGATGGTGCAGGTCCGGGGTGAGGTCGCCAG
G
IO
CCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCAGTGAGCTGGAT
G
TGCTGTATCCGGATGGTGCAGGTCTGGCGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGATATGCGGTGTCGGATGGTGC
A
GGTCCGGGGTGAGGTCACCAGGCCCTGCGGTTAGCTGGATGTGCGGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTCGC
C
AGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTGAGCTG
G
ATGTGCTGTATCCGGATGGTGCAGGTCTGGCGTGAGGTCGCCAGGCCCTGCGGTGAGCTGGATGTGCAGTGTACGGATG
G
IS
TGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTGGGCTGTATGTGTGTTGTCTGGATGGTGCAGGTCCGGGGTGAGT
T
CGCCAGGCCCTGCGGTGAGCTGGATGTGTGGTGTCTGGATGCTGCAGGTCCGGGGTGAGTTCGCCAGGCCCTCGGTGAG
C
TGGATATGCGGTGTCCCCGTGTCCGAATGGTGCAGGTCCAGGGTGAGGTCGCCAGGCCCTTGGTGGGCTGGATGTGCCG
T
GTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCCTTGGTGAGCTGGATGTGCGGTGTCCGGATGGTGCAGGTCC
G
GGGTGAGGTCACCAGGCCCTCGGTGATCTGGATGTGGCATGTCCTTCTCGTTTAAG
Intron 3 (SEQ ID NO 6)
GTACTGTATCCCCACGCCAGGCCTCTGCTTCTCGAAGTCCTGGAACACCAGCCCGGCCTCAGCATGCGCCTGTCTCCAC
T
TGCCTGTGCTTCCCTGGCTGTGCAGCTCTGGGCTGGGAGCCAGGGGCCCCGTCACAGGCCTGGTCCAAGTGGATTCTGT
G
CAAGGC'!'CTGACTGCCTGGAGCTCACGTTCTCTTACTTGTAAAATCAGGAGTTTGTGCCAAGTGGTCTCTAGGGTTT
GTA
2S
AAGCAGAAGGGATTTAAATTAGATGGAAACACTACCACTAGCCTCCTTGCCTTTCCCTGGGATGTGGGTCTGATTCTCT
C
i'CTCTTTTTTTTTTCTTTTTTGAGATGGAGTCTCACTCTGTTGCCCAGGCTGGAGTGCAGTGGCATAATCTTGGCTCA
CT
GCAACCTCCACCTCCTGGGTTTAAGCGATTCACCAGCCTCAGCCTCCTAAGTAGCTGGGATTACAGGCACCTGCCACCA
C
GCCTGGCTAATTTTTGTACTTTTAGGAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACTCATGACCTCAG
G
TGATCCACCCACCTTGGCCTCCCAAAGTGCTGGGTTTACAGGCTAAGCCACCGTGCCCAGCCCCCGATTCTCTTTTAAT
T
3O
CATGCTGTTCTGTATGAATCTTCAATCTATTGGATTTAGGTCATGAGAGGATAAAATCCCACCCACTTGGCGACTCACT
G
CAGGGAGCACCTGTGCAGGGAGCACCTGGGGATAGGAGAGTTCCACCATGAGCTAACTTCTAGGTGGCTGCATTTGAAT
G
GCTGTGAGATTTTGTCTGCAATGTTCGGCTGATGAGAGTGTGAGATTGTGACAGATTCAAGCTGGATTTGCATCAGTGA
G
GGACGGGAGCGCTGGTCTGGGAGATGCCAGCCTGGCTGAGCCCAGGCCATGGTATTAGCTTCTCCGTGTCCCGCCCAGG
C
TGACTGTGGAGGGCTTTAGTCAGAAGATCAGGGCTTCCCCAGCTCCCCTGCACACTCGAGTCCCTGGGGGGCCTTGTGA
C
3S
ACCCCATGCCCCAAATCAGGATGTCTGCAGAGGGAGCTGGCAGCAGACCTCGTCAGAGGTAACACAGCCTCTGGGCTGG
G
GACCCCGACGTGGTGCTGGGGCCATTTCCTTGCATCTGGGGGAGGGTCAGGGCTTTCCCTGTGGGAACAAGTTAATACA
C
AATGCACCTTACTTAGACTTTACACGTATTTAATGGTGTGCGACCCAACATGGTCATTTGACCAGTATTTTGGAAAGAA
T
TTAATTGGGGTGACCGGAAGGAGCAGACAGACGTGGTGGTCCCCAAGATGCTCCTTGTCACTACTGGGACTGTTGTTCT
G
CCTGGGGGGCCTTGGAGGCCCCTCCTCCCTGGACAGGGTACCGTGCCTTTTCTACTCTGCTGGGCCTGCGGCCTGCGGT
C
4O
AGGGCACCAGCTCCGGAGCACCCGCGGCCCCAGTGTCCACGGAGTGCCAGGCTGTCAGCCACAGATGCCCAGGTCCAGG
T
GTGGCCGCTCCAGCCCCCGTGCCCCCATGGGTGGTTTTGGGGGAAAAGGCCAAGGGCAGAGGTGTCAGGAGACTGGTGG
G
CTCATGAGAGCTGATTCTGCTCCTTGGCTGAGCTGCCCTGAGCAGCCTCTCCCGCCCTCTCCATCTGAAGGGATGTGGC
T
CTTTCTACCTGGGGGTCCTGCCTGGGGCCAG~~TTGGGCTACCCCAGTGGCTGTACCAGAGGGACAGGCATCCTGTGTG
G
AGGGGCATGGGTTCACGTGGCCCCAGATGCAGCCTGGGACCAGGCTCCCTGGTGCTGATGGTGGGACAGTCACCCTGGG
G
4S
GTTGACCGCCGGACTGGGCGTCCCCAGGGTTGACTATAGGACCAGGTGTCCAGGTGCCCTGCAAGTAGAGGGGCTCTCA
G
AGGCGTCTGGCTGGCATGGGTGGACGTGGCCCCGGGCATGGCCTTCAGCGTGTGCTGCCGTGGGTGCCCTGAGCCCTCA
C
TGAGTCGGTGGGGGCTTGTGGCTTCCCGTGAGCTTCCCCCTAGTCTGTTGTCTGGCTGAGCAAGCCTCCTGAGGGGCTC
T
CTATTGCAG
CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
-40-
Intron 4 (SEQ ID NO 7)
GTGGCTGTGCTTTGGTTTAACTTCCTTTTTAAACAGAAGTGCGTTTGAGCCCCACATTTGGTATCAGCTTAGATGAAGG
G
CCCGGAGGAGGGGCCACGGGACACAGCCAGGGCCATGGCACGGCGCCAACCCATTTGTGCGCACAGTGAGGTGGCCGAG
G
TGCCGGTGCCTCCAGAAAAGCAGCGTGGGGGTGTAGGGGGAGCTCCTGGGGCAGGGACAGGCTCTGAGGACCACAAGAA
G
S
CAGCCGGGCCAGGGCCTGGATGCAGCACGGCCCGAGGTCCTGGATCCGTGTCCTGCTGTGGTGCGCAGCCTCCGTGCGC
T
TCCGCTTACGGGGCCCGGGGACCAGGCCACGACTGCCAGGAGCCCACCGGGCTCTGAGGATCCTGGACCTTGCCCCACG
G
CTCCTGCACCCCACCCCTGTGGCTGCGGTGGCTGCGGTGACCCCGTCATCTGAGGAGAGTGTGGGGTGAGGTGGACAGA
G
GTGTGGCATGAGGATCCCGTGTGCAACACACATGCGGCCAGGAACCCGTTTCAAACAGGGTCTGAGGAAGCTGGGAGGG
G
TTCTAGGTCCCGGGTCTGGGTGGCTGGGGACACTGGGGAGGGGCTGCTTCTCCCCTGGGTCCCTATGGTGGGGTGGGCA
C
IO TTGGCCGGATCCACTTTCCTGACTGTCTCCCATGCTGTCCCCGCCAG
Intron 5 (SEQ ID NO 8)
GTGGGTGCCGGGGACCCCCGTGAGCAGCCCTGCTGGACCTTGGGAGTGGCTGCCTGATTGGCACCTCATGTTGGGTGGA
G
GAGGTACTCCTGGGTGGGCCGCAGGGAGTGCAGGTGACCCTGTCACTGTTGAGGACACACCTGGCACCTAGGGTGGAGG
C
IS
CTTCAGCCTTTCCTGCAGCACATGGGGCCGACTGTGCACCCTGACTGCCCGGGCTCCTATTCCCAAGGAGGGTCCCACT
G
GATTCCAGTTTCCGTCAGAGAAGGAACCGCAACGGCTCAGCCACCAGGCCCCGGTGCCTTGCACCCCAGTCCTGAGCCA
G
GGGTCTCCTGTCCTGAGGCTCAGAGAGGGGACACAGCCCGCCCTGCCCTTGGGGTCTGGAGTGGTGGGGGTCAGAGAGA
G
AGTGGGGGACACCGCCAGGCCAGGCCCTGAGGGCAGAGGTGATGTCTGAGTTTCTGCGTGGCCACTGTCAGTCTCCTCG
C
CTCCACTCACACAG
5'-region intron 6 (SEQ ID NO 9)
GTHAGGTTCACGTGTGATAGTCGTGTCCAGGATGTGTGTCTCTGGGATATGAATGTGTCTAGAATGCAGTCGTGTCTGT
G
AT:~CG'rTTCTGTGGTGGAGGTACTTCCATGATTTACACATCTGTGATATGCGTGTGTGGCACGTGTGTGTCGTGGTG
CAT
GTATCTGTGGCGTGCATATTTGTGGTGTGTGTGTGTGTGGCACGTGTGTGTCCATGGTGTGTGTGCCTGTGGTGTGCAT
G
ZS
TGTGTGTG'rCTGTGACACGTGCATGTTCATGCTGTGTGCTGCATGTCTGTGATGTGCCTATTTGTGGTGTGTGTGTGC
AT
GTGTCCGTGACATATGCGTGTCTATGGCATGGGTGTGTGTGGCCCCTTGGCCTTACTCCTTCCTCCTCCAGGCATGGTC
C
GCACCATTGTCCTCACGCTCTCGGGTGCTGGTTTGGGGAGCTCCACATTCAGGGTCCTCACTTCTAGCATGGGTGCCCC
T
GTCCTGTCACAGGGCTGGGCCTTGGAGACTGTAAGCCAGGTTTGAGAGGAGAGTAGGGATGCTGGTGGTACCTTCCTGG
A
CCCCTGGCACCCCCAGGACCCCAGTCTGGCCTATGCCGGCTCCATGAGATATAGGAAGGCTGATTCAGGCCTCGCTCCC
C
3O
GGGACACACTCCTCCCAGAGCGGCCGGGGGCCTTGGGGCTCGGCAGGGGTGAAAGGGGCCCTGGGCTTGGGTTCCCACC
C
AGTGGTCATGAGCACGCTGGAGGGGTAAGCCCTCAAAGTCGTGCCAGGCCGGGGTGCAGAGGTGAAGAAGTATCCCTGG
A
GCTTCGGTCTGGGGAGAGGCACATGTGGAAACCCACAAGGACCTCTTTCTCTGACTTCTTGAGCT
3'-region intron 6 (SEQ ID NO 10)
3S
TGTGGGATTGGTTTTCATGTGTGGGATAGGTGGGGATCTGTGGGATTGGTTTTTATGAGTGGGGTAACACAGAGTTCAA
G
G~GAGCTTTCTTCCTGTAGTGGGTCTGCAGGTGCTCCAACAGCTTTATTGAGGAGACCATATCTTCCTTTGA.~..~.T
ATGGT
CGGGTTTATAGTAAGTCAGGGGTGTGGAGGCCTCCCCTGGGCTCCCTGTTCTGTTTCTTCC'.ACTC.TGGGGT~G'GT
GGTG
C~TGCTGTGGTGTGTGGCCGGTGGGCAGGGCTTCCAGGCCTCCTTGTGTTCATTGGCCTGGATGTG.'CCC'GG~TACG
CT
CCGTCCTTGGAATTCCCCTGCGAGTTGGAGGCTTTCTTTCTTTCTTTT:T'~'CTTTCTTTTTTTTTT.
'_'TTTTGATAACAGA
GTCTCC~TCTTTTTTGCCCAGGCTGGAGTGGTTTGGCGTGATCTTGGCTCACTGCAACCTGTGCTT"~TG.'~.GT;CA
AGCA
A"TCT~_"TGCCTCAGCCTCCCA.T1GTAGCTGGAATTATAGGCGCCCACCACCATGCTGACT.=~.ATTTT
~TA.:,"T"_'TAGTAG
A~ACGA GTTTCTCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCTC~CACCT-
'~GCCTC~CAAAGT
G~TGG:GATGACAGGTGTGAACCGCCGCGCCCGGCCGAGACTCGCTTCCTGCAGCTTCCGT~AGATC:~CAG~G_~TAG
CT.G
C'TGCAGCCTTGGTGCTGACAACCTCCGTTTTCCTTCTCCAGGTCTCGCTAGGGGTCTTT~CATTT:'ATG:.~T~TCT
TCA
CA 02316282 2000-06-21
Le A 32 805-Forei~ountries
-41 -
CAGAAGAGTTTCACGTGTGCTGATTTCCCGGCTGTTTCCTGCGTAATTGGTGTCTGCTGTTTATCGATGGCCTCCTTCC
A
TTTCCTTTAGGCTTTGTTTATTGTTGTTTTTCCGGCTCCTTGAAGGAAAAGTTTCGATTATGGATGTTTGAACTTTCTT
T
TCTAAACAAGCATCTGAAGTTGCCGTTTTCCCTCTAAAGCAGGGATCCCGAGGCCCCTGGCTGTGGAGTGGCACCGGTC
T
GGGGCCTGTTAGGAACCCGGCGCACAGCGGGAGGCTAGGTGGGGTGTGGGGAGCCAGCGTTCCCGCCTGAGCCCCGCCC
C
TCTCAGATCAGCAGTGGCATGCGGTGCTCAGAGGCGCACACACCCTACTGAGAACTGTGCGTGAGAGGGGTCTAGATTC
T
GTGCTCCTTATGGGAATCTAATGCCTGATGATCTGAGGTGGAACCGTTTGCTCCCAAAACCATCCCCTTCCCCACTGCT
G
TCCTGTGGAAAAATCGTCTTCCACGAAACCAGTCCCTGGTACCACAATGGTTGGGGACCCTGTGCTAAAGACCTGCTTC
A
GCAGCCTCTCGTCAGTGTTGATATATTGGCTTTTCTGTGTTGAGTCCAGAATAATTACGGATTTCTGTGATGCTTTCCG
C
CGACCTCAGACCCATGGGCTATTTGTGGGCGTGTTGCCTGCTCCTGGGTTGGGAAGGGTGCAGGCCCCATGTACCTTCC
T
lO
GTTACTGCCTTCCAGGTTGGTTCTCAGGGTTGAATCGTACTCGATGTGGTTTTAGCCCACGGCCCTGCCGCCAGCTCCT
G
GGGGCTGGGGAACATGCTGAAGCACAGAGTCACCGTGCGCGTCTTTTGATGCCTCACAAGCTCGAGGCCTCCTGTGTCC
G
TGTTAGTGTGTGTCACGTGCCTGCTCACATCCTGTCTTGGGGACGCAGGGGCTTAGCAGGTCCCGTAGTAAATGACAAG
C
GTCCTGGGGGAGTCTGCAGAATAGGAGGTGGGGGTGCCGGTCTCTCTCCCGCGTCTTCAGACTCTTCTCCTGCCTGTGC
T
GTGGCTGCACCTGCATCCCTGCAATCCCTCCAGCACTGGGCTGGAGAGGCCCGGGAGCTCGAGTGCCACTTGTGCCACG
T
IS
GACTGTGGATGGCAGTCGGTCACGGGGGTCTGATGTGTGG'rGACTGTGGATGGCGGTTGGTCACAGGGGTCTGATGTG
TG
GTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTG
G
ATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGT
G
GGGTCTGATGTGGTGACTGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGAT
G
TGGTGACTGTGGATGGCAGTCG1'GGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGA
CT
2O
GTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATG
G
CGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTC
A
CAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACA
G
GGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTTGGTCCCGGGG
G
TCTGATGTGTGGTGACTGTGGATGGCGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTC
T
2S
GATGTGTGG'rGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTG
GT
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGA
T
GGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCA
G
TCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGG
G
TCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG
T
3O
GGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGG
T
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGA
T
GGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTAGGGTCTGATGTGTGGTGACTGTGGATGGCAGTC
G
GTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTG
G
GGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA
T
3S
GTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTAGCTGCAGGTGGAGTCCCAGGTGTGTCTGTAGC
T
ACTTTGCGTCCTCGGCCCCCCGGCCCCCGTTTCCCAAACAGAAGCTTCCCAGGCGCTCTCTGGGCTTCATCCCGCCATC
G
GGCTTGGCCGCAGGTCCACACGTCCTGATCGG~.AGAAACAAGTGCCCAGCTCTGGCC'vGGGCAGGCCACATTTGTGG
CTC
ATGCCCTCTCCTCTGCCGGCAG
40 Intron 7 (SEQ ID NO 11)
GTCTGGGCACTGCCCTGCAGGGTTGGGC~.~GGACTCCCAGCAGTGGGTCCTCCCCTGGGCAATCACTGGGCTCATGT;
~CG
GACAGACTGTTGGCCCTGGGGGGCAGTGGGGGGAATGAGCTGTGATGGGGGCATGA'IG.~~.GCTG'_"G"_'GCCTT
GGCGAF~TC
TGAGCTGGGCCATGCCAGGCTGC~ACAG~T'GCTGCATTCAGGCACCTGCTCACGTTTG::CTGCGC~GCCTCTCTCCA
~TT
CCGCAGTGCCTTTGTTCATGATTTGCTA-
_~.TG''CTTCTCTGCCAGTTTTGATCTTGA~GCCAAAGGAAAGGTGTCCC'CT
4~
CCTTTAGGAGGGCAGGCCATGTTTGAGC~~TGTCCTGCCCAGCTGGCCCCTCAGTGCT~GGTCTGAGGCC=;AAGGAA.
aCG
TGTCCCCCTTCTTAGGAGGACGGGCCGTG ~'TTCAGCCACGCCCCGCTGAGCGGGCC'~:;:'CAGTGC'~GGGT
C'"GT CCA .GT
CA 02316282 2000-06-21
Le A 32 805-Forei~~n Countries
- 42 -
GGCCCTGTGGCCCTTTGCAGATGTGGTCTGTCCACGTGGCCCTGTGGCTCTTTGCAGATGCCTGTTAGCACTTGCTCGG
C
TCTAGGGGACAGTCGTGTCCACCGCATGAGGCTCAGAGACCTCTGGGCGAATTTCCTTGGCTCCCAGGGTGGGGGTGGA
G
GTGGCCTGGGCTGCTGGGACCCAGACCCTGTGCCCGGCAGCTGGGCAGCAACTCCTGGATCACATATGCCATCCGGGCC
A
CGGTGGGCTGTGTGGGTGTGAGCCCAGCTGGACCCACAGGTGGCCCAGAGGAGACGTTCTGTGTCACACACTCTGCCTA
A
GCCCATGTGTGTCTGCAGAGACTCGGCCCGGCCAGCCCACGATGGCCCTGCATTCCAGCCCAGCCCCGCACTTCATCAC
A
AACACTGACCCCAAAAGGGACGGAGGGTCTTGGCCACGTGGTCCTGCCTGTCTCAGCACCCACCGGCTCACTCCCATGT
G
TCTCCCGTCTGCTTTCGCAG
Intron 8 (SEQ ID NO 12)
IO
GTGAGTCAGGTGGCCAGGTGCCATTGCCCTGCGGGTGGCTGGGCGGGCTGGCAGGGCTTCTGCTCACCTCTCTCCTGCC
C
CTTCCCCACTGNCCTTCTGCCCGGGGCCACCAGAGTCTCCTTTTCTGGCCCCCGCCCCCTCCGGCTCCTGGGCTGCAGG
C
TCCCGAGGCCCCGGAAACATGGCTCGGCTTGCGGCAGCCGGAGCGGAGCAGGTGCCACACGAGGCCTGGAAATGGCAAG
C
GGGGTGTGGAGTTGCTCCTGCGTGGAGGACGAGGGGCGGGGGGTGTGTCTGGGTCAGGTGTGCGCCGAGCGTTTGAGCC
T
GCAGCTTGTCAGCTCCAAGTTACTACTGACGCTGGACACCCGGCTCTCACACGCTTGTATCTCTCTCTCCCGATACAAA
A
IS
GGATTTTATCCGATTCTCATTCCTGTCCCTGTCGTGTGACCCCCGCGAGGGCGCGGGCTCTTCTCTCTGTGACTAGATT
T
CCCATCTGGAAAGTGCGGGGTTGACCGTGTAGTTTGCTCCTCTCGGGGGGCCTGTGGTGGCCATGGGGCAGGCGGCCTG
G
GAGAGCTGCCGTCACACAGCCACTGGGTGAGCCACACTCACGGTGGTAGAGCCACAGTGCCTGGTGCCACATCACGTCC
T
CTGGATTTTAAGTAAAACCACACACCTCCCGGCAGGCATCTGCCTGCGACCCTGTGTGTGCCTGGGGAGAGTGGTAGCA
C
GGAGGAAATTCGTGCACACTCAAGGTCATCAGCAAGGTCATCCGCAGTCAGGTGGAACGTGGAGGCCTCTCTCTGGGAT
C
2O
GTCTCCAGCGGATAAAGGACTGTGCACAGCTTCGGAAGCTTTTATTT_~1AAAATATAACTATTAATTATTGCATTATA
AGT
AATCACTAATGGTATCAGCAATTATAATATTTATTAAAGTATAAT'rAGAAATATTAAGTAGTACACACGTTCTGGAAA
AA
CACAAATTGCACATGGCAGCAGAGTGAATTTTGGCCGAGGGACACGTGTGCACATGTGTGTAAGCGGCCCCCAGGCCCA
C
AGAATTCGCTGACAAAGTCACCTCCCCAGAGAAGCCACCACGGGCCTCCTTCGTGGTCGTGAATTTTATTAAGATGGAT
C
AAGTCACGTACCGTCCACGTGTGGCAGGGCTTTGGGGAATGTGAGGTGATGACTGCGTCCTCATGCCCTGACAGACAGG
A
2S
GGTGACUGTGTCTGTCCTGTCCCTAGGACACGGACAGGCCCGAAGCTCTAGTCCCCATCGTGGTCCAGTTTGGCCTCTG
A
ATAAAAACGTCTTCAAAACCTGTTGCCCCAAAAACTAAGAACAGAGAGAGTTTCCCATCCCATGTGCTCACAGGGGCGT
A
TCTGCTTGCGTrGACTCGCTGGGCTGGCCGGACTCCTAGAGTTGGTGCGTGTGCTTCTGTGCAAAAAGTGCAGTCCTCT
T
GCCCATCACTGTGATATCTGCACCAGCAAGGAAAGCCTCTTTTCTTTTCTTTCTTTTTTTTTTTTTGAGACGGAACGTC
A
CTGTTGTCTGCCTGGGCTTGAGTGCAGTGGCGCGATCTCAACTCACTGCAACCTCCGCCTCCCGGGTTCCAGCATTTCT
C
3O
CTGCCTCAGCCTCCCGAGCAGCTGAGATTACAGGCACCCACCCCCTGCGCCTGGCTAATTTTTGTATTTTTAGTAGAGA
G
GGGTTTTTGCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCACCCACCTCGGCCTCCCAAAGTGCT
G
GGATTACAGGTGTGAGCCATCACGCCCAGCCGGAA_AGCCTCTTTTTAAGGTGACCACCTATAGCGCTTCCCGAAAATA
AC
AGGTCTTGTTTTTGCAGTAGGCTGCAAGCGTCTCTTAGCAACAGGAGTGGCGTCCTGTGGGCTCTGGGGATGGCTGAGG
G
TCGCGTGGCAGCCATGCCTTCTGTGTGCACCTTTAGGTTCCACGGGGCTATTCTGCTCTCACTGTTTGTCTGAA.~.AC
GCA
3S
CCCTTGGCATCCTTGTTTGGAGAGTTTCTGCT_"CTCGTTGGTCATGCTGAAACTAGGGGCAAGGTTGTATCCGTTGGC
GC
GCAGCGGCTACATGTAGGGTCATGAGTCTTTC.~CCGTGGACAAATTCCTTGAAAAAAAAAAAAGGAGTCCGGTTAAGC
AT
TCATTCCGGGTCAAGTGTCTGG T TCTGTGAA'~'.-"Lrlr, ~ T CTAAGA T
TTAAGAAA'~CTTAATGAAAGAAAACCTTGA T GaTTC
AGAGCAAGGATGTGGTCACACCTGTGGCTGC-
.~CT~T'rTCAGCCGCCCCAGTGCATGGTGAGAGTGGGGAGCAG,CG:~TTG
TTTGTTCAGAGGTCTCATCTGGTATGTTTCT
_~:':GG'1G':'TTGCCGGCTGAATGGTAGACGTGTCGTTTGTGTGTA: G.~GGT
4O TCTGTGTCTGTGTGTGGCTCGGTTTGAGTGT-
.'GC=,TGTCCAGCACATGCCC'"GCCCGTCTCTC=,CC:';GTGTC~_'"_'C~CGC
CCCAG
Intron 9 (SEQ ID NO 13)
GTGAGGCCTCCTCTTCCC ~AGG~GGGCTT: G;:= :' ~G ~ GGTTGATTTGCTTTTG:..TGCATTCAGT«
:'T. ~~.TA':'TCC : = ~TGC
4S TCTGGAGACCA'_"GACTGCTCTG~CTTGAGGA_=.:CA
~=~Cr".AGGTTGCAGCCCC'.":'CTTGGTA'."G-_=:G~.~.GCACGG~=..;GGG
-. CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
- 43 -
TTGCACAGCCTGAGGACTGCGGGCTCCACGCAGGCTCTGTCCAGCGGCCATGTCCAGAGGCCTCAGGGCTCAGCAGGCG
G
GAGGGCCGCTGCCCTGCATGATGAGCATGTGAATTCAACACCGAGGAAGCACACCAGCTTCTGTCACGTCACCCAGGTT
C
CGTTAGGGTCCTTGGGGAGATGGGGCTGGTGCAGCCTGAGGCCCCACATCTCCCAGCAGGCCCTCGACAGGTGGCCTGG
A
CTGGGCGCCTCTTCAGCCCATTGCCCATCCCACTTGCATGGGGTCTACACCCAAGGACGCACACACCTAAATATCGTGC
C
S
AACCTAATGTGGTTCAACTCAGCTGGCTTTTATTGACAGCAGTTACTTTTTTTTTTTTAATACTTTAAGTTCTAGGGTA
C
ATGTGCACGACGTGCAGGTTAGTTACATATGTATACATGTGCCATGTTGGTGTGCTGCACCCATTAACTCATCATTTAC
A
TTAGGTATATCTCCTAATGCTATCCCTCCCCACTCCCCCCATCCCATGACAGGCCCTGGTGTGTGATGTTCCCCACCCT
G
TGTCCAAGTGTTCTCATTGTTCAGTTCCCACCTGTGAGTGAGAACATGTGGTGTTTGGTTTTCTTTCCTTGCAATAGTT
T
GCTCAGAGTGATGGTTTCCAGCTTCGTCCATGTCCCTACAAAGGACATGAACTCATCCTTTTTTATGACTGCATAGTAT
T
IO
CCrTGGTGTATATGTGCCACATTTTCTTAATCCAGTCTATCATCGATGGACATTTGGGTTGGTTGCAAGTCTTTGCTAC
T
GTGAATAGTGCCGCAATAAACATACGTGTGCATGTGTCTTTATAGCAGCATGATTTATAATCCTTTGGGTATATACCCA
G
TAATGGGATGGCTGGGTCAAATGGTATTTCTAGTTCTAGATCCTTGAGGAATCACCACACTGTCTTCCACAATGGTTGA
A
CTAGTTTACACTCCCACCAACAGTGTAAAAGTGTTCTGGTGCTGGAGAGGATGTGGACAGCAGTTATTTTTTTATGAAA
A
TAGTATCACTGAACAAGCAGACAGTTAGTGAAGGATGCGTCAGGAAGCCTGCAGGCCACACAGCCATTTCTCTCGAAGA
C
IS
TCCGGGTTTTTCCTGTGCATCTTTTGAAACTCTAGCTCCAATTATAGCATGTACAGTGGATCAAGGTTCTTCTTCATTA
A
GGTTCAAGTTCTAGATTGAAATAAGTTTATGTAACAGAAACAAAAATTTCTTGTACACACAACTTGCTCTGGGATTTGG
A
GGAAAGTGTCCTCGAGCTGGCGGCACACTGGTCAGCCCTCTGGGACAGGATACCTCTGGCCCATGGTCATGGGGCGCTG
G
GCTTGGGCCTGAGGGTCACACAGTGCACCATGCCCAGCTTCCTGTGGATAGGATCTGGGTCTCGGATCATGCTGAGGAC
C
ACAGCTGCCATGCTGGTAAAGGGCACCACGTGGCTCAGAGGGGGCGAGGTTCCCAGCCCCAGCTTTCTTACCGTCTTCA
G
O
TTATTTTTCCCTAAGAGTCTGAGAAGTGGGGCCGCGCCTGATGGCCTTCGTTCGTCTTCAGCTGGCACAGAATTGCACA
A
GCTGATGGTP.AACACTGAGTACTTATAATGAATGAGGAATTGCTGTAGCAGT'TAACTGTAGAGAGCTCGTCTGTTGG
AAA
GAAi-
1TTTAAGTTTTTCATTTAACCGCTTTGGAGAATGTTACTTTA'rTTATGGCTGTGTAAATTGTTTGACATT.CAGTCCC
TCGTAGACAGATACTACGTAAAAAGTGTAAAGTTAACCTTGCTGTGTATTTTCCCTTATTTTAG
ZS Intron 10 (SEQ ID NO 14)
GTGAGGCCCGTGCCGTGTGTCTGTGGGGACCTCCACAGCCTGTGGGCTTTGCAGTTGAGCCCCCCGTGTCCTGCCCCTG
G
CACCGCAGCGTTGTCTCTGCCAAGTCCTCTCTCTCTGCCGGTGCTGGATCCGCAAGAGCAGAGGCGCTTGGCCGTGCAC
C
CAGGCCTGGGGGCGCAGGGGCACCTTCGGGAGGGAGTGGGTACCGTGCAGGCCCTGGTCCTGCAGAGACGCACCCAGGT
T
ACACACGTGGTGAGTGCAGGCGGTGACCTGGCTCCTGCTGCTCTTTGGAAAGTCAAGAGTGGCGGCTCCTGGGGCCCCA
G
3O
TGAGACCCCCAGGAGCTGTGCACAGGGCCTGCAGGGCCGAGGCGGCAGCCTCCTCCCCAGGGTGCACCTGAGCCTGCGG
A
GAGCAGGAGCTGCTGAGTGAGCTGGCCCACAGCGTTCGCTGCGGTCACGTTCCTGCGTGGGGTTGTTTGGGATCGGTGG
G
AGAATTTGGATTTGCTGAGTGCTGCTGTCTTGAACCACGGAGATGGCTAGGAGTGGGTTTCAGAGTTGATTTTTGTGAA
T
CAAAC1'AAAATCAGGCACAGGGGACCTGGCCTCAGCACAGGGGATTGTCCAATGTGGTCCCCCTCAAGGGCGCCCCAC
AG
AGCCGGTGGGCTTGTTTTAAAGTGCGATTTGACGAGGGACGAGAAACCTTGAAAGCTGTAAAGGGAACCCTCAGAAAAT
G
3S
TGGCCGCCAGGGGTGGTTTCAG~TGCTTTGCTGGGCT~TGTTTGTGAAAACCCATT".'GGACCCGCCCTCCAAGTCCA
CC~
TCCAGGTCCACCCTCCAGGGCC~CCCTGGGCTGGGGGTATGCCTGGCGTTCCTTGTG~CGCAGCCCGGAGCACAGCAGG
C
TGTGCACATTTAAATCCACTAA;~ATTCACTCGGGGG:~AGCCCAGGTCCCAAGCAACT;,AGGGCTCAGGAGTCCTGA
GGCT
GCTGAGGGGACAGAGCAGACGG~GAACGCTGCTTCT~TGTGGCAAGTTCCT~AGGGT.~CTGGCCAGGGAGGTGGCTCA
GA
GTGTATGTTGGGGTCCCACCGG=:GGC=,GF_~CTCTG_''-:'iCT'GATGAGTCGGCAGCCA~
~TAACAGGAAGGGGTGGCCAC.-';,~
4O
GGAGCTGGGAATGCACCAGGGG~.GCT~CGCAGCTGG~CGAGGTCCCAGGGCCAGGC':ACAGGAAGGGCAGGGGGACG
CCC
GGGGCCACAGCAGAGGCCGCAG,~AAGGGr~GGGGATCCCCAGGCCAGAGCAGAGGC"'=,CCGGGCACAGGGGGGCTC
CC"'G
AGCTGGGTGAGCGAGG CTCATG:=.CTCC.GC ~AGGGA.=,C ~ T C,~TTGACGTGA.AGCTGr.':
~ACTGGTGTTGCCC.~~,GCTCACA.~
CCCAGCCAGGTCCCGCGCC'_"GACAGGAACTCAGAACCCTCCCCTTTGTCTA.%,AGC:',CAGCAGATGCCTTCAGG
GCATC~
AG~CAGAAAACAGGCA~,AGT CGT'~GAG.=,AA CGTCT'."P.:'~.:~,A;~~GGTGGGAT.CGTGG
C:'.:,, T TTCTTGTCCAGA'?'TTTAG T C :'
4S
GCCCCGGACCACAGA"_'GAGTCT:',TAACGGGATTGTG:~'"GTTGCCATGGGGACACAT':'."~GATGGACCATC
ACAGAGGCC=,;
TGGGGCTGCACC'TCC:C=,'"C"'G~, :TCC':GGCTGTCC': ~::C. _CAGGCCAGG'~'TCT'r~..
'°,TGCTCACCTACCTGTCCTGC:C ='
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-44-
GGGAGACAGGGAAAGCACCCCGAAGTCTGGAGCAGGGCTGGGTCCAGGCTCCTCAGAGCTCCTGCCAGGCCCAGCACCC
T
GCTCCAAATCACCACTTCTCTGGGGTTTTCCAAAGCATTTAACAAGGGTGTCAGGTTACCTCCTGGGTGACGGCCCCGC
A
TCCTGGGGCTGACATTGCCCCTCTGCCTTAG
Intron 11 (SEQ ID NO 15)
GTGAGCGCACCTGGCCGGAAGTGGAGCCTGTGCCCGGCTGGGGCAGGTGCTGCTGCAGGGCCGTTGCGTCCACCTCTGC
T
TCCGTGTGGGGCAGGCGACTGCCAATCCCAAAGGGTCAGAGGCCACAGGGTGCCCCTCGTCCCATCTGGGGCTGAGCAG
A
AATGCATCTTTCTGTGGGAGTGAGGGTGCTCACAACGGGAGCAGTTTTCTGTGCTATTTTGGTAAAAGGAAATGGTGCA
C
CAGACCTGGGTGCACTGAGGTGTCTTCAGAAAGCAGTCTGGATCCGAACCCAAGACGCCCGGGCCCTGCTGGGCGTGAG
T
IO
CTCTCAAACCCGAACACAGGGGCCCTGCTGGGCATGAGTCCCTCTGAACCCGAGACCCTGGGGCCCTGCTGGGCGTGAG
T
CTCTCCGAACCCAGAGACTTCAGGGCCCTTTTGGGCGTGAGTCTCTCCGCTGTGAGCCCCACACTCCAAGGCTCATCCA
C
AGTCTACAGGATGCCATGAGTTCATGATCACGTGTGACCCATCAGGGGACAGGGCCATGGTGTGGGGGGGGTCTCTACA
A
AATTCTGGGGTCTTGTTTCCCCAGAGCCCGAGAGCTCAAGGCCCCGTCTCAGGCTCAGACACAAATGAATTGAAGATGG
A
CACAGATGCAGAAATCTGTGCTGTTTCTTTTATGAATAAAAAGTATCAACATTCCAGGCAGGGCAAGGTGGCTCACACC
T
IJ
ATAATCCCAGCACTTTGGGAGGCCGAGGTGGGTGGATCACTTGAGGCCAGGAGTTTGAGGCCAACCTAACCAACATAGT
G
AAATTCCATTTCTACTTAAAAAATACAAAAATTAGCCTGGCCTGGTGGCACACGCCTGTAGTCCCCGCTATGCGGGAGG
C
TGAGGCAGGAGAATCATTTGAACCCAGGAGGCAGAGGTTGCAGTGAGCCGAGATCACACCACTGCACTCCAGCCTGGGC
A
ACAGAGTGAGACTTCATCTTAAAAAAAAAAAAAAAAGTATCAGCATTCCAAAACCATAGTGGACAGGTGTTTTTTTATT
C
TGTCCTTCGATAATATTTACTGGTGCTGTGCTAGAGGCCGGAACTGGGGGTGCCTTCCTCTGAAAGGCACACCTTCATG
G
2O
GAAGAGAAATAAGTGGTGAATGGTTGTTAAACCAGAGGTTTAAACTGGGGTCCTGTCGTTCTGAGTTAACAGTCCAGAT
C
TGGACTTTGCCTCTTTCCAGAATGCTCCCTGGGGTTTGCTTCATGGGGGAGCAGCAGGTGTGGACACCCTCGTGATGGG
G
GAGCAGCAGGTGCAGACGCCCTCATGATGGGGGAGTGGCAGGTGCAGACACCCTTGTGCATGGTGCCCAGCATGTCCCT
G
TTGCAGCTCCCTCCCCACAAGGATGCCGGTCTCCTGTGCTCCCCACAGTCCCTGCTTCCCTCTCACAGCCTTACCTGGT
C
CTGGCCTCCACTGGCTTTGTCTGCATGATTTCCACATTTCCTGGGCTCCCAGCACCTCTTCGCCTCTCCCAGGCACCTC
T
ZS
GCAGTCCTGGCCATACCAGTCAGCTGTGAACTGTCCACTGCTTATTTTGCTCCCCATGAAATGTATTTTTTAGGACAGG
C
ACCCCTGGTTCCAGCCTCTGGCACAGCATCAGTGAATGTTATTGAAGGACAAAGGACAGACAAACAAATCAGGAAAATG
G
GTTCTCTCTAAACACATTGCAAAGCCACAGAGGCTAGTGCAGGATGGGTGGGCATCAGGTCATCAGATGTGGGTCCAAT
G
CCAGAATATTCTGTGCTCCCAAAGGCCACTTGGTCAGAGTGTGTGCTTGCAGAGGTGGCTCTAAAAGCTCAGCAGTGGA
G
GCAGTGGTTCGCCATACTCAGGGTGAACTCACATCCTCTGTGTCTGAAGTATACAGCAGAGGCTTGAAGGGCATCTGGG
A
3O
GAAGAAAACAGGCAAAATGATTAAGAAAAGTGAAAAAGGAAAAGTGGTAAGATGGGAATTTTCTTGTCCAGATTTTAGT
C
TCCCAAACCACAGCTCAGATGGTAGAATGTGGTCAGAACTGATGGACAGAACAATAGAACAAAACGGAAGCCCTATCTC
T
CAGAAACGTGTGTTAATGTGGTATGTGGCACAGCTGATGGAAAAGAGAGTGTGTGTGTAATTTTTTTTTCTGAGAAAAC
T
GACTGGAAGCAAATAAGTTGTGTCTTTACAGCATATACCAGAGCAGATTCTAGGTAGAAGAGGAGACACATGCAAACAA
C
ACCAGCAACAGAAATAAAACAAA.~1GACTCAAAGGGAAGGGAGGTGAACGTTCCCTGGTTTGGTGTTGGGGAAGGACA
CAC
3S
AGGGAGGCGGATGAAACCAGTGAGGCAACGGGCATTGCTTTCACTGCAGAGAAACTCAGCTTGCCTGAGCCACAGTGAA
A
ATGGCCATTCCCTGGAGCGTTTGTGCACGTGATTTATTTAAGGCGCCCTGTGAGGTCCTGCACATTCATCCTCTCACTT
T
GTTCTCCTAACCACCTGAGAGG'~AGAGGAGG~~vGGCTCC.aGGGGAGCAGCCGCCCTTGGTCACCCAGCTGGCAAAG
GGC
ATGCATGATTGCAGCCTGGCCT~CTGCTCCGGGGCCCTTG~TCTGCCCG:~GGACCCCACACAAGTCAGACCCATAGGC
TC
~GGGTGAGCCGGAGCCCAAGGi~GTGTTGGGGA':GGC':GT~AAAGAAGA_=,ATGGACGTCTGATGCACACTTGGGA
AGGTC
4O
~TACCAGCAGCGTCAAAGAAA"'~CATGTGAA.1CTGACAGC~AGACCCATCCCTCAAAGAAACGCACGTGAAACTGAT
GGC
~AGACCTGTCCCCATCCCTCAi'~CTGGCTCC'~".'TTCTGGG~TTGCCAAG.=,GCCAGCATCAGGTTGAGGCAAGC
TGGAAAG
=;CTTTTCTGGAAAG~AGCTTG =' _' :'GCATGG~..y~ :'CCT~:AC.-~,ATGTCCTG
:'GTCTTCCCAGTAATTCCACTTCTGAAGTGA
~CAGACATTATCACGGGTCTT ~.:'?'TACCATTr~;.~AGT~;TT
.'CAGGCAGG:~GGACTTGCCACAGCAAGTCACGAACCTGCC
,AA~1TACAGGGCTAAGGAGAT_°~. = TAT. GCAT~~ ",.~.-
'..A.~A':TT.~CTCTGCCA'~TAAACATTTTTCAAAGAATTTTTGAAGAAT
4S pTTTAATGGCACAAP.ACGTTT='; TTCAATGT:;~ ;':AGTGTT
~AAAGCTGG.,TG'rAAAAGAACAGACCCCAGGAGCCTGCCG
!'GAATGTCATGTGT.CTTCAT~': "'~~GACaT:~ "=.'=~''A':AT
~GGCAGTGA:~TGGTGGTGAGGCCCTGGAGGACATCGGTGG
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GATGCCTCCATCCTGCCCCTCTGGAGACACCATGTGTGCCACGTGCACTCACTGGAGCCCTGTTTAGCTGGTGCCACCT
G
GCTCTTCCATCCCTGAGATTCAAACACAGTGAGATTCCCCACGCCCAACTCAGTGTTCTCCCACAAAAAACCTGAGTCA
C
ACCTGTGTTCACTCGAGGGACGCCCGGGAGCCAGGGCTCCACAGTTTATTATGTGTTTTTGGCTGAGTTATGTGCAGAT
C
TCATCAGGGCAGATGATGAGTGCACAAACACGGCCGTGCGAGGTTTGGATACACTCAACATCACTAGCCAGGTCCTGGT
G
GAGTTTGGTCATGCAGAGTCTGGATGGCATGTAGCATTTGGAGTCCATGGAGTGAGCACCCAGCCCCCTCGGGCTGCAG
C
GCATGCCCCAGGCAGGACAAGGAAGCGGGAGGAAGGCAGGAGGCTCTTTGGAGCAAGCTTTGCAGGAGGGGGCTGGGTG
T
GGGGCAGGCACCTGTGTCTGACATTCCCCCCTGTGTCTCAG
Intron 12 (SEQ ID NO 16)
IO
G'fGAGCAGGCTGATGGTCAGCACAGAGTTCAGAGTTCAGGAGGTGTGTGCGCAAGTATGTGTGTGTGTGTGTGCGCGC
GT
GCCTGCAAGGCTGATGGTGACTGGCTGCACGTAAGAGTGCACATGTACGCATATACACGTGAGCACATACATGTGTGCA
T
GTGTGTACATGAAGGCATGGCAGTGTGTGCACAGGTGTGCAAGGGCACAAGTGTGTGCACATGCGAATGCACACCTGAC
A
TGCATGTGTGTTCGTGCACAGTCGTGTGGGCATTCACGTGAGGTGCATGCGTGTGGGTGTGCAGTGTGAGTAGCATGTG
T
GCACATAACATGTATTGAGGGGTCCTCGTGTTCACCCCGCTAGGTCCTCAGCACCAGTGCCACTCCTTACAGGATGAGA
C
IS
GGGGTCCCAGGCCTTGGTGGGCTGAGGCTCTGAAGCTGCAGCCCTGAGGGCATTGTCCCATCTGGGCATCCGCGTCCAC
T
CCCTCTCCTGTGGGCTTCTGTGTCCACTCCCCCTCTCCTGTGGGCATTTACATCCACTCCACTCCCTCTCTCCTGTGGG
C
ATCCGCGTCCACTCCCCCTCTCTGTGGGCATCTGCGTCCACCTCCCCTCTCTGTGGGCATTTGCGTCCACTCCCTCTCC
T
GGTTCCTTCCTGTCTTGGCCGAGCCTCGGGGGCAGGCAGATGACACAGAGTCTTGACTCGCCCAGGGTGGTTCGCAGCT
G
CCGGGTGAGG~CCAGGCCGGATTTCACTGGGAAGAGGGATAGTTTCTTGTCAAAATGTTCCTCTTTCTTGTTCCATCTG
A
2O
?TGGATGATA~'~.AGCAAAAAGTAAAAACTTAAAATCCCAGAGAGGTTTCTACCGTTTCTCACTCTTTCTTGGCGACT
CTAG
Intron 13 (SEQ ID NO 17)
GTGAGCCGCCACCAAGGGGT~CAGGCCCAGCCTCCAGGGACCCTCCGCGCTCTGCTCACCTCTGACCCGGGGCTTCACC
T
TGGAACTCCTGGGTTTTAGGGGCAAGGAATGTCTTACGTTTTCAGTGGTGCTGCTGCCTGTGCACAGTTCTGTTCGCGT
G
GCTCTGTGCAAAGCACCTGTTCTCCATCTCTGGGTAGTGGTAGGAGCCGGTGTGGCCCCAGGTGTCCCCACTGTGCCTG
T
GCACTGGCCGTGGGACGTCATGGAGGCCATCCCAGGGCAGCAGGGGCATGGGGTAAAGAGATGTTTATGGGGAGTCTTA
G
CAGAGGAGGCTGGGAAGGTGTCTGAACAGTAGATGGGAGATCAGATGCCCGGAGGATTTGGGGTCTCAGCAAAGAGGGC
C
GAGGTGGGTGCAGGTGAGGGTCGCTGGCCCCACCCCCGGGAAGGTGCAGCAGAGCTGTGGCTCCCCACACAGCCCGGCC
A
GCACCTGTGCTCTGGGCATGGCTGTGCTCCTGGAACGTTCCCTGTCCTGGCTGGTCAGGGGGTGCCCCTGCCAAGAATC
G
3O
ACAACTTTATCACAGAGGGAAGGGCCAATCTGTGGAGGCCACAGGGCCAGCTTCTGCCTGGAGTCAGGGCAGGTGGTGG
C
ACAAGCCTCGGGGCTGTACCAAAGGGCAGTCGGGCACCACAGGCCCGGGCCTCCACCTCAACAGGCCTCCCGAGCCACT
G
GGAGCTGAATGCCAGGAGGCCGAAGCCCTCGCCCCATGAGGGCTGAGAAGGAGTGTGAGCATTTGTGTTACCCAGGGCC
G
AGGCTGCGCGAATTACCGTGCACACTTGATGTGAAATGAGGTCGTCGTCTATCGTGGAAACCCAGCAAGGGCTCACGGG
A
GAGTTTTCCATTACAAGGTCGTACCATGAAAATGGTTTTTAACCCGAGTGCTTGCGCCTTCATGCTCTGGCAGGGAGGG
C
AGAGCCACAGCTGCATGTTACCGCC'_"TTGCACC~ GCTCCAGAGG:'?'TGG
GACCAGGCTGTCTCAGTTCCAGGGTGCGTCC
GGCTCAGACCG:~CCTCCTCTCTGC''_'"'CTCTCTCTGCCTCAAATCTTCC~~TCGTTTGCATCTCCCTGACGCGTG
CCTGGG
CCCTCGTGCA.%~ ~~CTGCTTGACTCC :'T "CCGGA.=_A CCCTTGGG GTGTG C".' GG=.TAC
AGGTGCCACTGAGGACTGGAGGTGT
CTGACACTGTG~TTGACCCCAGGG~~CAGCTGG~GTGCTTGGGG~CTCCTTGGGCCATGATGAGGTCAGAGGAGTTTTC
C
CAGGTGAAAA~ :'u.CTGGGAAACT~~
~.=,GGGCC.TGTGACCTGCCA:'.CTG"T:"~TCC~ATA':'TCAGCTCAGTCTTGTCCTC
ATTTCCCCAC~,GGGTCTCTAGCT:CGAGGAGCTCCCGTAGAGG'~C._~TG~G::TCAGGGCAGGGCGGCTGAGTTTC
CCCAC
CCATGTGGGGA."CCTTGGGTAG~'~»~TGATTC~G"_':,GCCCTG.A,~G..~~~C;~
AGATGCGA"'GGGCCACGGGCCGTTTCCA
A.ACACAGAGTC=.GGCACGTGGP=.G~~CCAGGA.'-
_~~CCCTTCC~T~CACG~A:GAGTGGGAGAACGGAGAGCTGGGCCCCG
ATTTCACGGCA'CCAGGCTGCAG':i:~GCGAGG~"_'GTGGTGGT~C;CGTG~C=~CTGGGGGCGGGGTCTGATTCAA
ATCCGC
TGGGGCTCGGC .TTCCTGGC~C~"_ ~ ~ i GGCCG~ ~ ~CTCCACA~~ ~~C-r'_':~G,~ ~TGGA~GC~~
~CGACCTCTAGCAGGTGGC
TATTTCTCCC:'~TGGAAGAGAGCC,~;'CACCC=.~'.GCTAGGTG:'"'"'"~C'"'C. GGTCAGG.-"-
.~~CGTGGCCGTGTGGCAACC
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CCGGGACCTTAGGCTTATTTATTTGTTTAAAAACATTCTGGGCCTGGCTTCCGTTGTTGCTAAATGGGGAAAAGACATC
C
CACCTCAGCAGAGTTACTGAGAGGCTGAAACCGGGGTGCTGGCTTGACTGGTGTGATCTCAGGTCATTCCAGAAGTGGC
T
CAGGAAGTCAGTGAGACCAGGTACATGGGGGGCTCAGGCAGTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGTGGG
T
GAGGCCAGGTACATGGGGGGCTCAGGCACTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGAGGGTCAGACCAGGTA
C
ACGGGGGCTCTGATCACACGCACATATGAGCACATGTGCACATGTGCTGTTTCATGGTAGCCAGGTCTGTGCACACCTG
C
CCCAAAGTCCCAGGAAGCTGAGAGGCCAAAGATGGAGGCTGACAGGGCTGGCGCGGTGGCTCACACCTGTAGTCCCAGC
A
CTTTGGGAGGCCGAGGCGAGAGGATCCCTTGAGCCCAGGAGTTTAAGACCAGCCTGAGCAACATAGTAGAACCCCATCT
C
TATGAAAAATAAAAACAAAAATTAGCTGAACATGGTGGTGTGCGCCTGTAGTTCCAATACTTGGGAGGCTGAAGTGGGA
G
GATCACTTGAGCCCAGGAGGTGGAAGCTGCAGTGAGCTGAGATTGCACCACTGTACTGCAGCCTGGGTGACAGAGTGAG
A
IO
GCCCATCTCAACAACAACAAAGAAGACTGACAAATGCAGTTTCTTGGAAAGAAACATTTAGTAGGAACTTAACCTACAC
A
CAGAAGCCAAGTCGGTGTCTCGGTGTCAGTGAGATGAGATGATGGGTCCTCACACCATCACCCCAGACCCAGGGTTTAT
G
CACCACAGGGGCGGGTGGCTCAGAAGGGATGCGCAGGACGTTGATATACGATGACATCAAGGTTGTCTGACGAAGGGCA
G
Gr'1TTCATGATAAGTACCTGCTGGTACACAAGGAACAATGGATAAACTGGAAACCTTAGAGGCCTTCCCGGAACAGGG
GCT
AATCAGAAGCCAGCATGGGGGGCTGGCATCCAGGATGGAGCTGCTTCAGCCTCCACATGCGTGTTCATACAGATGGTGC
A
IS
CAGAAACGCAGTGTACCTGTGCACACACAGACACGCAGCTACTCGCACACACAAGCACACACACAGACATGCATGCATG
C
ATCCGTGTGTGTGCACCTGTGCCCATGAGGAAACCCATGCATGTGCATTCATGCACGCACACAGGCACCGGTGGGCCCA
T
GCCCACACCCACGAGCACCGTCTGATTAGGAGGCCTTTCCTCTGACGCTGTCCGCCATCCTCTCAG
Intron 14 (WEQ ID NO 18)
ZO
GTATGTGCAGGTGCCTGGCCTCAGTGGCAGCAGTGCCTGCCTGCTGGTGTTAGTGTGTCAGGAGACTGAGTGAATCTGG
G
CTTAGGAAGTTCTTACCCCTTTTCGCATCAGGAAGTGGTTTAACCCAACCACTGTCAGGCTCGTCTGCCCGCCCTCTCG
T
GGGGTGAGCAGAGCACCTGATGGAAGGGACAGGAGCTGTCTGGGAGCTGCCATCCTTCCCACCTTGCTCTGCCTGGGGA
A
GCG~~TGGGGGGCCTGGTCTCTCCTGTTTGCCCCATGGTGGGATTTGGGGGGCCTGGCCTCTCCTGTTTGCCCTGTGGT
GG
GATTGGGCTGTC'TCCCGTCCATGGCACTTAGGGCCCTTGTGCAAACCCAGGCCAAGGGCTTAGGAGGAGGCCAGGCCC
AG
ZS
GCTACCCCACCCCTCTCAGGAGCAGAGGCCGCGTATCACCACGACAGAGCCCCGCGCCGTCCTCTGCTTCCCAGTCACC
G
TCCTCTGCCCCTGGACACTTTGTCCAGCATCAGGGAGGTTTCTGATCCGTCTGAAATTCAAGCCATGTCGAACCTGCGG
T
CCTGAGCTTAACAGCTTCTACTTTCTGTTCTTTCTGTGTTGTGGAAATTTCACCTGGAGAAGCCGAAGAAAACATTTCT
G
TCGTGACTCCTGCGGTGCTTGGGTCGGGACAGCCAGAGATGGAGCCACCCCGCAGACCGTCGGGTGTGGGCAGCTTTCC
G
GTGTCTCCTGGGAGGGGAGCTGGGCTGGGCCTGTGACTCCTCAGCCTCTGTTTTCCCCCAG
Intron 15 (SEQ ID NO 19)
GCAAGTGTGGGTGGAGGCCAGTGCGGGCCCCACCTGCCCAGGGGTCATCCTTGAACGCCCTGTGTGGGGCGAGCAGCCT
C
AGATGCTGCTGAAGTGCAGACGCCCCCGGGCCTGACCCTGGGGGCCTGGAGCCACGCTGGCAGCCCTATGTGATTAAAC
G
CTGGTGTCCCCAGGCCACGGAGCCTGGCAGGGTCCCCAACTTCTTGAACCCCTGCTTCCCATCTCAGGGGCGATGGCTC
C
3S
CCACGCTTGGGAGCCTTCTGACCCCTGACCTGTGTCCTCTCACAGCCTCTTCCCTGGCTGCTGCCCTGAGCTCCTGGGG
T
CCTGAGCAAGTTCTCTCCCCGCCCCGCCGCTCCAGCGTCACTGGGCTGCCTGTCTGCTCGCCCCGGTGGAGGGGTGTCT
G
TCCCTTCACTGAGGTTCCCACCAGCCAGGGCCACGAGGTGCAGGCCCTGCCTGCCCGGCCACCCACACGTCCTAGGAGG
G
TTGGAGGATGCCACCTCTGGCCTCTTCTGGAACGGAGTCTGATTTTGGCCCCGCAG
3'-untranscribed region (SEQ ID NO 20)
ATCTCATGTTTGAATCCTAATGTGCACTGCATAGACACCACTGTATGCAATTACAGAAGCCTGTGAGTGAACGGGGTGG
T
GGTCAGTGCGGGCCCATGGCCTGGCTGTGCA'rTTACGGAAGTCTATGAGTGAATGGGGTTGTGGTCAGTGCGGGCCCA
TG
GCCTGGCTGGGCCTGGGAGGTTTCTGATGCTGTGAGGCAGGAGGGGAAGGAGGGTAGGGGATAGACAGTGGGAGCCCCC
A
C;~~CTGGAAGACATAACAGTAAGTCCAGGCCCGAAGGGCAGCAGGGATGCTGGGGGCCCAGCTTGGGCGGCGGGGATG
ATG
-~S
G~.GGGCCTGGCCAGGGTGGC:,GGGATGATGGGGGCCCCAGCTGGGGTGGCAGGGGTGATGGGGGGGGCTGGTCTGGG
TGG
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CGGGGAAGATGGGGAAGCCTGGCTGGGCCCCCTCCTCCCCTGCCTCCCACCTGCAGCCGTGGATCCGGATGTGCTTCCC
T
GGTGCACATCCTCTGGGCCATCAGCTTTCATGGAGGTGGGGGGCAGGGGCATGACACCATCCTGTATAAAATCCAGGAT
T
CCTCCTCCTGAACGCCCCAACTCAGGTTGAAAGTCACATTCCGCCTCTGGCCATTCTCTTAAGAGTAGACCAGGATTCT
G
ATCTCTGAAGGGTGGGTAGGGTGGGGCAGTGGAGGGTGTGGACACAGGAGGCTTCAGGGTGGGGCTGGTGATGCTCTCT
C
S
ATCCTCTTATCATCTCCCAGTCTCATCTCTCATCCTCTTATCATCTCCCAGTCTCATCTGTCTTCCTCTTATCTCCCAG
T
CTCATCTGTCATCCTCTTACCATCTCCCAGTCTCATCTCTTATCCTCTTATCTCCTAGTCTCATCCAGACTTACCTCCC
A
GGGCGGGTGCCAGGCTCGCAGTGGAGCTGGACATACGTCCTTCCTCAGGCAGAAGGAACTGGAAGGATTGCAGAGAACA
G
GAGGGGCGGCTCAGAGGGACGCAGTCTTGGGGTGAAGAAACAGCCCCTCCTCAGAAGTTGGCTTGGGCCACACGAAACC
G
AGGGCCCTGCGTGAGTGGCTCCAGAGCCTTCCAGCAGGTCCCTGGTGGGGCCTTATGGTATGGCCGGGTCCTACTGAGT
G
IO
CACCTTGGACAGGGCTTCTGGTTTGAGTGCAGCCCGGACGTGCCTGGTGTCGGGGTGGGGGCTTATGGCCACTGGATAT
G
GCGTCATTTATTGCTGCTGCTTCAGAGAATGTCTGAGTGACCGAGCCTAATGTGTATGGTGGGCCCAAGTCCACAGACT
G
TGTCGTAAATGCACTCTGGTGCCTGGAGCCCCCGTATAGGAGCTGTGAGGAAGGAGGGGCTCTTGGCAGCCGGCCTGGG
G
GCGCCTTTGCCCTGCAAACTGGAAGGGAGCGGCCCCGGGCGCCGTGGGCGGACGACCTCAAGTGAGAGGTTGGACAGAA
C
AGGGCGGGGACTTCCCAGGAGCAGAGGCCGCTGCTCAGGCACACCTGGGTTTGAATCACAGACCAACaGGTCAGGCCAT
T
IS
GTTCAGCTATCCATCTTCTACAAAGCTCCAGATTCCTGTTTCTCCGGGTGTTTTTTGTTGAAATTTTACTCAGGATTAC
T
TATATTTTTTGCTAAAGTATTAGACCCTTAAAAAAGGTATTTGCTTTGATATGGCTTAACTCACTAAGCACCTACTTTA
T
TTGTCTGTTTTTATTTATTATTATTATTATTATTAGAGATGGTGTCTACTCTGTCACCCAGGTTGTTAGTGCAGTGGCA
C
AGTCATGGCTCGCTGTAGCCGCAAACCCCCAGGCTCAAGTGATCCTCCGGCCTCAGCTTCCCAGAGTGCTGGGATTACA
G
GTGTGAGCCACTGCCCTTGCCTGGCACTTTTAAAAACCACTATGTAAGGTCAGGTCCAGTGGCTTCCr'~CACCTGTCA
TCC
2O
CAGTAG'fTTGGGAAGCCGAGGCAGAAGGATTGTCTGAGGCCAGGAGTTTGAGACCAGCATGGGTAACATAGGGAGACC
CC
AT.'CTCTIaCAAAAP.ATGCAAAAAGTTATCCGGGCGTGGGGTCCAGCATCTGTAGTCCCAGCTGCTCGGGAGGCTGA
GTGGG
AGGATCGCTTGAGCCCGGGAGGTCATGGCTGCAGTGAGCTGTGATTG'fACCATCGCACTCCAGCCTGGGCAACAGAGT
GA
GACCCTGTCTC GAAGGAGAAGGAGAAGAGAAGAAGAAGGAAGAAGGAAAGAGAAGAAGAAG
C~AAGAAGGAAGAAAGAAGGAGAAGGAGGCCTGCTAGGTGCTAGGTAGACTGTCAAATCTC?~GAGCAAAATGAAAATA
ACA
2J
AAGTTTTAAAGGGAAAGAAAAACCCCAGCTCTTTGGACTTCCTTAGGCCTGAACTTCATCTCAAGCAGCTTCCTTCCAC
A
GAC.~AGCGTGTATGGAGCGAGTGAGTTCAAAGCAGAAAGGGAGGAGAAGCAGGCAAGGGTGGAGGCTGTGGGTGACAC
CA
GCCAGGACCCCTGAAAGGGAGTGGTTGTTTTCCTGCCTCAGCCCCACGCTCCTGCCGGTCCTGCACCTGCTGTAACCGT
C
GATGTTGGTGCCAGGTGCCCACCTGGGAAGGATGCTGTGCAGGGGGCTTGCCAAACTTTGGTGGGTTTCAGAAGCCCCA
G
GCACTTGTGGCAGGCACAATTACAGCCCCTCCCCAAAGATGCCCACGTCCTTCTCCTGGAACCTGTGAATGTGTCACCC
G
3O
CAAGGCAGAGGCTGGTGAAGGCTGCAGGTGGAATCACGGCTGCCAGTCAGCCGATCTTAAGGTCATCCTGGATTATCTG
G
TGGGCCTGATATGGCCACAAGGGTCCCTAGAAGTGAGAGAGGGAGGCAGGGGAGAGTCAGAGAGGGGACGTGAGAAGGA
C
CACTGGCCACTGCTGGCTTTGAGATGGAGGAGGGGGTCCCCAGCCAAGGAATGGGGGCAGCCGCTCCATGCTGGAAAAG
C
:~AGCAATCCTCCCCGGTCCTGAGGGCACACGGCCCTGCCCACGCCTCGATTTCAGGCCAGTGGGACCTGTTTCAGCTT
TC
CGGCCTCCAGAGCTGTAAGATGATGCGTTTGTGTTCAGCCACTAAGCTGCAGTGATTCGTCACAGCAGCAAATGGAATA
G
3S ~AGTACAGGGAAATGAATACAGGGACAGTTCTCAGAGTGACTCTCAGCCCACCCCTGGG
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Characterization of the exons showed, interestingly, that the functionally
important
hTC protein domains which are described in our Patent Application
PCT/EP/98/03469 are arranged on separate exons. The telomerase-characteristic
T
motif is located on exon 3. The RT (reverse transcriptase) motifs I-7, which
are
important for the catalytic function of the telomerase, are located on the
following
exons: RT motifs I and 2 on exon 4, RT motif 4 on exon 9, RT motif 5 on exon
10,
and RT motifs 6 and 7 on exon 11. RT motif 3 is shared by exons 5 and 6 (see
Fig. 8).
Elucidation of the exon-intron -structure of the hTC gene also shows that the
four
deletions or insertion variants of the hTC cDNA which were described in our
Patent
Application PCT/EP/98/03469, as well as three additional hTC insertion
variants
which are described in the literature (Kilian et al., 1997), in all
probability represent
alternative splicing products. As shown in Fig. 8, the splicing variants can
be divided
into two groups: deletion variants and insertion variants.
The hTC variants in the deletion group lack specific sequence segments. The 36
by
in-frame deletion in variant DEL1 in all probability results from using an
alternative
3' splice acceptor sequence in exon 6, resulting in a part of RT motif 3 being
lost. In
variant DEL2, the normal 5' splice donor and 3' splice acceptor sequences of
introns
6, 7 and 8 are not used. Instead exon 6 is fused directly to exon 9, resulting
in a
displacement arising in the open reading frame and a stop codon appearing in
exon
10. Variant Del3 is a combination of variants 1 and 2.
The insertion variant group is characterized by the insertion of intron
sequences
which lead to premature cessation of translation. Instead of the 5' splice
donor
sequence of intron 5, which is normally used, use is made, in variant INS l,
of an
alternative, 3'-located splice site, resulting in the insertion of the first
38 by from
intron 4 between exon 4 and exon 5. The insertion, in variant I'.~iS2, of a
region of the
intron 11 sequence likewise results from using an alternative 5' splice donor
sequence m intron 11. Since this variant was only described inadequately in
the
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literature (Kilian et al., 1997), it is not possible to determine the precise
alternative S'
splice donor sequence in this variant. The insertion of intron 14 sequences
between
exon 14 and exon 15 in variant INS3 comes from using an alternative 3' splice
acceptor sequence, resulting in the 3' part of intron 14 not being spliced.
The hTC variant INS4 (variante 4), which is described in our Patent
Application
PCT/EP/98/03469, is characterized by exon 15, and the 5' part region of exon
16,
being replaced by the first 600 by of intron 14. This variant can' be
attributed to the
use of an alternative internal 5 ' splice donor sequence in intron 14 and an
alternative
3 ' splice acceptor sequence in exon 16, resulting in an altered C terminus.
The in vivo generation of hTC protein variants which are probably non-
functional
and which could interfere with the function of the complete hTC protein
constitutes a
possible mechanism, in addition to transcription regulation, for controlling
hTC
protein function. The function of the hTC splicing variants is not yet known.
Although most of these variants presumably encode proteins without reverse
transcriptase activity, they could nevertheless play a crucial role as
transdominant-
negative telomerase regulators by, for example, competing for interaction with
important binding partners.
The search for possible transcription factor binding sites was carried out
using the
"find pattern" algorithm from the Genetics Computer Group (Madison, USA) GCG
Sequence Analysis program package. This resulted in the identification of a
variety
of potential binding sites for transcription factors in the nucleotide
sequence of intron
2, which binding sites are listed in Tab. 2. In addition, an Sp 1 binding site
was found
in intron 1 (pos. 43), and a c-Myc binding site was found in the 5'-
untranslated region
(cDNA position 29-34, cf. Fig. 6).
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Example 6
In order to ascertain the start points) of hTC transcription in HL 60 cells,
the 5' end
of the hTC mRNA was determined by means of primer extension analysis.
2 Itg of polyA+ RNA from HL-60 cells were denaturated at 65°C for 10
min. 1 ul of
RNasin (30-40 U/ml) and 0.3-1 pmol of radioactively labelled primer
(5'GTTAAGTTGTAGCTTACACTGGTTCTC 3'; 2.5-8x105 cpm) were added for
primer annealing, and the whole was incubated, at 37°C for 30 min, in a
total volume
of 2U pl. After the addition of 10 Ill of 5xreverse transcriptase buffer (from
Gibco-
BRL), 2 pl of 10 mM dNTPs, 2 Ill RNasin (see above), 5 pl of 0.1 M DTT (from
Gibco-BRL) 2 pl of ThermoScript RT (15 U/pl; from Gibco-BRL) and 9 ~1 of
i~EPC-treated water, primer extension took place, at 58°C for 1 h, in a
total volume
flacunaJ. The reaction was stopped by adding 4 pl of 0.5 M EDTA, pH 8.0, and
the
RNA was degraded, at 37°C for 30 min, after having added 1 pl of
RNaseA
(10 mg/ml). 2.5 pg of sheared calf thymus DNA and 100 pl of TE were then
added,
and the mixture was extracted once with 150 pl of phenol/chloroform (1:1). The
DNA was precipitated, at -70°C for 45 min, after adding 15 pl of 3 M Na
acetate and
450 pl of ethanol, and then centrifuged at 14,000 rpm for 15 min. The
precipitate was
washed once with 70% ethanol, dried in air and dissolved in 8 ~1 of sequencing
stop
solution. After 5 min of denaturation at 80°C, the samples were loaded
onto a 6%
polyacrylamide gel and fractionated electrophoretically (Ausubel et al., 1987)
(Fig. 5).
In this connection, a main transcription start site was identitied which is
located
1767 by 5' of the ATG start codon of the hTC cDNA sequence (nucleotide
position
3346 in Fig. 4). In addition to this, the nucleotide sequence around this main
transcription start (TTA+iTTGT) represents an initiator element ( Inr). which,
in 6 out
of 7 nucleotides, matches the consensus motif (PyPyA+iNaltPyPy) (Smale, 1997)
of
an initiator element.
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It was not possible to identify any unambiguous TATA box in the immediate
vicinity
of the experimentally identified main transcription start, which means that
the hTC
promoter has probably to be classified in the family of TATA-less promoters
(Smale,
1997). However, a potential TATA box from nucleotide position 1306 to
nucleotide
S position 1311 (Fig. 4) was found by means of bioinformatics analysis. The
subsidiary
transcription starts which were additionally observed around the main
transcription
start have also been described in the case of other TATA-less promoters (Geng
and
Johnson, 1993), for example in the strongly regulated promoters of some cell
cycle
genes (Wick et al., 1995).
Example 7
In addition to the start point of the hTC transcript which was described in
Example 6
and identified in HL60 cells, a further transcription start region was also
identified in
HL60 cells. With the aid of RT-PCR analyses, the region of the hTC gene
transcription start in HL60 cells was localized to by -60 to by -105.
The cDNA for this was synthesized using a First Strand cDNA Synthesis kit
(Clontech), in accordance with the manufacturer's instructions, and employing
0.4 ~g
of HL60 cell polyA RNA (Clontech) and the gene-specific primer GSP 13
(5 '-CCTCCAAAGAGGTGGCTTCTTCGGC-3 ', cDNA position 920-897). In a final
volume of 50 pl, 10 pmol dNTP mix were added to 1 pl of cDNA, and a PCR
reaction was carried out in 1 xPCR reaction buffer F (PCR-Optimizer kit from
InVitrogen) and using one unit of platinum Taq DNA polymerase (from
Gibco/BRL).
10 pmol of each of the 5' and 3' primers defined below were added as primers.
The
PCR was carried out in 3 steps. A two-minute denaturation at 94°C was
followed by
36 PCR cycles in which the DNA was first of all denatured at 94°C for
4~ sec and,
after that, the primers were annealed, and the DNA chain was extended at
68°C for
~ min. The cycles were concluded by a chain extension at 68°C for 10
min. In all, six
different 5' PCR primers (primer HTRTSB:
~'-CGCAGCCACTACCGCGAGGTGC-3', cDNA position 10~ to 126; primer CSS:
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5'-CTGCGTCCTGCTGCGCACGTGGGAAGC-3', 5'-flanking region -49 to -23;
primer PRO-TEST 1: 5 '-CTCGCGGCGCGAGTTTCAGGCAG-3 ', 5 '-flanking
region -74 to -52; primer PRO-TEST2: 5 '-CCAGCCCCTCCCCTTCCTTTCC-3 ',
5'-flanking region -112 to -91; primer PRO-TEST4:
S 5'-CCAGCTCCGCCTCCTCCGCGC-3', 5'-flanking region -191 to -171; primer
RP-3A: 5'-CTAGGCCGATTCGACCTCTCTCC-3', 5'-flanking region -427 to
-405) were combined with the 3' PCR primer CSRback
(5'-GTCCCAGGGCACGCACACCAG-3', cDNA position 245 to 225). Genomic
DNA was also employed for the PCR, as a control, in addition to the Oligo dT-
and
GSP 13-primed cDNAs. As Fig. 9 shows, a PCR product was only obtained with the
primer combinations HTRTSB-CSRback, CSS-CSRback and PRO-TEST1-CSRback,
indicating that the start point for hTC transcription lies in the region
between bp-60
and bp-1 O5.
Example 8
Several extremely GC-rich regions, so-called CpG Islands, are located in the
isolated
5'-flanking region, of about 11.2 kb in size, of the hTC gene. One CpG Island,
having
a GC content of > 70%, extends from by - 1214 into intron 2. Two further GC-
rich
regions having a GC content of > 60% extend from by -3872 to by -3113 and from
by -5363 to by -3941, respectively. The positions of the CpG Islands are shown
graphically in Fig. 11.
The search for possible transcription factor binding sites was carried out
using the
"Find Pattern" algorithm from the Genetics Computer Group (Madison, USA) GCG
Sequence Analysis program package. This resulted in the identification of a
variety
of potential binding sites in the region up to -900 by upstream of the
translation start
codon ATG: five Sp l binding sites, one c-Myc binding site, and one CCAC box
(Fig. IO). In addition, a CCAAT box and a second c-Myc binding site were found
at
positions -1788 and -3995, respectively, of the 5'-flanking region.
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Example 9
In order to analyse the activity of the hTC promoter, PCR amplification was
used to
generate four hTC promoter sequence segments of differing length, which
segments
were cloned into the Promega vector pGL2 5' in front of the luciferase
reporter gene.
The 8.5 kb SacI fragment which was subcloned from phage clone P 12 was
selected
as the DNA source for the PCR amplification. In a final volume of 50 pl, 10
pmol of
dNTP mix were added to 35 ng of this DNA, and a PCR reaction was carried out
in
IxPCR reaction buffer (PCR-Optimizer kit from InVitrogen) and using one unit
of
platinum Taq DNA polymerase (from Gibco/BRL). In each case 20 pmol of the 5'
and 3' primers which are defined below were added as primers. The PCR was
carried
out in three steps. A two-minute denaturation at 94°C was followeed by
30 PCR
cycles in which the DNA was first of all denaturated at 94°C for 45
sec, after which
the primers were annealed, and the DNA chain was extended, at 68°C for
5 min. The
cycles were concluded by a chain extension at 68°C for l0 min. The
selected 3' PCR
primer was in each case the primer PK-3A
(5'-GCAAGCTTGACGCAGCGCTGCCTGAAACTCG-3', position ~3 to -65),
which primer recognizes a sequence region 42 by upstream of the ATG START
codon. A promoter fragment of 4051 by in size (NPKB) was amplified by
combining
the PK-3A primers with the 5' PCR primer PK-5B
(5 '-CCAGATCTCTGGAACACAGAGTGGCAGTTTCC-3 ', position -4093 to
-4070). Combining the pair of primers PK-3A and PK-5C
(5 '-CCAGATCTGCATGAAGTGTGTGGGGATTTGCAG-3 ', position -3120 to
-3096) led to the amplification of a promoter fragment of 3078 by in size
(NPK15).
Use of the primer combination PK-3A and PK-5D
(5 '-GGAGATCTGATCTTGGCTTACTGCAGCCTCTG-3 ', position -2110 to
-2087) amplified a promoter fragment of 2068 by in size (NPK22). Finally,
using the
primer combination PK-3A and PK-5E
(5'-GGAGATCTGTCTGGATTCCTGGGAAGTCCTCA-3', position -1125 to
-1 102) led to the amplification of a promoter fragment of 1083 by in size
(NPK27).
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The PK-3A primer contains a HindIII recognition sequence. The different 5'
primers
contain a BgIII recognition sequence.
The resulting PCR products were purified using the Qiagen QIA quick spin PCR
purification kit, in accordance with the manufacturer's instructions, and then
digested
with the restriction enzymes BgIII and HindIII. The pGL2 promoter vector was
digested with the same restriction enzymes, and the SV40 promoter contained in
this
vector was released and removed. The PCR promoter fragments ligated into the
vector, which was then transformed into competent DHSa bacteria (from
Gibco/BRL). DNA for the promoter activity analyses, which are described below,
was isolated from transformed bacterial clones using the Qiagen plasmid kit.
Example 10
The activity of the hTC promoter was analysed in transient transfections in
eukaryotic cells.
All the work with eukaryotic cells was carried out at a sterile workstation.
CHO-K1
and HEK 293 cells were obtained from the American Type Culture collection.
CHO-K1 cells were kept in DMEM Nut Mix F-12 cell culture medium (from Gibco-
BRL, order number: 21331-020) containing 0.15% streptomycin/penicillin, 2 mM
glutamine and 10% FCS (from Gibco-BRL).
HEK 293 cells were cultured in DMOD cell culture medium (from Gibco-BRL, order
number: 41965-039) containing 0.15% streptomycin/penicillin, 2 mM glutamine
and
10% FCS (from Gibco-BRL).
CHO-K1 and HEK 293 cells were cultured at 37°C in a water-saturated
atmosphere
while being gassed with 5% COZ. When the cell lawn was confluent, the medium
was sucked off, after which the cells were washed with PBS ( 100 mM KH~P04 pH
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7.2; 1 SO mM NaCI) and released by adding a trypsin-EDTA solution (from Gibco-
BRL). The trypsin was inactivated by adding medium and the cell count was
determined using a Neubauer counting chamber in order to plate out the cells
at the
desired density.
For the transfection, in each case 2x 105 HEK 293 cells were plated out, per
well, in a
24-well cell culture plate. The HEK 293 medium was removed after 3 hours. For
the
transfection, up to 2.5 pg of plasmid DNA, 1 pg of a CMV 13-Gal plasmid
construct
(from Stratagene, order numner: 200388), 200 p.l of serum-free medium and 10
pl of
l0 transfection reagent (DOTAP from Boehringer Mannheim) were incubated at
room
temperature for 15 minutes and then dropped uniformly onto the HEK 293 cells.
1.5
ml of medium were added after 3 hours. The medium was changed after 20 hours.
After a further 24 hours, the cells were harvested for determining the
luciferase
activity and the f3-Gal activity. For this, the cells were lysed, at room
temperature for
15 minutes, in the cell culture lysis reagent (25 mM Tris [pH 7.8J containing
H3P0.~;
2 mM CDTA; 2 mM DTT; 10% glycerol; 1% Triton X-100). Twenty pl of this cell
lysate were mixed with 100 pl of luciferase assay buffer (20 mM Tricin; 1.07
mM
(MgC03)4 Mg(OH)2'SH20; 2.67 mM MgS04; 0.1 mM EDTA; 33.3 mM DTT;
270 pM coenzyme A; 470 pM luciferin, 530 pM ATP), and the light generated by
the luciferase was measured.
In order to measure the !3-galactosidase activity, equal quantities of cell
lysate and (3-
galactosidase assay buffer ( 100 mM sodium phosphate buffer, pH 7.3; 1 mM
MgCl2;
50 mM f3-mercaptoethanol; 0.665 mg of ONPG/ml) were incubated at 37°C
for at
least 30 minutes or until a slight yellow coloration appeared. The reaction
was
stopped by adding 100 ul of 1 M Na2C03, and the absorption was determined at
420 nm.
In order to analyse the hTC promoter, four hTC promoter sequence segments of
differing length were cloned 5' in front of the luciferase reporter gene (cf.
Example
9).
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The relative luciferase activities of two independent transfections in HEK 293
cells,
using the constructs NPKB, NPK15, NPK22 and NPK27, are plotted in Fig. 11.
Each
experiment was carned out in duplicate. The standard deviation has also been
given.
The construct NPK 27 exhibits a luciferase activity which is 40 times higher
than the
basal activity of the promoterless luciferase control construct (pGL2-basic)
and from
2 to 3 times higher than that of the SV40 promoter control construct
(pGL2PR0).
lnterestingly, a luciferase activity which was from 2 to 3 times lower than
that
obtained with the NPK 27 construct was observed in cells which were
transfected
with longer hTC promoter constructs (NPKB, NPK15, NPK22). Similar results were
also observed in CHO cells (data not shown).
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SEQUENCE LISTING
<110> Bayer AG
<120> Regulatory DNA sequences from the 5i region of the gene
for the human catalytic telomerase subunit, and
their diagnostic and therapeutic use
<130> LeA32805-Foreign Countries
1
<140>
<141>
<160> 20
IS
<170> PatentIn Vers. 2.0
<210> 1
<211> 5126
2n <212> DNA
<213> Homo sapiens
<400> 1
gagctctgaaccgtggaaacgaacatgacccttgcctgcctgcttccctgggtgggtcaa60
25 gggtaatgaagtggtgtgcaggaaatggccatgtaaattacacgactctgctgatgggga120
ccgttccttccatcattattcatcttcacccccaaggactgaatgattccagcaacttct180
tcgggtgtgacaagccatgacaaaactcagtacaaacaccactcttttactaggcccaca240
gagcacgggccacacccctgatatattaagagtccaggagagatgaggctgctttcagcc300
accaggctggggtgacaacagcggctgaacagtctgttcctctagactagtagaccctgg360
3o caggcactcccccaaattctagggcctggttgctgcttcccgagggcgccatctgccctg420
gagactcagcctggggtgccacactgaggccagccctgtctccacaccctccgcctccag480
.Jcctcagcttctccagcagcttcctaaaccctgggtgggccgtgttccagcgctactgtc540
tcacctgtcccactgtgtcttgtctcagcgacgtagctcgcacggttcctcctcacatgg600
ggtgtctgtctccttccccaacactcacatgcgttgaagggaggagattctgcgcctccc660
3J agactggctcctctgagcctgaacctggctcgtggcccccgatgcaggttcctggcgtcc720
ggctgcacgctgacctccatttccaggcgctccccgtctcctgtcatctgccggggcctg780
ccggtgtgttcttctgtttctgtgctcctttccacgtccagctgcgtgtgtctctgcccg340
ctagggtctcggggtttttataggcataggacgggggcgtggtgggccagggcgctcttg900
ggaaatgcaacatttgggtgtgaaagtaggagtgcctgtcctcacctaggtccacgggca960
caggcctggggatggagcccccgccagggacccgcccttctctgcccagcactttcctgc1020
ccccctccctctggaacacagagtggcagtttccacaagcactaagcatcctcttcccaa1080
aagacccagcattggcacccctggacatttgccccacagccctgggaattcacgtgacta1140'
cgcacatcatgtacacactcccgtccacgaccgacccccgctgttttattttaatagcta1200
caaagcagggaaatccctgctaaaatgtcctttaacaaactggttaaacaaacgggtcca1260
45
tccgcacggtggacagttcctcacagtgaagaggaacatgccgtttataaagcctgcagg1320
catctcaagggaattacgctgagtcaaaactgccacctccatgggatacgtacgcaacat1380
gctcaaaaagaaagaatttcaccccatggcaggggagtggttaggggggttaaggacggt1440
gggggcggcagctgggggctactgcacgcaccttttactaaagccagtttcctggttctg1500
5o atggtattggctcagttatgggagactaaccataggggagtggggatgggggaacccgga1560
ggctgtgccatctttgccatgcccgagtgtcctgggcaggataatgctctagagatgccc1620
acgtcctgattcccccaaacctgtggacagaacccgcccggccccagggcctttgcaggt1680
gtgatctccgtgaggaccctgaggtctgggatccttcgggactacctgcaggcccgaaaa1740
gtaatccaggggttctgggaagaggcgggcaggagggtcagaggggggcagcctcaggac1800
55 gatggaggcagtcagtctgaggctgaaaagggagggagggcctcgagcccaggcctgcaa1860
gcgcctccagaagctggaaaaagcggggaagggaccctccacggagcctgcagcaggaag1920
gcacggctggcccttagcccaccagggcccatcgtggacctccggcctccgtgccatagg1980
agggcactcgcgctgcccttctagcatgaagtgtgtggggatttgcagaagcaacaggaa2040
acccatgcactgtgaatctaggattatttcaaaacaaaggtttacagaaacatccaagga2100
cagggctgaagtgcctccgggcaagggcagggcaggcacgagtgattttatttagctatt2160
ttattttatttacttactttctgagacagagttatgctcttgttgcccaggctggagtgc2220
agcggcatgatcttggctcactgcaacctccgtctcctgggttcaagcaattctcgtgcc2280
tcagcctcccaagtagctgggatttcaggcgtgcaccaccacacccggctaattttgtat2340
ttttagtagagatgggctttcaccatgttggtcaagctgatctcaaaatcctgacctcag2400
65 gtgatccgcccacctcagcctcccaaagtgctgggattacaggcatgagccactgcacct2460
ggcctatttaaccattttaaaacttccctgggctcaagtcacacccactggtaaggagtt2520
catggagttcaatttcccctttactcaggagttaccctcctttgatattttctgtaattc2580
ttcgtagactggggatacaccgtctcttgacatattcacagtttctgtgaccacctgtta2640
tcccatgggacccactgcaggggcagctgggaggctgcaggcttcaggtcccagtggggt2700
tgccatctgccagtagaaacctgatgtagaatcagggcgcaagtgtggacactgtcctga2760
atctcaatgtctcagtgtgtgctgaaacatgtagaaattaaagtccatccctcctactct2820
actgggattgagccccttccctatccccccccaggggcagaggagttcctctcactcctg2880
tggaggaaggaatgatactttgttatttttcactgctggtactgaatccactgtttcatt2940
tgttggtttgtttgttttgttttgagaggcggtttcactcttgttgctcaggctggaggg3000
agtgcaatggcgcgatcttggcttactgcagcctctgcctcccaggttcaagtgattctc3060
7J
ctgcttccgcctcccatttggctgggattacaggcacccgccaccatgcccagctaattt3120
tttgtatttttagtagagacgggggtgggtggggttcaccatgttggccaggctggtctc3180
gaacttctgacctcagatgatccacctgcctctgcctcctaaagtgctgggattacaggt3240
CA 02316282 2000-06-21
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gtgagccaccatgcccagctcagaatttactctgtttagaaacatctgggtctgaggtag3300
gaagctcaccccactcaagtgttgtggtgttttaagccaatgatagaatttttttattgt3360
tgttagaacactcttgatgttttacactgtgatgactaagacatcatcagcttttcaaag3420
acacactaactgcacccataatactggggtgtcttctgggtatcagcaatcttcattgaa3480
tgccgggaggcgtttcctcgccatgcacatggtgttaattactccagcataatcttctgc3590
ttccatttcttctcttccctcttttaaaattgtgttttctatgttggcttctctgcagag3600
aaccagtgtaagctacaacttaacttttgttggaacaaattttccaaaccgcccctttgc3660
cctagtggcagagacaattcacaaacacagccctttaaaaaggcttagggatcactaagg3720
to ggatttctagaagagcgacctgtaatcctaagtatttacaagacgaggctaacctccagc3780
gagcgtgacagcccagggagggtgcgaggcctgttcaaatgctagctccataaataaagc3840
aatttcctccggcagtttctgaaagtaggaaaggttacatttaaggttgcgtttgttagc3900
atttcagtgtttgccgacctcagctacagcatccctgcaaggcctcgggagacccagaag3960
tttctcgcccccttagatccaaacttgagcaacccggagtctggattcctgggaagtcct4020
cagctgtcctgcggttgtgccggggccccaggtctggaggggaccagtggccgtgtggct4080
15
tctactgctgggctggaagtcgggcctcctagctctgcagtccgaggcttggagccaggt4140
gcctggaccccgaggctgccctccaccctgtgcgggcgggatgtgaccagatgttggcct4200
catctgccagacagagtgccggggcccagggtcaaggccgttgtggctggtgtgaggcgc4260
ccggtgcgcggccagcaggagcgcctggctccatttcccaccctttctcgacgggaccgc4320
,7o cccggtgggtgattaacagatttggggtggtttgctcatggtggggacccctcgccgcct4380
gagaacctgcaaagagaaatgacgggcctgtgtcaaggagcccaagtcgcggggaagtgt4440
tgcagggaggcactccgggaggtcccgcgtgcccgtccagggagcaatgcgtcctcgggt4500
tcgtccccagccgcgtctacgcgcctccgtcctccccttcacgtccggcattcgtggtgc4560
ccggagcccgacgccccgcgtccggacctggaggcagccctgggtctccggatcaggcca4620
gcggccaaagggtcgccgcacgcacctgttcccagggcctccacatcatggcccctccct4680
25
cgggttaccccacagcctaggccgattcgacctctctccgctggggccctcgctggcgtc4740
cctgcaccctgggagcgcgagcggcgcgcgggcggggaagcgcggcccagacccccgggt4800
ccgcccggagcagctgcgctgtcggggccaggccgggctcccagtggattcgcgggcaca4860
gacgcccaggaccgcgctccccacgtggcggagggactggggacccgggcacccgtcctg4920
3o ccccttcaccttccagctccgcctcctccgcgcggaccccgccccgtcccgacccctccc4980
gggtccccggcccagccccctccgggccctcccagcccctccccttcctttccgcggccc5040
cgccctctcctcgcggcgcgagtttcaggcagcgctgcgtcctgctgcgcacgtgggaag5100
ccctggccccggccacccccgcgatg
5126
<210> 2
35 <211> 4042
<212> DNA
<213> Homo Sapiens
<400> 2
40 gtttcaggcagcgctgcgtcctgctgcgcacgtgggaagccctggccccggccacccccg60
cgatgccgcgcgctccccgctgccgagccgtgcgctccctgctgcgcagccactaccgcg120
aggtgctgccgctggccacgttcgtgcggcgcctggggccccagggctggcggctggtgc180
agcgcggggacccggcggctttccgcgcgctggtggcccagtgcctggtgtgcgtgccct240
gggacgcacggccgccccccgccgccccctccttccgccaggtgtcctgcctgaaggagc300
45
tggtggcccgagtgctgcagaggctgtgcgagcgcggcgcgaagaacgtgctggccttcg360
gcttcgcgctgctggacggggcccgcgggggcccccccgaggccttcaccaccagcgtgc420
gcagctacctgcccaacacggtgaccgacgcactgcgggggagcggggcgtgggggctgc480
tgctgcgccgcgtgggcgacgacgtgctggttcacctgctggcacgctgcgcgctctttg540
tgctggtggctcccagctgcgcctaccaggtgtgcgggccgccgctgtaccagctcggcg600
50
ctgccactcaggcccggcccccgccacacgctagtggaccccgaaggcgtctgggatgcg660
aacgggcctggaaccatagcgtcagggaggccggggtccccctgggcctgccagccccgg720
gtgcgaggaggcgcgggggcagtgccagccgaagtctgccgttgcccaagaggcccaggc780
gtggcgctgcccctgagccggagcggacgcccgttgggcaggggtcctgggcccacccgg840
gcaggacgcgtggaccgagtgaccgtggtttctgtgtggtgtcacctgccagacccgccg900
55
aagaagccacctctttggagggtgcgctctctggcacgcgccactcccacccatccgtgg960
gccgccagcaccacgcgggccccccatccacatcgcggccaccacgtccctgggacacgc1020
cttgtcccccggtgtacgccgagaccaagcacttcctctactcctcaggcgacaaggagc1080
agctgcggccctccttcctactcagctctctgaggcccagcctgactggcgctcggaggc1140
tcgtggagaccatctttctgggttccaggccctggatgccagggactccccgcaggttgc1200
cccgcctgccccagcgctactggcaaatgcggcccctgtttctggagctgcttgggaacc1260
acgcgcagtgcccctacggggtgctcctcaagacgcactgcccgctgcgagctgcggtca1320
ccccagcagccggtgtctgtgcccgggagaagccccagggctctgtggcggcccccgagg1380
aggaggacacagacccccgtcgcctggtgcagctgctccgccagcacagcagcccctggc1440
aggtgtacggcttcgtgcgggcctgcctgcgccggctggtgcccccaggcctctggggct1500
65
ccaggcacaacgaacgccgcttcctcaggaacaccaagaagttcatctccctggggaagc1560
atgccaagctctcgctgcaggagctgacgtggaagatgagcgtgcgggactgcgcttggc1620
tgcgcaggagcccaggggttggctgtgttccggccgcagagcaccgtctgcgtgaggaga1680
tcctggccaagttcctgcactggctgatgagtgtgtacgtcgtcgagctgctcaggtctt1740
tcttttatgtcacggagaccacgtttcaaaagaacaggctctttttctaccggaagagtg1800
tctggagcaagttgcaaagcattggaatcagacagcacttgaagagggtgcagctgcggg1860
agctgtcggaagcagaggtcaggcagcatcgggaagccaggcccgccctgctgacgtcca1920
gactccgcttcatccccaagcctgacgggctgcggccgattgtgaacatggactacgtcg1980
tgggagccagaacgttccgcagagaaaagagggccgagcgtctcacctcgagggtgaagg2040
cactgttcagcgtgctcaactacgagcgggcgcggcgccccggcctcctgggcgcctctg2100
75
tgctgggcctggacgatatccacagggcctggcgcaccttcgtgctgcgtgtgcgggccc2160
aggacccgccgcctgagctgtactttgtcaaggtggatgtgacgggcgcgtacgacacca2220
tcccccaggacaggctcacggaggtcatcgccagcatcatcaaaccccagaacacgtact2280
gcgtgcgtcggtatgccgtggtccagaaggccgcccatgggcacgtccgcaaggccttca2340
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-62-
agagccacgtctctaccttg 2400
acagacctcc
agccgtacat
gcgacagttc
gtggctcacc
tgcaggagaccagcccgctg
agggatgccg
tcgtcatcga
gcagagctcc
tccctgaatg
2460
aggccagcagtggcctcttcgacgtcttcc gtgccaccacgccgtgcgca2520
tacgcttcat
tcaggggcaagtcctacgtccagtgccagg ctctccacgc2580
ggatcccgca
gggctccatc
tgctctgcagcctgtgctacggcgacatgg gtttgcggggattcggcggg2640
agaacaagct
acgggctgctcctgcgtttggtggatgatttcttgttggtgacacctcacctcacccacg2700
cgaaaaccttcctcaggaccctggtccgaggtgtccctgagtatggctgcgtggtgaact2760
tgcggaagacagtggtgaacttccctgtagaagacgaggccctgggtggcacggcttttg2820
ttcagatgccggcccacggcctattcccctggtgcggcctgctgctggatacccggaccc2880
tggaggtgcagagcgactactccagctatgcccggacctccatcagagccagtctcacct2940
tcaaccgcggcttcaaggctgggaggaacatgcgtcgcaaactctttggggtcttgcggc3000
tgaagtgtcacagcctgtttctggatttgcaggtgaacagcctccagacggtgtgcacca3060
acatctacaagatcctcctgctgcaggcgtacaggtttcacgcatgtgtgctgcagctcc3120
catttcatcagcaagtttggaagaaccccacatttttcctgcgcgtcatctctgacacgg3180
IS
cctccctctgctactccatcctgaaagccaagaacgcagggatgtcgctgggggccaagg3240
gcgccgccggccctctgccctccgaggccgtgcagtggctgtgccaccaagcattcctgc3300
tcaagctgactcgacaccgtgtcacctacgtgccactcctggggtcactcaggacagccc3360
agacgcagctgagtcggaagctcccggggacgacgctgactgccctggaggccgcagcca3420
2o acccggcactgccctcagacttcaagaccatcctggactgatggccacccgcccacagcc3480
aggccgagagcagacaccagcagccctgtcacgccgggctctacgtcccagggagggagg3540
ggcggcccacacccaggcccgcaccgctgggagtctgaggcctgagtgagtgtttggccg3600
aggcctgcatgtccggctgaaggctgagtgtccggctgaggcctgagcgagtgtccagcc3660
aagggctgagtgtccagcacacctgccgtcttcacttccccacaggctggcgctcggctc3720
caccccagggccagcttttcctcaccaggagcccggcttccactccccacataggaatag3780
25
tccatccccagattcgccattgttcacccctcgccctgccctcctttgccttccaccccc3840
accatccaggtggagaccctgagaaggaccctgggagctctgggaatttggagtgaccaa3900
aggtgtgccctgtacacaggcgaggaccctgcacctggatgggggtccctgtgggtcaaa3960
ttggggggaggtgctgtgggagtaaaatactgaatatatgagtttttcagttttgaaaaa4020
aaaaaaaaaaaaaaaaaaaaas 4042
3O
<210> 3
<211> 11276
<212> DNA
<213> Homosapiens
~5
<400> 3
acttgagcccaagagttcaaggctacggtgagccatgattgcaacaccacacgccagcct60
tggtgacagaatgagaccctgtctcaaaaaaaaaaaaaaaaattgaaataatataaagca120
O tcttctctggccacagtggaacaaaaccagaaatcaacaacaagaggaattttgaaaact180
atacaaacacatgaaaattaaacaatatacttctgaatgaccagtgagtcaatgaagaaa240
ttaaaaaggaaattgaaaaatttatttaagcaaatgataacggaaacataacctctcaaa300
acccacggtatacagcaaaagcagtgctaagaaggaagtttatagctataagcagctaca360
tcaaaaaagtagaaaagccaggcgcagtggctcatgcctgtaatcccagcactttgggag420
45 gccaaggcgggcagatcgcctgaggtcaggagttcgagaccagcctgaccaacacagaga480
aaccttgtcgctactaaaaatacaaaattagctgggcatggtggcacatgcctgtaatcc540
cagctactcgggaggctgaggcaggataaccgcttgaacccaggaggtggaggttgcggt600
gagccgggattgcgccattggactccagcctgggtaacaagagtgaaaccctgtctcaag660
aaaaaaaaaaaagtagaaaaacttaaaaatacaacctaatgatgcaccttaaagaactag720
aaaagcaagagcaaactaaacctaaaattggtaaaagaaaagaaataataaagatcagag780
50
cagaaataaatgaaactgaaagataacaatacaaaagatcaacaaaattaaaagttggtt840
ttttgaaaagataaacaaaattgacaaacctttgcccagactaagaaaaaaggaaagaag900
acctaaataaataaagtcagagatgaaaaaagagacattacaactgataccacagaaatt960
caaaggatcactagaggctactatgagcaactgtacactaataaattgaaaaacctagaa1020
aaaatagataaattcctagatgcatacaacctaccaagattgaaccatgaagaaatccaa1080
55
agcccaaacagaccaataacaataatgggattaaagccataataaaaagtctcctagcaa1140
agagaagcccaggacccaatggcttccctgctggattttaccaatcatttaaagaagaat1200
gaattccaatcctactcaaactattctgaaaaatagaggaaagaatacttccaaactcat1260
tctacatggccagtattaccctgattccaaaaccagacaaaaacacatcaaaaacaaaca1320
6O aacaaaaaaacagaaagaaagaaaactacaggccaatatccctgatgaatactgatacaa1380
aaatcctcaacaaaacactagcaaaccaaattaaacaacaccttcgaaagatcattcatt1440
gtgatcaagtgggatttattccagggatggaaggatggttcaacatatgcaaatcaatca1500
atgtgatacatcatcccaacaaaatgaagtacaaaaactatatgattatttcactttatg1560
cagaaaaagcatttgataaaattctgcacccttcatgataaaaaccctcaaaaaaccagg1620
tatacaagaaacatacaggccaggcacagtggctcacacctgcgatcccagcactctggg1680
65
aggccaaggt cttgggcccaggagtttgagactagcctgggcaacaaaat1740
gggatgattg
gagacctggtctacaaaaaacttttttaaaaaattagccaggcatgatggcatatgcctg1800
tagtcccagctagtctggaggctgaggtgggagaatcacttaagcctaggaggtcgaggc1860
tgcagtgagc tcactgtactccagcctagacaacagaacaagaccccact1920
catgaacatg
gaataagaag agaagggagaagggagggagaagggaggaggaggagaagg1980
aaggagaagg
aggaggtgga aaggggaaggggaagggaaagaggaagaagaagaaacata2040
ggagaagtgg
tttcaacata tatatgacagaccgaggtagtattatgaggaaaaactgaa2100
ataaaagccc
agcctttcct gaaaatgacaagggcccactttcaccactgtgattcaaca2160
ctaagatctg
tagtactaga agagcaatca agaaataaaaggcatccaaa2220
agtcctagct gataagagaa
ctggaaagga ttatcctgtttgcagatgat atctggaaaa2280
agaagtcaaa atgatcttat
gacttaagac gatacaaaat2340
accactaaaa
aactattaga
gctgaaattt
ggtacagcag
caatgtacaa tatttctatattccaacagc aaaaagaaac2400
aaatcagtag aaacaatctg
caaaaaagca 2460
gctacaaata
aaattaaaca
gctaggaatt
aaccaaagaa
gtgaaagatc
tctacaatga aaaaaagaaa2520
aaactataaa
atgttgataa
aagaaattga
agagggcaca
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-63-
agatattccatgttcatagattggaagaataaatactgtt tactacccaa2580
aaaatgtcca
agcaatttacaaattcaatgcaatccctattaaaatacta tcacagaaat2640
atgacgttct
agaagaaacaattctaagatttgtacagaaccacaaaaga ccaaagctat2700
cccagaatag
cctgaccaaaaagaacaaaactggaagcatcacattacctgacttcaaattatactacaa2760
agctatagtaacccaaactacatggtactggcataaaaacagatgagacatggaccagag2820
gaacagaatagagaatccagaaacaaatccatgcatctacagtgaactcatttttgacaa2880
aggtgccaagaacatactttggggaaaagataatctcttcaataaatggtgctggaggaa2940
ctggatatccatatgcaaaataacaatactagaactctgtctctcaccatatacaaaagc3000
to aaatcaaaatggatgaaaggcttaaatctaaaacctcaaactttgcaactactaaaagaa3060
aacaccggagaaactctccaggacattggagtgggcaaagacttcttgagtaattccctg3120
caggcacaggcaaccaaagcaaaaacagacaaatgggatcatatcaagttaaaaagcttc3180
tgcccagcaaaggaaacaatcaacaaagagaagagacaacccacagaatgggagaatata3240
tttgcaaactattcatctaacaaggaattaataaccagtatatataaggagctcaaacta3300
IS ctctataagaaaaacacctaataagctgattttcaaaaataagcaaaagatctgggtaga3360
catttctcaaaataagtcatacaaatggcaaacaggcatctgaaaatgtgctcaacacca3420
ctgatcatcagagaaatgcaaatcaaaactactatgagagatcatctcatcccagttaaa3480
atggcttttattcaaaagacaggcaataacaaatgccagtgaggatgtggataaaaggaa3540
acccttggacactgttggtgggaatggaaattgctaccactatggagaacagtttgaaag3600
20 ttcctcaaaaaactaaaaataaagctaccatacagcaatcccattgctaggtatat~ctc3660
caaaaaagggaatcagtgtatcaacaagctatctccactcccacatttactgcagcactg3720
ttcatagcagccaaggtttggaagcaacctcagtgtccatcaacagacgaatggaaaaag3780
aaaatgtggtgcacatacacaatggagtactacgcagccataaaaaagaatgagatcctg3840
tcagttgcaacagcatggggggcactggtcagtatgttaagtgaaataagccaggcacag3900
25 aaagacaaacttttcatgttctcccttacttgtgggagcaaaaattaaaacaattgacat3960
agaaatagaggagaatggtggttctagaggggtgggggacagggtgactagagtcaacaa4020
taatttattgtatgttttaaaataactaaaagagtataattgggttgtttgtaacacaaa4080
gaaaggataaatgcttgaaggtgacagataccccatttaccctgatgtgattattacaca4140
ttgtatgcctgtatcaaaatatctcatgtatgctatagatataaaccctactatattaaa4200
3o aattaaaattttaatggccaggcacggtggctcatgtccgtaatcccagcactttgggag4260
gccgaggcgggtggatcacctgaggtcaggagtttgaaaccagtctggccaccatgatga4320
aaccctgtctctactaaagatacaaaaattagccaggcgtggtggcacatacctgtagtc4380
ccaactactcaggaggctgagacaggagaattgcttgaacctgggaggcggaggttgcag4440
tgagccgagatcatgccactgcactgcagcctgggtgacagagcaagactccatctcaaa4500
35 acaaaaacaaaaaaaagaagattaaaattgtaatttttatgtaccgtataaatatatact4560
ctactatattagaagttaaaaatCaaaacaattataaaaggtaattaaccacttaatcta4520
aaataagaacaatgtatgtggggtttctagcttctgaagaagtaaaagttatggccacga4680
tggcagaaatgtgaggagggaacagtggaagttactgttgttagacgctcatactctctg4740
taagtgacttaattttaaccaaagacaggctgggagaagttaaagaggcattctataagc4800
cctaaaacaactgctaataatggtgaaaggtaatctctattaattaccaataattacaga4860
40
tatctctaaaatcgagctgcagaattggcacgtctgatcacaccgtcctctcattcacgg4920
tgctttttttcttgtgtgcttggagattttcgattgtgtgttcgtgtttggttaaactta4980
atctgtatgaatcctgaaacgaaaaatggtggtgatttcctccagaagaattagagtacc5040
tggcaggaagcaggtggctctgtggacctgagccacttcaatcttcaagggtctctggcc5100
45 aagacccaggtgcaaggcagaggcctgatgacccgaggacaggaaagctcggatgggaag5160
gggcgatgagaagcctgcctcgttggtgagcagcgcatgaagtgcccttatttacgcttt5220
gcaaagattgctctggataccatctggaaaaggcggccagcgggaatgcaaggagtcaga5280
agcctcctgctcaaacccaggccagcagctatggcgcccacccgggcgtgtgccagaggg5340
agaggagtcaaggcacctcgaagtatggcttaaatctttttttcacctgaagcagtgacc5400
SO aaggtgtattctgagggaagcttgagttaggtgccttctttaaaacagaaagtcatggaa5460
gcacccttctcaagggaaaaccagacgcccgctctgcggtcatttacctctttcctctct5520
ccctctcttgccctcgcggtttctgatcgggacagagtgacccccgtggagcttctccga5580
gcccgtgctgaggaccctcttgcaaagggctccacagacccccgccctggagagaggagt5640
ctgagcctggcttaataacaaactgggatgtggctgggggcggacagcgacggcgggatt5700
caaagacttaattccatgagtaaattcaacctttccacatccgaatggatttggatttta5760
55
tcttaatattttcttaaatttcatcaaataacattcaggactgcagaaatccaaaggcgt5820
aaaacaggaactgagctatgtttgccaaggtccaaggacttaataaccatgttcagaggg5880
atttttcgccctaagtactttttattggttttcataaggtggcttagggtgcaagggaaa5940
gtacacgaggagaggcctgggcggcagggctatgagcacggcagggccaccggggagaga6000
gtccccggcctgggaggctgacagcaggaccactgaccgtcctccctgggagctgccaca6060
ttgggcaacgcgaaggcggccacgctgcgtgtgactcaggaccccataccggcttcctgg6120
gcccacccacactaacccaggaagtcacggagctctgaacccgtggaaacgaacatgacc6180
cttgcctgcctgcttccctgggtgggtcaagggtaatgaagtggtgtgcaggaaatggcc6240
atgtaaattacacgactctgctgatggggaccgttccttccatcattattcatcttcacc6300
cccaaggactgaatgattccagcaacttcttcgggtgtgacaagccatgacaaaactcag6360
65
tacaaacaccactcttttactaggcccacagagcacggsccacacccctgatatattaag6420
agtccaggagagatgaggctgctttcagccaccaggctggggtgacaacagcggctgaac6480
agtctgttcctctagactagtagaccctggcaggcactcccccagattctagggcctggt6540
tgctgcttcccgagggcgccatctgccctggagactcagcctggggtgccacactgaggc6600
7o cagccctgtctccacaccctccgcctccaggcctcagcttctccagcagcttcctaaacc6660
ctgggtgggccgtgttccagcgctactgtctcacctgtcccactgtgtcttgtctcagcg6720
acgtagctcgcacggttcctcctcacatggggtgtctgtctccttccccaacactcacat6780
gcgttgaagggaggagattctgcgcctcccagactggctcctctgagcctgaacctggct6840
cgtggcccccgatgcaggttcctggcgtccggctgcacgctgacctccatttccaggcgc6900
tccccgtctcctgtcatctgccggggcctgccggtgtgttcttctgtttctgtgctcctt6960
75
tccacgtccagctgcgtgtgtctctgcccgctagggtctcggggtttttataggcatagg7020
acgggggcgtggtgggccagggcgctcttgggaaatgcaacatttgggtgtgaaagtagg7080
agtgcctgtcctcacctaggtccacgggcacaggcctggggatggagcccccgccaggga7140
cccgcccttctctgcccagcactttcctgcccccctccctctggaacaca 7200
gagtggcagt
CA 02316282 2000-06-21
Le A 32 805-Forei~~n Countries
-64-
ttccacaagcactaagcatcctcttcccaaaagacccagcattggcacccctggacattt7260
gccccacagccctgggaattcacgtgactacgcacatcatgtacacactcccgtccacga7320
ccgacccccgctgttttattttaatagctacaaagcagggaaatccctgctaaaatgtcc7380
tttaacaaactggttaaacaaacgggtccatccgcacggtggacagttcctcacagtgaa7440
gaggaacatgccgtttataaagcctgcaggcatctcaagggaattacgctgagtcaaaac7500
tgccacctccatgggatacgtacgcaacatgctcaaaaagaaagaatttcaccccatggc7560
aggggagtggttaggggggttaaggacggtgggggcggcagctgggggctactgcacgca7620
ccttttactaaagccagtttcctggttctgatggtattggctcagttatgggagactaac7680
cataggggagtggggatgggggaacccggaggctgtgccatctttgccatgcccgagtgt7740
cctgggcaggataatgctctagagatgcccacgtcctgattcccccaaacctgtggacag7800
aacccgcccggccccagggcctttgcaggtgtgatctccgtgaggaccctgaggtctggg7860
atccttcgggactacctgcaggcccgaaaagtaatccaggggttctgggaagaggcgggc7920
aggagggtcagaggggggcagcctcaggacgatggaggcagtcagtctgaggctgaaaag7980
IS gg gggagggcctcgagcccaggcctgcaagcgcctccagaagctggaaaaagcggggaa8040
gggaccctccacggagcctgcagcaggaaggcacggctggcccttagcccaccagggccc8100
atcgtggacctccggcctccgtgccataggagggcactcgcgctgcccttctagcatgaa8160
gtgtgtggggatttgcagaagcaacaggaaacccatgcactgtgaatctaggattatttc8220
aaaacaaaggtttacagaaacatccaaggacagggctgaagtgcctccgggcaagggcag8280
2o ggcaggcacgagtgattttatttagctattttattttatttacttactttctgagacaga8340
gttatgctcttgttgcccaggctggagtgcagcggcatgatcttggctcactgcaacctc8400
cgtctcctgggttcaagcaattctcgtgcctcagcctcccaagtagctgggatttcaggc8460
gtgcaccaccacacccggctaattttgtatttttagtagagatgggctttcaccatgttg8520
gtcaagctgatctcaaaatcctgacctcaggtgatccgcccacctcagcctcccaaagtg8580
25 ctgggattacaggcatgagccactgcacctggcctatttaaccattttaaaacttccctg8640
ggctcaagtcacacccactggtaaggagttcatggagttcaatttcccctttactcagga8700
gttaccctcctttgatattttctgtaattcttcgtagactggggatacaccgtctcttga8760
catattcacagtttctgtgaccacctgttatcccatgggacccactgcaggggcagctgg8820
9aggctgcaggcttcaggtcccagtggggttgccatctgccagtagaaacctgatgtaga8880
atcagggcgcaagtgtggacactgtcctgaatctcaatgtctcagtgtgtgctgaaacat8940
30
gtagaaattaaagtccatccctcctactctactgggattgagccccttccctatcccccc9000
ccaggggcagaggagttcctctcactcctgtggaggaaggaatgatactttgttattttt9060
cactgctggtactgaatccactgtttcatttgttggtttgtttgttttgttttgagaggc9120
ggtttcactcttgttgctcaggctggagggagtgcaatggcgcgatcttggcttactgca9180
gcctctgcctcccaggttcaagtgattctcctgcttccgcctcccatttggctgggatta9240
35
caggcacccgccaccatgcccagctaattttttgtatttttagtagagacgggggtgggt9300
ggggttcaccatgttggccaggctggtctcgaacttctgacctcagatgatccacctgcc9360
tctgcctcctaaagtgctgggattacaggtgtgagccaccatgcccagctcagaatttac9420
tctgtttagaaacatctgggtctgaggtaggaagctcaccccactcaagtgttgtggtgt9480
tttaagccaar_gatagaatttttttattgttgttagaacactcttgatgttttacactgt9540
40
gatgactaagacatcatcagcttttcaaagacacactaactgcacccataatactggggt9600
gtcttctgggtatcagcaatcttcattgaatgccgggaggcgtttcctcgccatgcacat9660
ggtgttaattactccagcataatcttctgcttccatttcttctcttccctcttttaaaat9720
tgtgttttctatgttggcttctctgcagagaaccagtgtaagctacaacttaacttttgt9780
tggaacaaattttccaaaccgcccctttgccctagtggcagagacaattcacaaacacag9840
45
ccctttaaaaaggcttagggatcactaaggggatttctagaagagcgacctgtaatccta9900
agtatttacaagacgaggctaacctccagcgagcgtgacagcccagggagggtgcgaggc9960
ctgttcaaatgctagctccataaataaagcaatttcctccggcagtttctgaaagtagga10020
aaggttacatttaaggttgcgtttgttagcatttcagtgtttgccgacctcagctacagc10080
SO atccctgcaaggcctcgggagacccagaagtttctcgcccccttagatccaaacttgagc10140
aacccggagtctggattcctgggaagtcctcagctgtcctgcggttgtgccggggcccca10200
ggtctggaggggaccagtggccgtgtggcttctactgctgggctggaagtcgggcctcct10260
agctctgcagtccgaggcttggagccaggtgcctggaccccgaggctgccctccaccctg10320
tgcgggcgggatgtgaccagatgttggcctcatctgccagacagagtgccggggcccagg10380
55 gtcaaggccgttgtggctggtgtgaggcgcccggtgcgcggccagcaggagcgcctggct10440
ccatttcccaccctttctcgacgggaccgccccggtgggtgattaacagatttggggtgg10500
tttgctcatggtggggacccctcgccgcctgagaacctgcaaagagaaatgacgggcctg10560
tgtcaaggagcccaagtcgcggggaagtgttgcagggaggcactccgggaggtcccgcgt10620
gcccgtccagggagcaatgcgtcctcgggttcgtccccagccgcgtctacgcgcctccgt10680
6o cctccccttcacgtccggcattcgtggtgcccggagcccgacgccccgcgtccggacctg10740
gaggcagccctgggtctccggatcaggccagcggccaaagggtcgccgcacgcacctgtt10800
cccagggcctccacatcatggcccctccctcgggttaccccacagcctaggccgattcga10860
cctctctccgctggggccctcgctggcgtccctgcaccctgggagcgcgagcggcgcgcg10920
ggcggggaagcgcggcccagacccccgggtccgcccggagcagctgcgctgtcggggcca10980
ggccgggctcccagtggattcgcgggcacagacgcccaggaccgcgctccccacgtggcg11040
65
gagggactggggacccgggcacccgtcctgccccttcaccttccagctccgcctcctccg11100
cgcggaccccgccccgtcccgacccctcccgggtccccggcccagccccctccgggccct11160
cccagcccctccccttcctttccgcggccccgccctctcctcgcggcgcgagtttcaggc11220
agcgctgcgtcctgctgcgcacgtgggaagccctggccccggccacccccgcgatg 11276
<210> 4
<211> 104
<212> DNA
<213> Homosapiens
75 <400> 4
gtgggcctccccggggtcggcgtccggctggggttgagggcggccggggggaaccagcga60
catgcggagagcagcgcaggcgactcagggcgcttcccccgcag 104
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-65-
<210> 5
<211> 8616
<212> DNA
<213> Homo Sapiens
<400>
S
gtgaggaggtggtggccgtcgagggcccaggccccagagctgaatgcagtaggggctcag60
aaaagggggcaggcagagccctggtcctcctgtctccatcgtcacgtgggcacacgtggc120
to ttttcgctcaggacgtcgagtggacacggtgatctctgcctctgctctccctcctgtcca180
gtttgcataaacttacgaggttcaccttcacgttttgatggacacgcggtttccaggcgc240
cgaggccagagcagtgaacagaggaggctgggcgcggcagtggagccgggttgccggcaa300
tggggagaagtgtctggaagcacagacgctctggcgagggtgcctgcaggttacctataa360
tcctcttcgcaatttcaagggtgggaatgagaggtggggacgagaaccccctcttcctgg420
gggtgggaggtaagggttttgcaggtgcacgtggtcagccaatatgcaggtttgtgttta480
IS
agatttaattgtgtgttgacggccaggtgcggtggctcacgccggtaatcccagcacttt540
gggaagctgaggcaggtggatcacctgaggtcaggagtttgagaccagcctgaccaacat600
ggtgaaaccctatctgtactaaaaatacaaaaattagctgggcatggtggtgtgtgcctg660
taatcccagctacttgggaggctgaggcaggagaatcacttgaacccaggaggcggaggc720
tgcagtgagctgagattgtgccattgtactccagcctgggcgacaagagtgaaactctgt780
2~
ctttaaaaaaaaaaagtgttcgttgattgtgccaggacagggtagagggagggagataag840
actgttctccagcacagatcctggtcccatctttaggtatgaagagggccacatgggagc900
agaggacagcagatggctccacctgctgaggaagggacagtgtttgtgggtgttcagggg960
atggtgctgctgggccctgccgtgtccccaccctgtttttctggatttgatgttgaggaa1020
25 cctccgctccagcccccttttggctcccagtgctcccaggccctaccgtggcagctagaa1080
gaagtcccgatttcaccccctccccacaaactcccaagacatgtaagacttccggccatg1140
cagacaaggagggtgaccttcttggggctcttttttttctttttttctttttatggtggc1200
aaaagtcatataacatgagattggcactcctaacaccgttttctgtgtacagtgcagaat1260
tgctaactcggcggtgtttacagcaggttgcttgaaatgctgcgtcttgcgtgactggaa1320
3o gtccctacccatcgaacggcagctgcctcacacctgctgcggctcaggtggaccacgccg1380
agtcagataagcgtcatgcaacccagttttgctttttgtgctccagcttccttcgttgag1440
gagagtttgagttctctgatcaggactctgcctgtcattgctgttctctgacttcagatg1500
aggtcacaatctgcccctggcttatgcagggagtgaggcgtggtccccgggtgtccctgt1560
cacgtgcagggtgagtgaggcgttgcccccaggtgtccctgtcacgtgtagggtgagtga1620
ggcgcggcccccgggtgtccctgtcccgtgcagcgtgattgaggtgtggcccccgggtgt1680
35
ccctgtcacgtg.tagggtgagtgaggcgccatccccgggtgtccctgtcacgtgtagggt1740
gagtgaggcgtggtccccgggtgtccctgtcccgtgcagggtgagtgaggcactgtcccc1800
gggtgtccctgtcacgtgcagggtgagtgaggcgcggtccccgggtgtccctctcaggtg1860
tagggtgagtgaggcgcggccccagggtgtccctgtcacgtgtagggtgagtgaggcacc1920
gtccctgggtgtccctcccaggtatagggtgagtgaggcactgtccccgggtgtccctgt1980
40
cacgtgcagggtgagtgaggcgcggcccccgggtgtccctctcaggtgcagggtgagtga2040
ggcgctgtccctgggtgtccctgtctcgtgtagggtgagtgaggctctgtccccaggtgt2100
ccttggcgtttgctcacttgagcttgctcctgaatgtttgctctttctatagccacagct2160
gcgccggttgcccattgcctgggtagatggtgcaggcgcagtgctggtccccaagcctat2220
45 cttttctgatgctcggctcttcttggtcacctctccgttccattttgctacggggacacg2280
ggactgcaggctctcgcctcccgcgtgccaggcactgcagccacagcttcaggtccgctt2340
gcctctgttgggcctggcttgctcaccacgtgcccgccacatgcatgctgccaatactcc2400
tctcccagcttgtctcatgccgaggctggactctgggctgcctgtgtctgctgccacgtg2460
ttgctggagacatcccagaaagggttctctgtgccctgaaggaaagcaagtcaccccagc2520
5o cccctcacttgtcctgttttctcccaagctgcccctctgcttggcccccttgggtgggtg2580
gcaacgcttgtcaccttattctgggcacctgccgctcattgcttaggctgggctctgcct2640
ccagtcgccccctcacatggattgacgtccagccacaggttggagtgtctctgtctgtct2700
cctgctctgagacccacgtggagggccggtgtctccgccagccttcgtcagacttccctc2760
ttgggtcttagttttgaatttcactgatttacctctgacgtttctatctctccattgtat2820
gctttttcttggtttattctttcattccttttctagcttcttagtttagtcatgcctttc2880
SS
cctctaagtgctgccttacctgcaccctgtgttttgatgtgaagtaatctcaacatcagc2940
cactttcaagtgttcttaaaatacttcaaagtgttaatacttcttttaagtattcttatt3000
ctgtgatttttttctttgtgcacgctgtgttttgacgtgaaatcattttgatatcagtga3060
cttttaagtattctttagcttattctgtgatttctttgagcagtgagttatttgaacact3120
gtttatgttcaagatatgtagagtatcaagatacgtagagtattttaagttatcatttta3180
ttattgatttctaactcagttgtgtagtggtctgtataataccaattatttgaagtttgc3240
ggagccttgctttgtgatctagtgtgtgcatggtttccagaactgtccattgtaaatttg3300
acatcctgtcaatagtgggcatgcatgttcactatatccagcttattaaggtccagtgca3360
aagcttctgtctccttctagatgcatgaaattccaagaaggaggccatagtccctcacct3420
65 gggggatgggtctgttcatttcttctcgtttggtagcatttatgtgaggcattgttaggt3480
gcatgcacgtggtagaatttttatcttcctgatgagtgaatcttttggagacttctatgt3540
ctctagtaatctagtaattctttttttaaattgctcttagtactgccacactgggcttct3600
tttgattagtattttcctgctgtgtctgttttctgcctttaatttatatatatatatata3660
ttttttttttttttgagacagagtcttggtctgtcgcccagggtgagtgcagtggtgtga3720
tcacaggtcagtgtaacttttaccttctggcctgagccgtcctctcacctcagcctcctg3780
agtagctggaactgcagacacgcaccgctacacctggctaatttttaaattttttctgga3840
gacagggtcttgctgtgttgcccaggctggtctcaaactcttggactcaagggatccatc3900
tacctcggcttcccaaagtgctgaattacaggcatgagccaccatgtctggcctaatttt3960
caacacttttatattcttatagtgtgggtatgtcctgttaacagcatgtaggtgaatttc4020
caatccagtctgacagtcgttgtttaactggataacctgatttattttcatttttttgtc4080
t
ac cgcctggtgcactctgattctccacttgcctgttgcatgtcctcgttccc4140
agagacc
ttgtttctcaccacctcttgggttgccatgtgcgtttcctgccgagtgtgtgttgatcct4200
ctcgttgcctcctggtcactgggcatttgcttttatttctctttgcttagtgttaccccc4260
tgatctttttattgtcgttgtttgcttttgtttattgagacagtctcactctgtcaccca4320
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-66-
ggctggagtgtaatggcacaatctcggctcactgcaacctctgcctcctcggttcaagca4380
gttctcattcctcaacctcatgagtagctgggattacaggcgcccaccaccacgcctggc4440
taatttttgtatttttagtagagataggctttcaccatgttggccaggctggtctcaaac4500
tcctgacctcaagtgatctgcccgccttggcctcccacagtgctgggattacaggtgcaa4560
gccaccgtgcccggcataccttgatcttttaaaatgaagtctgaaacattgctacccttg4620
tcctgagcaataagacccttagtgtattttagctctggccaccccccagcctgtgtgctg4680
ttttccctgctgacttagttctatctcaggcatcttgacacccccacaagctaagcatta4740
ttaatattgttttccgtgttgagtgtttctgtagctttgcccccgccctgcttttcctcc4800
tttgttccccgtctgtcttctgtctcaggcccgccgtctggggtccccttccttgtcctt4860
tgcgtggttcttctgtcttgttattgctggtaaaccccagctttacctgtgctggcctcc4920
atggcatctagcgacgtccggggacctctgcttatgatgcacagatgaagatgtggagac4980
tcacgaggagggcggtcatcttggcccgtgagtgtctggagcaccacgtggccagcgttc5040
cttagccagtgagtgacagcaacgtccgctcggcctgggttcagcctggaaaaccccagg5100
catgtcggggtctggtggctccgcggtgtcgagtttgaaatcgcgcaaacctgcggtgtg5160
IS gcgccagctctgacggtgctgcctggcgggggagtgtctgcttcctcccttctgcttggg5220
aaccaggacaaaggatgaggctccgagccgttgtcgcccaacaggagcatgacgtgagcc5280
atgtggataattttaaaatttctaggctgggcgcggtggctcacgcctgtaatcccagca5340
ctttgggaggccaaggcgggtggatcacgaggtcaggaggtcgagaccatcctggccaac5400
atgatgaaaccccatctgtactaaaaacacaaaaattagctgggcgtggtggcgggtgcc5460
tgtaatcccagctactcgggaggctgaggcaggagaattgcttgaacctgggagttggaa5520
gttgcagtgagccgacattgcaccactgcactccagcctggcaacacagcgagactctgt5580
ctcaaaaaaaaaaaaaaaaaaaaaaaaaaaaattctagtagccacattaaaaaagtaaaa5640
aagaaaaggtgaaattaatgtaataatagattttactgaagcccagcatgtccacacctc5700
atcattttagggtgttattggtgggageatcactcacaggacatttgacattttttgagc5760
tttgtctgcgggatcccgtgtgtaggtcccgtgcgtggccatctcggcctggacctgctg5820
ggcttcccatggccatggctgttgtaccagatggtgcaggtccgggatgaggtcgccagg5880
ccctcagtgagctggatgtgcagtgtccggatggtgcacgtctgggatgaggtcgccagg5940
ccctgctgtgagctggatgtgtggtgtctggatggtgcaggtcaggggtgaggtctccag6000
gccctcggtgagctggaggtatggagtccggatgatgcaggtccggggtgaggtcgccag6060
3~ gccctgctgtgagctggatgtgtggtgtctggatggtgcaggtcaggggtgaggtctcca6120
ggccctcggtaagctggaggtatggagtccggatgatgcaggtccggggtgaggtcgcca6180
ggccctgctgtgagctggatgtgtggtgtctggatggtgcaggtctggggtgaggtcacc6240
aggccctgcggtgagctgggtgtgcggtgtctggatggtgcaggtctggagtgaggtcgc6300
cagacggtgccagaccatgcggtgagctggatatgcggtgtccggatggtgcaggtctgg6360
ggtgaggttgccaggccctgctgtgagttggatgtggggtgtccggatgctgcaggtccg6420
gtgtgaggtcaccaggccctgctgtgagctggatgtgtggtgtctggatggtgcaggtct6480
ggggtgaaggtcgccaggcccctgcttgtgagctggatgtgtggtgtctggatggtgcag6540
gtctggagtgaggtcgccaggccctcggtgagctggatgtgcagtgtccagatggtgcag6600
gtccggggtgaggtcgccagaccctgcggtgagctggatgtgcggtgtctggatggtgca6660
ggtctggagtgaggtcgccaggccctcggtgagctggatgtatggagtccggatggtgcc6720
ggtccggggtgaggtcgccagaccctgctgtgagctggatgtgcggtgtctggatggtac6780
aggtctggagtgaggtcgccagaccctgctgtgagctggatatgcggtgtccggatggtg6840
caggtcaggggtgaggtctccaggccctcggtgagctggaggtatggagtccggatgatg6900
caggtccggggtgaggtcgccaggccctgctgtgaactggatgtgcggcgtctggatggt6960
gcaggtctggggtgtggtcgccaggccctcggtgagctggaggtatggagtccggatgat7020
gcaggtccggggtgaggtcgccaggccctgctgtgagctggatgtgcggcgtctggatgg7080
tgcaggtctggggtgtggtcgccaggccctcggtgagctggaggtatggagtccggatga7140
tgcaggtccggggtgaggttgccaggccctgctgtgagctggatgtgctgtatccggatg7200
5o gtgcagtccggggtgaggtcgccaggccctgctgtgagctggatgtgctgtatccggatg7260
gtgcaggtctggggtgaggtcaccaggccctgcggtgagctggttgtgcggtgtccggtt7320
gctgcaggtccggggtgagttcgccaggccctcggtgagctggatgtgcggtgtccccgt7380
gtccggatggtgcaggtccagggtgaggtcgctaggcccttggtgggctggatgtgccgt7440
gtccggatggtgcaggtctggggtgaggtcgccaggcctttggtgagctggatgtgcggt7500
gtctgcatggtgcaggtctggggtgaggtcgccaggcccttggtgggctggatgtgtggt7560
gtccggatggtgcaggtccggcgtgaggtcgccaggccctgctgtgagctggatgtgcgg7620
tgtctggatggtgcaggtccggggtgaggtagccaaggccttcggtgagctggatgtggg7680
gtgtccggatggtgcaggtccggggtgaggtcgccaggccctgcggttagctggatatgc7740
ggtgtccggatggtgcaggtccggggtgaggtcaccaggccctgcggttagctggatgtg7800
6o cggtgtctggatggtgcaggtccggggtgaggtcgccaggccctgctgtgagctggatgt7860
gctgtatccggatggtgcaggtccggggtgaggtcgccaggccctgcagtgagctggatg7920
tgctgtatccggatggtgcaggtctggcgtgaggtcgccaggccctgcggttagctggat7980
atgcggtgtcggatggtgcaggtccggggtgaggtcaccaggccctgcggttagctggat8040
gtgcggtgtccggatggtgcaggtctggggtgaggtcgccaggccctgctgtgagctgga8100
tgtgctgtatccggatggtgcaggtccggggtgaggtcgccaggccctgcggtgagctgg8160
atgtgctgtatccggatggtgcaggtctggcgtgaggtcgccaggccctgcggtgagctg8220
gatgtgcagtgtacggatggtgcaggtccggggtgaggtcgccaggccctgcggtgggct8280
gtatgtgtgttgtctggatggtgcaggtccggggtgagttcgccaggccctgcggtgagc8340
tggatgtgtggtgtctggatgctgcaggtccggggtgagttcgccaggccctcggtgagc8400
tggatatgcggtgtccccgtgtccgaatggtgcaggtccagggtgaggtcgccaggccct8460
tggtgggctggatgtgccgtgtccggatggtgcaggtctggggtgaggtcgccaggccct8520
tggtgagctggatgtgcggtgtccggatggtgcaggtccggggtgaggtcaccaggccct8580
cggtgatctggatgtggcatgtccttctcgtttaag 8616
<210> 6
<211> 2089
<212> DNA
<213> Homo Sapiens
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-67-
<400> 6
gtactgtatccccacgccaggcctctgcttctcgaagtcctggaacaccagcccggcctc60
agcatgcgcctgtctccacttgcctgtgcttccctggctgtgcagctctgggctgggagc120
caggggccccgtcacaggcctggtccaagtggattctgtgcaaggctctgactgcctgga180
gctcacgttctcttacttgtaaaatcaggagtttgtgccaagtggtctctagggtttgta240
aagcagaagggatttaaattagatggaaacactaccactagcctccttgcctttccctgg300
gatgtgggtctgattctctctctcttttttttttcttttttgagatggagtctcactctg360
ttgcccaggctggagtgcagtggcataatcttggctcactgcaacctccacctcctgggt420
to ttaagcgattcaccagcctcagcctcctaagtagctgggattacaggcacctgccaccac480
gcctggctaatttttgtacttttaggagagacggggtttcaccatgttggccaggctggt540
ctcgaactcatgacctcaggtgatccacccaccttggcctcccaaagtgctgggtttaca600
ggctaagccaccgtgcccagcccccgattctcttttaattcatgctgttctgtatgaatc660
ttcaatctattggatttaggtcatgagaggataaaatcccacccacttggcgactcactg720
cagggagcacctgtgcagggagcacctggggataggagagttccaccatgagctaacttc780
IS t
t
agg catttgaatggctgtgagattttgtctgcaatgttcggctgatgagagtg840
ggctg
tgagattgtgacagattcaagctggatttgcatcagtgagggacgggagcgctggtctgg900
gagatgccagcctggctgagcccaggccatggtattagcttctccgtgtcccgcccaggc960
tgactgtggagggctttagtcagaagatcagggcttccccagctcccctgcacactcgag1020
20 tccctggggggccttgtgacaccccatgccccaaatcaggatgtctgcagagggagctgg1080
cagcagacctcgtcagaggtaacacagcctctgggctggggaccccgacgtggtgctggg1140
gccatttccttgcatctgggggagggtcagggctttccctgtgggaacaagttaatacac1200
aatgcaccttacttagactttacacgtatttaatggtgtgcgacccaacatggtcatttg1260
accagtattttggaaagaatttaattggggtgaccggaaggagcagacagacgtggtggt1320
25 ccccaagatgctccttgtcactactgggactgttgttctgcctggggggccttggaggcc1380
cctcctccctggacagggtaccgtgccttttctactctgctgggcctgcggcctgcggtc1440
agggcaccagctccggagcacccgcggccccagtgtccacggagtgccaggctgtcagcc1500
acagatgcccaggtccaggtgtggccgctccagcccccgtgcccccatgggtggttttgg1560
gggaaaaggccaagggcagaggtgtcaggagactggtgggctcatgagagctgattctgc1620
3o tccttggctgagctgccctgagcagcctctcccgccctctccatctgaagggatgtggct1680
ctttctacctgggggtcctgcctggggccagccttgggctaccccagtggctgtaccaga1740
gggacaggcatcctgtgtggaggggcatgggttcacgtggccccagatgcagcctgggac1800
caggctccctggtgctgatggtgggacagtcaccctgggggttgaccgccggactgggcg1860
tccccagggttgactataggaccaggtgtccaggtgccctgcaagtagaggggctctcag1920
aggcgtctggctggcatgggtggacgtggccccgggcatggccttcagcgtgtgctgccg1980
35
tgggtgccctgagccctcactgagtcggtgggggcttgtggcttcccgtgagcttccccc2040
tagtctgttgtctggctgagcaagcctcctgaggggctctctattgcag 2089
<210> 7
211> 687
~~<212>
DNA
213> Homo
Sapiens
<400> 7
45 gtggctgtgctttggtttaacttcctttttaaacagaagtgcgtttgagccccacatttg60
gtatcagcttagatgaagggcccggaggaggggccacgggacacagccagggccatggca120
cggcgccaacccatttgtgcgcacagtgaggtggccgaggtgccggtgcctccagaaaag180
cagcgtgggggtgtagggggagctcctggggcagggacaggctctgaggaccacaagaag240
cagccgggccagggcctggatgcagcacggcccgaggtcctggatccgtgtcctgctgtg300
5o gtgcgcagcctccgtgcgcttccgcttacggggcccggggaccaggccacgactgccagg360
agcccaccgggctctgaggatcctggaccttgccccacggctcctgcaccccacccctgt420
ggctgcggtggctgcggtgaccccgtcatctgaggagagtgtggggtgaggtggacagag480
gtgtggcatgaggatcccgtgtgcaacacacatgcggccaggaacccgtttcaaacaggg540
tctgaggaagctgggaggggttctaggtcccgggtctgggtggctggggacactggggag600
55 gggctgcttctcccctgggtccctatggtggggtgggcacttggccggatccactttcct660
gactgtctcccatgctgtccccgccag 687
<210> 8
<211> 494
<212> DNA
60 <213> HomoSapiens
<400> 8
gtgggtgccggggacccccgtgagcagccctgctggaccttgggagtggctgcctgattg60
gcacctcatgttgggtggaggaggtactcctgggtgggccgcagggagtgcaggtgaccc120
65
tgtcactgttgaggacacacctggcacctagggtggaggccttcagcctttcctgcagca180
catggggccgactgtgcaccctgactgcccgggctcctattcccaaggagggtcccactg240
gattccagtttccgtcagagaaggaaccgcaacggctcagccaccaggccccggtgcctt300
gcaccccagtcctgagccaggggtctcctgtcctgaggctcagagaggggacacagcccg360
7o ccctgcccttggggtctggagtggtgggggtcagagagagagtgggggacaccgccaggc420
caggccctgagggcagaggtgatgtctgagtttctgcgtggccactgtcagtctcctcgc480
ctccactcacacag 494
<210> 9
<211> 865
<212> DNA
<213> HomoSapiens
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-68-
<400> 9
gtaaggttcacgtgtgatagtcgtgtccaggatgtgtgtctctgggatatgaatgtgtct60
agaatgcagtcgtgtctgtgatgcgtttctgtggtggaggtacttccatgatttacacat120
ctgtgatatgcgtgtgtggcacgtgtgtgtcgtggtgcatgtatctgtggcgtgcatatt180
t
gtggtgtgt gtgtgtgtggcacgtgtgtgtccatggtgtgtgtgcctgtggtgtgcatg240
tgtgtgtgtctgtgacacgtgcatgttcatgctgtgtgctgcatgtctgtgatgtgccta300
tttgtggtgtgtgtgtgcatgtgtccgtgacatatgcgtgtctatggcatgggtgtgtgt360
ggccccttggccttactccttcctcctccaggcatggtccgcaccattgtcctcacgctc420
to tcgggtgctggtttggggagctccacattcagggtcctcacttctagcatgggtgcccct480
gtcctgtcacagggctgggccttggagactgtaagccaggtttgagaggagagtagggat540
gctggtggtaccttcctggacccctggcacccccaggaccccagtctggcctatgccggc600
tccatgagatataggaaggctgattcaggcctcgctccccgggacacactcctcccagag660
cggccgggggccttggggctcggcaggggtgaaaggggccctgggcttgggttcccaccc720
IS agtggtcatgagcacgctggaggggtaagccctcaaagtcgtgccaggccggggtgcaga780
ggtgaagaagtatccctggagcttcggtctggggagaggcacatgtggaaacccacaagg840
acctctttctctgacttcttgagct
865
<210> 10
<211> 3782
2~ <212> DNA
<213> Homo sapiens
<400> 10
25 tgtgggattggttttcatgtgtgggataggtggggatctgtgggattggtttttatgagt60
ggggtaacacagagttcaaggcgagctttcttcctgtagtgggtctgcaggtgctccaac120
agctttattgaggagaccatatcttcctttgaactatggtcgggtttatagtaagtcagg180
ggtgtggaggcctcccctgggctccctgttctgtttcttccactctggggtcgtgtggtg240
cctgctgtggtgtgtggccggtgggcagggcttccaggcctccttgtgttcattggcctg300
gatgtggccctggctacgctccgtccttggaattcccctgcgagttggaggctttctttc360
3~
tttctttttttctttctttttttttttttttgataacagagtctcgctcttttttgccca420
ggctggagtggtttggcgtgatcttggctcactgcaacctgtgcttcctgagttcaagca480
attctcttgcctcagcctcccaagtagctggaattataggcgcccaccaccatgctgact540
aatttttgtaattttagtagagacgaggtttctccatgttggccaggctggtctcgaact600
35 cctgacctcaggtgatcctcccacctcggcctcccaaagtgctgggatgacaggtgtgaa660
ccgccgcgcccggccgagactcgcttcctgcagcttccgtgagatctgcagcgatagctg720
cctgcagccttggtgctgacaacctccgttttccttctccaggtctcgctaggggtcttt780
ccatttcatgactctcttcacagaagagtttcacgtgtgctgatttcccggctgtttcct840
gcgtaattggtgtctgctgtttatcgatggcctccttccatttcctttaggctttgttta900
ttgttgtttttccggctccttgaaggaaaagtttcgattatggatgtttgaactttcttt960
tctaaacaagcatctgaagttgccgttttccctctaaagcagggatcccgaggcccctgg1020
ctgtggagtggcaccggtctggggcctgttaggaacccggcgcacagcgggaggctaggt1080
ggggtgtggggagccagcgttcccgcctgagccccgcccctctcagatcagcagtggcat1140
gcggtgctcagaggcgcacacaccctactgagaactgtgcgtgagaggggtctagattct1200
gtgctccttatgggaatctaatgcctgatgatctgaggtggaaccgtttgctcccaaaac1260
45
catccccttccccactgctgtcctgtggaaaaatcgtcttccacgaaaccagtccctggt1320
accacaatggttggggaccctgtgctaaagacctgcttcagcagcctctcgtcagtgttg1380
atatattggcttttctgtgttgagtccagaataattacggatttctgtgatgctttccgc1440
cgacctcagacccatgggctatttgtgggcgtgttgcctgctcctgggttgggaagggtg1500
caggccccatgtaccttcctgttactgccttccaggttggttctcagggttgaatcgtac1560
tcgatgtggttttagcccacggccctgccgccagctcctgggggctggggaacatgctga1620
agcacagagtcaccgtgcgcgtcttttgatgcctcacaagctcgaggcctcctgtgtccg1680
tgttagtgtgtgtcacgtgcctgctcacatcctgtcttggggacgcaggggcttagcagg1740
tcccgtagtaaatgacaagcgtcctgggggagtctgcagaataggaggtgggggtgccgg1800
55 tctctctcccgcgtcttcagactcttctcctgcctgtgctgtggctgcacctgcatccct1860
gcaatccctccagcactgggctggagaggcccgggagctcgagtgccacttgtgccacgt1920
gactgtggatggcagtcggtcacgggggtctgatgtgtggtgactgtggatggcggttgg1980
tcacaggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtggtgact2040
gtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtctga2100
6o tgtggtgactgtggatggcggtcgtggggtctgatgtggtgactgtggatggcggtcgtg2160
gggtctgatgtggtgactgtggatggcagtcgtggggtctgatgtgtggtgactgtggat2220
ggcggtcgtggggtctgatgtggtgactgtggatggcagtcgtggggtctgatgtgtggt2280
gactgtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggt2340
ctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtggatgg2400
65 cggtcgtggggtctgatgtggtgactgtggatggcggtcgtggggtctgatgtgtggtga2460
ctgtggatggtgatcggtcacaggggtctgatgtgtggtgactgtggatggcggtcgtgg2520
ggtctgatgtgtggtgactgtggatggtgatcggtcacaggggtctgatgtgtggtgact2580
gtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggttggtcccggggg2640
tctgatgtgtggtgactgtggatggcgatcggtcacaggggtctgatgtgtggtgactgt2700
ggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatg2760
tgtggtgactgtggatggcggtcgtggggtctgatgtggtgactgtggatggcggtcgtg2820
gggtctgatgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtggat2880
ggcggttggtcccgggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgat2940
gtggtgactgtggatggcagtcgtggggtctgatgtgtggtgactgtggatggcggtcgt3000
75 ggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtg3060
gatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgt3120
ggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtggatggtgatcggtc3180
acaggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgact3240
gtggatggcggtcgtggggtctgatgtggtgactgtggatggcggtcgtggggtctgatg3300
CA 02316282 2000-06-21
Le A 32 805-Forei , Countries
-69-
tgtggtgactgtggatggcggtcgtagggtctgatgtgtggtgactgtggatggcagtcg3360
gtcacaggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtg3420
actgtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtc3480
tgatgtgtggtgactgtggatggcggtcgtggggtctgatgtggtgactgtggatggtga3540
tcggtcacaggggtctgatgtgtggtagctgcaggtggagtcccaggtgtgtctgtagct3600
actttgcgtcctcggccccccggcccccgtttcccaaacagaagcttcccaggcgctctc3660
tgggcttcatcccgccatcgggcttggccgcaggtccacacgtcctgatcggaagaaaca3720
agtgcccagctctggccggggcaggccacatttgtggctcatgccctctcctctgccggc3780
ag
3782
<210> 11
<211> 980
<212> DNA
<213> Homosapiens
IS
<400> 11
gtctgggcactgccctgcagggttgggcacggactcccagcagtgggtcctcccctgggc60
aatcactgggctcatgaccggacagactgttggccctggggggcagtggggggaatgagc120
tgtgatgggggcatgatgagctgtgtgccttggcgaaatctgagctgggccatgccaggc180
tgcgacagctgctgcattcaggcacctgctcacgtttgactgcgcggcctctctccagtt240
ccgcagtgcctttgttcatgatttgctaaatgtcttctctgccagttttgatcttgaggc300
caaaggaaaggtgtccccctcctttaggagggcaggccatgtttgagccgtgtcctgccc360
agctggcccctcagtgctgggtctgaggccaaaggaaacgtgtcccccttcttaggagga420
cgggccgtgtttgagccacgccccgctgagcgggcctctcagtgctgggtctgtccacgt480
ggccctgtggccctttgcagatgtggtctgtccacgtggccctgtggctctttgcagatg540
cctgttagcacttgctcggctctaggggacagtcgtgtccaccgcatgaggctcagagac600
ctctgggcgaatttccttggctcccagggtgggggtggaggtggcctgggctgctgggac660
ccagaccctgtgcccggcagctgggcagcaactcctggatcacatatgccatccgggcca720
3o cggtgggctgtgtgggtgtgagcccagctggacccacaggtggcccagaggagacgttct780
gtgtcacacactctgcctaagcccatgtgtgtctgcagagactcggcccggccagcccac840
gatggccctgcattccagcccagccccgcacttcatcacaaacactgaccccaaaaggga900
cggagggtcttggccacgtggtcctgcctgtctcagcacccaccggctcactcccatgtg960
tctcccgtctgctttcgcag 980
<210> 12
<211> 2485
<212> DNA
<213> Homo Sapiens
<400> 12
gtgagtcaggtggccaggtgccattgccctgcgggtggctgggcgggctggcagggcttc60
tgctcacctctctcctgccccttccccactgnccttctgcccggggccaccagagtctcc120
ttttctggcccccgccccctccggctcctgggctgcaggctcccgaggccccggaaacat180
ggctcggcttgcggcagccggagcggagcaggtgccacacgaggcctggaaatggcaagc240
ggggtgtggagttgctcctgcgtggaggacgaggggcggggggtgtgtctgggtcaggtg300
tgcgccgagcgtttgagcctgcagcttgtcagctccaagttactactgacgctggacacc360
cggctctcacacgcttgtatctctctctcccgatacaaaaggattttatccgattctcat420
tcctgtccctgtcgtgtgacccccgcgagggcgcgggctcttctctctgtgactagattt480
cccatctggaaagtgcggggttgaccgtgtagtttgctcctctcggggggcctgtggtgg540
ccatggggcaggcggcctgggagagctgccgtcacacagccactgggtgagccacactca600
cggtggtagagccacagtgcctggtgccacatcacgtcctctggattttaagtaaaacca660
cacacctcccggcaggcatctgcctgcgaccctgtgtgtgcctggggagagtggtagcac720
ggaggaaattcgtgcacactcaaggtcatcagcaaggtcatccgcagtcaggtggaacgt780
ggaggcctctctctgggatcgtctccagcggataaaggactgtgcacagcttcggaagct840
SS t
t aatataactattaattattgcattataagtaatcactaatggtatcagca900
tatttaaa
attataatatttattaaagtataattagaaatattaagtagtacacacgttctggaaaaa960
cacaaattgcacatggcagcagagtgaattttggccgagggacacgtgtgcacatgtgtg1020
taagcggcccccaggcccacagaattcgctgacaaagtcacctccccagagaagccacca1080
6o cgggcctccttcgtggtcgtgaattttattaagatggatcaagtcacgtaccgtccacgt1140
t
g tttggggaatgtgaggtgatgactgcgtcctcatgccctgacagacagga1200
ggcagggc
ggtgactgtgtctgtcctgtccctaggacacggacaggcccgaagctctagtccccatcg1260
tggtccagtttggcctctgaataaaaacgtcttcaaaacctgttgccccaaaaactaaga1320
acagagagagtttcccatcccatgtgctcacaggggcgtatctgcttgcgttgactcgct1380
65 gggctggccggactcctagagttggtgcgtgtgcttctgtgcaaaaagtgcagtcctctt1440
gcccatcactgtgatatctgcaccagcaaggaaagcctcttttcttttctttcttttttt1500
ttttttgagacggaacgtcactgttgtctgcctgggcttgagtgcagtggcgcgatctca1560
actcactgcaacctccgcctcccgggttccagcatttctcctgcctcagcctcccgagca1620
gctgagattacaggcacccaccccctgcgcctggctaatttttgtatttttagtagagag1680
gggtttttgccatgttggccaggctggtctcgaactcctgacctcaggtgatccacccac1740
ctcggcctcccaaagtgctgggattacaggtgtgagccatcacgcccagccggaaagcct1800
ctttttaaggtgaccacctatagcgcttcccgaaaataacaggtcttgtttttgcagtag1860
gctgcaagcgtctcttagcaacaggagtggcgtcctgtgggctctggggatggctgaggg1920
tcgcgtggcagccatgccttctgtgtgcacctttaggttccacggggctattctgctctc1980
actgtttgtctgaaaacgcacccttggcatccttgtttggagagtttctgcttctcgttg2040
gtcatgctgaaactaggggcaaggttgtatccgttggcgcgcagcggctacatgtagggt2100
catgagtctttcaccgtggacaaattccttgaaaaaaaaaaaaggagtccggttaagcat2160
tcattccgggtcaagtgtctggttctgtgaataaactctaagatttaagaaaccttaatg2220
aaagaaaaccttgatgattcagagcaaggatgtggtcacacctgtggctggatctgtttc2280
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-70-
agccgccccagtgcatggtgagagtggggagcagggattgtttgttcagaggtctcatct2340
ggtatgtttctgaggtgtttgccggctgaatggtagacgtgtcgtttgtgtgtatgaggt2400
tctgtgtctgtgtgtggctcggtttgagtgtacgcatgtccagcacatgccctgcccgtc2460
tctcacctgtgtcttcccgccccag
2485
<210> 13
<211> 1984
<212> DNA
<213> Homosapiens
1
<400> 13
gtgaggcctcctcttccccaggggggcttgggtgggggttgatttgcttttgatgcattc60
agtgttaatattcctggtgctctggagaccatgactgctctgtcttgaggaaccagacaa120
IS ggttgcagccccttcttggtatgaagccgcacgggaggggttgcacagcctgaggactgc180
gggctccacgcaggctctgtccagcggccatgtccagaggcctcagggctcagcaggcgg240
gagggccgctgccctgcatgatgagcatgtgaattcaacaccgaggaagcacaccagctt300
ctgtcacgtcacccaggttccgttagggtccttggggagatggggctggtgcagcctgag360
gccccacatctcccagcaggccctcgacaggtggcctggactgggcgcctcttcagccca420
2o ttgcccatcccacttgcatggggtctacacccaaggacgcacacacctaaatatcgtgcc480
aacctaatgtggttcaactcagctggcttttattgacagcagttacttttttttttttaa540
tactttaagttctagggtacatgtgcacgacgtgcaggttagttacatatgtatacatgt600
gccatgttggtgtgctgcacccattaactcatcatttacattaggtatatctcctaatgc660
tatccctccccactccccccatcccatgacaggccctggtgtgtgatgttccccaccctg720
tgtccaagtgttctcattgttcagttcccacctgtgagtgagaacatgtggtgtttggtt780
25 t
tctttcctt gcaatagtttgctcagagtgatggtttccagcttcgtccatgtccctaca840
aaggacatgaactcatccttttttatgactgcatagtattccgtggtgtatatgtgccac900
attttcttaatccagtctatcatcgatggacatttgggttggttgcaagtctttgctact960
gtgaatagtgccgcaataaacatacgtgtgcatgtgtctttatagcagcatgatttataa1020
tcctttgggtatatacccagtaatgggatggctgggtcaaatggtatttctagttctaga1080
3~ t
ccttgagga atcaccacactgtcttccacaatggttgaactagtttacactcccaccaa1140
cagtgtaaaagtgttctggtgctggagaggatgtggacagcagttatttttttatgaaaa1200
tagtatcactgaacaagcagacagttagtgaaggatgcgtcaggaagcctgcaggccaca1260
cagccatttctctcgaagactccgggtttttcctgtgcatcttttgaaactctagctcca1320
attatagcatgtacagtggatcaaggttcttcttcattaaggttcaagttctagattgaa1380
35
ataagtttatgtaacagaaacaaaaatttcttgtacacacaacttgctctgggatttgga1440
ggaaagtgtcctcgagctggcggcacactggtcagccctctgggacaggatacctctggc1500
ccatggtcatggggcgctgggcttgggcctgagggtcacacagtgcaccatgcccagctt1560
cctgtggataggatctgggtctcggatcatgctgaggaccacagctgccatgctggtaaa1620
gggcaccacgtggctcagagggggcgaggttcccagccccagctttcttaccgtcttcag1680
40
ttatttttccctaagagtctgagaagtggggccgcgcctgatggccttcgttcgtcttca1740
gctggcacagaattgcacaagctgatggtaaacactgagtacttataatgaatgaggaat1800
tgctgtagcagttaactgtagagagctcgtctgttggaaagaaatttaagtttttcattt1860
aaccgctttggagaatgttactttatttatggctgtgtaaattgtttgacattcagtccc1920
tcgtagacagatactacgtaaaaagtgtaaagttaaccttgctgtgtattttcccttatt1980
45
ttag 1984
<210> 14
<211> 1871
<212> DNA
<213> Homo sapiens
<400>
14
gtgaggcccgtgccgtgtgtctgtggggacctccacagcctgtgggctttgcagttgagc60
55 cccccgtgtcctgcccctggcaccgcagcgttgtctctgccaagtcctctctctctgccg120
gtgctggatccgcaagagcagaggcgcttggccgtgcacccaggcctgggggcgcagggg180
caccttcgggagggagtgggtaccgtgcaggccctggtcctgcagagacgcacccaggtt240
acacacgtggtgagtgcaggcggtgacctggctcctgctgctctttggaaagtcaagagt300
ggcggctcctggggccccagtgagacccccaggagctgtgcacagggcctgcagggccga360
60 ggcggcagcctcctccccagggtgcacctgagcctgcggagagcaggagctgctgagtga420
gctggcccacagcgttcgctgcggtcacgttcctgcgtggggttgtttgggatcggtggg480
agaatttggatttgctgagtgctgctgtcttgaaccacggagatggctaggagtgggttt540
cagagttgatttttgtgaatcaaactaaaatcaggcacaggggacctggcctcagcacag600
gggattgtccaatgtggtccccctcaagggcgccccacagagccggtgggcttgttttaa660
agtgcgatttgacgagggacgagaaaccttgaaagctgtaaagggaaccctcagaaaatg720
65
tggccgccaggggtggtttcaggtgctttgctgggctgtgtttgtgaaaacccatttgga780
cccgccctccaagtccaccctccaggtccaccctccagggccgccctgggctgggggtat840
gcctggcgttccttgtgccgcagcccggagcacagcaggctgtgcacatttaaatccact900
aagattcactcggggggagcccaggtcccaagcaactgagggctcaggagtcctgaggct960
gctgaggggacagagcagacggggaacgctgcttctgtgtggcaagttcctgagggtgct1020
ggccagggaggtggctcagagtgtatgttggggtcccaccgggggcagaactctgtctct1080
gatgagtcggcagccatgtaacaggaaggggtggccacagggagctgggaatgcaccagg1140
ggagctgcgcagctggccgaggtcccagggccaggccacaggaagggcagggggacgccc1200
ggggccacagcagaggccgcaggaagggaaggggatgcccaggccagagcagaggctacc1260
gggcacaggggggctccctgagctgggtgagcgaggctcatgactcggcgagggaacctc1320
75
cttgacgtgaagctgacgactggtgttgcccagctcacagcccagccaggtcccgcgcct1380
gagcaggaactcagaaccctcccctttgtctaaagcacagcagatgccttcagggcatct1440
aggagaaaacaggcaaagtcgttgagaaacgtcttaaaagaaggtgggatggtggcaatt1500
tcttgtccagattttagtctgccccggaccacagatgagtctataacgggattgtggtgt1560
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-71-
tgccatgggg acacatgaga tggaccatca cagaggccac tggggctgca cctcccatct 1620
gagtcctggc tgtcccgggt ccaggccagg ttcttgcatg ctcacctacc tgtcctgccc 1680
gggagacagg gaaagcaccc cgaagtctgg agcagggctg ggtccaggct cctcagagct 1740
cctgccaggc ccagcaccct gctccaaatc accacttctc tggggttttc caaagcattt 1800
aacaagggtg tcaggttacc tcctgggtga cggccccgca tcctggggct gacattgccc 1860
ctctgcctta g 1871
<210> 15
<211> 3801
lO <212> DNA
<213> Homo Sapiens
<400>
15
gtgagcgcacctggccggaagtggagcctgtgcccggctggggcaggtgctgctgcaggg60
15
ccgttgcgtccacctctgcttccgtgtggggcaggcgactgccaatcccaaagggtcaga120
ggccacagggtgcccctcgtcccatctggggctgagcagaaatgcatctttctgtgggag180
tgagggtgctcacaacgggagcagttttctgtgctattttggtaaaaggaaatggtgcac240
cagacctgggtgcactgaggtgtcttcagaaagcagtctggatccgaacccaagacgccc300
gggccctgctgggcgtgagtctctcaaacccgaacacaggggccctgctgggcatgagtc360
2O
cctctgaacccgagaccctggggccctgctgggcgtgagtctctccgaacccagagactt420
cagggcccttttgggcgtgagtctctccgctgtgagccccacactccaaggctcatccac480
agtctacaggatgccatgagttcatgatcacgtgtgacccatcaggggacagggccatgg540
tgtggggggggtctctacaaaattctggggtcttgtttccccagagcccgagagctcaag600
gccccgtctcaggctcagacacaaatgaattgaagatggacacagatgcagaaatctgtg660
25
ctgtttcttttatgaataaaaagtatcaacattccaggcagggcaaggtggctcacacct720
ataatcccagcactttgggaggccgaggtgggtggatcacttgaggccaggagtttgagg780
ccaacctaaccaacatagtgaaattccatttctacttaaaaaatacaaaaattagcctgg840
cctggtggcacacgcctgtagtccccgctatgcgggaggctgaggcaggagaatcatttg900
aacccaggaggcagaggttgcagtgagccgagatcacaccactgcactccagcctgggca960
3O
acagagtgagacttcatcttaaaaaaaaaaaaaaaagtatcagcattccaaaaccatagt1020
ggacaggtgtttttttattctgtccttcgataatatttactggtgctgtgctagaggccg1080
gaactgggggtgccttcctctgaaaggcacaccttcatgggaagagaaataagtggtgaa1140
tggttgttaaaccagaggtttaaactggggtcctgtcgttctgagttaacagtccagatc1200
35 tggactttgcctctttccagaatgctccctggggtttgcttcatgggggagcagcaggtg1260
tggacaccctcgtgatgggggagcagcaggtgcagacgccctcatgatgggggagtggca1320
ggtgcagacacccttgtgcatggtgcccagcatgtccctgttgcagctccctccccacaa1380
ggatgccggtctcctgtgctccccacagtccctgcttccctctcacagccttacctggtc1440
ctggcctccactggctttgtctgcatgatttccacatttcctgggctcccagcacctctt1500
4O cgcctctcccaggcacctctgcagtgctggccataccagtcagctgtgaactgtccactg1560
cttattttgctccccatgaaatgtattttttaggacaggcacccctggttccagcctctg1620
gcacagcatcagtgaatgttattgaaggacaaaggacagacaaacaaatcaggaaaatgg1680
gttctctctaaacacattgcaaagccacagaggctagtgcaggatgggtgggcatcaggt1740
catcagatgtgggtccaatgccagaatattctgtgctcccaaaggccacttggtcagagt1800
45 gtgtgcttgcagaggtggctctaaaagctcagcagtggaggcagtggttcgccatactca1860
gggtgaactcacatcctctgtgtctgaagtatacagcagaggcttgaagggcatctggga1920
gaagaaaacaggcaaaatgattaagaaaagtgaaaaaggaaaagtggtaagatgggaatt1980
ttcttgtccagattttagtctcccaaaccacagctcagatggtagaatgtggtcagaact2040
gatggacagaacaatagaacaaaacggaagccctatctctcagaaacgtgtgttaatgtg2100
SO gtatgtggcacagctgatggaaaagagagtgtgtgtgtaatttttttttctgagaaaact2160
gactggaagcaaataagttgtgtctttacagcatataccagagcagattctaggtagaag2220
aggagacacatgcaaacaacaccagcaacagaaataaaacaaaagactcaaagggaaggg2280
aggtgaacgttccctggtttggtgttggggaaggacacacagggaggcggatgaaaccag2340
tgaggcaacgggcattgctttcactgcagagaaactcagcttgcctgagccacagtgaaa2400
atggccattccctggagcgtttgtgcacgtgatttatttaaggcgccctgtgaggtcctg2460
55
cacattcatcctctcactttgttctcctaaccacctgagaggtagaggaggaaaggctcc2520
aggggagcagccgcccttggtcacccagctggcaaagggcatgcatgattgcagcctggc2580
ctcctgctccggggcccttgctctgcccgaggaccccacacaagtcagacccataggctc2640
agggtgagccggagcccaaggtcgtgttggggatggctgtgaaagaagaaatggacgtct2700
6O gatgcacacttgggaaggtcctaccagcagcgtcaaagaaatgcatgtgaaactgacagc2760
gagacccatccctcaaagaaacgcacgtgaaactgatggcgagacctgtccccatccctc2820
atgctggctccttttctgggcttgccaagagccagcatcaggttgaggcaagctggaaag2880
acttttctggaaagcagcttgtttgcatggaagtcctcacaatgtcctgtgtcttcccag2940
taattccacttctgaagtgaccagacattatcacgggtcttatttaccatttccagtgtt3000
ccaggcagggggacttgccacagcaagtcacgaacctgcccaaatacagggctaaggaga3060
65
tattatgcatcacaaaacttgctctgccattaaacatttttcaaagaatttttgaagaat3120
gtttaatggcacaaaacgtttatttcaatgtagcagtgttcaaagctggatgtaaaagaa3180
cacaccccaggagcctgccgtgaatgtcatgtgtgttcatctttggacatggacatacat3240
gggcagtgagtggtggtgaggccctggaggacatcggtgggatgcctccatcctgcccct3300
ctggagacaccatgtgtgccacgtgcactcactggagccctgtttagctggtgccacctg3360
7O
gctcttccatccctgagattcaaacacagtgagattccccacgcccaactcagtgttctc3420
ccacaaaaaacctgagtcacacctgtgttcactcgagggacgcccgggagccagggctcc3480
acagtttattatgtgtttttggctgagttatgtgcagatctcatcagggcagatgatgag3540
tgcacaaacacggccgtgcgaggtttggatacactcaacatcactagccaggtcctggtg3600
75 gagtttggtcatgcagagtctggatggcatgtagcatttggagtccatggagtgagcacc3660
cagccccctcgggctgcagcgcatgccccaggcaggacaaggaagcgggaggaaggcagg3720
aggctctttggagcaagctttgcaggagggggctgggtgtggggcaggcacctgtgtctg3780
acattcccccctgtgtctcag 3801
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-72-
<210> 16
<211> 880
<212> DNA
<213> Homo sapiens
<400> 16
gtgagcaggctgatggtcagcacagagttcagagttcaggaggtgtgtgcgcaagtatgt60
gtgtgtgtgtgtgcgcgcgtgcctgcaaggctgatggtgactggctgcacgtaagagtgc120
lp acatgtacgcatatacacgtgagcacatacatgtgtgcatgtgtgtacatgaaggcatgg180
cagtgtgtgcacaggtgtgcaagggcacaagtgtgtgcacatgcgaatgcacacctgaca240
tgcatgtgtgttcgtgcacagtcgtgtgggcattcacgtgaggtgcatgcgtgtgggtgt300
gcagtgtgagtagcatgtgtgcacataacatgtattgaggggtcctcgtgttcaccccgc360
taggtcctcagcaccagtgccactccttacaggatgagacggggtcccaggccttggtgg420
gctgaggctctgaagctgcagccctgagggcattgtcccatctgggcatccgcgtccact480
IS
ccctctcctgtgggcttctgtgtccactccccctctcctgtgggcatttacatccactcc540
actccctctctcctgtgggcatccgcgtccactccccctctctgtgggcatctgcgtcca600
cctcccctctctgtgggcatttgcgtccactccctctcctggttccttcctgtcttggcc660
gagcctcgggggcaggcagatgacacagagtcttgactcgcccagggtggttcgcagctg720
2o ccgggtgagggccaggccggatttcactgggaagagggatagtttcttgtcaaaatgttc780
ctctttcttgttccatctgaatggatgataaagcaaaaagtaaaaacttaaaatcccaga840
gaggtttctaccgtttctcactctttcttggcgactctag gg0
<210> 17
<211> 3186
25 <212> DNA
<213> Homo sapiens
<400> 17
gtgagccgccaccaaggggtgcaggcccagcctccagggaccctccgcgctctgctcacc60
3~
tctgacccggggcttcaccttggaactcctgggttttaggggcaaggaatgtcttacgtt120
ttcagtggtgctgctgcctgtgcacagttctgttcgcgtggctctgtgcaaagcacctgt180
tctccatctctgggtagtggtaggagccggtgtggccccaggtgtccccactgtgcctgt240
gcactggccgtgggacgtcatggaggccatcccagggcagcaggggcatggggtaaagag300
atgtttatggggagtcttagcagaggaggctgggaaggtgtctgaacagtagatgggaga360
35
tcagatgcccggaggatttggggtctcagcaaagagggccgaggtgggtgcaggtgaggg420
tcgctggccccacccccgggaaggtgcagcagagctgtggctccccacacagcccggcca480
gcacctgtgctctgggcatggctgtgctcctggaacgttccctgtcctggctggtcaggg540
ggtgcccctgccaagaatcgacaactttatcacagagggaagggccaatctgtggaggcc600
acagggccagcttctgcctggagtcagggcaggtggtggcacaagcctcggggctgtacc660
aaagggcagtcgggcaccacaggcccgggcctccacctcaacaggcctcccgagccactg720
ggagctgaatgccaggaggccgaagccctcgccccatgagggctgagaaggagtgtgagc780
atttgtgttacccagggccgaggctgcgcgaattaccgtgcacacttgatgtgaaatgag840
gtcgtcgtctatcgtggaaacccagcaagggctcacgggagagttttccattacaaggtc900
45 gtaccatgaaaatggtttttaacccgagtgcttgcgccttcatgctctggcagggagggc960
agagccacagctgcatgttaccgcctttgcaccagctccagaggcttgggaccaggctgt1020
ctcagttccagggtgcgtccggctcagaccgccctcctctctgccttctctctctgcctc1080
aaatcttccctcgtttgcatctccctgacgcgtgcctgggccctcgtgcaagctgcttga1140
ctcctttccggaaacccttggggtgtgctggatacaggtgccactgaggactggaggtgt1200
ctgacactgtggttgaccccagggtccagctggcgtgcttggggcctccttgggccatga1260
tgaggtcagaggagttttcccaggtgaaaactcctgggaaactcccagggccatgtgacc1320
tgccacctgctcctcccatattcagctcagtcttgtcctcatttccccaccagggtctct1380
agctccgaggagctcccgtagagggcctgggctcagggcagggcggctgagtttccccac1440
ccatgtggggacccttgggtagtcgcttgattgggtagccctgaggaggccgagatgcga1500
tgggccacgggccgtttccaaacacagagtcaggcacgtggaaggcccaggaatcccctt1560
ss
ccctcgaggcaggagtgggagaacggagagctgggccccgatttcacggcagccaggctg1620
cagtgggcgaggctgtggtggtccacgtggcgctgggggcggggtctgattcaaatccgc1680
tggggctcggccttcctggcccgtgctggccgcgcctccacacgggcttggggtggacgc1740
cccgacctctagcaggtggctatttctccctttggaagagagcccctcacccatgctagg1800
6o tgtttccctcctgggtcaggagcgtggccgtgtggcaaccccgggaccttaggcttattt1860
atttgtttaaaaacattctgggcctggcttccgttgttgctaaatggggaaaagacatcc1920
cacctcagcagagttactgagaggctgaaaccggggtgctggcttgactggtgtgatctc1980
aggtcattccagaagtggctcaggaagtcagtgagaccaggtacatggggggctcaggca2040
gtgggtgagatgaggtacacggggggctcaggcagtgggtgaggccaggtacatgggggg2100
65 ctcaggcactgggtgagatgaggtacacggggggctcaggcagagggtcagaccaggtac2160
acgggggctctgatcacacgcacatatgagcacatgtgcacatgtgctgtttcatggtag2220
ccaggtctgtgcacacctgccccaaagtcccaggaagctgagaggccaaagatggaggct2280
gacagggctggcgcggtggctcacacctgtagtcccagcactttgggaggccgaggcgag2340
aggatcccttgagcccaggagtttaagaccagcctgagcaacatagtagaaccccatctc2400
tatgaaaaataaaaacaaaaattagctgaacatggtggtgtgcgcctgtagttccaatac2460
ttgggaggctgaagtgggaggatcacttgagcccaggaggtggaagctgcagtgagctga2520
gattgcaccactgtactgcagcctgggtgacagagtgagagcccatctcaacaacaacaa2580
agaagactgacaaatgcagtttcttggaaagaaacatttagtaggaacttaacctacaca2640
cagaagccaagtcggtgtctcggtgtcagtgagatgagatgatgggtcctcacaccatca2700
ccccagacccagggtttatgcaccacaggggcgggtggctcagaagggatgcgcaggacg2760
75
ttgatatacgatgacatcaaggttgtctgacgaagggcaggattcatgataagtacctgc2820
tggtacacaaggaacaatggataaactggaaaccttagaggccttcccggaacaggggct2880
aatcagaagccagcatggggggctggcatccaggatggagctgcttcagcctccacatgc2940
gtgttcatacagatggtgcacagaaacgcagtgtacctgtgcacacacagacacgcagct3000
CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-73-
actcgcacacacaagcacacacacagacatgcatgcatgcatccgtgtgtgtgcacctgt3060
gcccatgaggaaacccatgcatgtgcattcatgcacgcacacaggcaccggtgggcccat3120
gcccacacccacgagcaccgtctgattaggaggcctttcctctgacgctgtccgccatcc3180
tctcag 3186
<210> 18
<211> 781
<212> DNA
<213> HomoSapiens
<400> 18
gtatgtgcaggtgcctggcctcagtggcagcagtgcctgcctgctggtgttagtgtgtca60
ggagactgagtgaatctgggcttaggaagttcttaccccttttcgcatcagg8agtggtt120
taacccaaccactgtcaggctcgtctgcccgccctctcgtggggtgagcagagcacctga180
tggaagggacaggagctgtctgggagctgccatccttcccaccttgctctgcctggggaa240
gcgctggggggcctggtctctcctgtttgccccatggtgggatttggggggcctggcctc300
tcctgtttgccctgtggtgggattgggctgtctcccgtccatggcacttagggcccttgt360
gcaaacccaggccaagggcttaggaggaggccaggcccaggctaccccacccctctcagg420
agcagaggccgcgtatcaccacgacagagccccgcgccgtcctctgcttcccagtcaccg480
tcctctgcccctggacactttgtccagcatcagggaggtttctgatccgtctgaaattca540
agccatgtcgaacctgcggtcctgagcttaacagcttctactttctgttctttctgtgtt600
gtggaaatttcacctggagaagccgaagaaaacatttctgtcgtgactcctgcggtgctt660
gggtcgggacagccagagatggagccaccccgcagaccgtcgggtgtgggcagctttccg720
gtgtctcctgggaggggagctgggctgggcctgtgactcctcagcctctgttttccccca780
g 781
<210> 19
<211> 536
<212> DNA
<213> HomoSapiens
<400> 19
gcaagtgtgggtggaggccagtgcgggccccacctgcccaggggtcatccttgaacgccc60
tgtgtggggcgagcagcctcagatgctgctgaagtgcagacgcccccgggcctgaccctg120
ggggcctggagccacgctggcagccctatgtgattaaacgctggtgtccccaggccacgg180
agcctggcagggtccccaacttcttgaacccctgcttcccatctcaggggcgatggctcc240
ccacgcttgggagccttctgacccctgacctgtgtcctctcacagcctcttccctggctg300
ctgccctgagctcctggggtcctgagcaagttctctccccgccccgccgctccagcgtca360
ctgggctgcctgtctgctcgccccggtggaggggtgtctgtcccttcactgaggttccca420
ccagccagggccacgaggtgcaggccctgcctgcccggccacccacacgtcctaggaggg480
ttggaggatgccacctctggcctcttctggaacggagtctgattttggccccgcag 536
<210> 20
<211> 3179
<212> DNA
<213> HomoSapiens
<400> 20
atctcatgtttgaatcctaatgtgcactgcatagacaccactgtatgcaattacagaagc60
ctgtgagtgaacggggtggtggtcagtgcgggcccatggcctggctgtgcatttacggaa120
gtctatgagtgaatggggttgtggtcagtgcgggcccatggcctggctgggcctgggagg180
tttctgatgctgtgaggcaggaggggaaggagggtaggggatagacagtgggagccccca240
ccctggaagacataacagtaagtccaggcccgaagggcagcagggatgctgggggcccag300
cttgggcggcggggatgatggagggcctggccagggtggcagggatgatgggggccccag360
ctggggtggcaggggtgatggggggggctggtctgggtggcggggaagatggggaagcct420
ggctgggccccctcctcccctgcctcccacctgcagccgtggatccggatgtgcttccct480
ggtgcacatcctctgggccatcagctttcatggaggtggggggcaggggcatgacaccat540
cctgtataaaatccaggattcctcctcctgaacgccccaactcaggttgaaagtcacatt600
ccgcctctggccattctcttaagagtagaccaggattctgatctctgaagggtgggtagg660
gtggggcagtggagggtgtggacacaggaggcttcagggtggggctggtgatgctctctc720
atcctcttatcatctcccagtctcatctctcatcctcttatcatctcccagtctcatctg780
tcttcctcttatctcccagtctcatctgtcatcctcttaccatctcccagtctcatctct840
tatcctcttatctcctagtctcatccagacttacctcccagggcgggtgccaggctcgca900
gtggagctggacatacgtccttcctcaggcagaaggaactggaaggattgcagagaacag960
gaggggcggctcagagggacgcagtcttggggtgaagaaacagcccctcctcagaagttg1020
gcttgggccacacgaaaccgagggccctgcgtgagtggctccagagccttccagcaggtc1080
cctggtggggccttatggtatggccgggtcctactgagtgcaccttggacagggcttctg1140
7o gtttgagtgcagcccggacgtgcctggtgtcggggtgggggcttatggccactggatatg1200
gcgtcatttattgctgctgcttcagagaatgtctgagtgaccgagcctaatgtgtatggt1260
gggcccaagtccacagactgtgtcgtaaatgcactctggtgcctggagcccccgtatagg1320
agctgtgaggaaggaggggctcttggcagccggcctgggggcgcctttgccctgcaaact1380
ggaagggagcggccccgggcgccgtgggcggacgacctcaagtgagaggttggacagaac1440
agggcggggacttcccaggagcagaggccgctgctcaggcacacctgggtttgaatcaca1500
gaccaacaggtcaggccattgttcagctatccatcttctacaaagctccagattcctgtt1560
tctccgggtgttttttgttgaaattttactcaggattacttatattttttgctaaagtat1620
tagacccttaaaaaaggtatttgctttgatatggcttaactcactaagcacctactttat1680
ttgtctgtttttatttattattattattattattagagatggtgtctactctgtcaccca1740
CA 02316282 2000-06-21
Le A 32 805-Forei;~n Countries
-74-
ggttgttagtgcagtggcacagtcatggctcgctgtagccgcaaacccccaggctcaagt1800
gatcctccggcctcagcttcccagagtgctgggattacaggtgtgagccactgcccttgc1860
ctggcacttttaaaaaccactatgtaaggtcaggtccagtggcttccacacctgtcatcc1920
cagtagtttgggaagccgaggcagaaggattgtctgaggccaggagtttgagaccagcat1980
gggtaacatagggagaccccatctctacaaaaaatgcaaaaagttatccgggcgtggggt2040
ccagcatctgtagtcccagctgctcgggaggctgagtgggaggatcgcttgagcccggga2100
ggtcatggctgcagtgagctgtgattgtaccatcgcactccagcctgggcaacagagtga2160
gaccctgtctcaaaaaaaaaaaaaaaaaaagaaggagaaggagaagagaagaagaaggaa2220
gaaggaaagagaagaagaaggaagaaggaagaaagaaggagaaggaggcctgctaggtgc2280
taggtagactgtcaaatctcagagcaaaatgaaaataacaaagttttaaagggaaagaaa2340
aaccccagctctttggacttccttaggcctgaacttcatctcaagcagcttccttccaca2400
gacaagcgtgtatggagcgagtgagttcaaagcagaaagggaggagaagcaggcaagggt2460
ggaggctgtgggtgacaccagccaggacccctgaaagggagtggttgttttcctgcctca2520
IS gccccacgctcctgccggtcctgcacctgctgtaaccgtcgatgttggtgccaggtgccc2580
acctgggaaggatgctgtgcagggggcttgccaaactttggtgggtttcagaagccccag2640
gcacttgtggcaggcacaattacagcccctccccaaagatgcccacgtccttctcctgga2700
acctgtgaatgtgtcacccgcaaggcagaggctggtgaaggctgcaggtggaatcacggc2760
tgccagtcagccgatcttaaggtcatcctggattatctggtgggcctgatatggccacaa2820
gggtccctagaagtgagagagggaggcaggggagagtcagagaggggacgtgagaaggac2880
cactggccactgctggctttgagatggaggagggggtccccagccaaggaatgggggcag2940
ccgctccatgctggaaaagcaagcaatcctccccggtcctgagggcacacggccctgccc3000
acgcctcgatttcaggccagtgggacctgtttcagctttccggcctccagagctgtaaga3060
tgatgcgtttgtgttcagccactaagctgcagtgattcgtcacagcagcaaatggaatag3120
cagtacagggaaatgaatacagggacagttctcagagtgactctcagcccacccctggg3179