CA2316282A1

CA2316282A1 - Regulatory dna sequences of the human catalytic telomerase sub-unit gene, diagnostic and therapeutic use thereof

Info

Publication number: CA2316282A1
Application number: CA002316282A
Authority: CA
Inventors: Gustav Hagen; Maresa Wick; Dmitry Zubov
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1997-12-24
Filing date: 1998-12-22
Publication date: 1999-07-08
Also published as: AU2272999A; JP2003519462A; WO1999033998A3; AU742489B2; DE19757984A1; WO1999033998A2; EP1040195A2

Abstract

The present invention relates to regulatory DNA sequences containing promotor sequences, in addition to intervening sequences, for the human catalytic telomerase sub-unit gene. The invention also relates to the use of said DNA
sequences for pharmaceutical, diagnostic and therapeutic purposes, especially in the treatment of cancer and ageing.

Description

Le A 32 805-Foreign Countries/ Sto/Kr/Ke/NT
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).

Le A 32 805-Foreign Countries a 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

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 Le A 32 805-Foreign Countries 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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Le A 32 805-Foreign Countries 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 Le A 32 805-Foreign Countries 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.

Le A 32 805-Fore~Qn Countries 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_ Le A 32 805-ForeiQll Countries 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 Le A 32 805-Forei,tm Countries r -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.

Le A 32 805-Foreign Countries 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.
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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.

Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreien Countries 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 Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreign Countries 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 Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreign Countries J

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 Le A 32 805-Foreign Countries r 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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,ri ~ G U 1.~1~ 1~U U U J~ U U U 1~U .~.~
C1. ro tr~U U U J~U 1.iU .1.~U U +~U U
.-. 41 .~ U U b~ CTU 1~ (T1.~1~U U U U 1-c'J W b~ ~ b~ t~U U U CT 1.~CrU J~U ~
U O~ CTtr~ro~ 1.~U 1~ +~a~U 1~1~ b~
M ~ ~ O~ 1~b~ U U U U ~T rol~1~ 1~CT 1~
u1 r0 rob U 1~U t~1~ +~b 1~ U ~ 1~
U U O~ U U U U U b~U c0 t~U b~
J~
J.~
+~
U
1.~
1~
ro U
b~
U
1~
CT
U
ro +~

J ~' Le A 32 805-Foreign Countries Tab. 2 Factors Location in intron 2 CRE.2 2749 S 1 2378, 4094, 4526, 4787, 4835, 4995 AP-2 CS4 2213, 3699, 4667, 5878, 5938, 6059, 6180, AP-2 CS5 5350, 5798, 5880, 5940, 6061, 6182, 6375, PEA3 934, 2505 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, 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 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 CDEI 106, 1564, 1606, 1690, 1732, 1816, 1900, Le A 32 805-Foreign Countries 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 Le A 32 805-Foreign Countries 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 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.

~

Le A 32 805-Foreign Countries 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.~.

. CA 02316282 2000-06-21 Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreign Countries 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

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 (>

Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreign Countries Contigl:

AAGAGTTCAA ACGCCAGCCT
GGCTACGGTG

AAAAAAAAAA TCTTCTCTGG

CAAGAGGAAT ATGAAAATTA

AATGAAGAAA TTTATTTAAG

ACCCACGGTA GAAGGAAGTT

AGAAAAGCCA TAATCCCAGC

TGAGGTCAGG AACACAGAGA

GCTGGGCATG CAGCTACTCG

CAGGAGGTGG TGCGCCATTG

CTGTCTCAAG ACTTAAAAAT

AAAAGCAAGA GTAAAAGAAA

TGAAACTGAA AACAAAATTA

TTGACAAACC AGGAAAGAAG

ATAAAGTCAGAGATGAAAAA CAACTGATACCACAGAAATT .CTAGAGGCTA980 AGAGACATTA CAAAGGATCA

ATAAATTGAA AATTCCTAGA

AGAAATCCAA AATAATGGGA

AGAGAAGCCC CTGGATTTTA

CCTACTCAAA AAGAATACTT

CTGATTCCAA AAAACAAACA

GGCCAATATC AAATCCTCAA

CCTTCGAAAG GGGATTTATT

AAATCAATCA AAAATGAAGT

CAGAAAAAGC CTTCATGATA

ACATACAGGC TGCGATCCCA

CTTGGGCCCA GCAACAAAAT

AAATTAGCCA TAGTCCCAGC

TAAGCCTAGG CATGAACATG

O AGACCCCACT AGAAGGGAGA

AGGAGGTGGA GGAAGGGAAA

F~GAAACATATTTCAACATA TATATGACAGACCGAGGTAG AAAAACTGAA2100 ATAAAAGCCC TATTATGAGG

GAAAATGACA TGAT'rCAACA

GATAAGAGAA CTGGAAAGGA

S ATGATCTTAT ACCACTAAAA

GATACAAAAT TATTTCTATA

CAAAAAAGCA GCTAGGAATT

AAACTATAAA AGAGGGCACA

TTGGAAGAAT TACTACCCAA

TAAAATACTA AGAAGAAACA

TTGTACAGAACCACAAAAGA CCAAAGCTATCCTGACCAAA CTGGAAGCAT2%30 CCCAGAATAG AAGAACAAAA

TATACTACAA CATGGTACTG

GAACAGAATA ATGCATCTAC

AACATACTTT AATAAATGGT

S TAACAATACT ATACAAAAGC

AAACCTCAAA AACACCGGAG

ACTTCTTGAG CAACCAAAGC

AAAAAGCTTC CAACAAAGAG

TTTGCAAACT ATAACCAGTA

O AAAACACCTA AAGCAAAAGA

ACAAATGGCA CTCAACACCA

ACTATGAGAG ATGGCTTTTA

GAGGATGTGG ACTGTTGGTG

AGTTTGAAAG AAAGCTACCA

S CAAAAAAGGG ATCTCCACTC

CCAAGGTTTG CAACAGACGA

AATGGAGTAC TGAGATCCTG

AGTATGTTAA AAAGACAAAC

AAAATTAAAA GAGAATGGTG

E)O GGTGGGGGACAGGGTGACTA TAATTTATTGTATGTTTTAA AGAGTATAAT4060 GAGT.CAACAA AATAACTAAA

GAAAGGATAA CCCCATTTAC

GTATCAAAAT ATAAACCCTA

GGCACGGTGG ACTTTGGGAG

GTGGATCACCTGAGGTCAGG CAGTCTGGCCACCATGATGA ~TACTAAAGA4390 AGTTTGAAAC AACCCTGTCT

GGTGGCACAT AGGAGGCTGA

GAGGTTGCAG GCACTGCAGC

ACAAAAACAA TAATTTTTAT

AGAAGTTAAA GTAATTAACC

GGGTTTCTAG ATGGCCACGA

GTTACTGTTG TAAGTGACTT

TAAAGAGGCA CTGCTAATA.~

TAATCTCTATTAATTACCAA TATCTCTAAAATCGAGCTGC ~GTCTGATCA9900 TAATTACAG:. AGAATTGGC=, TGCTTTTTTT CGATTGTGTG

ATCCTGAAAC TCCAGAAGA
=.

75 TGGCAGGAAGCAGGTGGCTC AGCCACTTCA. 1AGACCCAGG5110 TGTGGACCTG ATCTTCAAGG
GTCTCTGGC~

Le A 32 805-Foreign Countries AAGCCTGCCT

TGGCT'GGGGGCGGACAGCGACGGCGGGATTCAAAGACTTAATTCCATGAGTAAATTCAACCTTTCCACAT5740 ACGTAGCTCGCACGGTTCCTCCTCACATGG'GGTGTCTGTCTCCTTCCCCAACACTCACATGCGTTGAAGG6790 )O CCCGCCCTTCTCTGCCCAGCACTTTCCTGCCCCCCTCCCTCTGGAACACAGAGTGGCAGTTTCCACAAGC7210 CACGTGACTACGCACATCATGTACACACTCCCGTCCACGACCGACCCCCGCTGTTTTATTTTA~1TAGCTA7350 .~S GAGTCAAAACTGCCACCTCCATGGGATACGTACGCAACATGCTCAAAAAGAAAGAATTTCACCCCATGGC7560 AAGCCAGTTTCCTGGTTCTGATGGTATTGGCTCAGTTATGGGAGACT_AACCATAGGGGAGTGGGGATGGG7700 O

O

S

GCTTACTGCAGCCTCTGCCTCCCAGGTTCAAGTGATTCTCCTGCTTCCGCCTCCCATT'rGGCTGGGATTA9290 GATTACAGGTGTGAGCCACCATGCCCAGCTCAG~.ATTTACTCTGTTTAGAAACATCTGGGTCTGAGGTAG9950 GAAGCTCACCCCACTCAAGTGTTGTGGTGTTTT:.nGCCAATGATAGAATTTTTTTATTGTTGTTAGAACA9520 GGTGTTAATTACTCCAGCATAATCTTCTGCTTCCi:TTTCTTCTCTTCCCTCTTTTAAA.ATTGTGTTTTCT9730 GCCCCTTTGCCCTAGTGGCAGAGACi-~ATTCACT;?.i:CACAGCCCTTTAAAAAGGCTTAGGGATCACTAAGG9870 GCCCAGGGAGGGTGCGAGGCCTGTTCAAATGCT=.GCTCCATAAATAAAGCAATTTCCTCCGGCAGTTTCT10010 GAAAGTAGGAAAGGTTACATTTAAGGTTGCGTT'_GTTAGCATTTCAGTGT.TTGCCGACCTCAGCTACAGC10080 ACAGAGTGCCGGGGCCCAGGGTCA.yGG'CCGTTGTGGCTGGTGTGAGGCGCCCGGTGCGCGGCCAGCAGGA10430 GCGCCTGGCTCCATTTCCCACCCTT'"CTCGACGGGACCGCCCCGGTGGGTGATTAACAGATTTGGGGTGG10500 TTTGCTCATGGTGGGGACCCCTCGCCGCCTGAGAACCTG::AAAGAGAAATGACGGGCCTGTGTCAAGGAG10570 Le A 32 805-Foreign Countries S

IO

GCG_ATGCCGCGCGCTCCCCGCTGCCGAGCCGTGCGCTCCCTGCTGCGCAGCCACTACCGCGAGGTGCTGC11390 IS

S

O

S

'~S

S

O

JS

GO

E)S

TCTTGGTCACCTCTC~GTTCCATTTTGCT;CGGGGACACGGGACTGCAGGCTCTCGCCTCCCGCGTGCCA15260 CTGCCACGTGTTGCTGGAGACATCCCAGA."1AGGGTTCTCTGTGCCCTGAAGGAAAGCAAGTCACCCCAGC15970 TCACCTTATTCTGGGCACCTGCCGCTCATTGCTTAGGCTGGGCTCTGCCTCCAGTCGCCCC~TCACATGG'5610 GTCTCCGCCAGCCTTCGTCAGACTTCCCT~TTGGGTCTTAGTTTTGAATTTCACTGATTTACCTCTGACG15750 TTTCTATCTCTCCATTGTATGCTTTTTCT"GGTTTATTCTTTCATTCCTTTTCTAGCTTC':'TAGTTTAGT.5820 CATGCCTTTCCCTCT.-",AGTGCTGCCTTAC~TGCPCCCTGTGTTTTGATGTGAAGTAATCTCAACATCAGC15890 CACTTTCAAGTGTTC'~TAAAATACTTCAAAGTGTTAATACTTCTTTTAAGTATTCTTATTCTGTGATTTT'_590'0 TTTCTTTGTGCACGCTGTGTTTTGACGTG:1AATCATTTTGATATCAGTGACTTTTAAGTAT;CTTTAG~".'10030 Le A 32 808-Foreign Countries AAGATATGTA

S

IO

IS

TGACTTAGTTCTATCTCAGGCATCTTGACA'CCCCCACAAGCTAAGCATTATTAATATTGTTTTCCGTGTT17710 G

TGTTTCT

O

JS
TGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATTGCTTGAACC'TGGGAGTTGGAAGTTGCAGTGA18980 S
O

SS

GO

C)S

GTGCAGGTCCGGGGTGAGGTAGCCAAGGCCTTCGGTGAGCTGGATGTGGGGTGTCCGGA"'GGTGCAGGTC20650 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

Le A 32 805-Foreign Countries GGGTGAGGTC CGGTGATCTG

S

IO

IS

O

S

S
O

SS

GGTGTGTGTGGCCCCTTGGCCTTr~CTCCTTCCTCCTCCAGGCATGGTCCGCACCATTGTCCTCACGCTCT25970 C)S

GGGCTGGGCCTTGGAGACTGTA.;~CC.aGGTTTGAGAGGAGAGTAGGGATGCTGGTGGTACCTTCCTGGAC26110 CCCTGGCACCCCCAGGACCCC~~TCTGG~CTATGCCGGCTCCATGAGATATAGGAAGGCTGATTCAGGCC26180 GGGTGCAGAGGTGAAGAAGTAT~~CCT~Ga,GCTTCGGTCTGGGGAGAGGCACATGTGGAAACCCACAAGGA26390 CCTCTTTCTCTGACTTCTTGA.~__ 26419 Le A 32 805-Foreign Countries Contig 2:

TGGGGATCTG TTTTATGAGT

S

AATTCCCCTG

IO

IS

TCTCAGATCAGCAGTGGCATGCi;GTGCTCAGAGGCGCACACACCCTACTGAGAACTGTGCGTGAGAGGGG1190 O

TGAGTCCAGAATAATTACGGATTTCTGTGA.TGCTTTCCGCCGACCTCAGACCCATGGGCTATTTGTGGGC1470 O

TGGTGAC'TGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG2290 S

TGTGTGG'PGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2450 GTCGivGv'GTCTGATGTGTGGTGACTGTGGATGGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTG2660 S

S
O

SS

CGACAGCTGCTGCATTCAGGCACCTGCTCACGTT.TGACTGCGCGGCCTCTCTCCAGTTCCGCAGTGCCTT913J

C
J

TGCAGATGCCTGTTAGCACTTGCTCGGCTCTAGGGGACAGTCGTGTCCACCGCATGAGGCTCAGAGACCT448:7 CTGGGCGAATTTCCTTGGCTCCCAGGGTGGGGGTGGAGGTGGCCTGGGCTGCTGGGACCCAGACCCTGTG455) CCCGGCAGCTGGGCAGCAACTCCTGGATCACATATGCCATCCGGGCCACGGTGGGCTGTGTGGGTGTGAG46~J

CTGCAGAGACTCGGCCCGGCCAGCCCACGATGGCCCTGCATTCCAGCCCAGCCCCGCACTTCATCACi-_i,A970 CACTGACCCC GAGGGTCTTGGCCACGTGGTCCTGCCTGTCTCAGCACCCACCGGCTCACT983;
AAAAGGGACG

CCCATGTGTC TTTCGCAGAGCTCC':CCCTG GCAGTGGCCTCTTCGACGTC49CJ
TCCCGTCTGC AATGAGGCCA

TTCCTACGCT CCACGCCGTGCGCATCAGGGGCAAGTGAGTCAGGTGGCCAGGTGCCATTG99,7 TCATGTGCCA

CCCTGCGGGT
GCTGGCAGGGCT.TC'_"GC':CACCTCTCTCCTGCCCC:'TCCCCACTGtICC'.".'S04J
GGCTGGGCGG

7J CCACCAGe'~GT v CCCCCGCC
CCCTCCGGCT

GGCCCCGGAA GCTTGCGGCAGCCGGAGCGG ACACGAGGCCTGGAAAT~~~C518J
ACATGGCTCG AGCAGGTGCC

P.AGCGGGGTG CCTGCGTGGAGGACGA~GGG GTCTGGGTCA~GTGTGC;~~~-.5:' TGGAGTTGCT CGGGGGGTGT

Le A 32 805-Foreign Countries AAGTTACTAC

AAAAGGATTT

S

IO

IS A

AGGGTCGCGTGGCAGCCATGCCTTCTGTG'I'GCACCTTTAGGTTCCACGGGGCTATTCTGCTCTCACTGTT6930 O

S

~TTAGTTACATATGTATACATGTGCCATGTTGGTGTGCTGCACCCATTAACTCATCATTTACATTAGGTA8190 TATC.TCCTAATGCTATCCCTCCCCACTCCCCCCATCCCATGACAGGCCCTGGTGTGTGATGTTCCCCACC8260 4S ' TGCAATAG

T'rCTAGTTCTAGATCCTTGAGGAATCACCACACTGTCTTCCACAATGGTTGAACTAGTTTACACTCCCAC8680 S
O

S
S

CTTCCTGTGGATAGGATCTGGGTCTCGGATCATGCTGAGGACCACAGCTGCCATGCTGGTAAAGGGCACC91'70 AA

GACATTCAGTCCCTCGTAGACAGATACTACGTA.a.AAAGTGTAAAGTTAACCTTGCTGTGTATTTTCCCTT9520 GS

ACCGTGCAGGCCCTGGTCCTG~AGAGACGCACCC.=,GGTTACACACGTGGTGAGTGCA~GGCGGTGACCTGG9370 CTCCTGCTGCTCTTTGGAAAG'."CAAG-~,GT_GGCGGCT~CTGGGGCCCCAGTGAGACCC:CAGGAGCTGTGC9940 GCTGAGTGAGCTGGCCCACAGCGTTCGCTGCGGT~~ACGT'"CCTGCGTGGGGTTGTTT.GGGATCGGTGGGA10080 GAATTTGGATTTGCTGAGTGCTGCTGTCTTGAS-.~_.=~CGGi,GATGGCTAGGAGTGGGTT.TCAGAGTTGATT10150 TTTGTGAATCAAACTAAAATC~GGC=,~=;GGGGA~~TGGC~TCAGCACAGGGGATTGTC~AATGTGGTCCC1220 CCTCAAGGGCGCCCCACAGAG;CGGT;>GGCTTGTT:'TAA~"-,GTGCGATTTGACGAGGGACGAGAAACCTTG1;7290 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~~

Le A 32 805-Forei~~n Countries TGGCCACAGG GAGCTGGGAA TGCACCAGGG GAGCTGCGCA GCTGGCCGAG

GAAGGGCAGG GGGACGCCCG GGGCCACAGC AGAGGCCGCA GGAAGGGAAG

GACTCGGCGA GGGAACCTCC

S CCCGCGCCTG AGCAGGAACT

GGAGAAAACA GGCAAAGTCG

TTTTAGTCTG CCCCGGACCA

GGACCATCAC AGAGGCCACT

TCTTGCATGC TCACCTACCT

IO GTCCAGGCTC CTCAGAGCTC

AAAGCATTTA ACAAGGGTGT

TCTGCCTTAG GACCCTGGTC

GAACTTCCCT GTAGAAGACG

CCCTGGTGCG GCCTGCTGCT

TGGCCGGAAG TGGAGCCTGT

CCGTGTGGGG CAGGCGACTG

CTGAGCAGAA ATGCATCTTT

GTAAAAGGAA ATGGTGCACC

AAGACGCCCG GGCCCTGCTG

TGGGCGTGAG TCTCTCCGCT

TCATGATCAC GTGTGACCCA

CTTGTTTCCC CAGAGCCCGA

ACAGATGCAG AAATCTGTGC

S

CAACCTAACC AACATAGTGA

ACGCCTGTAG TCCCCGCTAT

AGTGAGCCGA GATCACACCA

AAAAAGTATC AGCATTCCAA

O

AGTGGTGAAT GGTTGTTAAA

GGACTTTGCC TCTTTCCAGA

GTGATGGGGG AGCAGCAGGT

GGTGCCCAGC ATGTCCCTGT

S

TGGGCTCCCA GCACCTCTTC

TGTCCACTGC TTATTTTGCT

CACAGCATCA GTGAATGTTA

ACACATTGCA AAGCCACAGA

CAGAATATTC TGTGCTCCCA

GCAGTGGAGG CAGTGGTTCG

GCTTGAAGGG CATCTGGGAG

A.AGAAAACAG GCAAAATGAT TAAGAAAAGT GAAAAAGGAA AAGTGGTAAG13650 ATGGGAATTT TCTTGTCCAG

ATGGACAGAA CAATAGAACA

GTCTTTACAG CATATACCAG

AAATAAAACA AAAGACTCAA

GGGAGGCGGA TGAAACCAGT

ACAGTGAAAA TGGCCATTCC

S ACATTCATCC TCTCACTTTG
O

CGCCCTTGGT CACCCAGCTG

TCTGCCCGAG GACCCCACAC

GATGGCTGTG AAAGAAGAAA

TGCATGTGAA ACTGACAGCG

SS CCATCCCTCA TGCTGG~:.''::C

CTTTTCTGGA AAGCAGCTTG

CTGAAGTGAC CAGACATTAT

AGCAAGTCAC GAACCTGCCC

AAACATTTTT CAAAGAATTT

AAAGCTGGAT GTAAAAGAAC

GACATAC~~-.TG GGCAGTGAGT

TGGAGACACC ATGTGTGCCA

CCTGAGAT'.".~ AAACACAGTG

CCTGTGTTCA CTCGAGGG-iC

6S GTGCAGATCT CATCAGG~CA

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

TGTGTCTCAG CTATGC~~~G

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

GAGGCTCTW, AGCTGC,:;;C

CTGAGGGCAT TGT~CCATCT GGGCATCCGC GTCCACTCCC TCTC~TGTGG16100 GCTTCTG'."_~." CCACT~'::"~

TCTCCTGTGG GCATT"'ACAT Ci:~CTCU yCT CCCTCTCTCC TGTG~;;CATC16170 CGCGTCCa,::' CCCCC:'~.":'."

Le A 32 805-Foreign Countries GTGGGCATCTGCGTCCACCTCCCCTCTCTG CTCTCCTGGT
TGGGCATTTG TCCTTCCTGT

CTTGGCCGAGCCTCGGGGGCAGGCAGATGA TGACTCGCCCAGGGTGGTTC
CACAGAGTCT GCAGCTGCCG

GGTGAGGGCCAGGCCGGATTTCACTGGGAA TTCTTGTCAAAATGTTCCTC
GAGGGATAGT TTTCTTGTTC

S AAACTTAAAA TTTCTCACTC
TCCCAGAGAG

TTTCTTGGCGACTCTAGGTGAACAGCCTCC CACCAACATCTACAAGATCCTCCTGCTGCA

CAGGCCCAGC

GGTTTTAGGG

IO

IS

GTGAGC'rGAGATTGCACCACTGTACTGCAGCCTGGGTGACAGAGTGAGAGCCCATCTCAACAACAACAAA19110 GAAGACTGACAAATGCAGTTTCTTGGAAAGAAACATTTAGTAGGAACTTAACCTACACArAGAAGCCAAG19180 GA.~1GGGCAGGATTCATGATAAGTACCTGCTGGTACACAAGGAACAATGGATAAACTGGAAACCTTAGAGG19390 SO

SS

GO

GS

GTGTCACCTACGTGCCACTCCTGGGGTCACTCAGGACA~~CAAGTGTGGGTGGAGGCCAGTGCGGGCCCC20790 ACCTGCCCAGGGGTCATCCTTGAACGCCCTGTGTGGGG(';AGCAGCCTC~-.GATGCTGCTGAAGTGCAGAC20860 GCCCCCGGGCCTGACCCTGGGGGCCTGGAGCCACGCTG,~AGCCCTATGTGATTAAACGCTGGTGTCCCC20930 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

Le A 32 805-Foreign Countries S

lO

IS

S

TGAATCACAGACCAACaGGTCAGGCCATTGTTCAGCTATCCATCTTCTACAAAGCTCCAGATTCCTGTTT23520 O

~
S

ACAAGCGTGTATGGAGCGAGTGAGTTCAAAGCAGAAAGGGAGGAGAAGCAGGCAAGGGTGGAGGCTGTGG'9930 _ JO

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 Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreign Countries 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:

Le A 32 80S-Foreign Countries 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

ATGTAAGACTTCCGGCCATGCAGACAAGGAGGGTGACCTTCTTGGGGCTCTTTTTTTTCTTTTTTTCTTTTTATGGTGG
C
AAAAGTCATATAACATGAGATTGGCACTCCTAACACCGTTTTCTGTGTACAGTGCAGAATTGCTAACTCGGCGGTGTTT
A
CAGCAGGTTGCTTGAAATGCTGCGTCTTGCGTGAC'iGGAAGTCCCTACCCATCGAACGGCAGCTGCCTCACACCTGCT
GC
GGCTCAGGTGGACCACGCCGAGTCAGATAAGCGTCATGCAACCCAGTTTTGC'TTTTTGTGCTCCAGCTTCCTTCGTTG
AG
GAGAGTTTGAGTTCTCTGATCAGGACTCTGCCTGTCATTGCTGTTCTCTGACTTCAGATGAGGTCACAATCTGCCCCTG
G

CTTATGCAGGGAGTGAGGCGTGGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGTTGCCCCCAGGTGTCCC
T
GTCACGTGTAGGGTGAGTGAGGCGCGGCCCCCGGGTGTCCCTGTCCCGTGCAGCGTGATTGAGGTGTGGCCCCCGGGTG
T
CCCTGTCACGTGTAGGGTGAGTGAGGCGCCATCCCCGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCGTGGTCCCCG
G
GTGTCCCTGTCCCGTGCAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGCGGTC
C
CCGGGTGTCCCTCTCAGGTGTAGGGTGAGTGAGGCGCGGCCCCAGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCAC
C

GTCCCTGGGTGTCCCTCCCAGGTATAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAG
G
CGCGGCCCCCGGGTGTCCCTCTCAGGTGCAGGGTGAGTGAGGCGCTGTCCCTGGGTGTCCCTGTCTCGTGTAGGGTGAG
T
GAGGCTCTGTCCCCAGGTGTCCTTGGCGTTTGCTCACTTGAGCTTGCTCCTGAATGTTTGCTCTTTCTATAGCCACAGC
T
GCGCCGGTTGCCCATTGCCTGGGTAGATGGTGCAGGCGCAGTGCTGGTCCCCAAGCCTATCTTTTCTGATGCTCGGCTC
T
TCTTGGTCACCTCTCCGTTCCATTTTGCTACGGGGACACGGGACTGCAGGCTCTCGCCTCCCGCGTGCCAGGCACTGCA
G

CCACAGCTTCAGGTCCGCTTGCCTCTGTTGGGCCTGGCTTGCTCACCACGTGCCCGCCACATGCATGCTGCCAATACTC
C
TCTCCCAGCTTGTCTCATGCCGAGGCTGGACTCTGGGCTGCCTGTGTCTGCTGCCACGTGTTGCTGGAGACATCCCAGA
A
AGGGTTCTCTGTGCCCTGAAGGAAAGCAAGTCACCCCAGCCCCCTCACTTGTCCTGTTTTCTCCCAAGCTGCCCCTCTG
C
TTGGCCCCCTTGGGTGGGTGGCAACGCTTGTCACCTTATTCTGGGCACCTGCCGCTCATTGCTTAGGCTGGGCTCTGCC
T
CCAGTCGCCCCCTCACATGGATTGACGTCCAGCCACAGGTTGGAGTGTCTCTGTCTGTCTCCTGCTCTGAGACCCACGT
G

GAGGGCCGGTGTCTCCGCCAGCCTTCGTCAGACTTCCCTCTTGGGTCTTAGTTTTGAATTTCACTGATTTACCTCTGAC
G
TTTCTATCTCTCCATTGTATGCTTTTTCTTGGTTTATTCTTTCATTCCTTTTCTAGC'TTCTTAGTTTAGTCATGCCTT
TC
CCTCTAAGTGCTGCCTTACCTGCACCCTGTGTTTTGATGTGAAGTAATCTCAACATCAGCCACTTTCAAGTGTTCTTAA
A
ATACTTCAAAGTGTTAATACTTCTTTTAAGTATTCTTATTCTGTGATTTTTTTCTTTGTGCACGCTGTGTTTTGACGTG
A
AATCATTTTGATATCAGTGACTTTTAAGTATTCTTTAGCTTATTCTGTGATTTCTTTGAGCAGTGAGTTATTTGAACAC
T

GTTTATGTTCAAGATATGTAGAGTATCAAGATACGTAGAGTATTTTAAGTTATCATTTTATTATTGATTTCTAACTCAG
T
TGTGTAGTGGTCTGTATAATACCAATTATTTGAAGTTTGCGGAGCCTTGCTTTGTGATCTAGTGTGTGCATGGTTTCCA
G
AACTGTCCATTGTAAATTTGACATCCTGTCAATAGTGGGCATGCATGTTCACTATATCCAGCTTATTAAGGTCCAGTGC
A

Le A 32 80S-Foreign Countries 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

TGGCCAGGCTGGTCTCAAACTCCTGACCTCAAGTGATCTGCCCGCCTTGGCCTCCCACAGTGCTGGGATTACAGGTGCA
A
GCCACCGTGCCCGGCATACCTTGATCTTTTAAAATGAAGTCTGAAACATTGCTACCCTTGTCCTGAGCAATAAGACCCT
T
AGTGTATTTTAGCTCTGGCCACCCCCCAGCCTGTGTGCTGTTTTCCCTGCTGACTTAGTTCTATCTCAGGCATCTTGAC
A
CCCCCACAAGCTAAGCATTATTAATATTGTTTTCCGTGTTGAGTGTTTCTGTAGCTTTGCCCCCGCCCTGCTTTTCCTC
C
T'_TTGTTCCCCGTCTGTCTTCTGTCTCAGGCCCGCCGTCTGGGGTCCCCTTCCTTGTCCTTTGCGTGGTTCTTCTGTC
TTG

TTATTGCTGGTAAACCCCAGCTTTACCTGTGCTGGCCTCCATGGCA'rCTAGCGACGTCCGGGGACCTCTGCTTATGAT
GC
.?CAGATGAAGATGTGGAGACTCACGAGGAGGGCGGTCATCTTGGCCCGTGAGTGTCTGGAGCACCACGTGGCCAGCGT
TC
CTTAGCCAGTGAGTGACAGCAACGTCCGC'TCGGCCTGGGTTCAGCCTGG.~AAACCCCAGGCATGTCGGGGTCTGGTG
GCT
CCGCGGTGTCGAGTTTGAAATCGCGCAAACCTGCGGTGTGGCGCCAGCTCTGACGGTGCTGCCTGGCGGGGGAGTGTCT
G
CTTCCTCCCTTCTGCTTGGGAACCAGGACAAAGGATGAGGCTCCGAGCCGTTGTCGCCCAACAGGAGCATGACGTGAGC
C

ATGTGGATAATTTTAAAATTTCTAGGCTGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCGG
G
TGGATCACGAGGTCAGGAGGTCGAGACCATCCTGGCCAACATGATGAAACCCCATCTGTACTAAAAACACAAAAATTAG
C
TGGGCGTGGTGGCGGGTGCCTGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATTGCTTGAACCTGGGAGTTGGA
A
GTTGCAGTGAGCCGACATTGCACCACTGCACTCCAGCCTGGCAACACAGCGAGACTCTGTCTCP~~4AAAAAAAAAApA
AA
AAAAAAAAAAAATTCTAGTAGCCACATTAAAAAAGTAAAAAAGAAAAGGTGAAATTAATGTAATAATAGATTTTACTGA
A

GCCCAGCATGTCCACACCTCATCATTTTAGGGTGTTATTGGTGGGAGCATCACTCACAGGACATTTGACATTTTTTGAG
C
TTTGTCTGCGGGATCCCGTGTGTAGGTCCCGTGCGTGGCCATCTCGGCCTGGACCTGCTGGGCTTCCCATGGCCATGGC
T
GTTGTACCAGATGGTGCAGGTCCGGGATGAGGTCGCCAGGCCCTCAGTGAGCTGGATGTGCAGTGTCCGGATGGTGCAC
G
TCTGGGATGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCA
G
GCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGAT
G

TGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTAAGCTGGAGGTATGGAGTCCGGATGATGC
A
GGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGGGTGAGGTCAC
C
AGGCCCTGCGGTGAGCTGGGTGTGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGACGGTGCCAGACCATG
C
GGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTTGCCAGGCCCTGCTGTGAGTTGGATGTGGGG
T
GTCCGGATGCTGCAGGTCCGGTGTGAGGTCACCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTC
T

GGGGTGAAGGTCGCCAGGCCCCTGCTTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCA
G
GCCCTCGGTGAGCTGGATGTGCAGTGTCCAGATGGTGCAGGTCCGGGGTGAGGTCGCCAGACCCTGCGGTGAGCTGGAT
G
TGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGGCCCTCGGTGAGCTGGATGTATGGAGTCCGGATGGTGC
C
GGTCCGGGGTGAGGTCGCCAGACCCTGCTGTGAGCTGGATGTGCGGTGTCTGGATGGTACAGGTCTGGAGTGAGGTCGC
C
AGACCCTGCTGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTGAGCTGG
A

GGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAACTGGATGTGCGGCGTCTGGATGG
T
GCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTC
G
CCAGGCCCTGCTGTGAGCTGGATGTGCGGCGTCTGGATGGTGCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCT
G

Le A 32 $OS-Foreien Countries 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

AAGCAGAAGGGATTTAAATTAGATGGAAACACTACCACTAGCCTCCTTGCCTTTCCCTGGGATGTGGGTCTGATTCTCT
C
i'CTCTTTTTTTTTTCTTTTTTGAGATGGAGTCTCACTCTGTTGCCCAGGCTGGAGTGCAGTGGCATAATCTTGGCTCA
CT
GCAACCTCCACCTCCTGGGTTTAAGCGATTCACCAGCCTCAGCCTCCTAAGTAGCTGGGATTACAGGCACCTGCCACCA
C
GCCTGGCTAATTTTTGTACTTTTAGGAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACTCATGACCTCAG
G
TGATCCACCCACCTTGGCCTCCCAAAGTGCTGGGTTTACAGGCTAAGCCACCGTGCCCAGCCCCCGATTCTCTTTTAAT
T

CATGCTGTTCTGTATGAATCTTCAATCTATTGGATTTAGGTCATGAGAGGATAAAATCCCACCCACTTGGCGACTCACT
G
CAGGGAGCACCTGTGCAGGGAGCACCTGGGGATAGGAGAGTTCCACCATGAGCTAACTTCTAGGTGGCTGCATTTGAAT
G
GCTGTGAGATTTTGTCTGCAATGTTCGGCTGATGAGAGTGTGAGATTGTGACAGATTCAAGCTGGATTTGCATCAGTGA
G
GGACGGGAGCGCTGGTCTGGGAGATGCCAGCCTGGCTGAGCCCAGGCCATGGTATTAGCTTCTCCGTGTCCCGCCCAGG
C
TGACTGTGGAGGGCTTTAGTCAGAAGATCAGGGCTTCCCCAGCTCCCCTGCACACTCGAGTCCCTGGGGGGCCTTGTGA
C

ACCCCATGCCCCAAATCAGGATGTCTGCAGAGGGAGCTGGCAGCAGACCTCGTCAGAGGTAACACAGCCTCTGGGCTGG
G
GACCCCGACGTGGTGCTGGGGCCATTTCCTTGCATCTGGGGGAGGGTCAGGGCTTTCCCTGTGGGAACAAGTTAATACA
C
AATGCACCTTACTTAGACTTTACACGTATTTAATGGTGTGCGACCCAACATGGTCATTTGACCAGTATTTTGGAAAGAA
T
TTAATTGGGGTGACCGGAAGGAGCAGACAGACGTGGTGGTCCCCAAGATGCTCCTTGTCACTACTGGGACTGTTGTTCT
G
CCTGGGGGGCCTTGGAGGCCCCTCCTCCCTGGACAGGGTACCGTGCCTTTTCTACTCTGCTGGGCCTGCGGCCTGCGGT
C

AGGGCACCAGCTCCGGAGCACCCGCGGCCCCAGTGTCCACGGAGTGCCAGGCTGTCAGCCACAGATGCCCAGGTCCAGG
T
GTGGCCGCTCCAGCCCCCGTGCCCCCATGGGTGGTTTTGGGGGAAAAGGCCAAGGGCAGAGGTGTCAGGAGACTGGTGG
G
CTCATGAGAGCTGATTCTGCTCCTTGGCTGAGCTGCCCTGAGCAGCCTCTCCCGCCCTCTCCATCTGAAGGGATGTGGC
T
CTTTCTACCTGGGGGTCCTGCCTGGGGCCAG~~TTGGGCTACCCCAGTGGCTGTACCAGAGGGACAGGCATCCTGTGTG
G
AGGGGCATGGGTTCACGTGGCCCCAGATGCAGCCTGGGACCAGGCTCCCTGGTGCTGATGGTGGGACAGTCACCCTGGG
G

GTTGACCGCCGGACTGGGCGTCCCCAGGGTTGACTATAGGACCAGGTGTCCAGGTGCCCTGCAAGTAGAGGGGCTCTCA
G
AGGCGTCTGGCTGGCATGGGTGGACGTGGCCCCGGGCATGGCCTTCAGCGTGTGCTGCCGTGGGTGCCCTGAGCCCTCA
C
TGAGTCGGTGGGGGCTTGTGGCTTCCCGTGAGCTTCCCCCTAGTCTGTTGTCTGGCTGAGCAAGCCTCCTGAGGGGCTC
T
CTATTGCAG

Le A 32 80S-Foreign Countries 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

GGGACACACTCCTCCCAGAGCGGCCGGGGGCCTTGGGGCTCGGCAGGGGTGAAAGGGGCCCTGGGCTTGGGTTCCCACC
C
AGTGGTCATGAGCACGCTGGAGGGGTAAGCCCTCAAAGTCGTGCCAGGCCGGGGTGCAGAGGTGAAGAAGTATCCCTGG
A
GCTTCGGTCTGGGGAGAGGCACATGTGGAAACCCACAAGGACCTCTTTCTCTGACTTCTTGAGCT
3'-region intron 6 (SEQ ID NO 10) 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

Le A 32 805-Forei~ountries 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

GTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATG
G
CGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTC
A
CAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACA
G
GGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTTGGTCCCGGGG
G
TCTGATGTGTGGTGACTGTGGATGGCGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTC
T

GATGTGTGG'rGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTG
GT
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGA
T
GGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCA
G
TCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGG
G
TCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG
T

GGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGG
T
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGA
T
GGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTAGGGTCTGATGTGTGGTGACTGTGGATGGCAGTC
G
GTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTG
G
GGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA
T

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

Le A 32 805-Forei~~n Countries 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

GTCTCCAGCGGATAAAGGACTGTGCACAGCTTCGGAAGCTTTTATTT_~1AAAATATAACTATTAATTATTGCATTATA
AGT
AATCACTAATGGTATCAGCAATTATAATATTTATTAAAGTATAAT'rAGAAATATTAAGTAGTACACACGTTCTGGAAA
AA
CACAAATTGCACATGGCAGCAGAGTGAATTTTGGCCGAGGGACACGTGTGCACATGTGTGTAAGCGGCCCCCAGGCCCA
C
AGAATTCGCTGACAAAGTCACCTCCCCAGAGAAGCCACCACGGGCCTCCTTCGTGGTCGTGAATTTTATTAAGATGGAT
C
AAGTCACGTACCGTCCACGTGTGGCAGGGCTTTGGGGAATGTGAGGTGATGACTGCGTCCTCATGCCCTGACAGACAGG
A

GGTGACUGTGTCTGTCCTGTCCCTAGGACACGGACAGGCCCGAAGCTCTAGTCCCCATCGTGGTCCAGTTTGGCCTCTG
A
ATAAAAACGTCTTCAAAACCTGTTGCCCCAAAAACTAAGAACAGAGAGAGTTTCCCATCCCATGTGCTCACAGGGGCGT
A
TCTGCTTGCGTrGACTCGCTGGGCTGGCCGGACTCCTAGAGTTGGTGCGTGTGCTTCTGTGCAAAAAGTGCAGTCCTCT
T
GCCCATCACTGTGATATCTGCACCAGCAAGGAAAGCCTCTTTTCTTTTCTTTCTTTTTTTTTTTTTGAGACGGAACGTC
A
CTGTTGTCTGCCTGGGCTTGAGTGCAGTGGCGCGATCTCAACTCACTGCAACCTCCGCCTCCCGGGTTCCAGCATTTCT
C

CTGCCTCAGCCTCCCGAGCAGCTGAGATTACAGGCACCCACCCCCTGCGCCTGGCTAATTTTTGTATTTTTAGTAGAGA
G
GGGTTTTTGCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCACCCACCTCGGCCTCCCAAAGTGCT
G
GGATTACAGGTGTGAGCCATCACGCCCAGCCGGAA_AGCCTCTTTTTAAGGTGACCACCTATAGCGCTTCCCGAAAATA
AC
AGGTCTTGTTTTTGCAGTAGGCTGCAAGCGTCTCTTAGCAACAGGAGTGGCGTCCTGTGGGCTCTGGGGATGGCTGAGG
G
TCGCGTGGCAGCCATGCCTTCTGTGTGCACCTTTAGGTTCCACGGGGCTATTCTGCTCTCACTGTTTGTCTGAA.~.AC
GCA

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

.'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 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

TGAGACCCCCAGGAGCTGTGCACAGGGCCTGCAGGGCCGAGGCGGCAGCCTCCTCCCCAGGGTGCACCTGAGCCTGCGG
A
GAGCAGGAGCTGCTGAGTGAGCTGGCCCACAGCGTTCGCTGCGGTCACGTTCCTGCGTGGGGTTGTTTGGGATCGGTGG
G
AGAATTTGGATTTGCTGAGTGCTGCTGTCTTGAACCACGGAGATGGCTAGGAGTGGGTTTCAGAGTTGATTTTTGTGAA
T
CAAAC1'AAAATCAGGCACAGGGGACCTGGCCTCAGCACAGGGGATTGTCCAATGTGGTCCCCCTCAAGGGCGCCCCAC
AG
AGCCGGTGGGCTTGTTTTAAAGTGCGATTTGACGAGGGACGAGAAACCTTGAAAGCTGTAAAGGGAACCCTCAGAAAAT
G

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.-';,~

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 :' GCCCCGGACCACAGA"_'GAGTCT:',TAACGGGATTGTG:~'"GTTGCCATGGGGACACAT':'."~GATGGACCATC
ACAGAGGCC=,;
TGGGGCTGCACC'TCC:C=,'"C"'G~, :TCC':GGCTGTCC': ~::C. _CAGGCCAGG'~'TCT'r~..
'°,TGCTCACCTACCTGTCCTGC:C =' Le A 32 805-Foreign Countries 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

GAAGAGAAATAAGTGGTGAATGGTTGTTAAACCAGAGGTTTAAACTGGGGTCCTGTCGTTCTGAGTTAACAGTCCAGAT
C
TGGACTTTGCCTCTTTCCAGAATGCTCCCTGGGGTTTGCTTCATGGGGGAGCAGCAGGTGTGGACACCCTCGTGATGGG
G
GAGCAGCAGGTGCAGACGCCCTCATGATGGGGGAGTGGCAGGTGCAGACACCCTTGTGCATGGTGCCCAGCATGTCCCT
G
TTGCAGCTCCCTCCCCACAAGGATGCCGGTCTCCTGTGCTCCCCACAGTCCCTGCTTCCCTCTCACAGCCTTACCTGGT
C
CTGGCCTCCACTGGCTTTGTCTGCATGATTTCCACATTTCCTGGGCTCCCAGCACCTCTTCGCCTCTCCCAGGCACCTC
T
ZS
GCAGTCCTGGCCATACCAGTCAGCTGTGAACTGTCCACTGCTTATTTTGCTCCCCATGAAATGTATTTTTTAGGACAGG
C
ACCCCTGGTTCCAGCCTCTGGCACAGCATCAGTGAATGTTATTGAAGGACAAAGGACAGACAAACAAATCAGGAAAATG
G
GTTCTCTCTAAACACATTGCAAAGCCACAGAGGCTAGTGCAGGATGGGTGGGCATCAGGTCATCAGATGTGGGTCCAAT
G
CCAGAATATTCTGTGCTCCCAAAGGCCACTTGGTCAGAGTGTGTGCTTGCAGAGGTGGCTCTAAAAGCTCAGCAGTGGA
G
GCAGTGGTTCGCCATACTCAGGGTGAACTCACATCCTCTGTGTCTGAAGTATACAGCAGAGGCTTGAAGGGCATCTGGG
A

GAAGAAAACAGGCAAAATGATTAAGAAAAGTGAAAAAGGAAAAGTGGTAAGATGGGAATTTTCTTGTCCAGATTTTAGT
C
TCCCAAACCACAGCTCAGATGGTAGAATGTGGTCAGAACTGATGGACAGAACAATAGAACAAAACGGAAGCCCTATCTC
T
CAGAAACGTGTGTTAATGTGGTATGTGGCACAGCTGATGGAAAAGAGAGTGTGTGTGTAATTTTTTTTTCTGAGAAAAC
T
GACTGGAAGCAAATAAGTTGTGTCTTTACAGCATATACCAGAGCAGATTCTAGGTAGAAGAGGAGACACATGCAAACAA
C
ACCAGCAACAGAAATAAAACAAA.~1GACTCAAAGGGAAGGGAGGTGAACGTTCCCTGGTTTGGTGTTGGGGAAGGACA
CAC

AGGGAGGCGGATGAAACCAGTGAGGCAACGGGCATTGCTTTCACTGCAGAGAAACTCAGCTTGCCTGAGCCACAGTGAA
A
ATGGCCATTCCCTGGAGCGTTTGTGCACGTGATTTATTTAAGGCGCCCTGTGAGGTCCTGCACATTCATCCTCTCACTT
T
GTTCTCCTAACCACCTGAGAGG'~AGAGGAGG~~vGGCTCC.aGGGGAGCAGCCGCCCTTGGTCACCCAGCTGGCAAAG
GGC
ATGCATGATTGCAGCCTGGCCT~CTGCTCCGGGGCCCTTG~TCTGCCCG:~GGACCCCACACAAGTCAGACCCATAGGC
TC
~GGGTGAGCCGGAGCCCAAGGi~GTGTTGGGGA':GGC':GT~AAAGAAGA_=,ATGGACGTCTGATGCACACTTGGGA
AGGTC

~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

Le A 32 $OS-Foreign Countries 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

?TGGATGATA~'~.AGCAAAAAGTAAAAACTTAAAATCCCAGAGAGGTTTCTACCGTTTCTCACTCTTTCTTGGCGACT
CTAG
Intron 13 (SEQ ID NO 17) GTGAGCCGCCACCAAGGGGT~CAGGCCCAGCCTCCAGGGACCCTCCGCGCTCTGCTCACCTCTGACCCGGGGCTTCACC
T
TGGAACTCCTGGGTTTTAGGGGCAAGGAATGTCTTACGTTTTCAGTGGTGCTGCTGCCTGTGCACAGTTCTGTTCGCGT
G
GCTCTGTGCAAAGCACCTGTTCTCCATCTCTGGGTAGTGGTAGGAGCCGGTGTGGCCCCAGGTGTCCCCACTGTGCCTG
T
GCACTGGCCGTGGGACGTCATGGAGGCCATCCCAGGGCAGCAGGGGCATGGGGTAAAGAGATGTTTATGGGGAGTCTTA
G
CAGAGGAGGCTGGGAAGGTGTCTGAACAGTAGATGGGAGATCAGATGCCCGGAGGATTTGGGGTCTCAGCAAAGAGGGC
C
GAGGTGGGTGCAGGTGAGGGTCGCTGGCCCCACCCCCGGGAAGGTGCAGCAGAGCTGTGGCTCCCCACACAGCCCGGCC
A
GCACCTGTGCTCTGGGCATGGCTGTGCTCCTGGAACGTTCCCTGTCCTGGCTGGTCAGGGGGTGCCCCTGCCAAGAATC
G

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

Le A 32 805-Foreign Countries 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

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

Le A 32 80S-Foreign Countries 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

CAGTAG'fTTGGGAAGCCGAGGCAGAAGGATTGTCTGAGGCCAGGAGTTTGAGACCAGCATGGGTAACATAGGGAGACC
CC
AT.'CTCTIaCAAAAP.ATGCAAAAAGTTATCCGGGCGTGGGGTCCAGCATCTGTAGTCCCAGCTGCTCGGGAGGCTGA
GTGGG
AGGATCGCTTGAGCCCGGGAGGTCATGGCTGCAGTGAGCTGTGATTG'fACCATCGCACTCCAGCCTGGGCAACAGAGT
GA
GACCCTGTCTC GAAGGAGAAGGAGAAGAGAAGAAGAAGGAAGAAGGAAAGAGAAGAAGAAG
C~AAGAAGGAAGAAAGAAGGAGAAGGAGGCCTGCTAGGTGCTAGGTAGACTGTCAAATCTC?~GAGCAAAATGAAAATA
ACA

AAGTTTTAAAGGGAAAGAAAAACCCCAGCTCTTTGGACTTCCTTAGGCCTGAACTTCATCTCAAGCAGCTTCCTTCCAC
A
GAC.~AGCGTGTATGGAGCGAGTGAGTTCAAAGCAGAAAGGGAGGAGAAGCAGGCAAGGGTGGAGGCTGTGGGTGACAC
CA
GCCAGGACCCCTGAAAGGGAGTGGTTGTTTTCCTGCCTCAGCCCCACGCTCCTGCCGGTCCTGCACCTGCTGTAACCGT
C
GATGTTGGTGCCAGGTGCCCACCTGGGAAGGATGCTGTGCAGGGGGCTTGCCAAACTTTGGTGGGTTTCAGAAGCCCCA
G
GCACTTGTGGCAGGCACAATTACAGCCCCTCCCCAAAGATGCCCACGTCCTTCTCCTGGAACCTGTGAATGTGTCACCC
G

CAAGGCAGAGGCTGGTGAAGGCTGCAGGTGGAATCACGGCTGCCAGTCAGCCGATCTTAAGGTCATCCTGGATTATCTG
G
TGGGCCTGATATGGCCACAAGGGTCCCTAGAAGTGAGAGAGGGAGGCAGGGGAGAGTCAGAGAGGGGACGTGAGAAGGA
C
CACTGGCCACTGCTGGCTTTGAGATGGAGGAGGGGGTCCCCAGCCAAGGAATGGGGGCAGCCGCTCCATGCTGGAAAAG
C
:~AGCAATCCTCCCCGGTCCTGAGGGCACACGGCCCTGCCCACGCCTCGATTTCAGGCCAGTGGGACCTGTTTCAGCTT
TC
CGGCCTCCAGAGCTGTAAGATGATGCGTTTGTGTTCAGCCACTAAGCTGCAGTGATTCGTCACAGCAGCAAATGGAATA
G
3S ~AGTACAGGGAAATGAATACAGGGACAGTTCTCAGAGTGACTCTCAGCCCACCCCTGGG

Le A 32 805-Foreign Countries 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 Le A 32 805-Foreign Countries 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).

Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreign Countries t , 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:

Le A 32 805-Foreign Countries 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.

Le A 32 805-Foreign Countries 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 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).

> CA 02316282 2000-06-21 Le A 32 805-Forei Countries 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.

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

Le A 32 805-Foreign Countries 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).

Le A 32 805-Foreien Countries 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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Le A 32 805-Foreign Countries 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 <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 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 ctgcttccgcctcccatttggctgggattacaggcacccgccaccatgcccagctaattt3120 tttgtatttttagtagagacgggggtgggtggggttcaccatgttggccaggctggtctc3180 gaacttctgacctcagatgatccacctgcctctgcctcctaaagtgctgggattacaggt3240 Le A 32 805-Fore~n Countries gtgagccaccatgcccagctcagaatttactctgtttagaaacatctgggtctgaggtag3300 gaagctcaccccactcaagtgttgtggtgttttaagccaatgatagaatttttttattgt3360 tgttagaacactcttgatgttttacactgtgatgactaagacatcatcagcttttcaaag3420 acacactaactgcacccataatactggggtgtcttctgggtatcagcaatcttcattgaa3480 tgccgggaggcgtttcctcgccatgcacatggtgttaattactccagcataatcttctgc3590 ttccatttcttctcttccctcttttaaaattgtgttttctatgttggcttctctgcagag3600 aaccagtgtaagctacaacttaacttttgttggaacaaattttccaaaccgcccctttgc3660 cctagtggcagagacaattcacaaacacagccctttaaaaaggcttagggatcactaagg3720 to ggatttctagaagagcgacctgtaatcctaagtatttacaagacgaggctaacctccagc3780 gagcgtgacagcccagggagggtgcgaggcctgttcaaatgctagctccataaataaagc3840 aatttcctccggcagtttctgaaagtaggaaaggttacatttaaggttgcgtttgttagc3900 atttcagtgtttgccgacctcagctacagcatccctgcaaggcctcgggagacccagaag3960 tttctcgcccccttagatccaaacttgagcaacccggagtctggattcctgggaagtcct4020 cagctgtcctgcggttgtgccggggccccaggtctggaggggaccagtggccgtgtggct4080 tctactgctgggctggaagtcgggcctcctagctctgcagtccgaggcttggagccaggt4140 gcctggaccccgaggctgccctccaccctgtgcgggcgggatgtgaccagatgttggcct4200 catctgccagacagagtgccggggcccagggtcaaggccgttgtggctggtgtgaggcgc4260 ccggtgcgcggccagcaggagcgcctggctccatttcccaccctttctcgacgggaccgc4320 ,7o cccggtgggtgattaacagatttggggtggtttgctcatggtggggacccctcgccgcct4380 gagaacctgcaaagagaaatgacgggcctgtgtcaaggagcccaagtcgcggggaagtgt4440 tgcagggaggcactccgggaggtcccgcgtgcccgtccagggagcaatgcgtcctcgggt4500 tcgtccccagccgcgtctacgcgcctccgtcctccccttcacgtccggcattcgtggtgc4560 ccggagcccgacgccccgcgtccggacctggaggcagccctgggtctccggatcaggcca4620 gcggccaaagggtcgccgcacgcacctgttcccagggcctccacatcatggcccctccct4680 cgggttaccccacagcctaggccgattcgacctctctccgctggggccctcgctggcgtc4740 cctgcaccctgggagcgcgagcggcgcgcgggcggggaagcgcggcccagacccccgggt4800 ccgcccggagcagctgcgctgtcggggccaggccgggctcccagtggattcgcgggcaca4860 gacgcccaggaccgcgctccccacgtggcggagggactggggacccgggcacccgtcctg4920 3o ccccttcaccttccagctccgcctcctccgcgcggaccccgccccgtcccgacccctccc4980 gggtccccggcccagccccctccgggccctcccagcccctccccttcctttccgcggccc5040 cgccctctcctcgcggcgcgagtttcaggcagcgctgcgtcctgctgcgcacgtgggaag5100 ccctggccccggccacccccgcgatg <210> 2 35 <211> 4042 <212> DNA
<213> Homo Sapiens <400> 2 40 gtttcaggcagcgctgcgtcctgctgcgcacgtgggaagccctggccccggccacccccg60 cgatgccgcgcgctccccgctgccgagccgtgcgctccctgctgcgcagccactaccgcg120 aggtgctgccgctggccacgttcgtgcggcgcctggggccccagggctggcggctggtgc180 agcgcggggacccggcggctttccgcgcgctggtggcccagtgcctggtgtgcgtgccct240 gggacgcacggccgccccccgccgccccctccttccgccaggtgtcctgcctgaaggagc300 tggtggcccgagtgctgcagaggctgtgcgagcgcggcgcgaagaacgtgctggccttcg360 gcttcgcgctgctggacggggcccgcgggggcccccccgaggccttcaccaccagcgtgc420 gcagctacctgcccaacacggtgaccgacgcactgcgggggagcggggcgtgggggctgc480 tgctgcgccgcgtgggcgacgacgtgctggttcacctgctggcacgctgcgcgctctttg540 tgctggtggctcccagctgcgcctaccaggtgtgcgggccgccgctgtaccagctcggcg600 ctgccactcaggcccggcccccgccacacgctagtggaccccgaaggcgtctgggatgcg660 aacgggcctggaaccatagcgtcagggaggccggggtccccctgggcctgccagccccgg720 gtgcgaggaggcgcgggggcagtgccagccgaagtctgccgttgcccaagaggcccaggc780 gtggcgctgcccctgagccggagcggacgcccgttgggcaggggtcctgggcccacccgg840 gcaggacgcgtggaccgagtgaccgtggtttctgtgtggtgtcacctgccagacccgccg900 aagaagccacctctttggagggtgcgctctctggcacgcgccactcccacccatccgtgg960 gccgccagcaccacgcgggccccccatccacatcgcggccaccacgtccctgggacacgc1020 cttgtcccccggtgtacgccgagaccaagcacttcctctactcctcaggcgacaaggagc1080 agctgcggccctccttcctactcagctctctgaggcccagcctgactggcgctcggaggc1140 tcgtggagaccatctttctgggttccaggccctggatgccagggactccccgcaggttgc1200 cccgcctgccccagcgctactggcaaatgcggcccctgtttctggagctgcttgggaacc1260 acgcgcagtgcccctacggggtgctcctcaagacgcactgcccgctgcgagctgcggtca1320 ccccagcagccggtgtctgtgcccgggagaagccccagggctctgtggcggcccccgagg1380 aggaggacacagacccccgtcgcctggtgcagctgctccgccagcacagcagcccctggc1440 aggtgtacggcttcgtgcgggcctgcctgcgccggctggtgcccccaggcctctggggct1500 ccaggcacaacgaacgccgcttcctcaggaacaccaagaagttcatctccctggggaagc1560 atgccaagctctcgctgcaggagctgacgtggaagatgagcgtgcgggactgcgcttggc1620 tgcgcaggagcccaggggttggctgtgttccggccgcagagcaccgtctgcgtgaggaga1680 tcctggccaagttcctgcactggctgatgagtgtgtacgtcgtcgagctgctcaggtctt1740 tcttttatgtcacggagaccacgtttcaaaagaacaggctctttttctaccggaagagtg1800 tctggagcaagttgcaaagcattggaatcagacagcacttgaagagggtgcagctgcggg1860 agctgtcggaagcagaggtcaggcagcatcgggaagccaggcccgccctgctgacgtcca1920 gactccgcttcatccccaagcctgacgggctgcggccgattgtgaacatggactacgtcg1980 tgggagccagaacgttccgcagagaaaagagggccgagcgtctcacctcgagggtgaagg2040 cactgttcagcgtgctcaactacgagcgggcgcggcgccccggcctcctgggcgcctctg2100 tgctgggcctggacgatatccacagggcctggcgcaccttcgtgctgcgtgtgcgggccc2160 aggacccgccgcctgagctgtactttgtcaaggtggatgtgacgggcgcgtacgacacca2220 tcccccaggacaggctcacggaggtcatcgccagcatcatcaaaccccagaacacgtact2280 gcgtgcgtcggtatgccgtggtccagaaggccgcccatgggcacgtccgcaaggccttca2340 Le A 32 805-Foreign Countries agagccacgtctctaccttg 2400 acagacctcc agccgtacat gcgacagttc gtggctcacc tgcaggagaccagcccgctg agggatgccg tcgtcatcga gcagagctcc tccctgaatg 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 tccatccccagattcgccattgttcacccctcgccctgccctcctttgccttccaccccc3840 accatccaggtggagaccctgagaaggaccctgggagctctgggaatttggagtgaccaa3900 aggtgtgccctgtacacaggcgaggaccctgcacctggatgggggtccctgtgggtcaaa3960 ttggggggaggtgctgtgggagtaaaatactgaatatatgagtttttcagttttgaaaaa4020 aaaaaaaaaaaaaaaaaaaaas 4042 <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 cagaaataaatgaaactgaaagataacaatacaaaagatcaacaaaattaaaagttggtt840 ttttgaaaagataaacaaaattgacaaacctttgcccagactaagaaaaaaggaaagaag900 acctaaataaataaagtcagagatgaaaaaagagacattacaactgataccacagaaatt960 caaaggatcactagaggctactatgagcaactgtacactaataaattgaaaaacctagaa1020 aaaatagataaattcctagatgcatacaacctaccaagattgaaccatgaagaaatccaa1080 agcccaaacagaccaataacaataatgggattaaagccataataaaaagtctcctagcaa1140 agagaagcccaggacccaatggcttccctgctggattttaccaatcatttaaagaagaat1200 gaattccaatcctactcaaactattctgaaaaatagaggaaagaatacttccaaactcat1260 tctacatggccagtattaccctgattccaaaaccagacaaaaacacatcaaaaacaaaca1320 6O aacaaaaaaacagaaagaaagaaaactacaggccaatatccctgatgaatactgatacaa1380 aaatcctcaacaaaacactagcaaaccaaattaaacaacaccttcgaaagatcattcatt1440 gtgatcaagtgggatttattccagggatggaaggatggttcaacatatgcaaatcaatca1500 atgtgatacatcatcccaacaaaatgaagtacaaaaactatatgattatttcactttatg1560 cagaaaaagcatttgataaaattctgcacccttcatgataaaaaccctcaaaaaaccagg1620 tatacaagaaacatacaggccaggcacagtggctcacacctgcgatcccagcactctggg1680 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 Le A 32 805-Foreign Countries 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 tatctctaaaatcgagctgcagaattggcacgtctgatcacaccgtcctctcattcacgg4920 tgctttttttcttgtgtgcttggagattttcgattgtgtgttcgtgtttggttaaactta4980 atctgtatgaatcctgaaacgaaaaatggtggtgatttcctccagaagaattagagtacc5040 tggcaggaagcaggtggctctgtggacctgagccacttcaatcttcaagggtctctggcc5100 45 aagacccaggtgcaaggcagaggcctgatgacccgaggacaggaaagctcggatgggaag5160 gggcgatgagaagcctgcctcgttggtgagcagcgcatgaagtgcccttatttacgcttt5220 gcaaagattgctctggataccatctggaaaaggcggccagcgggaatgcaaggagtcaga5280 agcctcctgctcaaacccaggccagcagctatggcgcccacccgggcgtgtgccagaggg5340 agaggagtcaaggcacctcgaagtatggcttaaatctttttttcacctgaagcagtgacc5400 SO aaggtgtattctgagggaagcttgagttaggtgccttctttaaaacagaaagtcatggaa5460 gcacccttctcaagggaaaaccagacgcccgctctgcggtcatttacctctttcctctct5520 ccctctcttgccctcgcggtttctgatcgggacagagtgacccccgtggagcttctccga5580 gcccgtgctgaggaccctcttgcaaagggctccacagacccccgccctggagagaggagt5640 ctgagcctggcttaataacaaactgggatgtggctgggggcggacagcgacggcgggatt5700 caaagacttaattccatgagtaaattcaacctttccacatccgaatggatttggatttta5760 tcttaatattttcttaaatttcatcaaataacattcaggactgcagaaatccaaaggcgt5820 aaaacaggaactgagctatgtttgccaaggtccaaggacttaataaccatgttcagaggg5880 atttttcgccctaagtactttttattggttttcataaggtggcttagggtgcaagggaaa5940 gtacacgaggagaggcctgggcggcagggctatgagcacggcagggccaccggggagaga6000 gtccccggcctgggaggctgacagcaggaccactgaccgtcctccctgggagctgccaca6060 ttgggcaacgcgaaggcggccacgctgcgtgtgactcaggaccccataccggcttcctgg6120 gcccacccacactaacccaggaagtcacggagctctgaacccgtggaaacgaacatgacc6180 cttgcctgcctgcttccctgggtgggtcaagggtaatgaagtggtgtgcaggaaatggcc6240 atgtaaattacacgactctgctgatggggaccgttccttccatcattattcatcttcacc6300 cccaaggactgaatgattccagcaacttcttcgggtgtgacaagccatgacaaaactcag6360 tacaaacaccactcttttactaggcccacagagcacggsccacacccctgatatattaag6420 agtccaggagagatgaggctgctttcagccaccaggctggggtgacaacagcggctgaac6480 agtctgttcctctagactagtagaccctggcaggcactcccccagattctagggcctggt6540 tgctgcttcccgagggcgccatctgccctggagactcagcctggggtgccacactgaggc6600 7o cagccctgtctccacaccctccgcctccaggcctcagcttctccagcagcttcctaaacc6660 ctgggtgggccgtgttccagcgctactgtctcacctgtcccactgtgtcttgtctcagcg6720 acgtagctcgcacggttcctcctcacatggggtgtctgtctccttccccaacactcacat6780 gcgttgaagggaggagattctgcgcctcccagactggctcctctgagcctgaacctggct6840 cgtggcccccgatgcaggttcctggcgtccggctgcacgctgacctccatttccaggcgc6900 tccccgtctcctgtcatctgccggggcctgccggtgtgttcttctgtttctgtgctcctt6960 tccacgtccagctgcgtgtgtctctgcccgctagggtctcggggtttttataggcatagg7020 acgggggcgtggtgggccagggcgctcttgggaaatgcaacatttgggtgtgaaagtagg7080 agtgcctgtcctcacctaggtccacgggcacaggcctggggatggagcccccgccaggga7140 cccgcccttctctgcccagcactttcctgcccccctccctctggaacaca 7200 gagtggcagt Le A 32 805-Forei~~n Countries 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 gtagaaattaaagtccatccctcctactctactgggattgagccccttccctatcccccc9000 ccaggggcagaggagttcctctcactcctgtggaggaaggaatgatactttgttattttt9060 cactgctggtactgaatccactgtttcatttgttggtttgtttgttttgttttgagaggc9120 ggtttcactcttgttgctcaggctggagggagtgcaatggcgcgatcttggcttactgca9180 gcctctgcctcccaggttcaagtgattctcctgcttccgcctcccatttggctgggatta9240 caggcacccgccaccatgcccagctaattttttgtatttttagtagagacgggggtgggt9300 ggggttcaccatgttggccaggctggtctcgaacttctgacctcagatgatccacctgcc9360 tctgcctcctaaagtgctgggattacaggtgtgagccaccatgcccagctcagaatttac9420 tctgtttagaaacatctgggtctgaggtaggaagctcaccccactcaagtgttgtggtgt9480 tttaagccaar_gatagaatttttttattgttgttagaacactcttgatgttttacactgt9540 gatgactaagacatcatcagcttttcaaagacacactaactgcacccataatactggggt9600 gtcttctgggtatcagcaatcttcattgaatgccgggaggcgtttcctcgccatgcacat9660 ggtgttaattactccagcataatcttctgcttccatttcttctcttccctcttttaaaat9720 tgtgttttctatgttggcttctctgcagagaaccagtgtaagctacaacttaacttttgt9780 tggaacaaattttccaaaccgcccctttgccctagtggcagagacaattcacaaacacag9840 ccctttaaaaaggcttagggatcactaaggggatttctagaagagcgacctgtaatccta9900 agtatttacaagacgaggctaacctccagcgagcgtgacagcccagggagggtgcgaggc9960 ctgttcaaatgctagctccataaataaagcaatttcctccggcagtttctgaaagtagga10020 aaggttacatttaaggttgcgtttgttagcatttcagtgtttgccgacctcagctacagc10080 SO atccctgcaaggcctcgggagacccagaagtttctcgcccccttagatccaaacttgagc10140 aacccggagtctggattcctgggaagtcctcagctgtcctgcggttgtgccggggcccca10200 ggtctggaggggaccagtggccgtgtggcttctactgctgggctggaagtcgggcctcct10260 agctctgcagtccgaggcttggagccaggtgcctggaccccgaggctgccctccaccctg10320 tgcgggcgggatgtgaccagatgttggcctcatctgccagacagagtgccggggcccagg10380 55 gtcaaggccgttgtggctggtgtgaggcgcccggtgcgcggccagcaggagcgcctggct10440 ccatttcccaccctttctcgacgggaccgccccggtgggtgattaacagatttggggtgg10500 tttgctcatggtggggacccctcgccgcctgagaacctgcaaagagaaatgacgggcctg10560 tgtcaaggagcccaagtcgcggggaagtgttgcagggaggcactccgggaggtcccgcgt10620 gcccgtccagggagcaatgcgtcctcgggttcgtccccagccgcgtctacgcgcctccgt10680 6o cctccccttcacgtccggcattcgtggtgcccggagcccgacgccccgcgtccggacctg10740 gaggcagccctgggtctccggatcaggccagcggccaaagggtcgccgcacgcacctgtt10800 cccagggcctccacatcatggcccctccctcgggttaccccacagcctaggccgattcga10860 cctctctccgctggggccctcgctggcgtccctgcaccctgggagcgcgagcggcgcgcg10920 ggcggggaagcgcggcccagacccccgggtccgcccggagcagctgcgctgtcggggcca10980 ggccgggctcccagtggattcgcgggcacagacgcccaggaccgcgctccccacgtggcg11040 gagggactggggacccgggcacccgtcctgccccttcaccttccagctccgcctcctccg11100 cgcggaccccgccccgtcccgacccctcccgggtccccggcccagccccctccgggccct11160 cccagcccctccccttcctttccgcggccccgccctctcctcgcggcgcgagtttcaggc11220 agcgctgcgtcctgctgcgcacgtgggaagccctggccccggccacccccgcgatg 11276 <210> 4 <211> 104 <212> DNA

<213> Homosapiens 75 <400> 4 gtgggcctccccggggtcggcgtccggctggggttgagggcggccggggggaaccagcga60 catgcggagagcagcgcaggcgactcagggcgcttcccccgcag 104 Le A 32 805-Foreign Countries <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 ccctgtcacgtg.tagggtgagtgaggcgccatccccgggtgtccctgtcacgtgtagggt1740 gagtgaggcgtggtccccgggtgtccctgtcccgtgcagggtgagtgaggcactgtcccc1800 gggtgtccctgtcacgtgcagggtgagtgaggcgcggtccccgggtgtccctctcaggtg1860 tagggtgagtgaggcgcggccccagggtgtccctgtcacgtgtagggtgagtgaggcacc1920 gtccctgggtgtccctcccaggtatagggtgagtgaggcactgtccccgggtgtccctgt1980 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 Le A 32 805-Foreign Countries 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 Le A 32 805-Foreign Countries <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 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 tgtcactgttgaggacacacctggcacctagggtggaggccttcagcctttcctgcagca180 catggggccgactgtgcaccctgactgcccgggctcctattcccaaggagggtcccactg240 gattccagtttccgtcagagaaggaaccgcaacggctcagccaccaggccccggtgcctt300 gcaccccagtcctgagccaggggtctcctgtcctgaggctcagagaggggacacagcccg360 7o ccctgcccttggggtctggagtggtgggggtcagagagagagtgggggacaccgccaggc420 caggccctgagggcagaggtgatgtctgagtttctgcgtggccactgtcagtctcctcgc480 ctccactcacacag 494 <210> 9 <211> 865 <212> DNA

<213> HomoSapiens Le A 32 805-Foreign Countries <400> 9 gtaaggttcacgtgtgatagtcgtgtccaggatgtgtgtctctgggatatgaatgtgtct60 agaatgcagtcgtgtctgtgatgcgtttctgtggtggaggtacttccatgatttacacat120 ctgtgatatgcgtgtgtggcacgtgtgtgtcgtggtgcatgtatctgtggcgtgcatatt180 t gtggtgtgt gtgtgtgtggcacgtgtgtgtccatggtgtgtgtgcctgtggtgtgcatg240 tgtgtgtgtctgtgacacgtgcatgttcatgctgtgtgctgcatgtctgtgatgtgccta300 tttgtggtgtgtgtgtgcatgtgtccgtgacatatgcgtgtctatggcatgggtgtgtgt360 ggccccttggccttactccttcctcctccaggcatggtccgcaccattgtcctcacgctc420 to tcgggtgctggtttggggagctccacattcagggtcctcacttctagcatgggtgcccct480 gtcctgtcacagggctgggccttggagactgtaagccaggtttgagaggagagtagggat540 gctggtggtaccttcctggacccctggcacccccaggaccccagtctggcctatgccggc600 tccatgagatataggaaggctgattcaggcctcgctccccgggacacactcctcccagag660 cggccgggggccttggggctcggcaggggtgaaaggggccctgggcttgggttcccaccc720 IS agtggtcatgagcacgctggaggggtaagccctcaaagtcgtgccaggccggggtgcaga780 ggtgaagaagtatccctggagcttcggtctggggagaggcacatgtggaaacccacaagg840 acctctttctctgacttcttgagct <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 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 Le A 32 805-Forei , Countries tgtggtgactgtggatggcggtcgtagggtctgatgtgtggtgactgtggatggcagtcg3360 gtcacaggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtg3420 actgtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtc3480 tgatgtgtggtgactgtggatggcggtcgtggggtctgatgtggtgactgtggatggtga3540 tcggtcacaggggtctgatgtgtggtagctgcaggtggagtcccaggtgtgtctgtagct3600 actttgcgtcctcggccccccggcccccgtttcccaaacagaagcttcccaggcgctctc3660 tgggcttcatcccgccatcgggcttggccgcaggtccacacgtcctgatcggaagaaaca3720 agtgcccagctctggccggggcaggccacatttgtggctcatgccctctcctctgccggc3780 ag <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 Le A 32 805-Foreign Countries agccgccccagtgcatggtgagagtggggagcagggattgtttgttcagaggtctcatct2340 ggtatgtttctgaggtgtttgccggctgaatggtagacgtgtcgtttgtgtgtatgaggt2400 tctgtgtctgtgtgtggctcggtttgagtgtacgcatgtccagcacatgccctgcccgtc2460 tctcacctgtgtcttcccgccccag <210> 13 <211> 1984 <212> DNA

<213> Homosapiens <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 ataagtttatgtaacagaaacaaaaatttcttgtacacacaacttgctctgggatttgga1440 ggaaagtgtcctcgagctggcggcacactggtcagccctctgggacaggatacctctggc1500 ccatggtcatggggcgctgggcttgggcctgagggtcacacagtgcaccatgcccagctt1560 cctgtggataggatctgggtctcggatcatgctgaggaccacagctgccatgctggtaaa1620 gggcaccacgtggctcagagggggcgaggttcccagccccagctttcttaccgtcttcag1680 ttatttttccctaagagtctgagaagtggggccgcgcctgatggccttcgttcgtcttca1740 gctggcacagaattgcacaagctgatggtaaacactgagtacttataatgaatgaggaat1800 tgctgtagcagttaactgtagagagctcgtctgttggaaagaaatttaagtttttcattt1860 aaccgctttggagaatgttactttatttatggctgtgtaaattgtttgacattcagtccc1920 tcgtagacagatactacgtaaaaagtgtaaagttaaccttgctgtgtattttcccttatt1980 ttag 1984 <210> 14 <211> 1871 <212> DNA
<213> Homo sapiens <400>

gtgaggcccgtgccgtgtgtctgtggggacctccacagcctgtgggctttgcagttgagc60 55 cccccgtgtcctgcccctggcaccgcagcgttgtctctgccaagtcctctctctctgccg120 gtgctggatccgcaagagcagaggcgcttggccgtgcacccaggcctgggggcgcagggg180 caccttcgggagggagtgggtaccgtgcaggccctggtcctgcagagacgcacccaggtt240 acacacgtggtgagtgcaggcggtgacctggctcctgctgctctttggaaagtcaagagt300 ggcggctcctggggccccagtgagacccccaggagctgtgcacagggcctgcagggccga360 60 ggcggcagcctcctccccagggtgcacctgagcctgcggagagcaggagctgctgagtga420 gctggcccacagcgttcgctgcggtcacgttcctgcgtggggttgtttgggatcggtggg480 agaatttggatttgctgagtgctgctgtcttgaaccacggagatggctaggagtgggttt540 cagagttgatttttgtgaatcaaactaaaatcaggcacaggggacctggcctcagcacag600 gggattgtccaatgtggtccccctcaagggcgccccacagagccggtgggcttgttttaa660 agtgcgatttgacgagggacgagaaaccttgaaagctgtaaagggaaccctcagaaaatg720 tggccgccaggggtggtttcaggtgctttgctgggctgtgtttgtgaaaacccatttgga780 cccgccctccaagtccaccctccaggtccaccctccagggccgccctgggctgggggtat840 gcctggcgttccttgtgccgcagcccggagcacagcaggctgtgcacatttaaatccact900 aagattcactcggggggagcccaggtcccaagcaactgagggctcaggagtcctgaggct960 gctgaggggacagagcagacggggaacgctgcttctgtgtggcaagttcctgagggtgct1020 ggccagggaggtggctcagagtgtatgttggggtcccaccgggggcagaactctgtctct1080 gatgagtcggcagccatgtaacaggaaggggtggccacagggagctgggaatgcaccagg1140 ggagctgcgcagctggccgaggtcccagggccaggccacaggaagggcagggggacgccc1200 ggggccacagcagaggccgcaggaagggaaggggatgcccaggccagagcagaggctacc1260 gggcacaggggggctccctgagctgggtgagcgaggctcatgactcggcgagggaacctc1320 cttgacgtgaagctgacgactggtgttgcccagctcacagcccagccaggtcccgcgcct1380 gagcaggaactcagaaccctcccctttgtctaaagcacagcagatgccttcagggcatct1440 aggagaaaacaggcaaagtcgttgagaaacgtcttaaaagaaggtgggatggtggcaatt1500 tcttgtccagattttagtctgccccggaccacagatgagtctataacgggattgtggtgt1560 Le A 32 805-Foreign Countries 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>

gtgagcgcacctggccggaagtggagcctgtgcccggctggggcaggtgctgctgcaggg60 ccgttgcgtccacctctgcttccgtgtggggcaggcgactgccaatcccaaagggtcaga120 ggccacagggtgcccctcgtcccatctggggctgagcagaaatgcatctttctgtgggag180 tgagggtgctcacaacgggagcagttttctgtgctattttggtaaaaggaaatggtgcac240 cagacctgggtgcactgaggtgtcttcagaaagcagtctggatccgaacccaagacgccc300 gggccctgctgggcgtgagtctctcaaacccgaacacaggggccctgctgggcatgagtc360 cctctgaacccgagaccctggggccctgctgggcgtgagtctctccgaacccagagactt420 cagggcccttttgggcgtgagtctctccgctgtgagccccacactccaaggctcatccac480 agtctacaggatgccatgagttcatgatcacgtgtgacccatcaggggacagggccatgg540 tgtggggggggtctctacaaaattctggggtcttgtttccccagagcccgagagctcaag600 gccccgtctcaggctcagacacaaatgaattgaagatggacacagatgcagaaatctgtg660 ctgtttcttttatgaataaaaagtatcaacattccaggcagggcaaggtggctcacacct720 ataatcccagcactttgggaggccgaggtgggtggatcacttgaggccaggagtttgagg780 ccaacctaaccaacatagtgaaattccatttctacttaaaaaatacaaaaattagcctgg840 cctggtggcacacgcctgtagtccccgctatgcgggaggctgaggcaggagaatcatttg900 aacccaggaggcagaggttgcagtgagccgagatcacaccactgcactccagcctgggca960 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 cacattcatcctctcactttgttctcctaaccacctgagaggtagaggaggaaaggctcc2520 aggggagcagccgcccttggtcacccagctggcaaagggcatgcatgattgcagcctggc2580 ctcctgctccggggcccttgctctgcccgaggaccccacacaagtcagacccataggctc2640 agggtgagccggagcccaaggtcgtgttggggatggctgtgaaagaagaaatggacgtct2700 6O gatgcacacttgggaaggtcctaccagcagcgtcaaagaaatgcatgtgaaactgacagc2760 gagacccatccctcaaagaaacgcacgtgaaactgatggcgagacctgtccccatccctc2820 atgctggctccttttctgggcttgccaagagccagcatcaggttgaggcaagctggaaag2880 acttttctggaaagcagcttgtttgcatggaagtcctcacaatgtcctgtgtcttcccag2940 taattccacttctgaagtgaccagacattatcacgggtcttatttaccatttccagtgtt3000 ccaggcagggggacttgccacagcaagtcacgaacctgcccaaatacagggctaaggaga3060 tattatgcatcacaaaacttgctctgccattaaacatttttcaaagaatttttgaagaat3120 gtttaatggcacaaaacgtttatttcaatgtagcagtgttcaaagctggatgtaaaagaa3180 cacaccccaggagcctgccgtgaatgtcatgtgtgttcatctttggacatggacatacat3240 gggcagtgagtggtggtgaggccctggaggacatcggtgggatgcctccatcctgcccct3300 ctggagacaccatgtgtgccacgtgcactcactggagccctgtttagctggtgccacctg3360 gctcttccatccctgagattcaaacacagtgagattccccacgcccaactcagtgttctc3420 ccacaaaaaacctgagtcacacctgtgttcactcgagggacgcccgggagccagggctcc3480 acagtttattatgtgtttttggctgagttatgtgcagatctcatcagggcagatgatgag3540 tgcacaaacacggccgtgcgaggtttggatacactcaacatcactagccaggtcctggtg3600 75 gagtttggtcatgcagagtctggatggcatgtagcatttggagtccatggagtgagcacc3660 cagccccctcgggctgcagcgcatgccccaggcaggacaaggaagcgggaggaaggcagg3720 aggctctttggagcaagctttgcaggagggggctgggtgtggggcaggcacctgtgtctg3780 acattcccccctgtgtctcag 3801 Le A 32 805-Foreign Countries <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 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 ttgatatacgatgacatcaaggttgtctgacgaagggcaggattcatgataagtacctgc2820 tggtacacaaggaacaatggataaactggaaaccttagaggccttcccggaacaggggct2880 aatcagaagccagcatggggggctggcatccaggatggagctgcttcagcctccacatgc2940 gtgttcatacagatggtgcacagaaacgcagtgtacctgtgcacacacagacacgcagct3000 Le A 32 805-Foreign Countries 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 Le A 32 805-Forei;~n Countries 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

Claims

1. Regulatory DNA sequences for the gene for the human catalytic telomerase subunit.

2. DNA sequences according to Claim 1, characterized in that the sequences are intron sequences in accordance with SEQ ID NO 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and/or 20 or fragments of these sequences which have a regulatory effect.

3. DNA sequences according to Claim 1, characterized in that the sequences are the 5'-flanking regulatory DNA sequence for the gene for the human catalytic telomerase subunit as depicted in Fig. 10 (SEQ ID NO 3), or fragments of this DNA sequence which have a regulatory effect.

4. Recombinant construct which contains a DNA sequence according to one of Claims 1 to 3.

5. Recombinant construct according to Claim 4, characterized in that it additionally contains one or more DNA sequences which encode polypeptides or proteins.

6. Vector which contains a recombinant construct according to Claim 4 or 5.

7. Use of recombinant constructs or vectors according to one of Claims 4 to 6 for preparing medicaments.

8. Recombinant host cells which harbour recombinant constructs or vectors according to one of Claims 4 to 6.

9. Process for identifying substances which affect the promoter activity, silencer activity or enhancer activity of the human catalytic telomerase subunit, comprising the following steps:
A. adding a candidate substance to a host cell which harbours DNA
sequences according to one of Claims 1 to 3, which sequences are functionally linked to a reporter gene, and B. measuring the effect of the substance on expression of the reporter gene.

10. Process for identifying factors which bind specifically to the DNA
according to one of Claims 1 to 3, or to fragments thereof, characterized in that an expression cDNA library is screened using a DNA sequence according to one of Claims 1 to 3, or subfragments of widely differing length, as the probe.

11. Transgenic animals which harbour recombinant constructs or vectors according to Claims 4 to 6.

12. Process for detecting telomerase-associated conditions in a patient, comprising the following steps:
A. incubating a recombinant construct or vector according to Claims 4 to 6, which additionally contains a reporter gene, with body fluids or cell samples, B. detecting the activity of the reporter gene in order to obtain a diagnostic value, and C. comparing the diagnostic value with standard values for the reporter gene construct in standardized normal cells or body fluids of the same type as the test sample.