SG195562A1 - High efficiency gene transfer and expression in mammalian cells by a multiple transfection procedure of matrix attachment region sequences - Google Patents

Abstract

The present invention relates to purified and isolated DNA sequences having protein production increasing activity and more specifically to the use of matrix attachment regions (MARs) for increasing protein production activity in a eukaryotic cell. Also disclosed is a method for the identification of said active regions, in particular MAR nucleotide sequences, and the use of these characterized active MAR sequences in a new multiple transfection method. (FIG. 1)

Description

HIGH EFFICIENCY GENE TRANSFER AND EXPRESSION IN MAMMALIAN CELLS BY A

MULTIPLE TRANSFECTION PROCEDURE OF MATRIX ATTACHMENT REGION SEQUENCES

FIELD OF THE INVENTION

2

The present invention relates to purified and isolated DNA sequences having protein production increasing activity and more specifically to the use of matrix attachment : regions (MARs) for increasing protein production activity in a eukaryotic cell. Also disclosed is a method for the identification of said active regions, in particular MAR nucleotide sequences, and the use of these characterized active MAR sequences in a new multiple transfection method.

BACKGROUND OF THE INVENTION

Nowadays, the model of loop domain organization of eukaryotic chromosomes is well accepted (Boulikas T, “Nature of DNA sequences at the attachment regions of genes to the nuclear matrix”, J. Cell Biochem., 52:14-22, 1993). According to this model chromatin is organized in loops that span 50-100 kb attached to the nuclear matrix, a proteinaceous network made up of RNPs and other nonhistone proteins (Bode J,

Stengert-lber M, Kay V, Schalke T and Dietz-Pfeilstetter A, Cnt, Rev. Euk. Gene Exp., 6:115-138, 1996).

The DNA regions attached to the nuclear matrix are termed SAR or MAR for respectively scaffold (during metaphase) or matrix (interphase) attachment regions (Hart C and Laemmli U (1998), “Facilitation of chromatin dynamics by SARs” Curr Opin

Genet Dev 8, 518-525.)

As such, these regions may define boundaries of independent chromatin domains, such that only the encompassing cis-regulatory elements control the expression of the genes within the domain.

However, their ability to fully shield a chromosomal locus from nearby chromatin elements, and thus confer position-independent gene expression, has not been seen in stably transfected cells (Poljak 1, Seum C, Mattioni T and Laemmli U. (1994) “SARs stimulate but do not confer position independent gene expression”, Nucleic Acids Res 22, 4386-4394). On the other hand, MAR (or S/MAR) sequences have been shown to interact with enhancers to increase local chromatin accessibility (Jenuwein T, Forrester

W, Fernandez-Herrero L, Laible G, Dull M, and Grossched| R. (1997) "Extension of chromatin accessibility by nuclear matrix attachment regions” Nature 385, 269-272). 40 Specifically, MAR elements can enhance expression of heterologous genes in cell culture lines {Kalos M and Fournier R (1995) "Position-independent transgene expression mediated by boundary elements from the apolipoprotein B chromatin domain” Moi Cell Biol 15,198-207), transgenic mice {Castilla J, Pintado B, Sola, |,

Sanchez-Morgado J, and Enjuanes L (1998) “Engineering passive immunity in 45 transgenic mice secreting virus-neutralizing antibodies in milk” Nat Biotechnol 18, 349- 354) and plants (Alien G, Hall GJ, Michalowski S, Newman W, Spiker S, Wesissinger A, and Thompson W (1996), “High-level transgene expression in plant cells: effects of a strong scaffold attachment region from tobacco” Plant Cell 8, 899-813). The utility of

MAR sequences for developing improved vectors for gene therapy is also re cognized 50 (Agarwal M, Austin T, More! F, Chen J, Bohnlein E, and Plavec ! (1898), “Sc affoid . attachment region-mediated enhancement of retroviral vector expression in primary T cells” J Virol 72, 3720-3728).

Recently, it has been shown thatchromatin-structure modifying sequences including

MARs, as exemplified by the chicken lysozyme 5’ MAR is able to significantly enhance reporter expression in pools of stable Chinese Hamster Ovary (CHO) cells (Zahn-Zabal

M, et al., "Development of stable cell fines for production or regulated expression using matrix attachment regions” J Biotechnol, 2001, 87(1): p. 29-42). This property was used to increase the proportion of high-producing clones, thus reducing the number of clones that need to be screened. These benefits have been observed both for constructs with

MARS flanking the transgene expression cassette, as well as when constructs are co- transfected with the MAR on a separate plasmid. However, expression levels upon co- transfection with MARs were not as high as those observed for a construct in which two

MARs delimit the transgene expression unit. A third and preferable process was shown to be the transfection of transgenes with MARs both linked to the transgene and on a separate plasmid (Girod et al., submitted for publication). However, one persisting limitation of this technique is the quantity of DNA that can be transfected per cell.

Many multiples transfection protocois have been developed in order to achieve a high transfection efficiency to characterize the function of genes of interest. The protocol applied by Yamamoto et al, 1999 (“High efficiency gene transfer by multiple transfection protocol”, Histochem. J. 31(4), 241-243) leads to a transfection efficiency of about 80 % after 5 transfections events, whereas the conventional transfection protocol only achieved a rate of <40%. While this technique may be useful when one wishes to increase the proportion of expressing cells, it does not lead to cells with a higher intrinsic productivity. Therefore, it cannot be used to generate high producer monoclonal cell lines, Hence, the previously described technique has two major drawbacks: i) this technique does not generate a homogenous population of transfected cells, since it cannot favour the integration of further gene copy, nor does it direct the transgenes to favorable chromosomal loci, i) the use of the same selectable marker in multiple transfection events does not permit the selection of doubly or triply transfected cells.

In patent application W002/074989, the utility of MARS for the development of stable eukaryotic cell lines has also been demonstrated. However, this application does not disclose neither any conserved homology for MAR DNA element nor any technique for predicting the ability for a DNA sequence to be a MAR sequence.

In fact no clear-cut MAR consensus sequence has been found (Boulikas T, “Nature of

DNA sequences at the attachment regions of genes io the nuclear matrix”, J. Celf 40 Biochem., 52:14-22, 1993) but evolutionarily, the structure of these sequences seem {o be functionally conserved in eukaryotic genomes, since animal MARs can bind to plant nuclear scaffolds and vice versa (Mielke C, Kohwi Y, Kohwi-Shigematsu T and Bode J, “Hierarchical binding of DNA fragments derived from scaffold-attached regions: correlation of properties in vitro and function in vivo”, Biochemistry, 29:7475-7485, 45 1990).

The identification of MARs by biochemical studies is a long and unpredictable process; various results can be obtained depending on the assay (Razin SV, “Functional architecture of chromosomal DNA domains”, Crit Rev Eukaryot Gene Expr., 6:247-269, 50 1996). Considefing the huge number of expected MARS in a eukaryotic genome and the amount of sequences issued from genome projects, a tool able to filter potential

MARS in order {o perform targeted experiments would be greatly useful.

Currently two different predictive tools for MARs are available via the Internet.

The fist one, MAR-Finder (http://futuresoft. org/MarFinder; Singh GB, Kramer JA and

Krawetz SA, “Mathematical model to predict regions of chromatin attachment to the nuclear matrix”, Nucleic Acid Research, 25:1419-1425, 1997) is based on set of patterns identified within several MARS and a statistical analysis of the co-occurrence of these patterns. MAR-Finder predictions are dependent of the sequence context, meaning that predicted MARs depend on the context of the submitted sequence. The other predictive software, SMARTest {(hitp://www. genomatix.de; Frisch M, Frech K,

Klingenhoff A, Cartharius K, Liebich | and Werner T, “In silico prediction of scaffold/matrix attachment regions in large genomic sequences’, Genome Research, 12:349-354, 2001), use weight-matrices derived from experimentally identified MARs.

SMARTest is said to be suitable to perform large-scale analyses. But actually aside its relative poor specificity, the amount of hypothetical MARS rapidly gets huge when doing large scale analyses with it, and in having no way to increase its specificity to restrain the number of hypothetical MARs, SMARTest becomes almost useless to screen for potent MARS form large DNA sequences.

Some other softwares, not available via the Internet, also exists; they are based as well on the frequency of MAR motifs (MRS criterion;Van Drunen CM et al., “A bipartite sequence element associated with matrix/scaffold attachment regions”, Nucleic Acids

Res, 27:2924-2930, 1999), (ChrClass; Glazko GV et al., “Comparative study and prediction of DNA fragments associated with various elements of the nuclear matrix’,

Biochim. Biophys. Acta, 1517:351-356, 2001) or based on the identification of sites of stress-induced DNA duplex (SIDD; Benham C and al., “Stress-induced duplex DNA destabilization in scaffold/matrix attachment regions”, J. Mol. Biol., 274:181-196, 1997).

However, their suitability to analyze complete genome sequences remains unknown, and whether these tools may allow the identification of protein production-increasing sequences has not been reported.

Furthermore, due to the relatively poor specificity of these softwares (Frisch M, Frech K,

Klingenhoff A, Cartharius K, Liebich I and Werner T, “In silico prediction of scaffold/matrix attachment regions in large genomic sequences”, Genome Research, 12:349-354, 2001), the amount of hypothetical MARs identified in genomes rapidly gets unmanageable when doing large scale analyses, especially if most of these have no or poor activity in practice. Thus, having no way to increase prediction specificity to restrain the number of hypothetical MARs, many of the available programs become almost useless to identify potent genetic elements in view of efficiently increasing recombinant protein production.

Since all the above available predictive methods have some drawbacks that prevent 40 large-scale analyses of genomes to identify reliably novel and potent MARS, the object of this invention is to 1) understand the functional features of MARS that allow improved recombinant protein expression; 2) get a new Bioinformatic tool compiling MAR structural features as a prediction of function, in order to 3) perform large scale analyses of genomes to identify nove! and more potent MARS, and, finally 4) to 45 demonstrate improved efficiency to increase the production of recombinant proteins from eukaryotic cells or organisms when using the newly identified MAR sequences.

SUMMARY OF THE INVENTION

50

This object has been achieved by providing an improved and reliable method for the identification of DNA sequences having protein production increasing activity, in particular MAR nucleotide sequences, and the use of these characterized active MAR sequences in a new multiple transfection method to increase the production of recombinant proteins in eukaryotic cells.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows the distribution plots of MARs and non-MARs sequences. Histograms are density plots (relative frequency divided by the bin width) relative to the score of the observed parameter. The density histogram for human MARS in the SMARt DB database is shown in black, while the density histogram for the human chromosome 22 are in grey.

Fig. 2 shows Scatterplots of the four different criteria used by SMAR Scan® and the

AT-content with human MARs from SMARt DB.

Fig. 3 shows the distribution plots of MAR sequences by organism. MAR sequences from SMARt DB of other organisms were retrieved and analyzed. The MAR sequences density distributions for the mouse, the chicken, the sorghum bicolor and the human are plotted jointly.

Fig. 4 shows SMAR Scan® predictions on human chromosome 22 and on shuffled chromosome 22. Top plot : Average number of hits obtained by SMAR Scan® with five: rubbled, scrambled, shuffled within nonoverlapping windows of 10 bp, order 1 Markov chains model and with the native chromosome 22, Bottom plot: Average number of

MARs predicted by SMAR Scan® in five: rubbled, scrambled, shuffled within non- overlapping windows of 10 bp, order 1 Markov chains model and with the native chromosome 22.

Fig. 5 shows the dissection of the ability of the chicken lysozyme gene 5'-MAR to stimulate transgene expression in CHO-DG44 cells. Fragments B, K and F show the highest ability to stimulate transgene expression. The indicated relative strength of the elements was based on the number of high-expressor ceils.

Fig. 6 shows the effect of serial-deletions of the 5'-end (upper part) and the 3’-end (lower part) of the 5’-MAR on the loss of ability to stimulate transgene expression. The transition from increased to decreased activity coincide with B-, K- and F-fragments.

Fig. 7 shows that portions of the F fragment significantly stimulate transgene expression. The F fragment regions indicated by the light grey arrow were multimerized, 40 inserted in pGEGFP Control and transfected in CHO cells. The element that displays the highest activity is located in the central part of the element and corresponds to fragment Fill (black bar labelled minimal MAR). In addition, an enhancer activity is located in the 3'-flanking part of the FIil fragment (dark grey bar labelled MAR enhancer). 45 . Fig. 8 shows a map of locations for various DNA sequence motifs within the cf ysMAR.

Fig. 8 (B) represents a Map of locations for various DNA sequence motifs within the cLysMAR. Vertical lines represent the position of the computer-predicted sites or sequence motifs along the 3034 base pairs of the cLysMAR and its active regions, as 50 presented in Fig. 5. The putative transcription factor sites, (MEF2 05, Oct-1, USF-02,

GATA, NFAT) for activators and (CDP, SATB1, CTCF, ARBP/MeCP2) for repressors of transcription, were identified using Matlnspector (Genomatix), and CpG islands were identifed with CPGPLOT. Motifs previously associated with MAR elements are labelled in black and include CpG dinucleotides and CpG islands, unwinding motifs (AATATATT and AATATT), poly As and Ts, poly Gs and Cs, Drosophila topoisomerase [I binding sites (GTNWAYATTNATTNATNNR) which had identity to the 8 bp core and High mobility group | (HMG-I7Y) protein binding sites. Other structural motifs include : nucleosome-binding and nucleosome disfavouring sites and a motif thought to relieve the superhelical strand of DNA. Fig. 8(A) represents the comparison of the ability of portions of the cLysMAR to activate transcription with MAR prediction score profiles with MarFinder. The top diagram shows the MAR fragment activity as in Fig. 5, while the middle and bottom curves show MARFinder-predicted potential for MAR activity and for bent DNA structures respectively.

Fig. 9 shows the correlation of DNA physico-chemicai properties with MAR activity. Fig. 9(A), represents the DNA melting temperature, double helix bending, major groove depth and minor groove width profiles of the 5-MAR and were determined using the algorithms of Levitsky et al (Levitsky VG, Ponomarenko MP, Ponomarenko JV, Frolov

AS, Kolchanov NA “Nuciteosomal DNA property database”, Bioinformatics, 15; 582592, 1999). The most active B, K and F fragments depicted at the top are as shown as in

Figure 1. Fig. 9(B), represents the enlargement of the data presented in panel A to display the F fragment map aligned with the tracings corresponding to the melting temperature (top curve) and DNA bending (bottom curve). The position of the most active FIB fragment and protein binding site for specific transcription factors are as indicated.

Fig. 10 shows the distribution of putative transcription factor binding sites within the 5'- - cLysMAR, Large arrows indicate the position of the CUE elements as identified with

SMAR Scan®.

Fig. 11 shows the scheme of assembly of various portions of the MAR. The indicated portions of the cLysMAR were amplified by PCR, introducing Bglfl-BamH]I linker elements at each extremity, and assembled to generate the depicted composite elements. For instance, the {op construct consists of the assembly of all CUE and flanking sequences at their original location except that Bgli-BamHII linker sequences separate each element.

Fig. 12 represents the plasmid maps.

Fig. 13 shows the effect of re-transfecting primary transfectants on GFP expression.

Cells (CHO-DG44) were co-transfected with pSV40EGFP (left tube) or pMAR-

SV40EGFP (central tube) and pSVneo as resistance plasmid. Cells transfected with 40 pMAR-SV40EGFP were re-fransfected 24 hours later with the same plasmid and a different selection plasmid, pSVpuro {right tube). After two weeks selection, the phenotype of the stably transfected cell population was analysed by FACS.

Fig. 14 shows the effect of multiple load of MAR-containing plasmid. The pMAR- 45 SV40EGFP/ pMAR-SV40EGFP secondary transfectants were used in a third cycle of transfection at the end of the selection process. The tertiary transfection was accomplished with pMAR or pMAR-SV40EGFP to give tertiary transfectants. After 24 hours, cells were transfected again with either plasmid, resulting in the quaternary transfectants (see Table 4}. 50

Fig. 15 shows comparative performance of SMAR prediction algorithms exemplified by region WP18A10A7. (A) SMAR Scan® analysis was performed with default settings. (B) SIDD analysis (top curve and left-hand side scale), and the attachment of several

DNA fragments to the nuclear matrix in vitro (bar-graph, right-hand side scale) was taken from Goetze et al ( Goetze S, Gluch A, Benham C, Bode J, “Computational and in vitro analysis of destabilized DNA regions in the interferon gene cluster: potential of predicting functional gene domains.” Biochemistry, 42:154-166, 2003). :

Fig. 16 represents the results of a a gene therapy-like protocol using MARS.

The group of mice injected by MAR-network, induced from the beginning of the experiment, display a better induction of the hematocrit in comparison of mice injected by original network without MAR. After 2 months, hematocrits in "MAR-containing * group” is still at values higher (65%) than normal hematocrit levels (45-55%).

Fig. 17 represents the scatterplot for the 1757 S/MAR sequences of the AT (top) and

TA (bottom) dinucleotide percentages versus the predicted DNA bending as computed by SMAR Scan®.

Fig. 18 represents the dinucleotide percentage distribution plots over the 1757 non-

S/MARs sequences. Fig.19 shows the effect of various S/MAR elements on the production of recombinant green fluorescent protein (GFP). Populations of CHO cells transfected with a GFP expression vector containing or a MAR element, as indicated, were analyzed by a fluorescence-activated cell sorter (FACSY), and typical profiles are shown. The profiles display the celt number counts as a function of the GFP fluorescence levels.

Fig. 20 depicts the effect of the induction of hematocrit in mice injected by MAR- network.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a purified and isolated DNA sequence having protein production increasing activity characterized in that said DNA sequence comprises at least one bent DNA element, and at least one binding site for a DNA binding protein.

Certain sequences of DNA are known to form a relatively "static curve”, where the DNA follows a particular 3-dimensional path. Thus, instead of just being in the normal B-

DNA conformation {"straight"}, the piece of DNA can form a flat, planar curve also defined as bent DNA (Marini, ef al, 1982 "Bent helical structure in kinetoptast DNA", 40 Proc. Natl. Acad. Sci. USA, 79: 7664-7664).

Surprisingly, Applicants have shown that the bent DNA etement of a purified and isolated DNA sequence having protein production increasing activity of the present invention usually contains at least 10% of dinucleotide TA, and/or at least 12% of 45 dinucleotide AT on a stretch of 100 contiguous base paits. Preferably, the bent DNA element contains at least 33% of dinucleotide TA, and/or at least 33% of dinucleotide

AT on a stretch of 100 contiguous base pairs. These data have been obtained by the method described further. : 50 According to the present invention, the purified and isolated DNA sequence usually comprises a MAR nucieotide sequence selected from the group comprising the sequences SEQ ID Nos 1 to 27 or a cLysMAR element or a fragment thereof,

Preferably, the purified and isolated DNA sequence is a MAR nucleotide sequence

B selected from the group comprising the sequences SEQ ID Nos 1 to 27, more preferably the sequences SEQ ID Nos 24 to 27.

Encompassed by the present invention are as well complementary sequences of the above-mentioned sequences SEQ ID Nos 1 fo 27 and the cLysMAR element or fragment, which can be produced by using PCR or other means. :

An “element” is a conserved nuclectide sequences that bears common functional properties (i.e. binding sites for transcription factors) or structural (i.e. bent DNA sequence) features.

A part of sequences SEQ ID Nos 1 fo 27 and the cLysMAR element or fragment refers fo sequences sharing at least 70% nucleotides in length with the respective sequence of the SEQ ID Nos 1 to 27. These sequences can be used as long as they exhibit the same properties as the native sequence from which they derive, Preferably these sequences share more than 80%, in particular more than 90% nucleotides in length with the respective sequence of the SEQ ID Nos 1 to 27.

The present invention also includes variants of the aferementioned sequences SEQ ID

Nos 110 27 and the cLysMAR element or fragment, that is nuclectide sequences that vary from the reference sequence by conservative nuclectide substitutions, whereby one or more nucleotides are substituted by another with same characteristics.

The sequences SEQ ID Nos 1 to 23 have been identified by scanning human chromosome 1 and 2 using SMAR Scan®, showing that the identification of novel MAR sequences is feasible using the ools reported thereafter whereas SEQ ID No 24 to 27 have heen identified by scanning the complete human genome using the combined

SMAR Scan® method. 3C In a first step, the complete chromosome 1 and 2 were screened to identify bent DNA element as region corresponding to the highest bent, major groove depth, minor groove width and lowest melting temperature as shown in figure 3. In a second step, this collection of sequence was scanned for binding sites of regulatory proteins such as

SATB1, GATA, etc. as shown in the figure 8B) yielding sequences SEQ ID 1-23.

Furthermore, sequences 21-23 were further shown to be located next to known gene from the Human Genome Data Base.

With regard to SEQ ID No 24 to 27 these sequences have been yielded by scanning the human genome according to the combined method and were selected as 40 examples among 1757 MAR elements so detected.

Molecular chimera of MAR sequences are also considered in the present invention. By molecular chimera is intended a nucleotide sequence that may include a functional 45 portion of a MAR element and that will be obtained by molecular biology methods known by those skilled in the art.

Particular combinations of MAR elements or fragments or sub-portions thereof are also considered in the present invention. These fragments can be prepared by a variety of 5C methods known in the art. These methods include, but are not limited fo, digestion with restriction enzymes and recovery of the fragments, chemical synthesis or polymerase chain reactions (PCR).

Therefore, particular combinations of elements or fragments of the sequences SEQ ID

Nos 1 to 27 and cl.ysMAR elements or fragments are also envisioned in the present - invention, depending on the functional results to be obtained. Elements of the cLysMAR are e.g. the B, K and F regions as described in WO 02/074969, the disclosure of which is hereby incorporated herein by reference, in its entirety. The preferred elements of the c¢LysMAR used in the present invention are the B, K and F regions. Only one element might be used or multiple copies of the same or distinct elements (multimerized elements) might be used {see Fig. 8 A)).

By fragment is intended a portion of the respective nucleotide sequence. Fragments of a MAR nucleotide sequence may retain biological activity and hence bind to purified nuclear matrices and/or alter the expression patterns of coding sequences operably linked to a promoter. Fragments of a MAR nucleotide sequence may range from at least about 100 to 1000 bp, preferably from about 200 to 700 bp, more preferably from about 300 to 500 bp nucleotides. Also envisioned are any combinations of fragments, which have the same number of nucleotides present in a synthetic MAR sequence consisting of natural MAR element and/or fragments. The fragments are preferably assembled by linker sequences. Preferred linkers are Bglil-BamH| linker. “Protein production increasing activity” refers to an activity of the purified and isolated

DNA sequence defined as follows: after having been introduced under suitable conditions into a eukaryotic host cell, the sequence is capable of increasing protein ~ production levels in cell culture as compared to a culture of cell transfected without said

DNA sequence. Usually the increase is 1.5 to 10 fold, preferably 4 to 10 fold. This corresponds fo a production rate or a specific celiular productivity of at least 10 pg per cell per day {see Example 11 and Fig.13).

As used herein, the following definitions are supplied in order to facilitate the understanding of this invention. "Chromatin" is the protein and nucleic acid material constituting the chromosomes of a eukaryotic cell, and refers to DNA, RNA and associated proteins.

A "chromatin element" means a nucleic acid sequence on a chromosome having the property to modify the chromatine structure when integrated into that chromosome. "Cis" refers to the placement of two or more elements (such as chromatin elements) on the same nucleic acid molecule (such as the same vector, plasmid or chromosome). "Trans" refers to the placement of two or more elements (such as chromatin elements) 40 on two or more different nucleic acid molecules (such as on two vectors or two chromosomes).

Chromatin modifying elements that are potentially capable of overcoming position effects, and hence are of interest for the development of stabie cell lines, include 45 boundary elements (BEs), matrix attachment regions (MARS), locus control regions (LCRs), and universal chromatin opening elements (UCOEs).

Boundary elements ("BEs"}, or insulator elements, define boundaries in chromatin in many cases (Bell A and Felsenfeld G. 1999; “Stopped at the border: boundaries and 50 insulators, Curr Opin Genet Dev 9, 181-198) and may play a role in defining a transcriptional domain in vivo. BEs lack infrinsic promoter/enhancer activity, but rather are thought to protect genes from the transcriptional influence of regulatory elements in the surrounding chromatin. The enhancer-biock assay is commonly used to identify insulator elements. In this assay, the chromatin element is placed between an enhancer and a promoter, and enhancer-activated transcription is measured. Boundary elements have been shown to be able to protect stably transfected reporter genes against position effects in Drosophila, yeast and in mammalian cells. They have also been shown to increase the proportion of transgenic mice with inducible transgene expression.

Locus control regions ("LCRs") are cis-regulatory elements required for the initial chromatin activation of a locus and subsequent gene transcription in their native locations (Grosveld, F. 1999, "Activation by locus control regions?” Curr Opin Genet

Dev 9, 152-157). The activating function of LCRs also allows the expression of a coupled transgene in the appropriate tissue in transgenic mice, irrespective of the site of integration in the host genome. While LCRs generally confer tissue-specific levels of expression on linked genes, efficient expression in nearly all tissues in transgenic mice has heen reported for a truncated human T-cell receptor LCR and a rat LAP LCR. The most extensively characterized LCR is that of the globin locus. Its use in vectors for the gene therapy of sickle cell disease and (3-thalassemias is currently being evaluated. "MARS", according to a well-accepted model, may mediate the anchorage of specific

DNA sequence io the nuclear matrix, generating chromatin loop domains that extend outwards from the heterochromatin cores. While MARs do not contain any obvious consensus of recognizable sequence, their most consistent feature appears to be an overall high A/T content, and C bases predominating on one strand (Bode J, Schlake T,

RiosRamirez M, Mielke C, Stengart M, Kay V and KlehrWirth D, “Scaffold/matrix- attached regions: structural propreties creating transcriptionally active loci’, Structural and Functional Organization of the Nuclear Matrix: International Review of Citology, 162A:389453, 1295). These regions have a propensity to form bent secondary structures that may be prone to strand separation. They are often referred to as base- ~ unpairing regions (BURSs), and they contain a core-unwinding element (CUE) that might represent the nucleation point of strand separation (Benham C and al., Stress induced duplex DNA destabilization in scaffold/matrix attachment regions, J. Mol. Biol, 274:181- 196, 1987). Several simple AT-rich sequence motifs have often been found within MAR sequences, but for the most part, their functional importance and potential mode of action remain unclear. These include the A-hox {AATAAAYAAA), the T-box (TTWTWTTWTT), DNA unwinding motifs (AATATATT, AATATT), SATB1 binding sites (H-box, AfT/C25} and consensus Topoisomerase Il sites for vertebrates (RNYNNCNNGYNGKTNYNY) or Drosophila (GTNWAYATTNATNNR).

Ubiquitous chromatin opening elements ("UCCEs", also known as "ubiquitously-acting 40 chromatin opening elements") have been reported in WO 00/05393.

An "enhancer" is a nucieotide sequence that acts to potentiate the transcription of genes independent of the identity of the gene, the position of the sequence in relation to the gene, or the orientation of the sequence. The vectors of the present invention 45 optionally include enhancers.

A "gene" is a deoxyribonucleotide {DNA) sequence coding for a given mature protein.

As used herein, the term "gene" shall not include untranslated flanking regions such. as . RNA transcription initiation signals, polyadenylation addition sites, promoters or 50 enhancers.

A "product gene” is a gene that encodes a protein product having desirable characteristics such as diagnostic or therapeutic utility. A product gene includes, e. g.,

structural genes and regulatory genes.

A "structural gene" refers to a gene that encodes a structural protein. Examples of structural genes include but are not limited to, cytoskeletal proteins, extracellular matrix proteins, enzymes, nuclear pore proteins and nuclear scaffold proteins, jon channels and transporters, contractile proteins, and chaperones. Preferred structural genes encode for antibodies or antibody fragments.

A "regulatory gene" refers fo a gene that encodes a regulatory protein. Examples of regulatory proteins include, but are not limited to, franscription factors, hormones, growth factors, cytokines, signal transduction molecules, oncogenes, proto-oncogenes, transmembrane receptors, and protein kinases. "Orientation" refers to the order of nucleotides in a given DNA sequence. For example, an inverted orientation of a DNA sequence is one in which the 5' to 3' order of the sequence in relation to another sequence is reversed when compared to a point of reference in the DNA from which the sequence was obtained. Such reference points can include the direction of transcription of other specified DNA sequences in the source DNA and/or the origin of replication of replicable vectors containing the sequence. "Eukaryotic cell" refers to any mammalian or non-mammalian cell from a eukaryotic organism. By way of non-limiting example, any eukaryotic cell that is capable of being maintained under cell culture conditions and subsequently transfected would be included in this invention. Especially preferable cell types include, e. g., stem cells, embryonic stem cells, Chinese hamster ovary cells (CHO), COS, BHK21, NIH3T3,

Hela, C2C12, cancer cells, and primary differentiated or undifferentiated cells. Other suitable host cells are known to those skilled in the art.

The terms "host cell" and "recombinant host cell” are used interchangeably herein to indicate a eukaryotic cell into which one or more vectors of the invention have been introduced. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

The terms “introducing a purified DNA into a eukaryotic host cell" or “transfection” denote any process wherein an extracellular DNA, with or without accompanying 40 material, enters a host cell. The term "cell transfected” or "transfected cell’ means the cell into which the extracellular DNA has been introduced and thus harbours the extracellular DNA. The DNA might be introduced into the cell so that the nucleic acid is replicable either as a chromosomal integrant or as an extra chromosomal element. 45 "Promoter" as used herein refers to a nucleic acid sequence that regulates expression of a gene, "Co-transfection” means the process of transfecting a eukaryotic cell with more than one exogenous gene, or vector, or plasmid, foreign to the cell, one of which may confer 50 a selectable phenotype on the cell.

The purified and isolated DNA sequence having protein production increasing activity also comprises, besides one or mere bent DNA element, at least one binding site for a

DNA binding protein.

Usually the DNA binding protein is a transcription factor. Examples of transcription factors are the group comprising the polyQpolyP domain proteins.

Another example of a transcription factor is a transcription factor selected from the group comprising SATB1, NMP4, MEF2, S8, DLX1, FREACY, BRN2, GATA 1/3, TATA,

Bright, MSX, AP1, C/EBP, CREBP1, FOX, Freac?, HFH1, HNF3aipha, Nkx25, POUSFZ, Pit1, TTF1, XFD1, AR, C/EBPgamma, Cdcs, FOXD3, HFH3, HNF3 beta,

MRF2, Octt, POUSBF1, SRF, VSMTATA_B, XFD2, Bach2, CDP CR3, Cdx2, FOXJ2Z,

HFL, HP1, Myc, PBX, Pax3, TEF, VBP, XFD3, Brn2, COMP1, Evil, FOXP3, GATA4,

HEN, Lhx3, NKX3A, POU1F1, Pax8, TFI!A or a combination of two or more of these ~ transcription factors are preferred, Most preferred are SATB1, NMP4, MEF2 and polyQpolyP domain proteins.

SATB1, NMP4 and MEF2, for example, are known to regulate the development and/or tissue-specific gene expression in mammals. These transcription factors have the capacity {o alter DNA geometry, and reciprocally, binding to DNA as an allosteric ligand madifies their structure. Recently, SATB1 was found to form a cage-like structure circumscribing heterochromatin (Cai §, Han HJ , and Kohwi-Shigematsu T, "Tissue- specific nuclear architecture and gene expression regulated by SATB1" Nat Genet, 2D03. 34(1): p. 42-51).

Yet another object of the present invention is fo provide a purified and isolated cLysMAR element and/or fragment, a sequence complementary thereof, a part thereof sharing at feast 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants.

More preferably, the cLysMAR element and/or fragment are consisting of at least one nucleotide sequence selected from the B, K and F regions. . A further object of the present invention is to provide a synthetic MAR sequence comprising natural MAR element and/or fragments assembled between linker sequences.

Preferably, the synthetic MAR sequence comprises a cLysMAR element and/or fragment a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants. 40 Also preferably, linker sequences are Bglll-BamH] linker.

An other aspect of the invention is to provide a method for identifying a MAR sequence using a Bioinformatic tool comprising the computing of vaiues of one or more DNA sequence features corresponding to DNA bending, major groove depth and minor 45 groove width potentials and melting temperature. Preferably, the identification of one or mare DNA sequence features further comprises a further DNA sequence feature corresponding to binding sites for DNA binding proteins, which is also computed with this method. 50 Preferably, profiles or weight-matrices of said bioinformatic tool are based on dinucleotide recognition.

The bioinformatic tool used for the present method is preferably, SMAR Scan®, which contains algorithms developed by Gene Express (hitp://srs6.bionet.nsc.ru/srsébin/cgi- bin/wgetz?-e+[FEATURES-SitelD:'nR’]) and based on Levitsky ef al., 1998. These algorithms recognise profiles, based on dinucleotides weight-matrices, to compute the theoretical values for conformational and physicochemical properties of DNA.

Preferably, SMAR Scan® uses the four theoretical criteria also designated as DNA sequence features corresponding to DNA bending, major groove depth and minor groove width potentials, melting temperature in all possible combination, using scanning windows of variable size (see Fig. 3). For each function used, a cut-off value has to be set. The program returns a hit every time the computed score of a given region is above the set cut-off value for ali of the chosen criteria. Two data output modes are available ~ to handle the hits, the first (called "profile-like") simply returns all hit positions on the query sequence and their corresponding values for the different criteria chosen. The second mode (called "contiguous hits ") returns only the positions of several contiguous hits and their corresponding sequence. For this mode, the minimum number of contiguous hits is another cut-off value that can be set, again with a tunable window size. This second mode is the default mode of SMAR Scan®. Indeed, from a semantic point of view, a hit is considered as a core-unwinding element (CUE), and a cluster of CUEs accompanied by clusters of binding sites for relevant proteins is considered as a

MAR. Thus, SMAR Scan® considers only several contiguous hits as a potential MAR.

To tune the default cut-off values for the four theoretical structural criteria, experimentally validated MARs from SMARt DB (http:./transfac.gbf.de/- SMARt DB) were used. All the human MAR sequences from the database were retrieved and analyzed with SMAR Scan® using the "profile-like" mode with the four criteria and with no set cut-off value. This allowed the setting of each function for every position of the sequences. The distribution for each criterion was then computed according to these data {see Fig. 1 and 3).

The default cut-off values of SMAR Scan® for the bend, the major groove depth and the minor groove width were set at the average of the 75th quantile and the median. ~ For the melting temperature, the default cut-off value should be set at the 75th quantile.

The minimum length for the “contiguous-hits” mode should be set to 300 because it is assumed to be the minimum length of a MAR (see Fig. 8 and 9). However, one skilled in the art would be able to determine the cut-off values for the above-mentioned criteria for a given organism with minimal experimentation. 40 Preferably, DNA bending values are comprised between 3 to 5 ° (radial degree). Most preferably they are situated between 3.8 to 4.4 °, corresponding to the smallest peak of

Fig. 1.

Preferably the major groove depth values are comprised between 8.910 9.3 A 45 (Angstrom) and minor groove width values between 5.2 to 5.8 A. Most preferably the major groove depth values are comprised between 9.0 to 9.2 A and minor groove width values between 5.4 to 5.7 A.

Preferably the melting temperature is comprised between 55 to 75 ° C (Celsius degree). 50 Most preferably, the melting temperature is comprised between 55 to 62 ° C.

The DNA binding protein of which values can be computed by the method is usually a transcription factor preferably a polyQpolyP domain or a transcription factor selected from the group comprising SATB1, NMP4, MEF2, S8, DLX1, FREAC7, BRN2, GATA 1/3, TATA, Bright, MSX, AP1, C/EBP, CREBP1, FOX, Freac?, HFH1, HNF3alpha,

Nkx25, POU3F2, Pit1, TTF1, XFD1, AR, C/EBPgamma, Cdc5, FOXD3, HFH3, HNF3 beta, MRF2, Oct1, POUBF1, SRF, VSMTATA_B, XFD2, Bach2, CDP CR3, Cdx2,

FOXJ2, HFL, HP1, Myc, PBX, Pax3, TEF, VBP, XFD3, Brn2, COMP1, Evil, FOXP3,

GATA4, HFN1, Lhx3, NKX3A, POU1F1, Pax, TFHA or a combination of two or more of these transcription factors.

However, one skilled in the art would be able to determine other kinds of transcription factors in order to carry out the method according to the present invention.

In case SMAR Scan® is envisaged to perform, for example, large scale analysis, then, preferably, the above-mentioned method further comprises at least one filter predicting

DNA binding sites for DNA transcription factors in order to reduce the computation. .

The principle of this method combines SMAR Scan® to compute the structural features as described above and a filter, such as for example, the pfsearch, (from the pftools package as described in Bucher P, Karplus K, Moeri N, and Hofmann K, “A flexible search technique based on generalized profiles”, Computers and Chemistry , 20.324, 1996) to predict the binding of some transcription factors.

Examples of filters comprise, but are not limited to, pfsearch, Matinspector, RMatch

Professional and TRANSFAC Professional

This combined method uses the structural features of SMAR Scan® and the predicted binding of specific transcription factors of the filter that can be applied sequentially in any order to select MARS, therefore, depending on the filter is appiied at the beginning or at the end of the method.

The first level selects sequences out of the primary input sequence and the second level, consisting in the filter, may be used to restrain among the selected sequences those which satisfy the criteria used by the filter.

In this combined method the filter detects clusters of DNA binding sites using profiles or - weightmatrices from, for example, Matinspector (Quandt K, Frech K, Karas H,

Wingender E, Werner T, “Matind and Matinspector New fast and versatile tools for detection of consensus matches in nucleotide sequence data”, Nucleic Acids Research , 23, 48784884, 1995). The filter can also detect densities of clusters of DNA binding 40 sites.

The combined method is actually a "wrapper" written in Perl for SMAR Scan® and, in case the pfsearch is used as a filter, from the pftools. The combined method performs a twolevel processing using at each level one of these tools (SMAR Scan® or filter) as a 45 potential “filter”, each filter being optional and possible to be used to compute the predicted features without doing any filtering.

If SMAR Scan® is used in the first level to filter subsequences, it has to be used with the "all the contiguous hits” mode in order to retum sequences. If the pfsearch is used 50 in the first level as first filter, it has to be used with only one profile and a distance in nucleotide needs to be provided. This distance is used to group together pfsearch hits that are located at a distance inferior to the distance provided in order to return sequences, The combined method launches pfsearch, parses its output and returns sequences corresponding to pfsearch hits that are grouped together according to the distance provided. Then whatever the tool used in the first level, the length of the sub- sequences thus selected can be systematically extended at both ends according to a parameter called "hits extension”.

The second and optional level can be used to filter out sequences (already filtered sequences or unfiltered input sequences) or to get the results of SMAR Scan® and/or pfsearch without doing any filtering on these sequences. If the second level of combined method is used to filter, for each criteria considered cutoff values (hit per nucleotide)need to be provided to filter out those sequences (see Fig. 20}.

Another concern of the present invention is also to provide a method for identifying a

MAR sequence comprising at least one filter detecting clusters of DNA binding sites using profiles or weightmatrices. Preferably, this method comprises two levels of filters 16 and in this case, SMAR Scan® is totally absent from said method. Usually, the two levels consist in pfsearch.

Also embraced by the present invention is a purified and isolated MAR DNA sequence identifiable according to the method for identifying a MAR sequence using the described bioinformatic tool, the combined method or the method comprising at least one filter.

Analysis by the combined method of the whole human genome yielded a total of 1757 putative MARs representing a total of 1 085 305 base paires. In order to reduce the number of results, a dinucleotide analysis was performed on these 1757 MARS, computing each of the 18 possible dinucleotide percentage for each sequence considering both strands in the &’ to 3' direction.

Surprisingly, Applicants have shown that all of the “super” MARs detected with the combined method contain at least 10% of dinucleotide TA on a stretch of 100 contiguous base pairs. Preferably, these sequences contain at least 33% of dinucleotide TA on a stretch of 100 contiguous base pairs.

Applicants have also shown that these same sequences further contain at least 12% of dinucleotide AT on a stretch of 100 contiguous base pairs. Preferably, they contain at least 33% of dinucleotide AT on a stretch of 100 contiguous base pairs.

An other aspect of the invention is to provide a purified and isolated MAR DNA sequence of any of the preceding described MARs, comprising a sequence selected from the sequences SEQ ID Nos 1 fo 27, a sequence complementary thereof, a part 40 thereof sharing at least 70% nucleotides in length, a molecular chimera therecf, a combination thereof and variants.

Preferably, said purified and isolated MAR DNA sequence comprises a sequence selected from the sequences SEQ ID Nos 24 to 27, a sequence complementary thereof, a part thereof sharing at least 70% nuclectides in length, a molecular chimera 45 thereof, a combination thereof and variants. These sequences 24 to 27 correspond to those detected by the combined method and show a higher protein production increasing activity over sequences 1 {o 23.

The present invention alsc encompasses the use of a purified and isolated DNA 50 sequence comprising a first isolated matrix attachment region (MAR) nucleotide sequence which is a MAR nucleotide sequence selected from the group comprising

- a purified and isolated DNA sequence having protein production increasing activity, - a Surified and isolated MAR DNA sequence identifiable according to the method for identifying a MAR sequence using the described bioinformatic tool, the combined method or the method comprising at least one filter, - the sequences SEQ ID Nos 1 to 27, - a purified and isolated cLysMAR element and/or fragment, . a synthetic MAR sequence comprising natural MAR element and/or fragments assembled between linker sequences, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants or a MAR nucleotide sequence of a cLysMAR element and/or fragment, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants for increasing protein production activity in a eukaryotic host cell.

Said purified and isolated DNA sequence usually further comprises one or more regulatory sequences, as known in the art e.g. a promoter and/or an enhancer, polyadenylation sites and splice junctions usually employed for the expression of the protein or may optionally encode a selectable marker. Preferably said purified and isolated DNA sequence comprises a promoter which is operably linked to a gene of interest.

The DNA sequences of this invention can be isolated according to standard PCR protocols and methods well known in the art.

Promoters which can be used provided that such promoters are compatible with the host cell are, for example, promoters obtained from the genomes of viruses such as polyoma virus, adenovirus (such as Adenovirus 2), papilloma virus (such as bovine papilloma virus), avian sarcoma virus, cytomegalovirus (such as murine or human cytomegalovirus immediate early promoter), a retrovirus, hepatitis-B virus, and Simian

Virus 40 {such as SV 40 early and late promoters) or promoters obtained from heterologous mammalian promoters, such as the actin promoter or an immunoglobulin promoter or heat shock promoters. Such regulatory sequences direct constitutive expression.

Furthermore, the purified and isolated DNA sequence might further comprise regulatory sequences which are capable of directing expressian of the nucleic acid preferentially in a particular cell type {(e. g., tissue-specific regulatory elements are used to express the 40 nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promater (liver- specific; Pinkert,et al., 1987. Genes Dev.1: 268-277), lymphoid-specific promoters {Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBOJ. 8; 729-733) and immunoglobulins 45 (Banerji, etal., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Celi 33:741-748), neuron-specific promoters (e. g., the neurofilament promoter;Byrne and Ruddls, 1989.

Proc.Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-816), and mammary gland-specific promoters (e. g., milk whey promoter, U, 5S. Pat. No. 4,873,316 and European Application No. 264,166). 50

Developmentally-reguiated promoters are also encompassed. Examples of such promoters include, e.g., the murine hox promoters (Kessel and Gruss, 1990, Science 249: 374-379) and thea-fetoprotein promoter (Campes and Tilghman, 1989. Genes

Dev. 3: 537-548).

Regulatable gene expression promoters are well known in the art, and include, by way of non-limiting example, any promoter that modulates expression of a gene encoding a desired protein by binding an exogenous molecule, such as the CRE/LOX system, the

TET system, the doxycycline system, the NFkappaB/UV light system, the

Leu3p/isopropyimalate system, and theGLVPc/GAL4 system (See e. g., Sauer, 1998,

Methods 14 (4): 381-92 ; Lewandoski, 2001, Nat. Rev, Genet 2 (10): 743-55; Legrand-

Poels et al., 1998, J. Photochem. Photobiol. B. 45: 18; Guo et al., 1996, FEBS Lett. 390 (2): 191-5, Wang et al., PNAS USA, 1999,06 (15): 84838).

However, one skilled in the art would be able te determine other kinds of promoters that are suitable in carrying out the present invention.

Enhancers can he optionally included in the purified DNA sequence of the invention then belonging to the regulatory sequence, e.g. the promoter.

The “gene of interest” or “transgene” preferably encodes a protein (structural or regulatory protein). As used herein “protein” refers generally to peptides and polypeptides having more than about ten amino acids. The proteins may be “homologous” to the host (i.e., endogenous to the host cell being utilized), or heterologous,” (i.e., foreign to the host cell being utilized), such as a human protein produced by yeast. The protein may be produced as an insoluble aggregate or as a soluble protein in the periplasmic space or cytoplasm of the cell, or in the extraceliuiar medium. Examples of proteins Include hormones such as growth hormone or erythropoietin (EPO), growth factors such as epidermal growth factor, analgesic substances like enkephalin, enzymes like chymotrypsin, receptors to hormones or growth factors, antibodies and include as well proteins usually used as a visualizing marker e.g. green fluorescent protein.

Preferably the purified DNA sequence further comprises at least a second isolated matrix attachment region {MAR) nucleotide sequence selected from the group comprising - a purified and isolated DNA sequence having protein production increasing activity, - a purified and isolated MAR DNA sequence identifiable according to the method for identifying a MAR sequence using the described bioinformatic tool, the combined method or the method comprising at least one filter, - the sequences SEQ ID Nos 1 to 27, - a purified and isolated cLysMAR element and/or fragment, 40 - a synthetic MAR sequence comprising natural MAR element and/or fragments assembled between linker sequences, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants. The isolated matrix attachment region (MAR) nucleotide sequence might be identical or different. 45 Alternatively, a first and a second identical MAR nucleotide sequence are used.

Preferably, the MAR nucleotide sequences are located at both the 5’ and the 3’ ends of the sequence containing the promoter and the gene of interest. But the invention also envisions the fact that said first and or at least second MAR nucleotide sequences are 50 located on a sequence distinct from the one containing the promoter and the gene of interest.

Embraced by the scope of the present invention is aiso the purified and isolated DNA sequence comprising a first isolated matrix attachment region (MAR) nucleotide sequence which is a MAR nucleotide sequence selected from the group comprising - a purified and isolated DNA sequence having protein production increasing activity, - a purified and isolated MAR DNA sequence identifiable according to the method for identifying a MAR sequence using the described bioinformatic tool, the combined method or the method comprising at least one filter, - the sequences SEQ ID Nos 110 27, - a purified and isolated cLysMAR element and/or fragment, - a synthetic MAR sequence comprising natural MAR element and/or fragments assembled between linker sequences, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants that can be used for increasing protein production activity in a eukaryotic host cell by introducing the purified and isolated DNA sequence into a eukaryotic host cell according to well known protocols. Usually applied methods for introducing DNA into eukaryotic host cells applied are e.g. direct introduction of cloned DNA by microinjection or microparticle bombardment; electrotransfer ;use of viral vectors: encapsulation within a carrier system; and use of transfecting reagents such as calcium phosphate, diethylaminoethyl (DEAE) —dextran or commercial transfection systems like the Lipofect-AMINE 2000 (Invitrogen). Preferably, the transfection method used to introduce the purified DNA sequence into a eukaryotic host cell is the method for fransfecting a eukaryotic cell as described below,

The purified and isolated DNA sequence can be used in the form of a circular vector.

Preferably, the purified and isolated DNA sequence is used in the form of a linear DNA sequence as vector.

As used herein, "plasmid" and "vector" are used interchangeably, as the plasmid is the most commonly used vector form. However, the invention is intended to include such other forms of expression vectors, including, but not limited to, viral vectors (e. g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which 3 serve equivalent functions.

The present invention further encompasses a method for transfecting a eukaryotic host cell, said method comprising a) introducing into said eukaryotic host cell at least one purified DNA sequence comprising at least one DNA sequence of interest and/or at least one purified 40 and isolated DNA sequence comprising a MAR nucleotide sequence or other chromatin modifying elements, b) subjecting within a defined time said transfected eukaryotic host cell to at least one additional transfection step with at least one purified DNA sequence comprising at least one DNA sequence of interest and/or with at least one 45 purified and isolated DNA sequence comprising 2a MAR nucleotide sequence or other chromatin modifying elements c) selecting said transfected eukaryotic host cell.

Preferably at least two up to four transfecting steps are applied in step b). 50

In order to select the successfui transfected cells, a gene that encodes a selectable marker (e. g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. The gene that encodes a selectable marker might be located on the purified DNA sequence comprising at least one DNA sequence of interest and/or at least one purified and isolated DNA sequence consisting of a MAR nucleotide sequence or other chromatin modifying elements or might optionally be co-introduced in separate form e.g. on a plasmid. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. The amount of the drug can be adapted as desired in order to increase productivity

Usually, one or more selectable markers are used. Preferably, the selectable markers used in each distinct transfection steps are different. This allows selecting the transformed cells that are “multi-transformed” by using for example two different antibiotic selections.

Any eukaryotic host cell capable of protein production and lacking a cell wall can be used in the methods of the invention. Examples of useful mammalian host cell lines include human celis such as human embryonic kidney line (293 or 2983 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol 36, 59 (1977)), human cervical carcinoma celts (HELA, ATCC CCL 2), human lung cells (W138, ATCC CCL 75), human liver cells (Hep G2, HB 8085); rodent cells such as baby hamster kidney cells (BHK, ATCC CCL 10), Chinese hamster ovary cells/-DHFR (CHO, Urlaub and

Chasin, Proc. Natl. Acad. Sci. USA, 77, 4216 (1980)), mouse sertoli cells (TM4, Mather,

Biol. Reprod 23, 243-251 (1980)), mouse mammary tumor (MMT 060562, ATCC

CCL51}; and cells from other mammals such as monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1851); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); canine kidney cells (MDCK,

ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); myeloma (e.g. NSO) ~ [hybridoma cells.

Preferably, the selected transfected eukaryotic host cells are high protein producer cells with a production rate of at least 10 pg per cell per day.

Most preferred for uses herein are mammalian cells, more preferred are CHO cells.

The DNA sequence of interest of the purified and isolated DNA sequence is usually a gene of interest preferably encoding a protein operably linked to a promoter as described above. The purified and isclated DNA sequence comprising at least one DNA sequence of interest might comprise additionally to the DNA sequence of interest MAR nucleotide sequence or other chromatin modifying elements.

Purified and isolated DNA sequence comprising a MAR nucleotide sequence are for example selected from the group comprising the sequences SEQ ID Nos 1 to 27 and/or particular elements of the cLysMAR e.g. the B, K and F regions as well as fragment and 40 elements and combinations thereof as described above. Other chromatin modifying elements are for example boundary elements (BEs), locus control regions (LCRs), and universai chromatin opening elements (UCOESs) (see Zahn-Zabal et al. already cited).

An example of multiple transfections of host cells is shown in Exampie 12 (Table 3).

The first transfecting step (primary transfection) is carried out with the gene of interest 45 (SV40EGFP) alone, with a MAR nucleotide sequence (MAR) alone or with the gene of interest and a MAR nucleotide sequence (MAR-SV40EGFP). The second transfecting step (secondary transfection) is carried out with the gene of interest {SV40EGFP) alone, with a MAR nucleotide sequence (MAR) alone or with the gene of interest and a

MAR nuclectide sequence (MAR-SV40EGFP}), in all possible combinations resuiting 50 from the first fransfecting step.

Preferably the eukaryotic host cell is transfected by:

a) introducing a purified DNA sequence comprising one DNA sequence of interest and additionally a MAR nucleotide sequence, b) subjecting within a defined time said transfected eukaryotic host cell to at least one additional transfection step with the same purified DNA sequence comprising one DNA - sequence of interest and additionally a MAR nucleotide sequence of step a).

Also preferably, the MAR nucleotide sequence of the of the purified and isolated DNA sequence is selected form the group comprising - apurified and isolated DNA sequence having protein production increasing activity, - apurified and isolated MAR DNA sequence identifiable according to the method for identifying a MAR sequence using the described bicinformatic tool, the combined method or the method comprising at least one filter, - the sequences SEQ ID Nos 110 27, - a purified and isolated cLysMAR element and/or fragment, - asynthetic MAR sequence comprising natural MAR element and/or fragments assembled between linker sequences, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants.

Surprisingly, a synergy between the first and second transfection has been observed. A particular synergy has been observed when MAR elements are present at one or both of the transfection steps. Muitipte transfections of the cells with pMAR alone or in combination with various expression plasmids, using the method described above have been carried out. For example, Table 3 shows that transfecting the cells twice with the

PMAR-SVA0EGFP piasmid gave the highest expression of GFP and the highest degree of enhancement of all conditions (4.3 fold). In contrast, transfecting twice the vector without MAR gave little or no enhancement, 2.8-fold, instead of the expected two-fold increase. This proves that the presence of MAR elements at each transfection step is of particular interest fo achieve the maximal protein synthesis.

As a particular example of the transfection method, said purified DNA sequence comprising at least one DNA sequence of interest can be introduced in form of multiple unlinked plasmids, comprising a gene of interest operably linked to a promoter, a selectable marker gene, and/or protein production increasing elements such as MAR sequences.

The ratio of the first and subsequent DNA sequences may be adapted as required for the use of specific cell types, and is routine experimentation to one ordinary skilled in the art. : 40

The defined time for additional transformations of the primary transformed cells is tightly dependent on the cell cycle and on its duration. Usually the defined time corresponds to intervals related to the celi division cycle. ~ Therefore this precise timing may be adapted as required for the use of specific cell 45 types, and is routine experimentation to one ordinary skilled in the art.

Preferably the defined time is the moment the host cell just has entered into the same phase of a second or a further cell division cycle, preferably the second cycle.

This time is usually situated between 6h and 48 h, preferably between 20h and 24h after the previous transfecting event. 30

Also encompassed by the present invention is a method for transfecting a eukaryotic host cell, said method comprising co-transfecting into said eukaryotic host cell at least one first purified and isolated DNA sequence comprising at least one DNA sequence of interest, and a second purified DNA comprising at least one MAR nucleotide selected from the group comprising: - a purified and isclated DNA sequence having protein production increasing activity, - a purified and isofated MAR DNA sequence identifiable according to the method for identifying a MAR sequence using the described bioinformatic tool, the combined method or the method comprising at least one filter, - the sequences SEQ ID Nos 1 to 27, - a purified and isolated cLysMAR element and/or fragment, - a synthetic MAR sequence comprising natural MAR element and/or fragments assembled between linker sequences, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants.

Said first purified and isolated DNA sequence can also comprise at least one MAR nucleotide as described above.

Also envisioned is a process for the production of a protein wherein a eukaryotic host cell is transfected according to the transfection methods as defined in the present invention and is cultured in a culture medium under conditions suitable for expression of the protein. Said protein is finally recovered according to any recovering process known tothe skilled in the art.

Given as an example, the following process for protein production might be used.

The eukaryotic host cell transfected with the transfection method of the present invention is used in a process for the production of a protein by culturing said cell under conditions suitable for expression of said protein and recovering said protein. Suitable cuiture conditions are those conventionally used for in vitro cultivation of eukaryotic cells as described e.g. in WO 96/39488. The protein can be isolated from the cell culture by conventional separation techniques such as e.g. fractionation on immunoaffinity or ion-exchange columns; precipitation; reverse phase HPLC; chromatography; chromatofocusing; SDS-PAGE; gel filtration. One skilled in the art will appreciate that purification methods suitable for the polypeptide of interest may require modification {o account for changes in the character of the polypeptide upon expression in recombinant cell culture.

The proteins that are produced according fo this invention can be tested for functionality by a variety of methods. For example, the presence of antigenic epitopes and ability of the proteins to bind ligands can be determined by Western blof assays, fluorescence cell sorting assays, immunoprecipitation, immunochemical assays and/or competitive binding assays, as well as any other assay which measures specific binding 40 activity.

The proteins of this invention can be used in a number of practical applications including, but not limited to: 1. Immunization with recombinant host protein antigen as a viral/pathogen antagonist. 45 - 2. Production of membrane proteins for diagnostic or screening assays. 3. Production of membrane proteins for biochemical studies. 4. Production of membrane protein for structural studies. 3. Antigen production for generation of antibodies for immuno-histochemical mapping, including mapping of orphan receptors and ion channels, 50

Also provided by the present invention is a eukaryotic host cell fransfected according to any of the preceding transfection methods. Preferably, the eukaryctic host cell is a mammatian host cell line,

As already described, example of useful marmmalian host cell lines include human cells such as human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol 36, 58 (1977)), human cervical carcinoma cells (HELA, ATCC CCL 2), human tung cells (W138, ATCC CCL 75), human liver cells (Hep G2, HB 8065); rodent cells such as baby hamster kidney cells (BHK, ATCC CCL 10), Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin,

Proc. Natl. Acad. Sci. USA, 77, 4216 {1980)), mouse sertoli cells (TM4, Mather, Bio: - Reprod 23, 243-251 (1980), mouse mammary tumor (MMT 060562, ATCC CCL51); and cells from other mammals such as monkey kidney CV1 line transformed by SV40 {COS-7, ATCC CRL 1651); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587}; canine kidney cells (MDCK, ATCC

CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); myeloma (e.g. NSO} thybridoma cells.

Most preferred for uses herein are CHO cells.

The present invention also provides for a cell transfection mixture or Kit comprising at least one purified and isolated DNA sequence according to the invention.

The invention further comprises a transgenic organism wherein at least some of its cells have stably incorporated at least one DNA sequence of - a purified and isolated DNA sequence having protein production increasing activity, : - a purified and isolated MAR DNA sequence identifiable according to the method for identifying a MAR sequence using the described bioinformatic tool, the combined method or the method comprising at least one filter, - the sequences SEQ ID Nos 1 to 27, - a purified and isolated cLysMAR element and/or fragment, - a synthetic MAR sequence comprising natural MAR element and/or fragments assembled between linker sequences, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants.

Preferably, some of the cells of the transgenic crganisms have been transfected according the methods described herein.

Also envisioned in the present invention is a transgenic organism wherein its genome has stably incorporated at least one DNA sequence of - a purified and i{sofated DNA sequence having protein production increasing activity, - a purified and isolated MAR DNA sequence identifiable according to the method 40 for identifying a MAR sequence using the described bioinformatic tool, the combined method or the method comprising at least one filter, «the sequences SEQ ID Nos 1 to 27, : - a purified and isolated cLysMAR element and/or fragment, - a synthetic MAR sequence comprising natural MAR element and/or fragments 45 assembied between linker sequences, a sequence complementary thereof, a part thereof sharing at least 70% nucleotides in length, a molecular chimera thereof, a combination thereof and variants. 50 Transgenic eukaryotic organisms which can be useful for the present invention are for example selected form the group comprising mammals (mouse, human, monkey stc) and in particular laboratory animals such as rodents in general, insects (drosophila,

etc), fishes (zebra fish, etc.), amphibians (frogs, newt, etc..) and other simpler prganisms such as c. elegans, yeast, etc....

Yet another object of the present invention is to provide a computer readable medium comprising computer-executable instructions for performing the method for identifying a

MAR sequence as described in the present invention.

The foregoing description will be more fully understood with reference to the following

Examples. Such Examples, are, however, exemplary of methods of practising the present invention and are not intended to limit the scope of the invention.

EXAMPLES

Example 1: SMAR Scan® and MAR sequences

A first rough evaluation of SMAR Scan® was done by analyzing experimentally defined human MARs and non-MAR sequences. As MAR sequences, the previous results from the analysis of human MARs from SMARt Db were used to plot a density histogram for each criterion as shown in Fig. 1. Similarly, non-MAR sequences were also analyzed and plotted. As non-MAR sequences, all Ref-Seq-contigs from the chromosome 22 were used, considering that this latter was big enough to contain a negligible part of

MAR sequences regarding the part of non-MAR sequences.

The density distributions shown in Fig. 1 are all skewed with a long tail. For the highest bend, the highest major groove depth and the highest minor groove width, the distributions are right skewed. For the lowest melting temperature, the distributions are left-skewed which is natural given the inverse correspondence of this criterion regarding the three others. For the MAR sequences, biphasic distributions with a second weak : peak, are actually apparent. And between MAR and non-MAR sequences distributions, a clear shift is also visible in each plot.

Ameng all human MAR sequences used, in average only about 70% of them have a value greater than the 75th quantile of human MARS distribution, this for the four different criteria. Similarly concerning the second weak peak of each human MARS distribution, only 15% of the human MAR sequences are responsible of these outlying values. Among these 15% of human MAR sequences, most are very well documented

MARs, used to insulate transgene from position effects, such as the interferon locus

MAR, the beta-globin locus MAR (Ramezani A, Hawley TS, Hawley RG, “Performance- and safety-enhanced lentiviral vectors containing the human interferoti-beta scaffold attachment region and the chicken beta-globin insulator”, Blood, 101:4717-4724, 2003), or the apolipoprotein MAR {Namciu, S, Blochinger KB, Fournier REK, "Human matrix attachment regions in-sulate transgene expression from chromosomal position effects in Drosophila melanogaster”, Mol. Cell. Biol, 18:2382-2391, 1998),

Always with the same data, human MAR sequences were also used to determine the association between the four theoretical structural properties computed and the AT- content. Fig. 2 represents the scatterplot and the corresponding correlation coefficient r ~ for every pair of criteria.

Example 2: Distribution plots of MAR sequences by organism 40

MAR sequences from SMARt DB of other organisms were also retrieved and analyzed similarly as explained previously. The MAR sequences density distributions for the mouse, the chicken, the sorghum bicolor and the human are plotted jointly in Fig. 3. 45 Example 3: MAR prediction of the whole chromosome 22

All RefSeq contigs from the chromosome 22 were analyzed by SMAR Scan® using the default settings this time. The result is that SMAR Scan® predicted a total of 803

MARs, their average length being 446 bp, which means an average of one MAR 50 predicted per 42 777 bp. The total length of the predicted MARS corresponds to 1% of the chromosome 22 length. The AT-content of the predicted regions ranged from

65,1% to 93.3%: the average AT-content of all these regions being 73.5%. Thus, predicted MARs were AT-rich, whereas chromosome 22 is not AT-rich (62.1% AT).

SMARTest was also used to analyze the whole chromosome 22 and obtained 1387

MAR candidates, their average length being 494 bp representing an average of one

MAR predicted per 24 765 bp. The total length of the predicted MARs corresponds to 2% of the chromosome 22. Between all MARs predicted by the two softwares, 154 predicted MARS are found by both programs, which represents respectively 19% and 11% of SMAR Scan® and SMARTest predicted MARs. Given predicted MARs mean length for SMAR Scan® and SMARTest, the probability to have by chance an overlapping between SMAR Scan® and SMARTest predictions is 0.0027% per prediction.

To evaluate the specificity of SMAR Scan® predictions, SMAR Scan® analyses were performed on randomly shuffled sequences of the chromosome 22 (Fig. 4). Shuffted sequences were generated using 4 different methods: by a segmentation of the chromosome 22 into nonoverlapping windows of 10 bp and by separately shuffling the nucleotides in each window; by "scrambling” which means a permutation of al! nucleotides of the chromosome; by "rubbling” which means a segmentation of the chro- mosome in fragments of 10 bp and a random assembling of these fragments and finally by order 1 Markov chains, the different states being the all the different DNA dinucleotides and the transition probabilities between these states being based on the chromosome 22 scan. For each shuffling method, five shuffled chromosome 22 were generated and analyzed by SMAR Scan® using the default settings. Concerning the number hits, an average of 3 519 170 hits (sd: 18 353) was found for the permutated chromosome 22 within nonoverlapping windows of 10 bp, 171 936,4 hits (sd: 2 859,04 } for the scrambled sequences and 24 708,2 hits (sd: 1 191,59) for the rubbled chromosome 22 and 2 282 hits in average (sd: 334,7) for the chromosomes generated according to order 1 Markov chains models of the chromosome 22, which respectively represents 185% (sd: 0.5% of the mean), 9% (sd: 1.5%), 1% (sd: 5%) and 0.1% (sd: 15%) of the number of hits found with the native chromosome 22. For the number of

MARS predicted, which thus means contiguous hits of length greater than 300, 1 997

MARs were predicted with the shuffled chromosome 22 within windows of 10 bp (sd: 31.2), only 2.4 MARs candidates were found in scrambled sequences (sd: 0.96) and none for the rubbled and for the sequences generated according to Markov chains model, which respectively represents 249% and {ess than 0.3% of the number of predicted MARs found with the native chromosome 22. These data provide indications that SMAR Scan® detects specific DNA elements which organization is lost when the 40 DNA sequences are shuffled .

Example 4: Analysis of known matrix attachment regions in the Interferon locus with SMAR Scan® 45 The relevance of MAR prediction by SMAR Scan® was investigated by analyzing the recently published MAR regions of the human interferon gene cluster on the short arm of chromosome 9 (9p22). Goetze et al. {already cited) reported an exhaustive analysis of the WP18A10A7 locus to analyze the suspected correlation between BURs (termed in this case stress-induced duplex destabilization or SIDD) and jn vitro binding to the 90 nuclear matrix (Fig. 9, lower part). Three of the SIDD peaks were in agreement with the in vitro binding assay, while others did not match matrix attachment sites. Inspection of the interferon locus with SMAR Scan® (Fig. 9, top part) indicated that three majors peaks accompanied by clusters of SATE1, NMP4 and MEFZ regulators binding sites correlated well with the active MARs. Therefore, we conclude that the occurrence of predicted CUEs and binding sites for these transcription factors is not restricted to the cLysMAR but may be a general property of all MARs. These results also imply that the ; SMAR Scan® program efficiently detects MAR elements from genomic sequences.

Example 5: Accuracy of SMAR Scan® prediction and comparison with other predictive tools

The accuracy of SMAR Scan® was evaluated using six genomic sequences for which experimentally determined MARS have been mapped. In order to perform a comparison with other predictive tools, the sequences analyzed are the same with the sequences previously used to compare MAR-Finder and SMARTest. These genomic sequences are three plant and three human sequences (Table 1) totalizing 310 151 bp and 37 experimentally defined MARS. The results for SMARTest and MAR-Finder in Table 1 come from a previous comparison (Frisch M, Frech K, Klingenhoff A, Cartharius K,

Liebich | and Werner T, In silico pre-diction of scaffold/matrix attachment regions in large genomic sequences, Genome Research, 12:349-354, 2001.).

MAR-Finder has been used with the default parameters excepted for the threshold that has been set to 0.4 and for the analysis of the protamine locus, the AT-richness rule has been excluded (to detect the non AT-rich MARs as was done for the protamine locus).

Senuence, dezcrption ength xperment- | ShARTest | WAR-FInder | EET and reference ally defined | prediction | prediction prediction

MARS positions positions positions ! positions (lib) {kb} (kh) {kb} {t)

Oryza Saliva putative 0.034 0.01.2 - - -

ADF-ilucose pta- 5.4-7.4 6.5.7.0 - - phosphandase subunit 152-157 15.7168 | 15.8-16

SH2 and putative : i IB2-16.6 - -

MALPH dependant {173-185 17.6-18.3 17.5-18.4 17.6~-18.2 rerluctase Al genes 200-231 19.6-20.1 | 19.8-204 21.6-22 (UTE). 2] 207-213 2LE21.5 - 238-238 23.9-24.2 234-258 260-25.4 247-251 - . 2TR-ZTR - -

Sarghum bicolor ADF- | 42 444 0.0-1.5 - . - glunosa putaphapho- P78 - - 74-77 rvlase subwrit SHE, 24.3-24.9 - 215-21.5

MADPH-depsndant 224-247 22.5-24.0 23.2242 229-232 recucatze All gengs - ~ 23.6-24.0

PAFOT02830, [4] 27276 26.0275 273-276 { E25-337 - - 334-339 bo41.6-42.3 - - -

Sorgum bicofor BAU REE (0.8 - - - clare 110K5 «58 - - - (BF 124045), [27] ~B.3 - - - 0.4 - - - : ~15.0 121-158 - - +. 18.5 - - ‘ -

I ~219 247-220 - 214-219

Po w23.3 - . - 200 - - - ~29 1 - - 202-205 “34.8 - . - - - 30.0-40.0 44.1 44.1.44.5 - =48.5 47.9-49.5 47.9-40.4 48.1-48.6 - - 48.2-40.3

I o.578 . - -

Ca B2.0 63.1.63.7 - - ~07.1 - - - ~F37 T4.5.74.7 - 74.3-74.6

Haman alpha-T-antitry- | 30.481 BH. 5.5.6.0 3.0-3.2 54-58 in and corticosteroid - 5.4-G.0 - binding glotulin 22.0-30.4 25.7.26.2 24.9.25.1 258-264 intergenic region 27.5.27.8 25.5-25.8 { (&F 1365451, [33] . 26.2.26.4 - i - 27.5-28.2 -

Herman protamine focus | 53.06 B.-97 4.0-8.0" - 372-304 33.9-34.9* - 51.8530 - -

Hemi beta-globin Fh LEG T.6-3.0 - - S20 loci i 16.6-12.0 18.0-18.4 15.5-16,0 15.3-15.0 (U0137), [21] - 18.0-18.4 - 2.4-34.9 - - 44. 7-527 - 50.6.50,8 | - 5G3.6-57.1 56.5-57 2 = . 60.0-70.0 59.8.60.3 58.1-58.5 $2.8-63.1 65.6-66.0 63.0-83.6 -

67.6-67.9 GB8.7-69.2 66.3-66.7 66.8-60.1 - -

Total numbers 37 28 25 22 fverage ki predicted 11.076 12.408 14.087 {BAR

True positives [umist IN 20012) i TPN) of experimentally defined MAR found]

False positives 0 a 5

False redatives 23 25 23

Specificity 10/28= 68% | 20/25= 80% | 17/22= 777%

Sensitivity 14237= 38% | 12/37= 32% | 14/37- 32%

Table 1; Evaluation of SMAR Scan® accuracy

Six different genomic sequences, three plant and three human sequences, for which experimentally defined MARs are known, were analyzed with MAR-Finder, SMARTest and SMAR Scan®. True positive matches are printed in bold, minus (-) indicates false negative matches. Some of the longer experimentally defined MARs contained more than one in silico prediction, each of them was counted as true positive match.

Therefore, the number of true in silico predictions is higher than the number of experimentally defined MARS found. Specificity is defined as the ratio of true positive predictions, whereas sensitivity is defined as the ratio of experimentally defined MARs found. * AT-rich rule excluded using MAR-Finder.

SMARTest predicted 28 regions as MARS, 12 (true positives) of these correlate with experimentally defined MARs (specificity. 68%) whereas 9 (32%) are located in non-

MARS (false positives). As some of the longest experimentally determined

MARs contains more than one in silico prediction, the 19 true positives correspond actually to 14 different experimentally defined MARS (sensitivity: 38%). MARFinder predicted 25 regions as MARs, 20 (specificity. 80%) of these correlate with experimentally defined MARS corresponding to 12 different experimentally defined

MARS (sensitivity: 32%). SMAR Scan® predicted 22 regions, 17 being true positives (specificity: 77%) matching 14 different experimentally defined MARSs (sensitivity: 38%). 25 . As another example, the same analysis has been applied to human chromosomes 1 and 2 and lead to the determination of 23 MARs sequences (SEQ |D N° 1 to 23). These sequences are listed in Annex 1 in ST25 format.

Example 6: Analyses of the whole genome using the combined method (SMAR

Scan®-pfsearch)

In order to test the potential correlation between the structural features computed by

SMAR Scan® and the S/MAR functional activity, the whole human genome has been analyzed with the combined method with very stringent parameters, in order to get sequences with the highest values for the theoretical structural features computed, which are calted "super" S/IMARs below. This was done with the hope to obtain predicted MAR elements with a very potential to increase transgene expression and recombinant protein production. The putative S/MARs hence harvested were first analyzed from the bioinformatics perpective in an attempt to characterize and classify 40 them.

6.1 S/MARs predicted from the analysis of the whole human genome

As whole human genome sequence, all human RefSeq (National Center for

Biotechnology Information, The NCBI handbook [Internet]. Bethesda (MD): National

Librasy of Medicine {US}, Oct. Chapter 17, The Reference Sequence (RefSeq) Project, 2002 (Available from http://www.ncbi.nih.gov/entrez/query.fcgi?db=Books) contigs (release 5) were used and analyzed with the combined method, using SMAR Scan® as filter in the first level processing, employing default settings except for the highest bend cutoff value, whereas a stringent threshold of 4.0 degrees (instead of 3.202 degrees) has been used for the DNA bending criterion.

In the second level processing, predicted transcription factors binding have been sought in the sequences selected from the previous step without doing any filtering on these sequences.

The analysis by the combined method of the whole human genome came up with a {otal of 1757 putative "super” S/IMARSs representing a total of 1 065 305 bp {0.35% of the whole human genome}. Table 2 shows for each chromosome: its size, its number of genes, its number of S/MARs predicted, its S/MARs density per gene and its kb per

S/MAR. This table shows that there are very various gene densifies per S/MAR - predicted for the different chromosomes (standard deviation represents more than 50% of the mean of the density of genes per S/IMAR predicted and the fold difference between the higher and the lower density of genes per S/IMAR is 6,5). Table 2 also shows that the kb per S/IMAR varies less that the density of genes per SIMAR (standard deviation represents 25% of the mean of kb per S/MAR and the fold difference between the higher and the lower kb per S/IMAR is 3.2). " Chromosome " “Number of or Size of the Number of Density of Kb per " i genes per chromasome S/MARs ne SIVAR d chromosome {millions bp) | predicied per S/MAR

Sh 7 mE 250 TTR TTT 7s 2 : 1772 241 143 123 © 1685 3 : i404 198 101 13.9 1960 4 | 1036 | 190 | 18 IY | 1610 : 3 1233 : 180 | 116 i i0.6 1551

G 1247 ; 170 94 13.2 1808 : 7 1383 | 160 ; 179 17h 17s 8 942 145 | 77 122 1 188 9 i102 119 48 229 | 2479 10 1403 i £33 : 71 i 14.3 1873 i 11 1682 132 67 | 252 ! 1970 [pl 1278 i il : 78 163 ; 1677 i 13 506 97 0 7.2 1385 14 ; 1168 | 88 | 36 12.4 | 2444

O15 82s 43 3a 253 237 16 1107 81 I 41 27 1975 17 | 1421 80 37 _4 0 2162 ; 15 396 75 il 7.7 1470 f i 19 i 1621 56 36 43.02 1555 20 724 &0 28 | 23.8 2142 21 355 34 18 : 19.7 1888 22 TT 34 23 i 252 1214 } xX 1168 ! 154 170 6.8 aps : 251 25 1 8.3 ! §33 © Sum 26 055 3s0 1757 457. az

Mean | L123 127 | 73 19 | 1804

Isa 1 si sss be | se

Table 2: Number of S/MARs predicted per chromosome. The number of genes per chromosome corresponds to the NCBI human genome statistics (Build 34 Version 3) (National Center for

Biotechnology Information, The NCBI handbook [Internet]. Bethesda (MD): National Library of

Medicine (US), Oct. Chapter 17, The Reference Sequence (RefSeq) Project, 2002 (Available from http://www .ncbinih.gov/entrez/query.fegi?db=Books) based on GenBank annotations.

Chromosome sizes are the sum of the corresponding human RefSeq (National Center for

Biotechnology Information, The NCBI handbook [Internet]. Bethesda (MD): National Library of

Medicine (US), Oct. Chapter 17, The Reference Sequence (RefSeq) Project, 2002 (Available from http://www.nebi.nih. gov/entrez/query fegi?db=Books) (release 5) contig lengths 6.2 Bioinformatics analysis of “super” MARS for transcription factor binding sites

The 1757 predicted "super" S/MARs sequences obtained previously hy SMAR Scan® were then analyzed for potential transcription factors binding sites. This has heen achieved using RMatch ~~ Professional (Kel AE, Gossling E, Reuter |, Cheremushkin E,

KelMargoulis OV, Wingender E, MATCH: A tool for searching transcription factor hinding sites in DNA sequences, Nucleic Acids Res. 31(13):35769, 2003), a weight matrixbased tool based on TRANSFAC (Wingender E, Chen X, Fricke E, Geffers R,

Heh! R, Liebich I, Krull M, Matys V, Michael H, Ohnhauser R, Pruss M, Schacherer F,

Thiele S, Urbach S, The TRANSFAC system on gene expression regulation, Nucleic

Acids Research , 29(1):2813, 2001). Match 2.0 Professional has been used with most of the default settings Match analysis was based on TRANSFAC Professional, release 8.2 (20040630). The sums of all transcription factors binding prediction on the 1757 sequences analyzed according to Match are in Table 3. Based on this table, only the transcription factors totalizing af least 20 hits over the 1757 sequences analyzed were considered for further analyses.

Hereafter are some of the human transcription factors that are the most often predicted to bind on the 1757 putative SIMAR sequences and their Match description: Cdc5 (cell division controt protein 5) a transcriptional regulator/represser, Nkx3A a homeodomain protein regulated by androgen,

POU1F1 (pituitaryspecific positive transcription factor 1) which is specific to the pituitary and stimulates cells proliferation. Thus, in addition to SATB1, NMP4 and

MEF2, other transcription factors can participate in the activity of MARs.

API “1,AR 2 [ Bach2 1 [Bm2 1]

C/EBP 20 | C/EBPgamma 5 CDPCR3 1| COMPI 2

CREBPI 34 | Cde5 858 Cdx2 35 | Evil 472

FOX 78 1 T'OXD3 79 | FOXJ2 244 | FOXP3 29

I'reac’ 272 | GATAL 2 | GATA3 142] GATA4 125 ] HFII1 12 | HFH3 1) HLF 275 | HNF1 337!

HNF3alpha 23 | 1INF3beta 71 | HP} 2 | I.hx3 22 MEF2 114 | MREF2 57 | Myc 18 | NKX34A 849 ' Nkx25 2 | Qctl 191 1 PBX 51 POUIF1 483

POU3F2 11 | POUBK1 29 | Pax3 3 | Pax6 20

Pitl 505 | SRF 8 | TEF 2852 | TFA 14

TTF] 1 | VEMTATA B 4 VBP 53 Vmw6s 1 XFDI 65 | XFD2 418 | xFD3 0 2D a er

Table 3 is a summary of all transcription factors binding prediction (totalizing 20 hits or more) on the 1757 sequences analyzed. 8.3 Bioinformatics analysis of predicted “super” MARS for dinucleotide frequencies

Various computer analysis were performed in order to easily identify "super” S/IMAR sequences using an explicit criterion that could be identified without computing. Among those, a di-nuclectide analysis was performed on the 1757 superMARSs, computing each of the 16 possible dinucleotide percentage for each sequence considering both strands in the 5’ > 3’ direction.

A summary (min., max., median, mean, 25th percentile and 75th percentile) as well as the histograms of each dinucleotide percentage over the 1757 S/IMAR sequences are respectively presented in Table 4. A similar analysis was performed on randomly selected sequences from the human genome, representing randomly selected non-

S/MAR sequences {which might however contain some MARs). Table 5 represents respectively a summary of the dinucleotide content analysis for these sequences,

Table 4: Dinucleotide percentages over the 1757 S/MAR sequences

DR a

AA % ACH i AG % AT%

Minimo 0.000 06000 "70.0000 1850 25th percentile 4.234 0.9372 | 0.1408 32.11

Median 7.843 2.2408 0.4777 34.68

Meen 7.184 3.2117 1.0865 34.32 751h percentile i010 47718 1.5096 36.94

Maximum 17.290 12,9479 8.1230 ste

Minimum 0.0000 0.00060 0.0000 © T0.0000 25th percentile | 0.9695 3.00000 0.0000 0.1408

Median : 1.0776 0.00000 0.0000 0.4777

Mean i 2.6977 0.14123 0.2209 1.0863 75th percentile : 3.7543 0.09422 r1256 1.5096

Maximum 10.4061 4.24837 7.4410 81230 © Minimum 1.00000 0.0000 0.00000 | 0.0000 1 25th percentile 086% 0.0000 0.00000 0.9372 © Median ; 132616 0.0000 0.00000 2.2408

Mean ; 0.63347 0.2104 0.14123 32117 _ 75th percentile i 0.83333 0.1514 { 0.09422 4.7718 _ Maximum | s71see | 9.8795 4.24837 12.9479

TA % TC % “1G % TT %

Minima 28.43 © a.06000 0.0000 oT 0.000 25th percentile 33.48 0.08606 0.9695 4.234

Median 322 . 0.32616 1.9776 7.843

Mean jsze ; 0.63347 2.6977 7.184 { 75th percentile ’ 37.14 ' 0.83333 3.7543 10.110

Maximum . 30.00 : 5.77889 10.4061 ] 17.290

Considering the results of the predicted S/MAR elements and of the nonS/MAR se- quences in the summary tables, noticeable differences can be noticed in the AT et TA dinucleotide contents between these two groups of sequences. AT and TA represent respectively at least 18,5 % and 28.6 % of the dinucleotide content of the predicted

S/MAR sequences, whereas the minimum percentages for the same dinucleotides in nonS/MAR sequences are respectively 0.3 % and 0%. Similarly, the maximum CC and

GG content in S/MAR sequences is 4.2 %, whereas in nenS/MAR sequences the percentages for these two dinucleotides can amount up to 20.8 %.

The correlation between AT and TA dinucleotide percentages and the DNA highest bend as computed by SMAR Scan® is depicted in Fig. 17 for the predicted S/MAR sequences and in Fig.18 for the nonS/MAR sequences. The different scatterplots of these figures show that the TA percentage correlates well with the predicted DNA bend as predicted by SMAR Scan®.

Table 5: Dinucleotide percentages over the 1757 nonS/MAR sequences summary [ 0 CoTTaaA% AC% TTA | ATW “TMinimam ’ 0.000 L735 TIER 0357 25th percentile ! 7.096 4.586 6 466 5.1033 ¢ Median : 6.105 5.016 7.279 6.8695

Mean 8.976 5.054 7,184 7.0108 75th percentice 10.939 5.494 | 7.969 | 8.7913

Maximum iron | 13.816 I 12.232 | 23.1788 ! Ca : CC% CG % { CT% “Mimimom TI T0827 TT 0.0000 TT {25th percentile 6.765 41077 | 0.4727 5.466

Median 7.410 : 5.5556 0.8439 7279

Mean 7411 5.9088 1.2707 7.184 751 percentile 8.010 7.2460 : 1.5760 i 7.959

Maximum 15.714 20.8415 12.6074 12.232

TT TGA rn

Minimum ’ Time 0.4967 0.8278 1735 i Median 6.032 4.4092 ! 5.5556 : 5.016 ¢ Mean | 6.063 4.7408 5.9088 i 5.054 75th percentile 6.602 : 58824 : 7.2460 5.494

Maximum 10.423 16.0000 \ 20.8415 13.816 : - meee % Tw mma oom 1319 3571 TBool 25h percentile 3.875 5.495 6.765 7.096

Median 3.623 6.032 7.410 ; 9.106

Mean 8774 6.065 7.411 : 8976 75th percent e 7.464 6.602 J 8.010 ! 10.939 "| Maxiinum ] 24.338 [10423 | 1314 | 18m

Four of the novel super MARs were randemly picked and analyzed for AT and TA dinucleotide content, and compared with the previously known chicken lysMAR, considering windows of 100 base pairs (Table 6).

Surprinsigly, Applicants have shown that all of the super MARS have AT dinucleotide frequencies greater then 12%, and TA dinuclectides greater than 10% of the total dinucleotides analysed in a window of 100base pairs of DNA. The most efficient MARs display values around 34% of the two dinucleotide pairs.

Table 6. Summary of %AT and TA dinucleotide frequencies of experimentally verified

MARS

ClLysMAR (average of CUES) _ |AT% 12.03 |TA%:10.29 |SEQID No

P1 68 __JAT%:3378 |TA%:33.93 [SEQID No

P16 AT% : 34.67 TA% : 34.38 | SEQ ID No

[P1_42

Mean value for all human “super"MARs LL ‘Mean value for ail human non-MARs AT% : 7.01 TA% 8.77 6.4 Analysis of orthologous intergenic regions of human and mouse genomes

In order to get an insight on S/MAR evolution, orthologous intergenic regions of human and mouse genomes have been analysed with SMAR Scan®. The data set used is composed of 87 pairs of complete orthologous intergenic regions from the human and mouse genomes (Shabalina SA, Ogurtsov AY, Kondrashov VA, Kendrashov AS,

Selective constraint in intergenic regions of human and mouse genomes, Trends

Genet, 17(7):3736, 2001) (average length ~12 000 bp) located on 12 human and on 12 mouse chromosomes, the synteny of these sequences was confirmed by pairwise sequence alignment and consideration of the annotations of the flanking genes (experimentat or predicted).

Analysis of the 87 human and mouse orthologous intergenic sequences have been analysed with SMAR Scan® using its default settings. Analysis of the human : . sequences yielded a total of 12 S/MARs predicted (representing a total length of 4 760 bp), located on 5 different intergenic sequences.

Among the three human intergenic sequences predicted to contain a "super" S/IMAR using SMAR Scan® stringent settings, one of the corresponding mouse orthologous intergenic sequence is also predicted to contain a S/IMAR (human EMBL ID: Z96050, position 28 010 to 76 951 aothologous to mouse EMBL 1D: AC015932, positions 59 884 to 89 963). When a local alignement of these two orthologous intergenic sequences is performed, the best local alignement of these two big regions correspond to the regions predicted by SMAR Scan® fo be S/IMAR element. A manual search for the mouse orthologs of the two other human intergenic sequences predicted to contain a “super”

S/MAR was performed using the Ensembl! Genome Browser (http://fensembl.org). The mouse orthologous intergenic sequences of these two human sequences were retrieved using Ensembl orthologue predictions (based on gene names), searching the orthologous mouse genes for the pairs of human genes flanking these intergenic regions.

Because SMAR Scan® has been tuned for human sequences and consequently yields little “super"MARSs with mouse genomic sequences, its default cutoff vaiues were slightly relaxed for the minimum size of contiguous hits to be considered as S/IMAR . (using 200 bp instead of 300 bp). Analysis by SMAR Scan® of these mouse sequences predicted several 5/MARs having high values for the different computed structural features. This finding suggests that the human MAR elements are conserved across 40 species.

Example 7 : Dissection of the chicken lysozyme gene 5’- MAR

The 3000 base pair 5'-MAR was dissected into smaller fragments that were monitored 45 for effect on transgene expression in Chinese hamster ovary (CHO) cells. To do so, seven fragments of ~400 bp were generated by polymerase chain reaction (PCR).

These PCR-amplified fragments were contiguous and cover the entire MAR sequence when placed end-to-end. Four copies of each of these fragments were ligated in a head-to-tail orientation, to obtain a length corresponding to approximately half of that of the natural MAR. The tetramers were inserted upstream of the SV40 promoter in pGEGFPControl, a modified version of the pGL3Control vector (Promega). The plasmid pGEGFPControl was created by exchanging the luciferase gene of pGL3Contral for the

EGFP gene from pEGFP-N1 (Clontech). The &-MAR-fragment-containing plasmids thus created were co-transfected with the resistance plasmid pSVneo in CHO-DG44 "cells using LipofectAmine 2000 (Invitrogen) as transfection reagent, as performed previously (Zahn-Zabal, M., et al., “Development of stable cell lines for production or regulated expression using matrix attachment regions” J Biotechnol, 2001. 87(1): p. 28-42). After selection of the antibiotic (G-418) resistant cells, polyclonal cell populations were anatyzed by FACS for EGFP fluorescence.

Transgene expression was expressed at the percentile of high expressor cells, defined as the cells which fluorescence levels are at least 4 orders of magnitude higher than the average fluorescence of cells transfected with the pGEGFPCaontrol vector without MAR.

Fig. 5 shows that muitimerized fragments B, K and F enhance transgene expression, despite their shorter size as compared to the original MAR sequence. In contrast, other fragments are poorly active or fully inactive.

Example 8 ; Specificity of B, K and F regions in the MAR context

The 5-MAR was serially delefed from the 5'-end (Fig.6, upper part) or the 3'-end (Fig.6, lower part), respectively. The effect of the truncated elements was monitored in an assay similar to that described in the previous section. Figure 6 shows that the loss of ability to stimulate transgene expression in CHO cells was not evenly distributed.

In this deletion study, the loss of MAR activity coincided with discrete regions of transition which overlap with the 5-MAR B-, K- and F-fragment, respectively. In 5' deletions, aclivity was mostly lost when fragment K and F were removed. 3' deletions that removed the F and b elements had the most pronounced effects. In contrast, flanking regions A, D, E and G that have little or no ability to stimulate transgene expression on their own (Fig. 5}, correspondingly did not cantribute to the MAR activity in the 5'- and 3’-end deletion studies (Fig. 6).

Example 9:Structure of the F element

The 465 bp F fragment was further dissected into smaller sub-fragments of 234, 243, 213 bp and 122, 125 and 121 bp, respectively. Fragments of the former group were octamerized (8 copies) in a head-to-tail orientation, while those of the latter group were simitarly hexa-decamerized (16 copies), to maintain a constant length of MAR 40 sequence. These elements were cloned in pGEGFPControl vector and their effects were assayed in CHO cells as described previously. Interestingly, fragment Flli retained most of the activity of the full-length F fragment whereas fragment Fil, which contains the right-hand side part of fragment Fil}, lost all the ability to stimulate transgene expression (Fig. 7). This points to an active region comprised between nt 132 and nt 45 | 221 inthe FIB fragment. Consistently, multiple copies of fragments Fl and FiB, which encompass this region, displayed similar activity. FILA on its own has no activity.

However, when added to FIB, resulting in Flli, it enhances the activity of the former,

Therefore FIIA appears to contain an auxiliary sequence that has littie activity on its own, but that strengthens the activity of the minimal domain located in FIB. 50

Analysis of the distribution of individual motifs within ithe lysozyme gene 5-MAR is shown in Fig. 8 A, along with some additional motifs that we added to the analysis.

Most of these motifs were found to be dispersed throughout the MAR element, and not specifically associated with the active portions. For instance, the binding sites of transcription factors and other motifs that have been associated with MARs were not preferentially jocalized in the active regions. it has also been proposed that active MAR sequences may consist of combination of distinct motifs. Several computer programs (MAR Finder, SMARTest, SIDD duplex stability) have been reported to identify MARs as regions of DNA that associate with the DNA matrix. They are usually based on algorithms that utilizes a predefined series of sequence-specific patterns that have previously been suggested as containing MAR activity, as exemplified by MAR Finder, now known as MAR Wiz. The output of these programs did not correlate well with the , transcriptionally active portions of the cLysMAR. For instance, peaks of activity obtained with MAR Finder did not clearly match active MAR sub-portion, as for instance the B fragment is quite active in vivo but scores negative with MAR Finder (Fig. 8B, compare the top and middle panels). Bent DNA structures, as predicted by this program, did not correlate well either with activity (Fig. 8B, compare the top and bottom panels}. Similar results were obtained with the other available programs (data not shown).

The motifs identified by available MAR prediction computer methods are therefore unlikely to be the main determinants of the ability of the ¢LysMAR to increase gene expression. Therefore, a number of other computer tools were tested. Surprisingly, predicted nucleosome binding sequences and nucleosome disfavouring sequences were found to be arranged in repetitively interspersed clusters over the MAR, with the nucleosome favouring sites overlapping the active B, K and F regions. Nucleosome positioning sequences were proposed to consist of DNA stretches that can easily wrap around the nucleosomal histones, and they had not been previously associated with

MAR seguences.

Nucleosome-favouring sequences may be modelled by a collection of DNA features that include moderately repeated sequences and other physico-chemical parameters that may allow the correct phasing and orientation of the DNA over the curved histone 30 . surface. Identification of many of these DNA properties may be computerized, and up to 38 different such properties have been used to predict potential nucleosome positions. Therefore, we set up to determine if specific components of nucleosome prediction programs might correlate with MAR activity, with the objective to construct a tool allowing the identification of novel and possibly more potent MARS from genomic sequences.

To determine whether any aspects of DNA primary sequence might distinguish the active B, K and F regions from the surrounding MAR sequence, we analyzed the 5'-

MAR with MAR Scan®. Of the 38 nucleosomal array prediction tools, three were found 40 to correlate with the location of the active MAR sub-domains (Fig. 8A). Location of the

MAR B, K and F regions coincides with maxima for DNA bending, major groove depth and minor groove width. A weaker correlation was also noted with minima of the DNA melting temperature, as determined by the GC content. Refined mapping over the MAR

F fragment indicated that the melting temperature valley and DNA bending summit 45 indeed correspond the FiB sub-fragment that contains the MAR minimal domain (Fig. 9B). Thus active MAR portions may correspond to regions predicted as curved DNA regions by this program, and we will refer to these regions as CUE-B, CUE-K and CUE-

F in the text below, Nevertheless, whether these regions correspond to actual bent DNA and base-pair unwinding regions is unknown, as they do not correspond to bent DNA 50 - as predicted by MAR Wiz {Fig.9B8).

Example 10 : Imprints of other requlatory elements in the F fragment

Nucleosome positioning features may be considered as one of the many specific chromatin codes contained in genomic DNA. Although this particular code may coniribute to the activity of the F region, it is unlikely to determine MAR activity alone, as the 3’ part of the F region enhanced activity of the minimal MAR domain contained in the FIB portion. Using the Matinspector program (Genomatix}, we searched for transcription factor binding sites with scores higher than 0.92 and found DNA binding sequences for the NMP4 and MEF2 proteins in the 3’ part of the F fragment (Fig. 8B).

To determine whether any of these franscription factor-binding sites might localize close to the B and K active regions, the entire 5-MAR sequence was analyzed for binding by

NMP4 and MEF2 and proteins reported to bind to single-stranded or double-stranded form of BURs. Among those, SATB1 {special AT-rich binding protein 1) belongs to a class of DNA-binding transcription factor that can either activate or repress the expression of nearby genes. This study indicated that specific proteins such as SATB1,

NMP4 (nuclear matrix protein 4) and MEF2 (myogenic enhancer factor 2), havea - specific distribution and form a framework around the minimal MAR domains of cl.ysMAR (Fig. 10). The occurrence of several of these NMP4 and SATB1 binding sites has been confirmed experimentally by the EMSA analysis of purified recombinant proteins {data not shown).

Example 11 : Construction of artificial MARs by combining defined genetic elements

To further assess the relative roles of the various MAR components, the cLysMAR was deleted of all three CUE regions (Fig. 11, middle part), which resulted in the loss of part ofits activity when compared to the complete MAR sequence similarly assembled from aif of its components as a control (Fig. 11, top part). Consistently, one copy of each

CUE alone, or one copy of each of the three CUEs assembled head-to-tail, had little activity in the absence of the flanking sequences. These results strengthen the conclusion that optimal transcriptional activity requires the combination of CUEs with of flanking sequences. Interestingly, the complete MAR sequence generated from each of its components, but containing also Bgil-BamH| linker sequences (AGATCC) used to assemble each DNA fragment, displayed high transcriptional activity (6 fold activation) as compared to the 4.8 fold noted for the original MAR element in this series of assays {see Fig. 9).

We next investigated whether the potentially curved DNA regions may also be active in an environment different from that found in their natural MAR context. Therefore, we set up to swap the CUE-F, CUE-B and CUE-K elements, keeping the flanking sequences unchanged. The sequences flanking the CUE-F element were amplified by PCR and 40 assembled to bracket the various CUEs, keeping their original orientation and distance, or without a CUE, These engineered ~1.8 kb MARSs were then assayed for their ability to enhance transgene expression as above, All three CUE were active in this context, and therefore there action is not restricted to one given set of flanking sequences.

Interestingly, the CUE-K element was even more active than CUE-F when inserted 45 between the CUE-F flanking sequences, and the former composite construct exhibited an activity as high as that observed for the complete natural MAR (4.8 fold activation).

What distinguishes the CUE-K element from CUE-F and CUE-B is the presence of overlapping binding sites for the MEF-2 and SatB1 proteins, in addition to its CUE feature. Therefore, fusing CUE-B with CUE-F-flanking domain results in a higher 50 density of all three binding sites, which is fikely explanation to the increased activity,

These results indicate that assemblies of CUEs with sequences containing binding sites for proteins stich as NMP4, MEF-2, SatB1, and/or polyPpolyQ proteins constitute potent artificial MAR sequences,

Three expression vectors according to the present invention are represented on Figure 12.

Plasmid pPAGO1 is a 5640 bp pUC18 derivative. It contains a 2960 bp chicken DNA fragment cloned in BamH1 and Xbal restriction sites. The insert comes from the border of the 5'-end of the chicken lyzozyme locus and has a high A/T-content.

Plasmid pGEGFP (alsc named pSV40EGFP) control is a derivative of the pGL3- contro! vector (Promega) in which the luciferase gene sequence has been replaced by the EGFP gene sequence form the pEGFP-N1 vector (Clontech). The size of pPGEGFP plasmid is 4334bp. :

Plasmid pUbCEGFP control is a derivative of the pGL3 wit an Ubiquitin promoter.

Plasmid pPAGO1GFP (also named pMAR-SV40EGFP) is a derivative of pGEGFP with the 5'-Lys MAR element cloned in the MCS located just upstream of the SV40 ° promoter. The size of the pPAGO1EGF plasmid is 7285bp.

Example 13 : Effect of the additional transfection of primary transfectant cells on transgene expression

One day before transfection, cells were plated in a 24-well plate, in growth medium at a density of 1.35 x 10° cellsiwel! far CHO-DG44 cells. 16 hours past-inoculum, cells were transfected when they reached 30-40% confluence, using Lipofect-AMINE 2000 (hereinafter LF2000}, according to the manufacturer's instructions (Invitrogen). Twenty- seven microliters of serum free medium (Opti-MEM,; Invitrogen} containing 1.4 yi of

LF2000 were mixed with 27 ul of Opti-MEM containing 830 ng of linear plasmid DNA.

The antibiotic selection plasmid (pSVneo) amounted to one tenth of the reporter plasmid bearing the GFP transgene. The mix was incubated at room temperature for 20 min, to allow the DNA-LF2000 complexes to form. The mixture was diluted with 300 pl of Opti-MEM and poured into previously emptied celi-containing wells. Following 3 hours incubation of the cells with the DNA mix at 37°C in a CO; incubator, one ml of

DMEM-based medium was added to each well. The cells were further incubated for 24 hours in a COy incubator at 37°C. The cells were then transfected a second time according to the method described above, except that the resistance plasmid carried another resistance gene {pSVpuro). Twenty-four hours after the second transfection, 40 cells were passaged and expanded into a T-75 flask containing selection medium supplemented with 500 pg/ml G-418 and 5 pg/ml puromycin. After a two week selection period, stably transfected cells were cultured in 8-well plates. Alternatively, the cal} population was fransfected again using the same method, but pTKhygro (Clontech) and pSVdhfr as resistance plasmids. The expression of GFP was analysed with 45 Fluorescence-activated ceil sorter (FACS) and with a Fluoroscan.

Fig.13 shows that the phenotype of the twice-transfected cells (hereafter called secondary {ransfectants) not only was strongly coloured, such that special bulb and filter were not required to visualize the green color from the GFP protein, but also 50 contained a majority of producing cells (bottom right-hand side FACS histogram) as compared to the parental population (cenirai histogram). This level of fluorescence corresponds to specific cellular productivities of at least 10 pg per cell per day. Indeed,

cells transfected only ane time (primary transfectants) that did not express the marker protein were almost totally absent from the cell population after re-transfection. Bars below 10" units of GFP fluorescence amounted 30% in the central histogram and less than 5% in the right histogram. This suggested that additional cells had been : - transfected and successfully expressed GFP.

Strikingly, the amount of fluorescence exhibited by re-transfected cells suggested that the subpopulation of cells having incorporated DNA twice expressed much more GFP than the expected two-fold increase. Indeed, the results shown in Table 2 indicate that the secondary transfectants exhibited, on average, more than the two-fold increase of

GFP expected if two sets of sequences, one at each successive transfection, would have been integrated independently and with similar efficiencies. Interestingly, this was not dependent on the promoter sequence driving the reporter gene as both viral and cellular promoter-containing vectors gave a similar GFP enhancement (compare lane 1 and 2). However, the effect was particularly marked for the MAR-containing vector as compared to plasmids without MAR- {lane 3), where the two consecutive transfections resulted in a 5.3 and 4.6 fold increase in expression, in two distinct experiments.

Type of plasmids Primary Secondary | EGFP fluorescence _ transfection transfection Fold increase

EE 4'992 14'334 2.8 i pSV40EGFP 4324 12'237 28 —] pMAR-SV40EGFP 6'996 53

Type of plasmids | Primary Secondary | EGFP fluorescence transfection HN transfection | Fold increase pUbCEGFP 6'452 15794 2.5 7 1 PSV40EGFP 4'433 11735 2.6 pMAR-SV40EGFP 8118 37'475 4.6 :

Table 7, Effect of re-transfecting primary transfectants at 24 hours interval on GFP expression. Two independent experiments are shown. The resistance plasmid pSVneo was co-transfected with various GFP expression vectors. One day post- transfection, cells were re-transfected with the same plasmids with the difference that the resistance plasmid was changed for pSVpuro. Cells carrying both resistance genes were selected on 500 pg/ml G-418 and 5pg/mi puromycin and the expression of the reporter gene marker was guantified by Fluoroscan. The fold increases correspond to the ratio of fluorescence obtained from two consecutive transfections as compared fo the sum of fluorescence obtained from the corresponding independent transfections. The fold increases that were judged significantly higher are shown in bold, and correspond to fluorescence values that are consistently over 2-fold higher than the addition of those obtained from the independent transfections:

The increase in the level of GFP expression in multiply tranfected cells was not expected from current knowledge, and this effect had not been observed previously.

Taken together, the data presented here support the idea that the plasmid sequences that primarily integrated into the host genome would facilitate integration of other 40 plasmids by homologous recombination with the second incoming set of plasmid molecules. Plasmid recombination events occur within a 1-h interval after the plasmid

DNA has reached the nucleus and the frequency of homologous recombination between co-injected plasmid molecules in cultured mammalian cells has been shown to be extremely high, approaching unity (Folger, K.R., K. Thomas, and M.R. Capecchi,

Nonreciprocal exchanges of information between DNA duplexes coinjected into mammalian cell nuclei. Mol Cell Biol, 1985. 5(1): p. 59-69], explaining the integration of multiple piasmid copies. However, homologous recombination between newly introduced DNA and its chromosomal homoiog normally occurs very rarely, at a frequency of 1 in 10° cells receiving DNA to the most [ Thomas, K.R., K.R. Folger, and

M.R. Capecchi, High frequency targeting of genes to specific sites in the mammalian genome, Cell, 1986. 44(3): p. 419-28.1. Thus, the results might indicate that the MAR + element surprisingly acts to promote such recombination events. MARs would not only madify the organization of genes in vivo, and possibly also allow DNA replication in conjunction with viral DNA sequences, but they may also act as DNA recombination signals.

Example 14 : MARs mediate the unexpectedly high levels of expression in multiply transfected cells

If MAR-driven recambination events were to occur in the multiple transfections process, we expect that the synergy between the primary and secondary plasmid DNA would be affected by the presence of MAR elements at one or both of the transfection steps. We examined this possibility by multiply transfections of the cells with pMAR alone or in combination with various expression plasmids, using the method described previously.

Table 3 shows that transfecting the cells twice with the pMAR-SV40EGFP plasmid gave the highest expression of GFP and the highest degree of enhancement of all conditions (4.3 fold). In contrast, transfecting twice the vector without MAR gave little or no enhancement, 2.8-fold, instead of the expected two-fold increase. We conclude that the presence of MAR elements at each transfection step is necessary to achieve the maximal protein synthesis.

Table 8

Primary transfection Secondary transfection

Type of plasmid | EGFP- ! Type of plasmid | EGFP- Fold { _ fluorescence | } | fluorescence | increase pPMAR 0 pPMAR 0 0 i pSV40EGFP 15'437 2.3-2.5 i pMAR-SV40EGFP 30'488 2.6-2.7 pMAR-SV40EGFP 11'278 47'027 4.35.3

J pMAR 12'318 1.0-1.1 pSV40EGFP 6'114 pSV40EGFP 17'200 , 2.8 i | pMAR ; 11169 1.8-2.3

Interestingly, when celis were first transfected with pMAR alone, and then re- transfected with pSV40EGFP or pMAR-SV40EGFP, the GFP levels were more than doubled as compared to those resulting from the single transfection of the later 356 plasmids (2.5 and 2.7 fold respectively, instead of the expected t-fold). This indicates that the prior transfection of the MAR can increase the expression of the plasmid used in the second transfection procedure. Because MARs act only locally on chromatin ~ structure and gene expression, this implies that the two types of DNA may have integrated at a similar chromosomal locus. In contrast, transfecting the GFP expression 40 vectors alone, followed by the MAR element in the second step, yielded little or no improvement of the GFP levels. This indicates that the order of plasmid transfection is important, and that the first transfection event should contain a MAR element to allow significantly higher levels of transgene expression.

If MAR elements favoured the homologous recombination of the plasmids remaining in episomal forms from the first and second transfection procedures, followed by their co- integration at one chromosomal locus, one would expect that the order of plasmid transfection would not affect GFP levels. However, the above findings indicate that it is more favourable to fransfect the MAR element in the first rather than in the second transfection event. This suggests the following molecular mechanism: during the first transfection procedure, the MAR elements may concatemerize and integrate, at least in pari, in the cellular chromosome. This integrated MAR DNA may in {urn favour the further integration of more plasmids, during the second transfection procedure, at the same or at a nearby chromosomal locus. = Example 15 : MARs as long term DNA transfer facilitators if integrated MARs mediated a persistent recombination-permissive chromosomal structure, one would expect high levels of expression even if the second transfection was performed long after the first one, at a time when most of the transiently introduced episomal DNA has been eliminated. To address this possibility, the cells from Table 3, selected for antibiotic resistance for three weeks, were transfected again once or twice and selected for the incorporation of additional DNA resistance markers. The tertiary, or the tertiary and quaternary transfection cycles, were performed with combinations of pMAR or pMAR-SV40EGFP, and analyzed for GFP expression as before.

Table 9 n Tertiary transfection Quaternary transfection

Type of plasmid | EGFP- . Fold | Tyme of plasmid | EGFP. | Fold i fluorescence increase t increas fluorescence e pMAR 18368 22 |pMAR 43'186 24 pMAR- 140'000 76

SV40EGFP pMAR-SV40EGF 16544 © 2.0 pMAR- 81000 55

SVADEGFP

MAR 33814 | 20

Table 9. MARS act as facilitator of DNA integration.

The pMAR-SVA0OEGFP/ pMAR-SV40EGFP secondary transfectants were used in a third cycle of transfection at the end of the selection process. The tertiary transfection was accomplished with pMAR or pMAR-SV40EGFP, and pTKhygro as selection plasmid, to give tertiary transfectants. After 24 hours, cells were transfected again with either plasmid and pSVdhfr, resulting in the quaternary transfectants which were selected in growth medium containing 500 ug/ml G-418 and 5pg/ml puromycin, 300 ug/ml hygromycin B and 5uM methotrexate. The secondary transfectants initially exhibited a GFP fluorescence of 8300. The fold increases correspond to the ratio of 40 fluorescence obtained from two consecutive transfections as compared to the sum of fluorescence obtained from the corresponding independent transfections. The fold increases that were judged significantly higher are shown in bold, and correspond to fluorescence values that are 2-fold higher than the addition of those obtained from the independent transfections.

These results show that loading more copies of pMAR or pMAR-SV40EGFP resulted in similar 2-fold enhancements of total celi fluorescence. Loading even more of the MAR in the quaternary transfection further enhanced this activity by another 2.4-fold. This is consistent with our hypothesis that newly introduced MAR sequences may integrate at the chromosomal transgene locus by homologous recombination and thereby further increase transgene expression.

When the cells were transfected a third and fourth time with the pMAR-SV40EGFP plasmid, GFP activity further increased, once again to levels not expected from the addition of the fluorescence levels obtained from independent transfections. GFP expression reached levels that resulted in cells visibly glowing green in day light (Fig.14). These results further indicate that the efficiency of the quaternary transfection was much higher than that expected from the efficacy of the third DNA transfer, indicating that proper timing between transfections is crucial to obtain the optimal gene expression increase, one day being preferred over a three weeks period.

We believe that MAR elements favour secondary integration events in increasing recombination frequency at their site of chremosomal integration by relaxing closed chromatin structure, as they mediate a local increase of histone acetylation (Yasui, D., et al., SATB1 targets chromatin remodelling to regulate genes over long distances.

Nature, 2002. 419(6907): p. 641-5.]. Alternatively, or concomitantly, MARs potentially relocate nearby genes to subnuclear locations thought to be enriched in trans-acting factors, including proteins that can participate in recombination events such as topoisomerases. This can result in a locus in which the MAR sequences can bracket the pSVAOEGFP repeats, efficiently shielding the transgenes from chromatin-mediated silencing effects.

Example 18 : Use of MARS identified with SMAR Scan® Il to increase the expression of a recombinant protein.

Four MAR elements were randomly selected from the sequences obtained from the analysis of the complete human genome sequence with SMAR Scan® or the combined method. These are termed 1_6, 1 42, 1 68, {where the first number represents the chromosome from which the sequence originates, and the second . number is specific to the predicted MAR along this chromosome) and X_S29, a “super” 40 MAR identified on chromosome X. These predicted MARS were inserted into the pGEGFPControl vector upstream of the SV40 promoter and enhancer driving the expression of the green fluorescent protein and these plasmids were transfected into cultured CHO ceils, as described previously {Zahn-Zabal, M_, et al., Development of stable cell lines for production or regulated expression using matrix attachment regions. 45 J Biotechnol, 2001. 87(1). p. 28-42). Expression of the transgene was then analyzed in the total population of stably transfected cells using a fluorescent cell sorter (FACS) machine. As can be seen from Fig. 19, all of these newly identified MARs increased the expression of the transgene significantly above the expression driven by the chicken lysosyme MAR, the “super” MAR X_S29 being the most potent of all of the newly 50 identified MARS.

Example 17: Effect on hematocrit of in vivo expression of mEpo by electrotransfer of Network system with and without Human MAR (1-68),

The therapeutic gene encodes EPO (erythropoietin), an hormone used for the treatment of anemia. The EPO gene is placed under the control of a doxycycline inducible promoter, in a gene switch system described previously cailed below the : Network system (Imhof, M. O., Chatellard, P., and Mermod, N. (2000). A regulatory network for efficient control of transgene expression. J. Gene. Med. 2, 107-116.). The

EPO and regulatory genes are then injected in the muscle of mice using an jn vivo alectroporation procedure termed the electrotransfer, so that the genes are transferred to the nuclei of the muscle fibers. When the doxycycline antibiotic is added to the drinking water of the mice, this compound is expected to induce the expression of EPO, which will lead to the elevation of the hematocrit level, due to the increase in red blood cell counts mediated by the high levels of circulating EPO. Thus, if the MAR improved expression of EPO, higher levels of hematocrit would be expected.

In vivo experiments were carried out on 5 week-old C57BL6E female mice (Iffa Credo-

Charles River, France). 30ug of plasmid DNA in normal safine solution was delivered by trans-cutaneous injections in the tibialis anterior muscle. All injections were carried out under Ketamino! (75 mg/kg) and Narcoxyl (10 mg/kg) anesthesia. Following the intramuscular injection of DNA, an electrical field was applied to the muscle. A voltage of 200 V/cm was applied in 8 ms pulses at 1Hz (Bettan M, Darteil R, Caillaud JM,

Soubrier F, Delaere P, Branelec D, Mahfoudi A, Duverger N, Scherman D. 2000. “High- level protein secretion into blood circulation after electric pulse-mediated gene transfer into skeletal muscle”. Mof Ther. 2. 204-10). 16 mice were injected by the Network system expressing EPO without the 1_68 MAR and 16 other mice were injected with the Network system incorporating the MAR in 5° of the promoter/enhancer sequences driving the expression of the activator and EPO genes. In each group, half of the mice were submitted to doxycycline in drinking water from the beginning of the experiment (day 0 — the day of electrotransfer) and in the other half, doxycycline was put in drinking water starting at day 21.

Blood samples were collected using heparinated capillaries by retro-orbital punction at different times after the injection of plasmids. Capillaries were centrifugated 10 minutes at 5000 rpm at room temperature and the volumetric fraction of blood cells is assessed in comparison to the total blood volume and expressed as a percentile, determining the hematocrit level, 40

As can be deduced from Fig. 16 The group of mice injected by MAR-network, induced fram the beginning of the experiment, display a better induction of the hematocrit in comparison of mice injected by original network without MAR. After 2 months, : - haematocrits in "MAR-containing group” is still at values higher (65%) than normal 45 hematacrit levels (45-55%).

More importantly, late induction (day 21} is possible only in presence of MAR but not from mice where the Network wwas injected without the MAR. Thus the MAR likely protects the transgenes from silencing and allows induction of its expression even after 50 prolong period in non-inducing conditions.

Overall, the MAR element is able to increase the expression of the therapeutic gene as detected from its increased physiological effect on the hematocrit.

SEL PCT 012.5T25

SEQUENCE LISTING

<110> Selexis S.A. <120> HIGH EFFICIENCY GENE TRANSFER AND EXPRESSION IN MAMMALIAN

CELLS BY AMULTIPLE TRANSFECTION PROCEDURE OF MAR SEQUENCES

<130> SELPCT 012 <150> US 60/513,574 <151> 2003-10-24 <150> EP 04 002 722.9 <151> 2004-02-06 <160> 241 : <170> Patentln version 3.1 <210> 1 : <Z211> 320 <212> DNA <213> Homo sapiens <220> - <221> misc_binding :

Seite 1

SEL PCT 012.5725 <222> {1)..(320) <223> MAR of human chromosome 1, nt from 36688 to 37008 <220> <221> mis¢_binding <222> (1)..{320) <223> MAR of human chromosome 1, genomic contig; 36686 to 37008 <400> 1 ttatattatg ttgttatata taitatatia tgttattaga Hataltatg ttgttatatt 60 atataataat attatattat atattatata ttatattata taatatataa taatattata 120 taattatata ttacattata taatatataa taataltata taattatata itacattata 180 taatatataa taatattata taataatata taattatata atatataata atattatata 240 atattatata atattatata atatataaat atataataat atatattata ttatataata 300 gtatataata ttatataata 320 <210> 2 <211> 709 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(709) <223> MAR of human chromosome 1, nt from 142276 to 142084

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SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(709) <223> MAR of human chromosome 1, genomic contig; 142276 to 142984 <400> 2 tacaatatat ttictattat atatattttg tattatatat aatatacaat atattticia 60 ttatatataa tatatitigt attatatata ttacaatata tttigtatta tataatatat 120 aatacaatat aiaatatatt gtaitatata ttatataata caatatatta tatatigtat 180 tatatattat atataatact atataatata tigtatiata tattatatat aatactatat 240 aatatatitt attatatatt atatataata caatatataa tatattgtat tataatacaa 300 tgtattataa tgtattatat tgtattatat attatatata atacaatata taataatata 360 ftataatata taataataat ataatataat aataatatat attgtatiat atattatata 420 atacaatata taatatatty tattatatat atittattac atataatata taatacatta 480 tataatatal ittgtattat atataatata tittattatg tattatagat aatatatttt 540 attatatatt atatataata caatatataa tatatttigt attgtatata atatataata 600 caatatataa tatattgtat tatatataat attaatatat tttgtattat atatttatat 660 tttatattat aattatgitt tgcattatat atttcatatt atatatacc 709 <210> 3 <211> 409 <212> DNA <213> Homo sapiens «220> <221> misc_binding

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SEL PCT 012.8725 <222> (1)..(409) <223> MAR of human chromosome 1, nt from 1368659 to 1369067 <220> <221> misc binding <222> (1)..(409) <223> MAR of human chromosome 1, genomic contig; 1368659 to 1369067 <400> 3 tacacataaa tacatatgca tatatattat gtatatatac ataaatacat atgcatatac 60 attatgtata tatacataaa tacatatgca tatacattat gtatatatac ataaatacat 120 atgcatatac attatgtata {atacataaa tacatatgca tatacattat gtatatatac 180 ataaatacat atgcatatac attafgtata tatacataaa tacatatgca tatacattat 240 gitatatatac alaaatacat atgcatatat tatatacata aattatatta tatacataat 300 : acatatacat atattatgtg tatatataca taaatacata tacatatatt atgtgtatat 360 atacatgata catatacata tattatgtat atatatacat aaatacata 409 <210> 4 <211> 394 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(394) <223> MAR of human chromosome 1, geqomie contig: 2839089 to 2839482 eite

SEL PCT 012.8725 <400> 4 tatgtatata tacacacata tgtatatata cacacatatg tatatacgta tatatgtata 60 tatacacaca tatgtatata cgtatatatg tatatataca cacatatgta tatacgtata 120 tatgtatata tacacacata tgtatatacg tatatatgta tatatacaca catatgtata 180 tatgtatata tacacacata tgtatatacg tatatatgta tatatacaca catgigtata 240 tatatataca catatgtata tatgtatata tacacacata tgtatatatg tgtatgtata 300 : tatacacaca tatgtatata tacacatata tatgtatata tacacacata cttatatata 360 cacatatata tgtatatata cacatatgta taca 394 : <210> 5 <211> 832 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(832) <223> MAR of human chromosome 1, genomic contig; 1452269 to 1453100 <400> 5 tatattacta tatatacaat atacatatfa ctatatatac catgtattac tatatatatc 60 tactatatat attactatat atacaaaata tatattacta tatatacaat atacatatta 120 ctatatatac catatattac tatatatatc tactatatat attactatat atacaaaata 180 tataftacta tatatactat atattactgt atatacaata tatattacta tatatatact 240 atatattact atatatacac tatatattac tatatataca caatatatat attactatat 300

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SEL PCT 012.5725 atacacaatg tatataacta tatatacaat atatattact atatatacta tatatattac 360 tatacatact atatattact ctatatatac aatatatata ttacaatata tactacatat 420 tactacatat actttatata ttactatata tactatatat tactglatat acaatatata 480 ttactaaata tacacaatat atatiactat atatacacaa tatatatalt actatatata 540 cacatfatat atgactatat atacacacta tatatattac tatatataca caatatataa 600 ctatatatac acagtataca tattactata tatacacaat atatatatta ctatatatac 660 actatatatt actatatata cacaatatat attactctat gtatacacta tatatattac 720 tatatataca gaatatatat aactatatat acactatatt actatatata ctatatatta 780 ctatatgtac tatatatatt actatatata ctatatatta ctatatatac ac 832 <210> § <211> 350 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(350) <223> MAR of human chromosome 1, genomic contig; 831495 to 831844 <400> 6 aatatataat atataaatat taatatgtat tatataatat atattaatat attatattat 60 aftactatat aaataatatt aatataitat attaaaatat taataaatat atcatattaa 120 atattatatt aattaaatat taataaatat attatattaa tatatttata tattaaacet 180 ataacatatg catatactta tttatatata acatgcatgt acttatitat atatacaata 240 tatatttata tattatataa tatattatat gtatttatat attatatatc atatattata 300

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SEL PCT 012.5725 tgtatitata tattatatat catataatat atatatttat attatatata 350 <210> 7 <211> 386 <212> DNA «<213> Home sapiens <220> <221> misc_bhinding <222> (1)..(386) <223> MAR of human chromosome 1, genomic contig; 1447225 to 1447610 <400> 7 acatttaatt taatiatata ctgctatata taattaaatc tatatatcta tataacttat 60 aatttattit aattaatta tatatactat atagttatat atacatatat gtaattatat 120 atagtataat tatagtatat atgtatatat aatgtaagta aatatatagt atatatttat 180 atatactata tattlataca tafgtcttta tatatactaa tatatataca catatgtaat 240 atgtacatat ggcatatait ttatagtgta tatatacata tatgtaatat atatagtaat 300 atgtaaatat atagtacata tttaattata tggtaatata tacacatata tgtaatatgt 360 gtattatagt acatatttta tagtat 386 <10> 8 <211> 585 <212> DNA <213> Homo sapiens <220>

Seite 7

SEL PCT 012.5T25 <221> misc_binding <222> (1)..(585) <223> MAR of human chromosome 1, genomic contig, 4955365 to 4955949 <400> 8 atacacacat atacacatat gtacgtatat atactatata tacacacata tacacatatg 60 tacgtatata tactatatat acacacatat acacatatgt acgtatatat actatatata 120 cacacatata cacatatgia cgtaiatata clatatatac acacatatac acatatgtac 180 gtatatatac tatatataca cacatataca catatgtacg tatatattat atatacacac 240 atatacacat atgtacgtat atatactata tatacacaca tatacacata tgtacgtata 300 tatactatat atacacacat atacacatat gtacgtatat atactatata tacacacata 360 tacacatatg tacgtatata tactatatat acacacatat acacatatgt acgtatatat 420 actatatata cacacatata cacatatgta cgtatatata ctatatatac acacatatac 480 acatatgtac gtatatatac tatatataca cacatataca catatgtacg tatatatact 540 atatataccc atacacatac gtatatacgt acatatatat acgta 585 <210> 9 <214> 772 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(772) <223> MAR of human chromosome 1, genomic contig; 5871862 to 5972633

Seite 8

SEL PCT 012.8725 <400> 9 agtaaacata tatatagtaa atatatatag tgtatataia gtaaatatat atagtgcata G0 tatatagigc atatatatag tgtatatata gtaaatatat agtgtatata tatagtaaat 120 atatatagtg tatatatagt aaatatatat agtaaatata tatatactat atatagtaaa 180 tatatatata ctatatatag taaatatata tatagtatat atatagtaaa tatatatata 240 gtatatatat agtaaatata tatatagtat atatatagta satatatata tagtatatat 300 _. agtaaatata tatagtatat atatagtaaa tatatatata gtatatatat agtaaatata™ 360 : tatatagtat atatatagta aatatatata tagtatatat atagtaaata tatatagtat 420 atatatagta aatatatata gtatatatat agtaaatata tatagtatat atatagtaaa 480 tatatataca ctgtatatat atagtaaata tatatacact gtalatatat agtaaatata 540 tatacactgt atatatatag taaatatata tacactgtat atatatagta aatatatata 600 cacigtatat acatagtaaa {atatataca cigtatatac atagtaaata tatatacact 660 gtatatacat agtaaatata tatacacitgt atatacatag taaatatata tacagigtat 720 atacatagta aatatatata cagigtatat acatagtaaa tatatataca gt 772 <210> 10 oo <211> 304 . <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(304) So <223> MAR of human chromosome 1, genomic contig; 6221897 to 8222200 © <400> 10

Seite 9

SEL PCT 012.8T25 atatataata tatataatia tattatatat aatatataat atatataatt atattatata 60 ttatatataa tatattatat attatatata taatatatat tatatattaa atatatatta 120 tatatataat atatattata tattaaatat atattatata tataatatat attatatata 180 atatatataa tatatattat atatatatta tatattatat atatatatta tatatatata 240 atatatataa tatatattat atataatata tattatatat atataatata tataatatat 300 atta 304 <210> 11 <211> 311 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(311) <223> MAR of human chromosome 1, genomic contig; 9418531 to 9418841 <400> 11 tatatataat atttatatat aataticatg tatttatata taaatattta tatatttata 60 tataaatatt tatatatita tatataaata tttatatatt tatatataat atitatacat 120 tatatataat atttatatat tatatataat atttatatat aatatttata tattatatat 180 aatattiata tatttatatg tataatatat attttatata tgtatgtata atatatattt 240 tatatatgta tgtataatat atittatata tgtaigtata atatattait atatataata 300 tataatitat a 311 <210> 12 <211> 302

Seite 10

SEL PCT 012.8T25 <212> DNA 2135 Homo sapiens <220> <221> misc binding <222> {1)..(302) <223> MAR of human chromosome 1, genomic contig; 15088789 to 15089090 <400> 12 atataatata tatattataf atataaatat atataaatat ataacatata tattatatat 60 aaatatatat aaatatataa catatatatt atatatataa atatatataa atatataaca 120 tatatattat atatataaat atatataaat atataacata tatattatat atataaatat 180 atattatata titatatata taatatatat aaatatataa tatatatita tatatataat 240 atatataaat atataatata tatatitata tataatatat ataaatatat aatatataat 300 at 302 <210> 13 <211> 461 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(461) <223> MAR of human chromosome 1, genomic conti; 8791827 to 8782287

Seite 11

SEL PCT 012.8725 <400> 13 tatataatat atattatata tacacatata taatatatat {atatataca catatataat 60 atatattata tatacacata tataatatat attatatata cacatatata atatatatta 120 tatatacaca tatataatat ataftatata tacacatata taatatatat tatatataca 180 catatataat atataftata tatacacata tataatatat attatatata cacatatata 240 atatataita tatatacaca tatgtaatat atattataca cacacatata atataiatta 300 tatacacata tataatatat attatatata catatataat atatattata tatacacata 360 tataatatat attatatata cacatatata atatatatta tatatacaca tataatatat 420 aatatataca cataiataat atatatatta tatatgcaca t 461 <210> 14 <211> 572 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(572) <223> MAR of human chromosome 1, genomic contig; 163530 to 164101 <400> 14 atattataat tatatatatt atatataatt atataaaata tatattataa ttatatatat 60 titatataat atatatatta taattaatat attatatata atatatatat tatatataat 120 atatatatta tatatattat atataatata tataatatat ataatatata atataatata 180 tatattatat ataatatata atatatataa tatattataa tataatatat ataatatata 240 atataatata tataatatat aatataatat ataatatata atatatataa tatataatat 300

Seite 12

SEL PCT 012.8725 aatatataat atatataata tataatataa tatataatat atataatata ftataatata 360 atatatataa tatataatat aatatatata atatataata taatatataa tatataatat 420 atatttaata tatttattaa ttattigtta tataittatt aatatataat atataatata 480 tttaatatat tataactata tattatatta taattatata tattatatat atacaattat 540 aattatatat tatatatact tataatafat at 572 <210> 15 <211> 357 <212> DNA <213> Homo sapiens <220> <221> misc_bhinding <222> {1)..(357) «223> MAR of human chromosome 1, genomic contig; 1842332 tc 1842688 <400> 15 tatatctata tatatctata tatatataat atagataata tctatatata taatatagat 60 aatattatct atatataata tagataatat tatctatata taatatagat aatattatct 120 atatataaaa ttatattata tctatatata itatatatat aaaattatat tatatctata 180 tataatatag ataatatcta tatataaata gataatatct atatatataa tatagatait 240 atctatatta tagatataga taatattatc tatattatag atattatcta tatataatat 300 agataatalt atctatatta tatatataat atatctatat tatctataat attatet 357 <210> 16 <211> 399 <212> DNA

Seite 13

SEL PCT 012.8725 <213> Homo sapiens : : <220> <221> misc_binding <222> {1}..(399) <223> MAR of human chromosome 1, genomic contig; 2309560 to 2309958 <400> 16 altatatata atatatatta tatattatat atatcaagca gcagatataa tatataatat 60 atataatata tataatatat attgtatatt atataatata taatatatat aatatatatt 120 gtataitata {aatatataa tatatataat atatatigta tattatataa tatataatat 180 atataatata tatigtatat tatataatat ataatatatg taatatatta tgtaatatat 240 tatataatat atattatata ttatatataa tatatattat atataatata tattacataa 300 tatattacat atattacgta atatatgita tatattacat ataatatata acatatatta 360 cgtaatatat gtaatatatt acatataata tatacatta 398 <210> 17 <211> 394 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(394) <223> MAR of human chromosome 1, genomic contig; 2231758 to 2232152

Seite 14

SEL PCT 012.8T25 <400> 17 atatatactt ataaattata tacttatata tacttataaa ttatatactt atatatactt 60 ataaattata tacttatata tacttataaa ttatatactt atatatactt ataaattata 120 tacttatata tacttataaa ttatatactt atatatactt ataaattata tacttatata 180 tacttataaa ttatatactt atatataatt ataaattata tacttatata taattataaa 240 ttatatactt atatataatt ataaattata tacttatata taattataaa ttatatactt 300 atatataatt ataaattata tacatatata taattataaa ttatatacat atataattat 360 aaattatata catatataat tataaattat atac 394 <210> 18 <211> 387 <212> DNA <213> Homo sapiens <220> <221> misc _ binding <222> (1)..(387) <223> MAR of human chromosome 1, genomic contig; 7406524 to 7406910 <400> 18 tatattatat ataatatata ttatatataa tataaataat atatattata tataatatat 60 aaataatata taatatataa ataatatata atatataata tataaataat atataatata 120 taacatataa ataatatata taatatataa ataatatata taatatataa ataatatata 180 taatatataa aaatatataa tatataatac atatataaat aataiattat attatatatg 240 atacataata tattatatat aatatattat atgatacata atatattata tagaatatat 300 tatatgatac ataatatatt atatagaata tattatatga tacataatat attatatgat 360

Seite 15

SEL PCT 012.8T25 acataatata tiatatataa tatatta 387 : <210> 19 <211> 370 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1..(370) <223> MAR of human chromosome 1, genomic contig; 9399572 to 9399941 <400> 19 catatataca tatatacaca tatatacaca tatatataca catacatatg tacacatata 60 tatacacata tgtatacaca tatatacaca tatatacaca catatataca catatataca 120 cacatatata cacatatata cacatatata cacatataca catatataca catatataca 180 tatatacaca tatatataat atacacacat atatatacac atalatacac acatatatac 240 acatatatac acatatatat acacatatat acacatatat acatatatac acatatatat 300 acatatatac acatatatac atatatacac atatatacat atatacacac atatatacac 360 atacatatac 370 <210> 20 <211> 377 <212> DNA <213> Homo sapiens : <220>

Seite 16

SEL PCT 012.8725 <221> misc_binding <222> (1)..(377) <223> MAR of human chromosome 1, genomic contig; 12417411 to 12417787 <400> 20 attatatata atacatataa ttatatatit atatataaat tataataaat acatataatt 60 atatatitat atataaatta tatataataa atacatataa ttacatatat ttataaatta 120 taataaatac atataattac atatatttat atatgaatia tatataataa atacatataa 180 ttatatatat ttatatgtag attatatata aatatatata atttatatat ataataatat 240 atataattta tatatataat tatatatata ataaatatat ataatitata tatataatta 300 tatatataat aaatatataa taatatatat aatitatata tataattata tatataataa 360 atatatataa tttatat 377 <210> 21 <211> 1524 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1524) <223> MAR of human chromosome 1, genomic contig; 1643307 to 1644830 <400> 21 tataaatata tataaatata taaatatata taaatatata aatatatata aatatatata 60 aatatatnaa aatatataaa tatatataaa tatatataaa tatataaaaa cataaaaata 120

Seite 17

SEL PCT 012,ST25 tatataaata tatataaata tataaaaata tataaatata taaatatata aaaatataca 180 aatatataaa tatatacata aatatatata aatatatata aatatataaa aatatatata 240 aatatataaa tatatataaa talatataaa tatatataaa fatataaaaa tatatataaa 300 tatataaata tataaaaata tatataaata tataaatata taaatatata taaatatata 360 aaiatataaa taaatataag tatttatgaa tatatatgaa tatataaata tataaaaaat 420 atatataaat atataaaiat atataaatat ataaatatat acatatatac atatataaat 480 aaataaatat aagtafttat gaatatatat gaatatataa atatataaaa aatatatata 540 aatatataaa tatatataaa tataaatata taaaaatata taaaaatata tataaatata 600 taaatatata taaatatata aatatatata aatatatata aatatataaa tatatataaa 660 tatatataaa tatataaata tataaatata talaaatata {ataaatata taaatatata 720 aatataaata tataaatata tataaatata tataaatata taaatatata taaatatata 780 taaatatata taaatatata taaatatata aatatatata aatatatata taaatatata 840 taaatatata aatatataaa tatataaaaa taiataacaa tatataaata tatataaaaa 900 tatataacaa tatataaata taaatatata taaaaatata taacaatata taaatataaa 960 tatatataaa tatataaata taaatataaa aaatatatat azatatataa atatatataa 1020 atatataaat gtataaatat atataaaaat atataacaat atataaatat ataaatatat 1080 aacaatatat aaatatataa aaatatataa caatatataa atataaatat atataaaaat 1140 atataacaat atataaatat aaatatatat ataaatatat aaatataaat ataaaaaata 1200 tatataaata tataaatata tatataaata tatataaata tataaatgta taaatatata 1260 taaatatata aatatataaa aatatataaa tatatataaa tatatataaa tatatagata 1320 tagatatata aatatatata aatatataaa tataaatata taaacatata taaatatata 1380 tanataaaca tatataaaga tatataaaga tataaagata tataaatata taaatatata 1440 aagatatata aatatataaa gatatataaa {atataaaga tatataaata tataaagata 1500 tataaatata atatataaat atat 1524 <210> 22

Seifle 18

SEL PCT 012.8T25 <211> 664 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(664) <223> MAR of human chromosome 1, genomic contig; 1398763 to 1399426 <400> 22 : acacatatat atataaaata tatatatata cacacatata tataaaatat atatatatac 60 acacatatat ataaaatata tatatacaca catatatata aaatatatat atacacacat 120 atatataaaa tatatatata cacacatata tataaaatat atatatacac acatatatat 180 aaaatatata tatacacaca tatatataaa atatatatat acacacatat atataaaata 240 tatatataca cacatatata taaaatatat atatacacac atatatataa aatatatata 300 tacacacata tatataaaat atatatatac acacatatat aaaatatata tatacacaca 360 tatataaaat atatatatac acatatatat aaaatatata tatacacata tatataaaat 420 atatatacac acatatatat aaaatatata tatacacaca tatatataaa atatatatat 480 acacatatat ataaaatata tatatacaca tatatataaa atatatatat atacacatat 540 atataaaata tatatacaca catatatata aagtatatat atacacacat atatataaaa 600 tatatatata cacatatata taaaatatat atatacacat atatataaaa tatatatata 660 caca 664 <210> 23 <211> 1428 <212> DNA

Seite 18

SEL PCT 012.5725 <213> Homo sapiens <220> <221> misc_binding <222> (1)..{1428) <223> MAR of human chromosome 2, genomic contig; 17840365 to 17841792 <400> 23 aaittattat atattatata ttatatatat tatatatatt atatattata tatattatat 60 atattatata ttatatatat tatatattat atatttatat ataatatata tctaatatat 120 atattagata taatatatat ctaatatata tatattttat atatataata tatctctaat 180 atatatatit tatatgtata taatatatct ctaatatata tatatttiat atgtatataa 240 tatatctcta atatatatat tttttatata taatatatct ctaatatata tattitatat 300 atataatata tatctaatat atataatata tatattagat atatataaaa tatatatgat 260 atalttatta tatatataat atataatata taatatatat attatattat atacatatat 420 attatataca atatatatta tatatattit atatacatta tatattatat atattitata 480 tacaatatat attatatatt ttatatacaa tatataitat atatatitta tattittata 540 tacaatatat attatatata tittatatat aatatatatt atatatattt tatataatat 600 atattatata tattttatat ataatatata ttatataaat tatatataat atatattata 660 ataaattata atatttitta tatatataat atgtattita tatataatat attataatat 720 afattttata tataatatat tataatatat attitatata taatatatta taatatatat 780 titatatiat aatatattat aatatatait ttatatataa tatattataa tatatattit 840 atatataata tattataata tatatittat atataatata ttataatata tatattataa 900 tatatatttt atatataata tattatcata tatatattaa atatatatit tatatataat 960 atattataat atatatatta {aatatatat titatatata atatattata atatatatat 1020

Seite 20

SEL PCT 012.8725 tataatatat atitiatata taatatatta taatatatat titatatata atataftata 1080 atatatattf tatatataat atattataat atatattita tatataatat aatatatatt 1140 {tatatataa tatattataa tatatattit atatataata tattataata tatattttat 1200 atataatata ttataatata tattttatat ataatatatt alaatatata ttitatatat 1260 aatatattat aatatafatt ttatatataa tatattataa tatataittt atatataata 1320 tattataata tatatitiat atataatata ttaattaaat ttattaattt attaattatt 1380 aatatttatt atattattaa ttaataatat ataaattatt aatatata 1428 <210> 24 <211> 4624 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(4624) <223> MAR 1_86 of chromosome 1 <400> 24 ggatctiaaa tctattttat ttatitattt ttcatgtgge caataccete caccecette 60 ttetgtetet ttcaactiat tgtggttace tigaggetac ctgagacagt aggettgggt 120 ggggaagtat gcattctaag tgtaaagtit gatgagcltt gacaaatgtc aacccatgta 180 ccagaacatt ttcatcacce ataaaatctc cettgigtca cttgecagte agigtctatt 240 ctagtatcca actcctgget ccaagaaace attgaactgt tictgtcac tataaattag 300 : atttgtettt tetagagttit catgtaaatg gaatcataca ctaagtacte tttgtgectg 360 gcttctgete ageataatgt ttttgagaat cattecatget getgeatgtt ticagtagtt 420

Seite 21

SEL PCT 012.8725 ~ catittitta aataggtgaa ttgtaactca ttctgtgaat ataccatatt ctgteticca 480 tttatctgtt agtggatett taggtegtit ctagttttgg getatigeaa ataaagetge 540 tgtaaatatt aatgcacaag ttitccatgt tcatatgttt catitcactt aggaaaatac 600 ctaagagagg aattgcacat attaaaaaaa ttttaaaaac tactaagctg ttctccaaaa 660 tggttgtaca attittattc ccaagagcaa tatgagtgtt taattgcice acattctcac 720 caacacttgg tgcitgitag ttttatittc attgttttca tgttatgte tgtgaggcag 780 cattgatgtg catgtctetg agtgtcatct tagcggtgat getgageatce agttcacgtc 840 citataggec gtttgtatat ctgctitgtg aaatgtetgt tcaaatcttt tgectatttt 900 aaattgagtt gtgttcgtct tcttaggatt aagtaatgag ttaaaaatat ttctgataca 960 aatctttcat tatatatttc taatgcttic {catctatag fitattttct catattctit 1020 aactgtatct tttgaagagce aaattttact tttgattatg cccaatttat caagtttita 1080 tatggctctt tigattatge ccataatcac attagacttt gcctaaccea agtitgcaga 1140 gattititct titatgetit tatctagaaa ttttgtagtt ttaggtitta aaaaagtita 1200 atttatttat ttgagacagg gtattgctct ttacatatac tggagtgcag tgatgeaatc 1260 atggctcact gcagcectcaa celettggge tcaageggtt cteccatcte agagtectga 1320 gtagctggee aggtgeatge cagottcaat gigttttica tttgeatttc cotgataatt 1380 attgacgttg agcattttit tcatatatca gttagctatt tgtacgtctt citttgagaa 1440 acatctattc gggictttty cceattttaa agtcagatgg tttgttigtc agetattgag 1500 ttgtttgagt tectigtata ttetggatat taccatettg tcagatgeac agtttgcaaa 1560 tttttttttt ctattttgta gottgtetcet tictetgtty ttecicegg tatgcagaag 1620 ttitttagtg tgatgtaatt teatttgtct gittttgett ttgttgectg tactttctta 1680 ticttatcca aaaaatcttt atctagatca atgtcacgaa gagtitctee tetgtfitct 1740 tcgagtagtt tittataatt ttgggtatac atttaagtct ttaatctatt tggaatigat 1800 tttigcatat ggtgagagat cagagtctaa tttcatactt ttggatgtgg aaagctagtt 1860 ttitcagcac catttattga agagactgtc tctictcoaa tgtgigtict ttgtgeettc 1920

Seite 22.

SEL PCT 012.8725 gtcaaaaatc agitggctgt gegtggatit atttetgtgt tetctattti gticcatigg 1980 tctagtttta gecttaaatt taggtctgea atitiftttt tittgtatat ggtgtgaagt 2040 aagagtcaaa gttcattatt tttcatatgg atatgtaatt actccagtac catcatttag 2100 tttgaatgga ctgtcetttc tccatggaat tacatgggea tetitigtct gaaaccaatt 2160 atgtatgtit acgtatgtgt atgtitatge atatgttata ggtitaatat atattaatat 2220 atataatata taatatataa atattaatat gtattatata atatatatta atatatiata 2280 ttatattact atataaataa tattaatata ttatatiaaa atattaataa atatatcata 2340 itaaatatta tattaattaa ataltaataa atatattata ttaatatatt tatatattaa 2400 acctataaca fatgcatata ctiatttata tataacatgc atgtacttat ttatatatac 2460 aatatatatt tatatattat ataatatait atatgtatit atatattata tatcatatat 2520 tatatgtatt tatatattat ataicatata atatatatat ttatattata tatattatat 2580 gatatataat attatataat gtattaatat atattaaacc tatatttata aftctggact 2640 cactatlttg tttcattggt gtetgtgtgt atctaaccct atgecaataa tgtactatct 2700 taattaccat agctttatag taagctttga aatcagatag tgtatititt atcaftgttt 2780 tttaaaataa tagtttatcet ttttattiga atttgtaate agctagtcag titctgcaaa 2820 aagcttactg ggattitgct tggaattatg ttacatctgt ageatgtact atccaatatt 2880 ctagccttta tccacatgty getatiaagg titaaattaa ftaaattaaa atttaattaa 2940 ttaaaattaa aacttaataa ttggttccte atfcacacta ccataigtca agtgttcaat 3000 agccacatat ggtcaatgtc ttggaaaagt caatacagta catticcatt attgcagtaa 3060 gttctgtcaa acagceactat cgtagaccga ttaggagaga actgacttaa cagtattgga 3120 tgctccagtc aatgaacatc tttittttt teatttattt cagtagtetc tgcagtatat 3180 tatagattic agtttacata tittgcatat attttattaa atgtataacg gtagaagtac 3240 tattattgga tgatgtgtic tatagatgta ttitaggtca agtttgtiga tagtgtigtt 3300 taaatctegt atacctcttg aftittttat ttacttgttc tttgaattac tgagacagga 3360 atgitatatc cttaactata titgtgaatt tattcactte ttccttcagt totgttaact 3420

Seite 23

SEL PCT 012.8725 tttgcttagg tgcitittaa aaatgaaact ttcaatctct gectittaat tgtagceattt 3480 agaccattta caticaatgt aattatcaat atcagtttat ttaagtciga agtigtgcaa 3540 tttttoctet acctatatta taaatctttc tatatacaaa acacatgcta tgttttctge 3600 atatgittta aatgacaccc ggaaagcatt gacactattt ttgctitagg ttatctttca 3660 aagatgitaa aaatgagaaa gaaatattct geatttatce atacactiat atttgcaaa 3720 ggttttitta aatacctitg tgtagattic agttaccaac tigtatttcc ticagctiga 3780 agaacttaca attictigta ggacaggtct ctgacaacaa attatctcag citttctity 3840 tctaaaaaag tiaftgectt tatttitaaa atatatttic actggatatt gaatittagg 3900 tgataatctt titttttttg ttagcacttt aaatatgtct tctaatgtce tettgettic 3960 atagtttctg atgagaagtc tactgttatt agtatctctt tgigtgtgte toteittttt 4020 coctetotge tattatgget attttitttt tittittttt ttttggteac tggtgtcage 4080 aatttaatta tggtgtgcct tggtatgtit tgtgtgtgty tgtgtgtgty tgtgtgtgtg 4140 tgtgtgtatg tagctgatgt ictttgagcet ttagaatety tgagttigta gttticatca 4200 attattittt ctittcattc ctittatita ctcatgtteg tgtittatit tatattitta 4260 agaatttigt gcgtatttgt aataactgtt taaatgtcat tigtgaattc cattgettct 4320 aggtaggatt ctattgacag atattttitc cctgacgaga ggtcatactt tecttatict 4380 tcatgtatct agtgoftttt ggtigaatac tggatatitt gaattttatg ggagtgctga 4440 attctacaat aticcttaaa aatgigtigg atttigtttt agcagatage tatcttactt 4500 gaagatcaat ticatatitt ttgatgttca tittticatt tattaaagaa taggtccatg 4560 gtagagttta ctgatatcaa ccftictggt gictctaata aatgcaacat attcaataag 4620 atce 4624 <210> 25 <211> 3616 <212> DNA <213> Homo sapiens

Seite 24

SEL PCT 012.5725 <220> <2271> misc_binding <222> (1)..(3616) <223> MAR 1_68 of chromosome 1 <400> 25 gactctagat tataccaacc {cataaaata agagcatata taaaagcaaa tgctcitatc 60 ttgcagatcce ctgaactgay gaggcaagat cagtitggca gttgaageag ctggaatctg 120 caaftcagag aatctaagaa aagacaaccc tgaagagaga gacccagaaa cctagcagga 180 gittciccaa acattcaagg ctgagggata aatgttacat gcacagggtg agectccaga 240 ggcttgtcca itagcaactg ctacagtttc attatctcag ggatcacaga ttgtgctace 300 tatigcctac catctgaaaa cagttgcette ctatattica tccagtitaa tatttattta 360 aaccaagaag gitaatctgg caccagetat tecgttgtga gtggatgtga aagtaccaat 420 tccatictgt tttactatta actatcctit gocttaatat gtatcagtag gtggcttgtt 480 gclaggaaat attaaatgaa tggcatgtit cataggtigt gtttaaagtt gtttitigag 540 : ttaaatctit ctttaataat actttctgat gicaaaaaca cttagaagtc atggtgttga 600 acatctatat agggttggat ctaaaatage fttcitaacet ftectaacca ctgttttigt 660 tigtitgttt ttaactaagce atccagtttg ggaaattetg aattagggga atcataaaag 720 gtttcattit agetgggeca cataaggaaa gtaagatatc aaattgtaaa aatcgitaag 780 aacttctatc ccatctgaag tgtgggtiag gtgcctctte tetgtgetec cttaacatce 840 tattttatct gtatatatat atattcttcc aaataiccat gcatgggaaa aaaaatctga 900 tcataaaaat attitaggct gggagtggtg getcacgect gtaatcccag cactitggga 960 ggctgaggtg ggcggatecat gaggicaaga gatcgagace atcctgacca atatggtgaa 1020 accccatcic tactaaagat acaaaactat tagctggacg tggtggcacg tgcctgtagt 1080

Seite 25

SEL PCT 012.8T25 cecagetact cgggaggcetyg aggcaggaga acggceitgaa cccaggaggt ggaggtigea 1140 gtgagetgag atcgegeeac tgcactecag cetgggegac agagegagac fetgtetcaa 1200 aaaaaaaata tatatatata tatatataca catatatata taaaatatat atatatacac 1260 acatatatat ataaaatala tatatataca cacatatata taaaatatat atatatacac 1320 acatatatat aaaatatata tatacacaca tatatataaa atatatatat acacacatat 1380 atataaaata tatatataca cacatatata taaaatatat atatacacac atatatataa 1440 aatatatata tacacacata tatataaaat atatatatac acacatatat ataaaatata 1500 tatatacaca catatatata aaatatatat atacacacat atatataaaa tatatatata 1560 cacacalata tataaaatat atatatacac acatatataa aatatafata tacacacata 1620 tataaaatat atatatacac atatatataa aatatatata tacacataia tataaaatat 1680 atatacacac atatatataa aatatatata tacacacata tatataaaat atatatatac 1740 acatatatat aaaatatata tatacacata tatataaaat atatatatat acacatatat 1800 ataaaatata tatacacaca tatatataaa gtatatatat acacacatat atataaaata 1860 tatatataca catatatata aaatatatat atacacatat atataaaata tatatataca 1920 catatatata aaaatatata tatatatttt ttaaaatatt ccaattgtct cactttgtgg 1280 atgagaaaaa gaagtagtta gaggtcaagt aacttggect acatctiitc tcaagattgt 2040 aaactcctag tgagcaataa ccacatctic attitciitg tataaaacaa gaaagtttag 2100 catgaaaaag gtactcaatt acaaatgtgt tggattgaat tfgaagaccct tggaagggga 2160 tittgtacct gaggatetet ticttttgge catattgtic aatggacaaa atttagectt 2220 cgaaggceagg cegatttgag gttaatacta cetttaceac ttgatageta tgtgaccttg 2280 gccatgtggt ticaacagtc tgaaccicat ttictetgty tatgtgtggt cetecttaca 2340 agtttgtgaa aaatgtgaag tccttagceca tgatagecca atataacagg ctaaatgata 2400 ataggtttat gtictitice tttatattct cagataagea ctgtccaagt tigaggtatt 2460 tigaggtcte gectgatttg gattgtttga gtitatgcta ttctitgaat tetttgaget 2520 gttctgaagc agtgtatcat gaacaaaaac atccccagtt cagtccaaac ceetggtiac 2580

Seite 26

SEL PCT 012.5T25 atatcattct tatgccatgt tataaccagt ttgagagtgt tcoctotgtt attgeatita 2640 agtttcagce tcacacagaa attcagcagce caatttctaa gecctaagea taaaatctgg 2700 gatgggagag ggggatggec tgaagageag cattatgaat agcaccatta taattaatga 2760 tctctcagga agatttacaa tcacaggtag cagataaaac aaatagtact gettetgcac 2820 ttccectect ittattcget atgaaatttt atgggaaatc agtccagtga aaaatgtaag 2880 ctcttaatct ticccagaaa tectaccica tttgatgaat actttgaggg aatgaattag 2940 agceatttitt tettttatag tetacttcge atttacgaag tgaggacggt agettagget 3000 gcctggecaa ctgatgagaa ggtcagagge atititagag accteigttg tetitcatte 3060 atgttcattt tccacaagge aagtaatttc caacaaatca gtgtcticat tagtaataag 3120 attaitaaca acaataatag icatagtaac taticagtga gagtccatta tatatcagge 3180 atictacaag glactitata tacatctgag taaacctcac acaattctac agggaggtat 3240 tictatccee atttaacaaa taaggaaacg aagiccaagt aaattaactt gcccaaggte 3300 acacagatag tacctggcag aacaggaatt taaacctaaa tttgtccaac tccaaaagea 3360 gccttotatt tgttataaat getgecteic attatcacat attttattat taacaacaac 3420 aaacatacca atiagcttaa gatacaatac aaccagataa tcatgatgac aacagtaatt 3480 gttatactat tataataaaa tagatgtttt gtatgttact ataatcttga attigaatag 3540 aaatttgcat tictgaaage atgttcetgt catctaatat gattctgtat ctattaaaat 3600 agtactacat ctagag 3616 <210> 28 <211> 4660 <212> DNA <213> Homo sapiens <220> <221> misc_binding

Seite 27

SEL PCT 012.5725 <222> (1)..(4660) <223> MAR 1_42 of chromosome 1 <400> 26 gatccetiga ggteagtagt ttaagaccag cetgaccaac atggtgaaac ccatctetac 60 taaaaataca aaaatitagcc aggcgtggty gecgggggect gtaaccecag ctactcagga 120 ggctgaggca caagaatctc ttgaaccegg gaggceggagg ttgcagtgag ctgagattgt 180 gtcactgcac tccagcectgg geaacagtge cagactcige cttaaaaaaa aaaaaaaaaa 240 aaaaaaggcc gggegeggatg getgacgect gtaatceeag cactttggga ggccgaggeg 300 ggtggatcat gaggtcagga gatcgagacc acagtgaaac ccecgtctcaa ctaaaaatac 360 aaaaaattag ccgggcegegg tgatgggege tigtagtece agetactcag gaggetgagg 420 caggagaatg gecgtgaacct gggaggcegga gettgeagtg agecgagatg gcaccactge 480 actccagect gggcgaaaga gtgagacice gictcaaaaa aaaaaaaaaa ttagetgggt 540 atggtggtge gtgcctgtaa tcecagetac tcgggagget gaggcaggag aatcectiga 600 acclgggagg cggaggttge agtgatetge catectgtca ctgecatcact acactecage 660 ctgggtgaca gagegagact ctgtctcaaa aaaaaaaaaa aaaaaaaaag ctgggigtaag 720 tggtatgcac cagetgtagt cccagctact tgggaggctg agttggggag attgectgag 780 ccagggaggt cgaggcetica gggagecatg attatgccac {geactccag cetgggecac 840 agagtgaaac ctictgicaa aaacaasaaa acaaaaaaac acagigigtt agatctiget 900 agactiggtg atataattaa gaggccatta tgggcagaac tgigccecct tccaaaattc 960 atatataaat atatataaat atatataaat atataaatat atataaatat ataaatatat 1020 ataaatatat aaatatatat aaatatataa atatatataa atatatataa atatataaaa 1080 alatataaat atatataaat atatataaat atataaaaac ataaaaatat atataaatat 1140 atataaatat ataaaaatat ataaatatat aaatatataa aaatatacaa atatataaat 1200 atatacataa atatatataa atatatataa atatataaaa atatatataa atatataaat 1260

Seite 28

SELL PCT 012.5T25 atatataaat atatataaat atatataaat atataaaaat atatataaat atataaatat 1320 ataaaaatat atataaatat ataaatatat aaatatatat aaatatataa atatataaat 1380 aaatataagt atitatgaat atatatgaat atataaatat ataaaaaata tatataaata 1440 tataaatata tataaatata taaatatata catatataca tatataaata aataaatata 1500 agtaittatg aatatatatg aatatataaa tatataaaaa atatatataa atatataaat 1560 atatataaat ataaatatat asaaatatat aaaaatatat ataaatatat aaatatatat 1620 agatatataa atatatataa atatatataa atatataaat atatataaat atatataaat 1680 atataaatat ataaatatat ataaatatat ataaatatat aaatatataa atataaatat 1740 ataaatatat ataaatatat ataaatatat aaatatatat aaatatatat aaatatatat 1800 aaatatatat aaatatataa atatatataa afatatatat aaatatafai aaatatataa 1860 atatataaat atataaaaat atataacaat atataaatat atataaaaat atataacaat 1920 atataaatat aaatatatat aaaaatalat aacaatatat aaatataaat atatataaat 1980 atataaatat anatataaaa aatatatata aatatataaa tatatataaa tatataaatg 2040 tataaalata tataaaaata tataacaata tataaatata taaatatata acaatatata 2100 aatatataaa aatatataac aatatataaa tataaatata tataaaaata tataacaata 2160 tataaatata aatatatata taaatatata aatataaata taaaaaatat atataaatat 2220 ataaatatat atataaatat alataaatat ataaatgiat aaatatatat aaatatataa 2280 atatataana atatataaat atatataaat atatataaat atataaatat aaatatataa 2340 atatatataa atatalanat ataaatatat aaacatatat aaatatatat agataaacat 2400 atataaagat atataaagat ataaagatat ataaatatat aaatatataa agatatataa 2460 atatataaag atatataaat atataaagat atataaatat ataaagatat ataaatataa 2520 tatatanata tataaagata tataaatata atataaaaat atataaatat atattaaaaa 2580 tatatacata taaatatatg tatatttttt {gagatgggg tctegetcag ccacccacge 2640 tggagtgcag tggcacgage tcggetcact gecaaccactg tetetcgggt ccaageaatt 2700 ctgtctcage cteccaagta getgggatta caggeacctg ceatcatgee cggetaattt 2760

: Seite 29

SEL PCT 012.5725 tigtatttia gtagagatgg agtticacca tgitggccag gttggtcteg aattcctgac 2820 ctcaggtgat ctgccggect cggectecea gtgetgggat tacaggceatg agicaccacg 2880 cceggecota tatatatttt tgagacaage tetgigtetc ccaggetgga gtgecagcage 2940 atgatcatga ctcactgtag cctagaccic cagggeteaa gtgatictee cacctcagec 3000 tcccaagtag ctgggattac aggcatgeac caccacacce agetaatitt tgttttgttt 3060 tgttttggag acagaatcte tetctgtcac ceaggotgga gigeagtggt gtgatetcag 3120 ctcagtgcaa cctecaccte ctgggttcaa gtgattctea tgectecagec tectgagtag 3180 ctgggactac aggcgtgage caccacgecce igataaattt tgtattittt ititcagatg 3240 gagtcteact ctgtcatact caggetggag tgcagiggeg tgattttggt itattgcaac 3300 ctetgettee tgggtteaag cgattcteet gectecagect ccagagtage tgggattaca 3360 ggcgectgece accatgecca cetagctaac tiittittt ttitttttga gatagagtet 3420 cactctgtca cccaggetgg agigeaatgg ggegatattg getcactaca acctecacet 3480 cccaggttca agegatteic ctgectcage cicctgagta getgggatta caggtgggtg 3540 ccaccacgcc agactaatat tigtattatt agtagagacg gggtttcace acattggtea 3600 ggctggtitc gaactectgg ccteaggtga tetgectgec teggectece aaagtgetgg 3660 gattacaggc atgagccact gcggcetggcece caattttige atttttigg tagagacggg 3720 gatitcacta tgcticccag getggtetea aactcetgga ctcaagegat ctgectgtct 3780 cagcctceca aagigeaggg attacagtca tgagccacca ctgcacggec ccaaaatita 3840 : tttatittat taitattatt attttttaga tggagtetec tietgitgee agatiggaat 3900 gcagtgccac gatctcaget cactgeaacc tcececteet gggatcaagt gattettttt 2960 fttttaagac fctgictcaa aaaaaaagaa aaaaaaaaaa aatatatata tatatatata 4020 tatacacgaa ttttgggcca ggcacagtgg cttatgcctg taatcccagce actttgggag 4080 ggccgaggtg gatggatcac aaggtcagga gtttgagace agectggcca atatggtgaa 4140 acccigtcic tactaaaaaa tacaaaaatt agetgagegt ggtggeacaa gectgtaate 4200 ctggctactc tggaggctaa ggcaggagaa tegettgaac cggggaggcea gagatigcag 4260

Seite 30

SEL PCT 012.5725 tgagccagga tcgeatcact geactecage ctgggtaaca gagcaagact ctgtctcaaa 4320 aaacaaacaa aacaaaacaa aacaaaataa ataacqgigc aaaattgaat atgecttttt 4380 gactcictaa atgectcaga tecatttace ctggggattt gicetttcia gecccaccac 4440 catctceect ctggaagact getgacciat aaggataaag accagactct tgageaggeca 4500 cttagggtct tectgeccat coctatecee aactcceect cagtaatitt ggctactagt 4560 atttctccac atctgaggcet atcgtgggte teectteagt ggteatgaag gacaaggtty 4620 gagaagtity ccetegtgag tetgatgagg gattgggtag 4660 <210> 27 <211> 3354 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(3354) <223> MAR X_S29 of chromosome X <400> 27 gatcccitta taaaaccaca atataatgga gtgctataat ftcaaacagt gtttggtcty 60 ctggeagagt ggtcaticta acageagtea cagtagagta gaaataagac tgcagtatat 120 ctaaggcaaa aagctgaggt ttcaggaget tgaaggtaaa gaggaagaaa gaaatgggaa 180 tgggaattgg aaagacaaat atcgttaaga gaaaattgct titaggagag gggaaagaat 240 ctatgtgtac ttaagactat ggaatcaate ccatttaagce tgggaaacta gittcatata 300 taactaataa attitattta cagaatatct atttacctga tctaggctic aagccaaagy 360 gactgtgtga aaaaccatca gttctgtcat attcctaaaa anaaattaaa aagttaaaaa 420

Seite 31

SEL PCT 012.8T25 taaataaata ataaaactic ttitctitca aaataatcaa ggtgettatt cacatccatt 480 ccaatttggg gaaatactta titicctaty attagcgaag agaaaagtaa citgcatitc 540 aaticaagtt gatacatgtc acttitaaga ggtcaactaa fatitgctag ttgagctaac 600 catataggct ttaaatactt tcatagtaga aagaaaatga aaatcattag tgaactgtat 660 aaaatagatc atactittty aaagaatcag actgaagtit ccgaaaaaaa gaagtaaget 720 tcaatgaaaa ggtaagtgaa tttagcattt actcagcate tactatggac ttaacaccta 780 acagtagata atctgaaggc aaacatattt gtatagggac tgcagaatga tagatgataa 840 atatcatcic tictattiga atgaatattt tttcaaatct ttcacacaca gtggttiget 900 atggaaagat tigtagtaca ttaaacaaat ctgaagatgg agttagaaag cttaggctat 960 gitttgagca caacatataa tttctctgtg attgtttett catctttcaa atgaggttac 1020 tgtgaagatt aaatgagata actaaatgat gataaaataa tgtaatctta gcagcacctt 1080 atitaatctg tgcaacaact ctgtgaagtg agtagggctce agcttcagtc acttctetge 1140 catttattaa ctaagatagt ttggaaagtt acccatctct tcagctgtaa aatgatgagg 1200 atcataccta tittatgggg cigcttitag gtacaaatat acaggcaagc actiigttaa 1260 tactaaagca ttacaccaat tagitttact cttttccatt cacacatgaa attaatgtaa 1320 tcagaattct gtagattacce taaatcttct gttaacacgt gatatgcagt tcaggttaaa 1380 tgtcagitga gttaccaaag cacatacata ctcaccacce tatccaaatc tacaagectc 1440 ccagttigtc ttcactattt iggttaaatt aatatgaatt cctagatgaa aatttcactg 1500 atccaaatga aataaaaaat atattacaaa actcacacct gtaatcicaa catitiggga 1560 ggccaaggea ggtagateac ttgaggecag gagitcaaga ccagectgat caacatggty 1620 aaaccciglc tctactaaaa atacaaaaat tagccaggty tggtggeatg fgectgtagt 1680 cctacctact cgggaggcety aggcacaaga atcgcettgaa tgtgggaggt ggaggttgea 1740 gtgacctgag atcgtgecac igcactceag cctaggcaac agagtgagat catgigtcat 1800 atatatatat atatatatat atatatatat atatatatac acacacacac acatatatat 1860 atacacatat atatacgtat atatatatat gtatatatat acatatatat acatatatat 1920

Seite 32

SEL PCT 012.8725 atatacgtat atatatacgt atatatatat caatgtaaat tatttgggaa attiggtatg 1980 aatagtictic cctgtgaaca cagatcataa aatcatatat caageagaca aataagiagt 2040 agtcacttat atgcttatac tgtaactta aagtaaaaga attacaaaag catatgacaa 2100 agactaattt taagatatcc taatitaaat tgtttictaa aagtgigtat accatittac 2160 ctatcatatg aataatttag aaacatgttt ataaaattaa tgtccaaatc cattcaaaag 2220 tttigtaatg cagatcaccc acaacaacaa agaatcctag cctattaaaa aagcaacace 2280 acctacatat aatgaaatat tagcagcatc tatgtaacca aagttacaca gtgaatttgg 2340 gccatccaac actttgagea aagtgttgaa ttcatcaaat gaatgtgtaa tcatttactt 2400 actaatgcca atacacttta aggtaatcit aagtagaaga gatagagitt agaatitttt 2460 aaatiiatct ctigtigtaa agcaatagac ttgaataaat aaattagaag aatcagtcat 2520 tcaagccacc agagtatitg atcgagattt cacaaactct aacttictga tacccattct 2580 cccaaaaacy igtaacctce tgicgatagg aacaacccac tgeagggatg fitctcgtgg 2640 aaaaaggaaa tttctttige attggttica gacctaactg gitacaagaa aaaccaaagg 2700 ccatigcaca atgetgaagt acttititca aatttaaaat ttgaaagttg ttcttaaaat 2760 ctatcattta ttttaaaata cggatgaatg agaaagcata gatttgataa agtgaatict 2820 tttctgeaat ctacagacac ttccaaaaat cactacagac actacagaca ctacagaaaa 2880 tcataaataa acaagtgcta gtatcaatat ttitaccaaa aaatggcatt cttagaatit 2940 tttataggct agaaggtitg tacaaactaa tctgccacqgg atttiaaaat atgagtgaat 3000 aaattatatt gcaaaaaaaa tcaggttaca gagaactgge aaggaagact cttatgtaaa 3060 acacagaaaa catacaaaac gtattittaa gacaaataaa aacagaacit gtacctcaga 3120 tgatactgga gattgtgtig acatattage attatcactg {ctigciaaa acataaaaat 3180 aaaaagatgg aagatgaaat tacaatacaa atgatgattt aaacatataa aaggaaaata 3240 aaaatigtic igaccaacta ctaaaggaag acctactaaa gatatgccat ccagcacatt 3300 gccactctac atgtggictg taaaccagcea gecatagggat ceictagceta gagt 3354 <210> 28

Seite 33

SEL PCT 012.8725 <211> 877 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(677) <223> MAR of chromosome 1 genomic contig; 12803267..12803943 <400> 28 ttatatagia tatataatag tatatatiat atagtataca taatagiata tattatatag 60 tatacataat agtatatatt ataatataca taattgtata tatcatatag tatacattat 120 agiatatatc atatagtata cattatagta tatatcatat agtatacatt atatagtata 180 tatcatatag tatacattat agtatatatc atatagtata cattatagta tatatcatat 240 agtatacgta atagtatata tcatatagta tacgtaatag tatatatcat atagtatacg 300 taatagtata tatcatatag tatacgtaat agtaiatatc atatagtata cgtaatagta 360 tatatcatat agtatacgta atagtatata tcatatagta tacgtaatag tatatatcat 420 atagtatacg taatagtata tatcatatag tatacgtaat agtatatatc atatagtata 480 tattatatag tatatatcat atagtatata ttatatagta tataicatat agtatatatt 540 atatagiata tatcatatag tatatattat atagtatata tcatatagta tatataatag 600 tatatatcat atagtatata taatagtata tatcatatag tatatatact atactatatt 8660 atatatagta tacataa 877 <210> 28 <211> 332 <212> DNA

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SEL PCT 012.8T25 <213> Homo sapiens <220> <221> misc_binding <222> (1)..(332) <223> MAR of chromosome 1 genomic contig; 13079684..13080015 <400> 29 ttaattatat tatatatatt atataattat atattaatat atattaatta tattatatat 60 atiatataat tatatattaa tatatattaa ftatattata tatattatat aattatatat 120 taatatatat taattatatt atatatatta tataattata tattaatata tattaattat 180 attatatata ttatatatta {aattatata ttatataatt afaatatata tgttaatata 240 atatatataa ttaatatata altaaaacta tttaattata tgtatattat atataataty 300 tattatttaa ataataaata tattatttat at 332 <210> 30 <211> 479 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(479) <223> MAr of chromosome 1 genomic contig; 15682296..15682774 <400> 30

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SEL PCT 012.8725 acaagtacat atatatatag tatatatata caagtacata tatatagtat atatatatat 60 acaagtacat atatatagta tatatatata tacaagtaca tatatatagt afatatatat 120 acaagtacat atatatagta tatatatata caagtacata tatatatagt atatatatat 180 acaagtacat atatatagta tatatatata caagtacata tatatatagt atatatatat 240 acaagtacat atatatagta tatatatata caagtacata tatatatagt atatatatat 300 acaagtacat atatatatag tatatatata tacaagtaca tatatatata gtatatatat 360 atacaagtac atatatatag tatatataca tatatacaag tacatatata tagtgtatat 420 atatatatac aagtacatat atatacttgt attagtatat atatatatat atacaagta 479 <210> 31 <211> 531 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1}..(531) <223> MAr of chromosome 1 genomic contig; 15694611..15695141 <400> 31 tataatatat ataatacata atagatatat tatattatat aatagatata taattataaa 60 : cataataata tataatgaat ataatataaa ataaatataa taaaatatat aatatatcta 120 ttaigtatta tatattatat atgtttatat ataatataat tatatatgtt tatatataat 180 ataattatat atgitiatat ataatataat tatatattat atattataga tataatatat 240 aatatactat atatiataga tataaiatat aatatactat atattataga tataatatat 300 aatatactat atattataga tataatatat aatatactat atatiataga tataatatat 360

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SEL PCT 012.5725 aatatactat atattataga tataatatat aatatatatt atatattata gatataatat 420 ataatatatt atatattata tctatatata atataitgta tattatatat aatatatigt 480 ataftatata taatatatty tatattatat ataatatatt gtatattata t 531 <210> 32 <211> 378 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(378) <223> MAR of chromosome 1 genomic contig; 886276..886653 : <400> 32 ttatattata tatcitacat aaattatata tatatattac ataaattata tacaatataa 60 attatataca atataatita tatataaaat ataaattata taaataattt atatataaaa 120 tataaattat ataaataatt tatatataaa atataaatta igtataaaat ttatatataa 180 aatataaatt gtgtataaaa ttatatataa aatataaatf gigtataaaa titatatata 240 aaatataaat tatatataat ttatatatta taatataaat tatatataat atatatcata 300 agatataaat tatatataat atatatcata agatataaat tatatataat atatatcata 360 agatataaaa tatataat 378 <210> 33 <211> 585 <212> DNA <213> Homo sapiens

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SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(595) <223> MAR of chremosome 1 genemic contig; 3326732..3327326 <400> 33 azaatatata aatatatata aaaatatata aaaatatata aatatatata aaaatatata 60 aafatatata aatatatata aaaatatata aatatatata aatatatata aaatatataa 120 atatatataa aatatatata aatatatata aatatatata aaaatalaaa tatatataaa 180 aatataaata tatataaata tatataaaaa tataaatata tataaatata tataaatata 240 taaalatata taaafatata taaatatata aatatatata aatatatata aatatatata 300 aatatataaa tatataaaaa tatatataaa tatataaata tatataaata tataaatata 360 taaaaatata tataaatata taaatatata taaatatata taaatatata tataaatata 420 tataaatata tatatatata aatatatata aatatatata taaatatata taaatatata 480 tatatatata {aaatatata taaatatata taaatatata tataaatata tataaatata 540 tataaatata tatataaata tatataaata tatatataaa tatatataaa tatat 595 <210> 34 <211> 738 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(738)

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SEL PCT 012.8725 <223> MAR of chromosome 1 genomic contig; 4485716..4486453 <400> 34 ataatagata atatatatta tatgatagat atataatata ttatataata tataatatat 60 tatatatcta fcatataata tatataatat ataatatatt atatatctat catataatat 120 aatatatata atatataata tatatcatat tatattgtat ataatatata tcatattata 180 tigtatataa tatatatcat attatatigt atataatata tatcatatta taltgtatat 240 aatatatatc atattatatt gtatataata tatatcatat tatatigtat ataatatata 300 tcatattata tigtatataa tatatatcat attatatigt atataatata tatcataita 360 tattgtatat aatatataic atattatatt gtatataata tatatcatat tatatigtat 420 ataatatata tcatattata ttgtatataa tatatatcat attatatigt atataatata 480 tatcatatta tattgtatat aatatatatc atatatiatc taltatattg tatataatat 540 atattatata ftatctatta tattgtatat aatatatatt atatattatc tattatattg 600 tatataatat atattatata tiatctatta tatigtatat aatatataat aaatatagta 660 tatataatag ataatatata gtatatatga tatattatat atactatata ttatatatca 720 tatatactat atactata 738 <210> 35 <211> 386 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(386) <223> MAR of chromosome 1 genomic contig; 5423067..5423452

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SEL PCT 012.8725 <400> 35 taaatatata aaaatatata taaaaatata aaaatatita tataaatata taaaaatatt 60 tatataaata tataaatata taaatatata tttatataaa tatataaata tataaatata 120 tam atatata tttatataaa tatataaata tatatttata taaatatata aatatatata 180 aaatatataa atatatattt atataaatat ataaatatat ataaaatata taaatatata 240 tattttatat aaatatataa atatatataa aatatataaa tatatatatt ttatataaat 300 atataaatat atataaaata tataaatata tatattttat atatttatat atataaatac 360 atataftica tatatcacat atatga 386 <210> 38 <211> 584 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(584) <223> MAR of chromosome 1 genomic contig; 5805559..5806142 <400> 36 taaatatitt taaaatatat atattitata atatataatt tatattataa tgtgtacata 60 atatatatta taatataata tatataatac tgtatattat attatatata ttataatata 120 : tattattata tattatatta tatataatat aatatatatt ataatatait atattataca 180 tattataatg taltataata tatattatat tatatattat aatatatatt atattatata 240 ttataatata tattatatta tatatiataa tatatattat aitatattat atatattata 300

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SEL PCT 012.8T25 . atacatatta taatacatat tatataatat attataatat gtattataat acatattata 360 taatatatta taatatatta tatataataa tatattataa tacatattat atataatata 420 tattatgtat attatatata atatatatta caatgtatat tatgtatatt atatatatta 480 tatatcatat aatatatatt atatataata tgatatataa tatatattat ataatatatt 540 atatgatata tataataigt attacatgta atatataica taat 584 <210> 37 <211> 345 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(345) <223> MAR of chromosome 1 genomic contig; 10802644..10802988 <400> 37 tgtatatata tactatatat atactatata tatagtigtat atatatacta tatatatact 60 atatatatag tgtatatata tactatatat atagtatata giatatatag taatatatat 120 atatagtata tatatacact atatatagta tatatagtat atatatattg tgtatatagt 180 atatatatag tgtatatata gtatatatat attgtatata tagtatatat attgtgtata 240 tatagtatat atatagtata tatagtatat atagtatata tatagtatat atatactata 300 tatatagtat atatatattg tatatatata ctatatatat agtat 345 <210> 38 <211> 474 <212> DNA

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SEL PCT 012.5725 <213> Homo sapiens <220> <221> misc_binding <222> (1)..(474) <223> MAR of chromosome 1 genomic contig; 13496468..13496941 <400> 38 atattatata taatataatt ataictataa ttatatatta tatataatat aattatatat 60 ctataattat atattatata taatatatat tatatataat atataattat atataattta 120 {ataatataa tatataatat ataattatat ataattatat aatataatat ataatatata 180 attatatata atttatataa tataatatat aatatataat tatatatatt tatataatat 240 aattatatat aatatataat {atatataat ttatataata taattatata taatatataa 300 ttatatataa titatataat ataattatat ataattatat attatatata atttatataa 360 tataattata tata atatat aattatatat aatatataat tatatataat tatatataat 420° atataattat atataattta tataatataa ttatatatta tatatattat atat 474 <210> 38 <211> 483 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{(483) <223> MAR of chromosome 1 genomic contig; 2509163..2500645

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SEL PCT 012.8725 <400> 39 cagaatacat aatatataat agtattatat aatagtatgt atagttataa tatatagtat 60 aattacaata tatgatatgg ittatatatt atatatagta taatataata taacataata 120 ctatiataat atataaacta tataatatat actattataa fatatgaact attataatat 180 ataaactata tataatatat aatatgtact attataatat ataaactatt ataatataat 240 atataaacta ttataataca taaactatta taatatatat aatactatgt atacatatat 300 : tacattatgt acatactaca ttatgtatta tgtatgtata tatacacaaa atacataata 360 tataatagta ttatataata gtatatatag ttataatata tagtataatt acaatatata 420 atatggttta tatattatat atagtataat acaatataac ataatactat tatatataaa 480 cta 483 <210> 40 <211> 641 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(641) <223> MAR of chromosome 1 genomic contig; 2776349..2776989 <4Q0> 40 tgitatatat atataacata gatattatat atacatgtta tatatataac atagatatta 60 tatatacatg ttatatatat aacatagata ttatatatat aacatagata ttatatatac 120 atgtiatata taacatagat attatatata catgtiatat ataacagata ttatatatac 180

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SEL PCT 012.5725 atgttatata taacatagat attatatatg tatgttatat ataacataga tattatatat 240 gtttatataa tatataacat atgtttaaca tatataatat ataacatgtt tatataatat 300 ataacataat tatatgttat atatgatata aaacatatat attatatacg ttatatgtaa 360 tatataacat atatigtata cgttatatgt aatatataac atatatigta tacgttatat 420 gtaatatata acatatattg tatacgitat atgtaatata taacatatat tgcatacgtt 480 atatgtaata tataacatat attgtatacg ttatatgtaa tatgtaacat atattgtata 540 cgttatatgt aataigtaat atataataca tataacatgt atatataaca tatatgtata 600 taacatatat ataacatata taacatatat gttataitat a 641 <210> 41 : <211> 745 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{745) <223> MAR of chromosome 1 genomic contig; 2858703..2859447 <400> 41 : atatttatat atgtaataat atataatata titatatgta ttigtatatg taataatata 60 tatataataa aatatgtaat aatatataat atatftatat ataaatatat tatattatat 120 atatattatt atatitataa tataatatat atttatatta tatattataa atatatatta 180 tataatatat attataaata tatattatat aatatatatt ataaatatat attatattat 240 atattataaa tatataitat ataatatata ttataaatat atattatata atatatatta 300 {anatatata ttatatitat aatatatatt titgtatatt atatattata tattataaat 360

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SEL PCT 012.8T25 attattatat ttataatata ttatatatit tatatataat atatgatata tattataaat 420 atatcitata aatatatata tttatatata tatattataa atatataaat ataaatatat 480 aatataatat aatataatat aataaatata atatataata tatataatat ataataaata 540 taataaatat aaatatatca tataaatata aatataaata taaatatatc atataaatat 600 atatatttat atgatatatt atagtatata taaatatatt tatatattat aaaatattta 660 tataatatat aattataata tatttatata tataaattaa ctaatatata taaactaata 720 taatatataa tgtaataata tagta 745 <210> 42 <211> 307 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{307) <223> MAR of chromosome 1 genomic contig; 945522..945828 <400> 42 catatataat atatattacc {atgttatat aggtcatata taacataaat atattacata 60 tatgtaatat atattaaata taaatatata acatatatgt gtaactatat atgtaaatat 120 gtacatatac atatatgtaa atatataata tatatitaca ttatattata taatatatat 180 ttacattata tatttatata tacattatat atatttacat tataaatatt tatataatat 240 atatttacat tatattacat tatataaaat acaatatatt acattataat acattataac 300 agataaa 307 <210> 43

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SEL PCT 012.8725 <211> 357 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(357) <223> MAR of chromosome 1 genomic contig; 3402743..3403099 <400> 43 aatattatat taaatataat atattaatat ttaatatatt taatataata ttaaataaat 60 atattataaa taaatiataa tatataaata tatattaigt atttatgtat aatatataaa 120 aattatatat aatatatata tttttataaa tatataaata tataataaat aaatatatta 180 aataaataat aatatattaa atattaatat attaaatatt atatattaaa tataatatgt 240 aatatgaaat atattaaata ttatatatta aatataatat ataatgtgaa atatattaaa 300 taltatatat taaatataat atataatatg aaatatatta aatattatat attaaat 357 <210> 44 <211> 323 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(323) <223> MAR of chromosome 1 genomic contig; 3485830..3486152

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SEL PCT 012.8T25 <400> 44 atatttatag actatatatt tatatattta gtgtattigt atactatata tttatatagt 60 tagtatattt gtatactata tatttatata tttagtatat ttgtatacta tatatttata 120 tatttagaat atttgtatac tatatattta tatatttagt atattigtat actatatatt 180 tagtataitt gtatactata tatttatata tttagtatat tigtatacta tatatttata 240 tatitagtat atttatatac tatatactta tatatttagt atatttatat actatatact 300 tatatattta gtatatttat ata 323 <210> 45 <211> 408 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(498) <223> MAR of chromosome 1 genomic contig; 3548336..3548833 «400> 45 aattattact atattgitaa tataattait atataatata atataattat afcactatta 60 ttatattata gtattaatat aatagtgtat aacattaata taatatagta ttaatataat 120 agcgtataac attaatataa tatagtatta atataatagc gtataacatt aatataatat 180 agtattaata taatagtgta tattaatata atatagtatt aatatataat attaatataa 240 tatatcaata taatagtata taatataata taatatatca atataatagt atataatata 300 atataatata tcaatataat agtatataat ataatataat atatcaatat aatagtatat 3860

Seite 47

SEL PCT 012.8725 aatattaata taatataata {caatataat agtatataat attaatatat taatataata 420 gtatataata ttaatgtaat ataatattaa cataatgtat atataatat aatagtatat 480 aatactaata taatataa 498 <210> 46 <211> 400 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1}..(400) <223> MAr of chromosome 1 genomic contig; 4595109..4595508 <400> 45 aaatatatta tattatatat tatatattat tcaatatact ataatatata ttatatatgt 60 ttaatacaat atataatatt tacatatatt cccatttatt tatataacat atattatatg 120 atattatata ttactccata taatataata {attatacat aatatattac tcagtataat 180 acataatata tataatatat tactcggtat aatatataat attatatgtt atgcaatata 240 atatataata ttatatataa tacattatic aatataatat ataatattat atataataca 300 : ttattcaata taatatataa tacactattc aatataatat acaatattat atataataca 360 ttattcaata taatatatat tatataatat atatatttat 400 <210> 47 <211> 403 <212> DNA <213> Homo sapiens

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SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(403) <223> MAr of chromosome 1 genomic contig; 7205508..7205911 <400> 47 agtatatata tgigtatata tatgagtata tatatgtgta tatatatgag tatatatatg 60 totatatata tgagtatata tatgtgtata tatatgagta tatatatgtg tatatatatg 120 agtatatata tgigtatata tatgagiata tatatgtgta tatatatgag tatatatatg 180 tgtatatata {gagtatata tatgtgtata tatgagtata tatatgigta tatatgagta 240 tatatatatg tgtatatatg tgagtatata tatgtgtata tatatgagta tatatgtgta 300 tatatatgag tatacatatg tgtatatata tgagcatata tgtgtatata tatgagtata 360 tatatgtgta tatatatgag tatatatgtg tatatatatg agt 403 <210> 48 <211> 309 <212> DNA <213> Homo sapiens <220> <221> misc_hinding : <222> {1)..(309) <223> MAR of chromosome 1 genomic contig; 7507280..7507588 <400> 48

Seite 49

SEL PCT 012.5725 tataaaatat atattatita tataitatat ataaaatata tattatatta tatattatag 60 atataataaa taaataatat ataatatalt atataattat ttatacataa ttatatataa 120 ttatatgtaa tigtacaatt atatataatt atatacaatt atacacataa ttatatacaa 180 ttatacaatt atatacataa itatatatat aatatacata aftatatatt aattatacaa 240 ttatatacat aattatatat aattatacaa ttatatacat aattattaty tatattatat 300 tatataata 309 2105 49 <211> 516 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(516) <223> MAR of chromosome 1 genomic contig; 3581085..3581600 <400> 49 atatatatat atatatatat atitatatat atatatatta atatatatta tatataaaaa 60 tatataaaat ttatatatat aatttatata tataaaaata tataaaattt atatatataa 120 ittatatata taaaaatata taaaatttat atatataatt tatatatata aaaatatata 180 aaatitatat atataattta tatatataaa aatatataaa atitatatat ataatttata 240 tatataaaaa {atataaaat ttatatatat aatttatata tataaaaata tataaaattt 300 atatatataa titatatata taaaatatat aaattatata tataattata tatataatat 360 aaaattalat atataattat atatataata taaaattata tatataatta tatatataat 420 : ataaaattat atatatatly tatatatata aaatatacaa aatttatata tataaaatat 480

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SEL PCT 012.8T25 aaaatataca taaaaataaa tatatataat ttatat 516 <210> 50 <211> 534 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> {1}..(534) <223> MAR of chromosome 1 genomic contig; 3084851..3085384 <400> 50 atataatata tatgactata tattttatat tatattctat {tcaataaaa tatttatatt 60

Htattatata tataatata taattatata {gtaataata tataatatat aatatatatt 120 ttatattata tittatattt atitttatat tttatattat attttattat atatattata 180 atatataatlt atatatgcaa taatatatta tatattataa tatataatta tatatgcaat 240 aatatattat atatlataat atataattat atatgcaata atatattata gattataata 300 tataattata tatgcaataa tatatiatat attatatatt agataatata ttaatatata 360 tiataacata taatatataa catataatat ataatatatt atctaatata taatataaca 420 tataatatat aatatattat ataatatait attacatata taatatatig taatatataa 480 tattacatat atcticaaaa agagttatgt gtatataata catatatata ccat 534 <210> 51 <211> 583 <212> DNA <213> Homo sapiens

Seite 51

SEL PCT 012.8T25 <220> <221> misc_binding <222> (1)..(583) <223> MAR of chromosome 1 genomic contig; 160087..160669 <400> 51 tatttatata aaatatataa aatatattat atataaatat attatatata atatatttat 60 atattataca atatatttat atattatata taatatattt tataiaatat acataatata 120 tittatatat tatatataat atattttata tataatgtac aatatattit atatattata 180 : tataatatat tttatatata ctatacaata tattttatat attatatatt ttatatatat 240 titicatgta acatatatat titatatata atatatatac catatataat atattitata 300 tataatatat ataccatata taatatatit tatatataat atgtatatca tatatagtat 360 attitatata taataggtat accatatata atatatitta tatataatag gtataacata 420 tataatatat ittatatata atatgtatac catatataat atattttata tattatagat 480 accataigta atatacttta tatataatat agataccata tgtaatatac titatatata 540 atatagatac catatgtaat atactttata tataatatag ata 583 <210> 52 <211> 314 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(314)

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SEL PCT 012.8T25 <223> MAR of chromosome 1 genomic contig; 4350424..4350737 <400> 52 tatgtgtata taaatatatg tatatatgtg tatataaata tatataaata tatgtatata 60 tgtatatata catatatita tatataaata tatgcatata tttatatata aaatatatge 120 atatatgtat atatataaaa tatatacata tatgtatata tataaaatat atacatatat 180 giatatatat aaaatatata catatatgta tatatataaa atatatacat atatgtatat 240 atataaaata tatacatata tgtatatata taaaatatat acatatattt atatatataa 300 aataccaagt ctta 314 <210> 53 <211> 828 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(828) <223> MAR of chromosome 1 genomic contig; 8443267..8444094 <400> 53 tattatataa ttatatatac tatataatia tataatatat agttatatag tatatataat 60 atatataata tatactatag tatatataat atatataata tatactatag tatatataat 120 atataattat atataatata tataatatag tatatattat atatataita tatatatata 180 atatatatat aatatatata atatagtata tataatatat aattatatat aatatataat 240 atagtatata taatatataa tatatatata attalatact ataatatata taatatataa 300

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SEL PCT 012.8725 ttatatatta tatactatag tatatattat tatatataat agatataata tatataatta 360 ttatataata tagtatatat aatatataat tatatataat agatataata taatataatt 420 alatataata tagtatatat aatatataat tatattatat tatatataat atataattat 480 aatatataat tatattatat aatatatata atatataatt atattatata attatattat 540 ataatatata taatatataa ttatattata taatatatat aatatataat tatattatat 600 satatatata atatataatt atattatata atatatataa tatataatta tattatataa 660 tatatataat atataatiat atatiatata taatatagta tatataatat giaattatat 720 atcatataat atataacatt gtatataata tataattaca tattatataa tgtatataat 780 atataattat atacattata taatatagta tataattata tattaigt 828 <210> 54 <211> 573 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(573) <223> MAR of chromosome 1 genomic contig: 8703190..8703762 <400> 54 tatattatat ataaaatata catataatat acctataata tacatataat atataatata 60 tattatgtac atataatata catataatat atataatata taatgtacat ataatataca 120 tataatatat gttatatatt atatataaaa tataggatat atataatata gaatatatat 180 actatattgt atatataaga tatataatat atagtatata tactatataa tatataatat 240 atagtatata taatatataa tatagaatat atatacaata tataatatag aatataggat 300

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SEL PCT 012.5725 atatatagaa tatacatata taatatgtat atattatata ttatattata tattatataa 360 aaatatataa tatataatat aaaaatatat tatatattat ataatataaa atatattata 420 tatiatatat tatataatat aaaatatatt atatattata tattatatat aaaatatatt 480 atatatiata tattatatat aaaaatatat tatatattat atattatata taaaaatata 540 ttatataita tatataaaaa tatatattat tac 573 : <210> 55 <211> 597 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(597) <223> MAR of chromosome 1 genomic coniig; 8819076..8819672 <400> 55 acatatctta tatataaaat atataaatat acacatattt tatatataat atatattata 60 tatatgaaat atacacatat ttttatatat ataatatata tattatatat aatatatgca 120 tatattatat ataaaatata tatattatat ataaaataty catatattat atataatata 180 tataatataa aatatataat atatattata tattatatat aatatatatt atatataata 240 catatatata atatataata tatataaaat ataatatata tattatataa tatatatata 300 aatatatata atatatatat aatatatata ttatatataa aatatatatt atatgtaaaa 360 tatataatat atataatata tatatiatat gtaaaatata tattatatat aaaatatata 420 atatataaaa tatatattat atataaaata tataatatat aaaatatata atatatataa 480 aatatataat atatataaat atatattata tataaaataf ataatatata taaatatata 540

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SEL PCT 012.5725 ttatatataa aatatataat atatataaat atatattata tataaaatat atattat 597 <210> 56 <211> 645 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(646) <223> MAr of chromosome 1 genomic contig; 759619..760264 <400> 56 taatatatat aatatatatt atataataat atataatata tattatatta taatatataa 60 tatattatat aataatatat attatataat atataataat atatataata catattattt 120 aataatatat aatatatatt atataataat atataatata tattatataa taatatacat 180 tatattatat aatatataat atatataata tatattatat aataatatat aatatatatt 240 atagaatgat atattagata ttatataatt atatatataa tattatatat tatataataa 300 tatataatat atattatata attatatata taatattata tattatataa ttatatataa 360 tatattatat aattatatat ataatattat atattatata aftatatata atatafatta 420 tataatiata tatataatac tatatattat ataattatat ataatactat atattatata 480 atitatataa ttatatatat tatatattat ataattatat atattatata ttatataata 540 acatatatat tatatattat ataataacat atatattata tattatataa tacatatata 600 ttatatatta tataatacat tattatataa tatataatat atatta 646 <210> 57 <211> 752

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SEL PCT 012.8T26 <212> DNA Co <213> Homo sapiens <220> <221> misc_binding <222> (1)..(752) <223> MAR of chromesome 1 genomic contig; 1226710..1227461 <400> 57 taaacatata tataaatata tataaatata tatataaata tatataaata tataaatata 60 taaatatata tgaatatata aatatatata aatatatatg aatatataaa tatatatata 120 aatatatata aatatatata taaatatata {aaatatata taaatatata taaatatata 180 : taaataaata tataaatata tataaatata taaatatata tataaatatg faaataaata 240 tatataaata tataaatata tataaatata tataaatata tatagaaata tatatagaaa 300 tatatataaa tatatataga aatatataga aatatatata gaaatatata taaatatata 360 taaatataga aatatatata aatatatata aatatatata gaaatatata atatatataa 420 atatatataa atatataaat atatatataa atatatatat aaatatatat aaatatatat 480 aaatatatat aaatatatat aaatatatat attaatatat aaatctatat taatatatat 540 taatatataa atctatatta atatatatta atatatatat taatatatat taatatataa 600 atatatatat taatatataa atatatataa atatatatgt aaatatatat ataaatatat 660 ataaatatat atataaatac atataaatat atatataaat atatataaat atatatataa 720 atatatataa atatatatat aaatatatat aa 7562 <210> 58 <211> 300 <212> DNA

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SEL PCT 012.8725 <213> Homo sapiens <220> <221> misc_binding <222> (1)..(300) <223> MAR of chromosome 1 genomic contig; 1119049..1119348 <4(0> 58 taatatacat tttatataat atatglaata tatattttat atatatgtaa tatatatttt 60 atataatata tgtaatatat atttiatata tatgtaatat atatttfata taatatatgt 120 aatatatatt t{atataata taigtaatat atattttata taatatatgt aatatatatt 180 itatataata tatgtaatat atatittata taatatatgt aatatatatt ttatataata 240 tatgtaatat atattttata taatatatgt aatatatatt ttatatatat gtaatacata 300 <210> 59 : <211> 617 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1).(617) <223> MAR of chromosome 1 genomic contig; 3603613..3604229 <400> 59 aaaatataat atatataata tataatatat ataatatatt atatataaaa tatataatat 60

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SEL PCT 012.8T25 ataatatata taataaaata tacataatat ataatgtata ataaaatata cataatatat 120 aatatataat aaatatataa tatataatat ataataaaat atataatata taatatataa 180 taaaatatat aatatattat atataataaa atatataata tattatatat aataaaatat 240 ataatatatt atatataata aaatatataa tatattatat ataataaaat atataatata 300 ttatatataa taaaatatat aatatattat atataataaa atatataata tataatatat 360 aataatatat ataatatata atatatataa taaaatatat ataatatata atatatataa 420 taaaatatat aatatataat atatataata aaatatatat gatatataat atatataata 480 saatatatga tatataatat atataataaa atatataata tataatataa tatataatat 540 atatactaaa aaatatataa tatataataa aaaatatata atatataata tatataatat 600 ataataaaat atatata 617 <210> 60 <211> 674 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(674) <223> MAR of chromosome 1 genomic contig; 2592480..2593133 <400> 60 taagcttata tatatatata agcttatata tatatatata agcttatata tatatagaaa 60 gcttatatat atatagaaag citatatata taagaagctt atatataaaa gettatgtat 120 aaatatatat aaatatatit atttatgct! atagatacat atataaatat atttatitat 180 atttatatat aaacatatat tlatatatat ttatataata tttatttait atataaataa 240

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SEL PCT 012.5725 atatataata aataataaat atatataata tatitattgt attatttata taaatttatt 300 aatataatat ataataaaat aataattata taaatatata aatatctata aatatatata 360 aatatatata atatctataa atatatataa atataaatat atataatatc tataaatata 420 gataaatata aatatatata atatctataa atatagataa atataaatat atataactat 480 atataaatat atataactat atataaatat atatataaat atatataact atatatataa 540 ctatatatat aaatatatat aactatatat ataaatatat atataaatat atataactat 600 atatataaat atatataact atatataaat atatatataa atatatataa ctatatatat 660 : aaatatatat ataa 674 <210> 61 <211> 1694 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1694) <223> MAR of chromosome 1 genomic contig; 2891680..2893373 <400> 61 atatgtaata catatattat atatgcatat atacatgcat atgtatatac atatattata 60 tatgcatata tacatgcata tgtatataca tatataaagt atgattatat ataatatata 120 catgtatatg tatatacatg tatatattat attatatatt atttatacat attattatgt 180 ctatatataa tataatatat acatattaat aatataatac ataatataat ataatatatt 240 atataataca taatataata taatatatta tataatacat aatataatat aatatattat 300 aigatacata atataatata atafattata tgatacataa tataatataa tacatattaa 360

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SEL PCT 012.5725 taatatatta ttaitattaa tataatatat acatattaat atacatacat atatattata 420 ttatatataa tatacatata atataatatg taatattata tataatataa tacataatat 480 aatacatatt aataatatat tattaataag ataatatata tgfatctata atatatacat 540 atatgtatat gtatgtatat attatagata tacatgtita tacatgtata tattatagat 600 atatacatgt atatacatgt atatattala gatatataca tgtatatacg tatatattat 660 agafatacat gtatatatgt atatatatta tagatataat atatacaaga atataagaat 720 atatataaia taatatataa tacacataat acgiataiat tatatataca tgtatattat 780 atatgtacat atatacatgt ataitatata tacatgtata tiatatatac aigcatatta 840 tatatattit tatatataat atccatgtat atiatgtata tttgtgtata ttatatatac 900 atgtatatta tatatacatg caiattatat atatttitat atataatatc catatatatt 960 atgtatatit gtgtatatta tatatacaca tatattatat atacatggat attatatata 1020 cacatatatt atatatacat atatattata tatacacata tattatatat acatgtatat 1080 tatatataca cgtatattat atatacacac gtatattata tatacacgta tattatatat 1140 acacacgtat attatatata cacgtatatt atatatacac acgtatatta tatatacacg 1200 tatattatat atacacacgt atattatata tacacgtata ttatatatac acacgtatat 1260 tatatataca cgtatattat atatacacac gtatatiata tatacacgfa tattatatat 1320 acacacgtat attatatata cacgtatait atatatacac acgtatatta tatatacatg 1380 tatattatat atacatgtat attatatata cacatgtata ttatatatac atgtatatta 1440 tatatacaca tgtatatiat atatgcatgt atattatata tacacatgta tattatatat 1500 acacatgtat attatatata catatatatt atatatacat gtatattatg tatacatata 1560 tattatatat acatgtatat tatagataca tatatattaa atatacatgt atattatgta 1620 tacatatata ttaaatatac atgtatattg tatatacata tatattatat acatgtatat 1680 tacatgiata cata 1694 <210> B62 <211> 587

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SEL PCT 012.8725 <212> DNA . <213> Homo sapiens <220> <221> misc_binding <222> (1)..(587) <223> MAR of chromosome 1 genomic contig; 3432560..3433146 <400> 62 gaattatata tatatagcty aattatatac atatataata tatacaatat atattatata 60 titatatatg atatatacaa tatatattac atattatata tacaatatat aatatataat 120 atataatatt atatattata tatigtatat aatatatatt atataacatt atataatata 180 taatattata tattatatat tgtatataat atatattata taacattata taatatatac 240 tattatatat tataatatat aatatataat aatatataat agtatatatt atatatatty 300 tatatattat atataaatat ataatatata atatatatia tataatatat attatataat 360 atatattatt atatattata tatitatata taatatatat tatatatatt atattttata 420 tataaatata taatatataa taatatataa tttaatatat ataatatata caatatataa 480 tatataatat attaatatat ataatatata caatatataa tatataatat ataatatata 540 atataaatta tatatataa tatatatlat atatagctga attatat 287 <210> 83 <211> 313 <212> DNA <213> Homo sapiens <220>

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SEL PCT 012.8726 <221> misc_binding <222> (1)..(313) <223> MAR of chromosome 1 genomic contig; 3805392..3805704 <400> 63 tatataatat gtatattatg taatattfta tatagcatat atgtatatta tatataatct 60 tttatatata gtatataata tgtatattat atattatata attatataat tatgtattat 120 ataaaatata ttatataata tataattata tatiititga aatatagatt atatataata 180 tatatggcag tgagceigaga tataatatat attatctata ctatataata tatattatat 240 atactctata ttatatatgt atatattata tataatatat acatatataa tgtgtatata 300 ttatatataa taa 313 <210> 64 <211> 349 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(349) <223> MAR of chromosome 1 genomic contig; 4521378..4521726 <400> 64 ttatatacac tatataatat gtatttatat atacttatat acactatata tgtatttata 60 tataattata tacactatat aatatgtatt tatatataat tatatacact atataatatyg 120 tatttatata taattatata cactatataa tatgtattta tatataattg tatacactat 180

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SEL PCT 012.5725 ataatgtata titatatata attgtataca ctatataatg tatatttatg tataatigta 240 tacactatat aatgtatatt tatgtataat tgtatacact atataatgta tatttatgta 300 taattgtata taccatataa tgtatattta igtataattg tatatacca 349 <210> 65 <211> 500 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(500) <223> MAR of chromosome 1 genomic contig; 3240166..3240665 <400> 65 tftaatatata atatatatta tatatitata tatiaatata taatatatat ttatatateaa 60 tatatattat atatttatat tacatatatt tatatgttaa tatatatttt atatatttat 120 atatittata tatttatata ttatataitt atatatiata tttatatatt atatatttat 180 attatatatt tatatattat atitatatat tatatattia tattatatat ttatatatty 240 tatatitata ttatatattt atatattgia tttatatatt atatafttat atactatata 300 tatttatata tattatatat ttatatatta tatatatita tatatattat atatttatat 360 attatatata tttatatata ttatatattt atatattata tatatttata tatattatat 420 atatitatat atatfatata titatatata atatatatta tatatittat ctatatattt 480 atataitaat atatattata | 500 <210> 66 <211> 866

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SEL PCT 012.8725 <212> DNA <213> Homo sapiens <220> <221» misc_binding <222> (1)..(866) <223> MAR of chromosome 1 genomic contig; 409429,.410294 <400> 66 atatatataa tatattatat atattatata ttatatatat aatacatata ttatatatat 60 aatatataat acatatatia tatatattat atattatata taatatataa tacatatatt 120 atatataata tataatatat aatatattat ataatataat tatataatia tataatataa 180 tataatatat aatattatat aattatataa tatatataat tatattatat attataaata 240 ttatataata tatatattac aaatatatat tatatatatt ataaatatta tataacatat 300 alaltatata atatatataa tataiaatat atataaaaat ataatatata agatatatat 360 aatatatgat atatatgata tataatatat gatatatatg atatatataa tatatgatat 420 afatgatata tatgatatat ataatatatg atatatatga tatatatgat atatgatata 480 tatgatatat gatatatatg atatatatga tatatgatat atatgatata tatgatatat 540 gatatatatg atatatafga tatatgatat gatatatata atatatgata tgatatatat 600 aatatatgat atatatgata tatgatatgt aatatatatg atatattata tataatatat 660 aatatataca taatatataa tatataatat ataatatata taatatgtga tatatataat 720 atatgatata tgatatatga tatatattat ataatatata taatatatat tatatataat 780 atatattata taatatatat aatatatatt atatataata tataagatat aagatataat 840 atatataata tataatatat ataata 866 <210> 67

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SEL PCT 012.8725 <211> 335 <212> DNA <213> Homo sapiens <220> : <221> misc_binding <222> (1)..(335) <223> MAR of chromosome 1 genomic contig; 614754..615088 <400> 67 acccaatata tgtgtatata tgtatgtata tatacatata catacataca tatatgtaca 60 tacatatata catacataca tatatatgta catacatata tacatacata catatataca 120 tataacatat atacacacat atatacagat atacatatat acatacatat atacatataa 180 catatataca tacatatata catataacac atacatacat acatatatac atacaacata 240 tatacataca talatacata tgtatacata catatatgta tacatatatg tatacatata 300 tgtatacata tatgtatata tafattgtta tatat 335 : <210> 68 <241> 455 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(455) <223> MAR of chromosome 1 genomic contig; 1299520..1299974

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SEL PCT 012.8T25 <400> 68 ggatatatat attattagtt gttatattat tatatattat atatattatt atatataata 60 tattatatca tatatattat tatatataat atattataic atatatatia Hatataata 120 tattatatca tatataitat tatatataat atatattata tatattatta tatataatat 180 atattatata tattattatg tataatatat atattatata ttatitatat atatataaat 240 tatataataa tatataatia aftatacata tatacatata taagtataca tataatatat 300 ttatatagta tatataaata tatatacaat atatttatat attatatatt atatataaat 360 atatacaata tatttatatc atatatttta tatatgatac atataatata tattatatat 420 gatatataat atatatcata tatgatatat aacat 455 <210> 69 <211> 404 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(404) <223> MAR of chromosome 1 genomic contig; 1970778..1971181 <400> 69 atatataata tgtataatat ataatatata tcatatatig ttctatgtat attacatata 60 atatgcatta tatattatat attgcatata atatgcatta tatattatat attgcatata 120 atatgcatta tatattatat attgcatata atatgcatta tatattatat attgcatata 180 atatgcatta tatattatat attgcatata atatgcatta tatattatat attgeatata 240

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SEL PCT 012.5T25 atatgcatta tatattatat aatatataca catataatat atataatita tatatattta 300 tatatatita catttatiat atatitatta tatataaata tatitttata tatfactiat 360 atattatata taatatatat aatatatata ttatatataa tata 404 <210> 70 <211> 805 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(605) <223> MAR of chromosome 1 genomic contig; 35682918..3563522 <400> 70 tatatatata aaatacatat atattatata tattatatat aatacatata ttatatatta 60 tatataatac acgtatataa tatataatat ataatacata taatatatat gatatataat 120 acatataata tatatgatat ataatacata tataatatat atgatatata atacatatat 180 aatatatatt atatataata catatataat atatattata tataatacat atataatata 240 tattatatat aatacatata taatatatat tatatataat acatatataa tatatattat 300 ataatacata tataatatat attatataat acatgtatat aatatatait atatataata 360 catatatatt atataataca tgtatataat atatatiata tataatacat atatattata 420 tattatatat taatatattt atataatagt aatatataat attaatata! tatatatait 480 aafattatat ataatacata taftatatat aatataaata tatataatac atatataata 540 cacatattat atataataca tatattatat ataatatata {attatatat aatatatatg 600 taata 605

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SEL PCT 012.8725 <210> 71 <211> 317 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..{(317} <223> MAR of chromosome 1 genomic contig; 189743..190059 <400> 71 tatttittat atttatatat tatatataft titatatgta atatattata tataaaatta 60 tataatita ctacatataa tatataaaat tatataattt tactacatat aatatataaa 120 attatataat tttactatat ataatatata aaattatata attttatata taatatatat 180 tataatatat attatatgca atatatatta tatattatat tataatatat tgfatafttt 240 tgtatataaa atatataata tataatatat ttatagacaa taatatataa tataatatat 300 aaaattttat atataaa 317 <210> 72 <211> 522 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(522)

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SEL PCT 012.8725 <223> MAR of chromosome 1 genomic contig; 229111..229632 <400> 72 gatatatata {ttatatata {aaaagatat atattatita {atataaaga tatatattta 60 tatatataaa agatatatat tatttatata tataaaagat atatatttat atatatgata 120 tatatiattt atatatataa aagatatata titatatata tgatatatat tatttatata 180 taaaagatat atataaaaga tatatattat ttatatatat aaaagatata tatataaaag 240 atatatatta ittatatata taaatgatat atatiatfta tatataaaag atatatatta 300 tttatatata aaagatatat attatttata tatataaaag atatacatat aaaagatata 360 tatttatata taaaagatat atatatttat atataaaaga tacatatatt tatatatata 420 aaagatatat atatttitat atataaaata tatattatat atataaaaga tatatataaa 480 tatatatatc tittatatat aaaagatata tataaatata ta 522 <210> 73 <211> 1110 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{1110) <223> MAR of chromosome 1 genomic contig; 1138030..1139139 <400> 73 tatgtatgta tacataatat attatatatg tatattatgt atacataata tattatatat 60 gtatatiatg tatacaiaat atattatata tgtatattat gtatacataa tatattatat 120

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SEL PCT 012.8725 attataigta tattatgtat acataatata ttatatatta tatgtatatt atgtatacat 180 aatatattal atattataty tatattatgt atacataata tattatatat tatatgtata 240 ttatgtatac ataatatatt atatattata tgtatattat gtatacataa tatattatat 300 attatatgta tattatgtat acataatata ttatatatia taigtatatt atgtatacat 360 aataiattat atattatatg tatattatgt atacataata taftatatat tatatgtata 420 ttatgtatac ataatatatt atatattata tgtatattat gtatacataa tatattatat 480 attatatgta tattatgtat acataatatt tatatattat atgtatatta igtatacata 540 atatattata taitatatgt ataftatgta tacataatat gtacacataa tatttatata 600 ttatatgtat attatgtata cataatatit atatattata tgtatattat gtatacataa 660 tatttatata itatatgtat attatgtata cataatatit atatattata tgtatattat 720 gtatacataa tatitatata ttatatgtat attatgtata cataatatat tatatattat 780 atgtatatta tgtatacata atatattata tattatatgt atattaigta tacataatat 840 altatatat! atatgtatat tatgtataca taatatttat atattatatg tatattatgt 900 atacataata taftatatat tatatgtata ttatgtatac ataatataft atatattata 960 tgtatattat gtatacataa tataitatat attatatatg tatattatgt atacataata 1020 tattatatat tatatatgta tattatgtat tatattatat attatgtata ttatagatta 1080 tgtatgcata cataatatgt atigtatatt 1110 <210> 74 <211> 521 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(521) :

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SEL PCT 012.5T25 <223> MAR of chromosome 1 genomic contig; 2863407..2863927 <400> 74 aataiatata aatatataaa tatatataaa talatataca tataaatata taaatatata 60 tatgtaaata tatgtaaata tatgtaaata tatgtatatg tatatatatg taaatgtatg 120 taaatatata taaatatatg taaatatata taaatatacg taaatatata aatatatata 180 aclatatata aatatatata aatataaata tataaatata tataaatata tataaatata 240 taaataaata calataaata tataaataaa tacatataaa tatatataaa tatataaaaa 300 - tatatataaa tatatatata aatatataaa catatataaa tatataaata tatataaata 360 tataaataca taaaatatat aaatatatat aaatatataa atatatataa atatagataa 420 atatagataa atatataaat atatataaat atataaatat agataaatat ataaatatat 480 aaatataaat atataaaaat alatataaat atataaaaat a 521 <210> 75 <211> 560 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(560) <223> MAR of chromosome 1 genomic contig; 5712303..5712869 <400> 75 atataattat atatatatta tatattatat ataattatat attatatata atgtataatt 60 atatattata tataatatat ataaatatat atatttiita tataaatata ttatatattt 120

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SEL PCT 012.8725 : atatattata tataaattta tatatataaa ttittatata ttatatatat ttatatatta 180 tatatigtat atatitatat attacatatt gtatataftt atatattata taftatatat 240 ttatatatta tatattatat atitatatat tatatattat atatatttat atattatata 300 taaattatit atatataata tataaatata tattatataa tataaatitg tatatataat 360 atatatttat attatatata aaatatttat attatatata aaatataata taaatatata 420 catataatat atatattata tatttataat tatatattat atataataca tataatatat 480 aatatataat acatatatat catatatgaa atatatatca tatattatac atattatata 540 taacatatat attatatatc 560 <210> 78 <211> 479 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(479) <223> MAR of chromosome 1 genomic contig: 8578812..8579290 <400> 76 tatggtatac atatagtata tatggggtac atatatggta tatatatggg ttatatatat 60 gatatatatt atatatgtat atggtatata tatggtatat atattataca tgcatatggt 120 aigtataigg tatatatatg atatatacat atggtgtata tatatgttat atatgatata 180 tataaggtat atatatggta tatataaggt atatatagta tatatatggt atatataagg 240 tatatattgt atatatatgg tatatataag gtatatatat tgtatatatg gtatatatat 300 ggtitatata tatggtgtgt atatatggtg tttatataca cactttatat actatatatt 360

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SEL PCT 012.5725 atatacacac tatatataat atatatiata tatagttaaa tatatggtat atgcaattag 420 atatatggta tatgtaatta tatatatggt atatagatgg tgtatatatg gtatatata 479 <210> 77 <211> 477 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{477) <223> MAR of chromosome 1 genomic contig; 8579294..8579770 <400> 77 tatagtatat atacacacta taggtaatat actacatatt atatacacac tataaataaa 60 atatataata tataatattt (ctatatagt atatatiata tatigtatat actatatata 120 atatatacta tagacagtag atacttiata tactatagac agtatatact atatactgta 180 tacactatag acagtatata ctatatactg tatacagtat atgtagtgta tatgtagtgt 240 atataatata tagtatatat tatctatact atatacagta tatatagtgt atacataata 300 tatattatat attatatata ctatatacag tatacatagt gtatatgtag tgtataatat 360 atataatgtg tatataaaat atatatacta tatataatat atatlatata taatatatac 420 actatatata ctatagatac actatatait cactatatat actatatata ctatata 477 <210> 78 <211> 331 <212> DNA <213> Homo sapiens

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SEL PCT 012.8725 <220> <221> misc_hinding <222> (1)..(331) <223> MAR of chromosome 1 gencmic contig; 8580024..85680354 <400> 78 actataigtt atatacataa gatatagtat ataccatata ttatatacat tatatatagt 60 gtatactata tataatgtat ataatatata gtatatatac actatatata ctatgtatat 120 atacactata tatactatgt atatatacac tatatatact atgtatatat acactatata 180 tactatgtat atatacacta tatatactat gtatatatac actatatata ctatgtatat 240 atacactata tatactatgt atatatacac tatatatact atgtatatat agigtatata 300 tactgtatat gttatagtgt atatatagta t 331 <210> 79 <211> 410 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(410) <223> MAR of chromosome 1 genomic contig; 8580705..8581114 <400> 79 tatagtctat attatataca gictatataa tatatagtat atactatata tactittcct 60

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SEL PCT 012.5725 cattctgact atatactata tatatactat atatagtata tgtagtgtat atatacacca 120 tatatactat atatagtata cataccatat atagtatact atacatacca tatatagtat 180 acataccgta tatagtatac tatacttacc atatatagta tacatactat atataatata 240 tctggtgtat atatacacta tatatactat atatactata tatagtatat gtacactatt 300 tatagtatit atagtatata tactgtatat atagtatgta gtatatatac tatatattat 360 gtagactata tataatatag actatgtgta gagtatatat actatatata 410 <210> 80 <211> 433 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(433) <223> MAR of chromosome 1 genomic contig; 12979167..12979599 <400> 80 atatataata tatatatgtc ctatatataa aatatatcat atatataaat atatatgata 60 taftttatat attaaatata taattatata taaatatata tttatatata aatatattat 120 ttcaatatat ataaatatat ttaaatatat ttaaatagaa tattaaatat ataaatatat 180 aattatattt aatatataaa tatatattaa atatataatt atatitaata tatataaata 240 tatattaaat atataattat atatttatat atttattata tataaatata fatttgttct 300 aaafaaatat atatictaaa tatataatat tttatattat ataatatata atataaaata 360 tataataaat atataatata taaataaata aatatttatt ataaaataca tataaatatt 420 aaatatatat taa 433

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SEL PCT 012.5725 <210> 81 <211> 3885 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(385) <223> MAR of chromosome 1 genomic contig; 16336644..16337028 <400> 81 tttatataaa taictatata aataaatata taaatatata aatataaata tatataaata 60 tataaataaa tatataaata tatataaata {aaatatata tataactatg aatttatatt 120 tatataaata tataictata igaatataaa tatatatita tataaatata aatatatata 180 taaatatata tatttatata gatataaata tatatataaa tatatatatt tatatagata 240 taaatatata tctatatatg aatatatatc tataggaata taaatatata tctatataaa 300 tataaatata tataagtata aatatatata aatatatatc tatataaata taaatatata 360 tataaatata aatatatata taaat 385 <210> 82 <211> 363 <212> DNA <213> Homo sapiens <220> <221> misc_binding

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SEL PCT 012.8725 <222> (1)..{383) <223> MAR of chromosome 1 genomic contig; 20624448..20624810 <400> 82 tatatatata gttatataia tatitatata tatagttata tatatatttt tatatagtta 60 (atatatagt tatatatata gttatatata tatagtiata tatatagtta tatatatagt 120 tatatatata tagttatata tatagtiata tatatagtta tatatatagt tatatatata 180 tagttatata tatagttata tatatatagt tatatatata gitatatata {atagitata 240 tatatagtta tatatatagt tatatatata gttatatata tagttatata tatatagtta 300 tatatatata gttatatata tatagttata tatatagtia tatatatata gitatatata 360 tag 363 <210> 83 <211> 310 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(310) <223> MAR of chromosome 1 genomic contig; 566025..566334 <400> 83 : tatatataat atatattgta tatattatat atigtatata taatatatat tgtatatatt 60 atatatigta tatataatat atattgtata tattatatat tgtatatata atatatatat 120 tgtatatait atatattgta tatataatat atatatigta tatattatat attgtatata 180

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SEL PCT 012.8T25 taatatatat attgtatata ttatatattg tatatataat atatatattg tatatattat 240 atattgtata tataatatat atattgtata tattatatat agtatatatt atatatagta 300 tatataatat 310 <210> 84 <211> 1236 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1236) <223> MAR of chromosome 1 genomic contig; 1171429..1172664 <400> 84 aaagtattat atgtattata tgtatatgta ttatatatta catatgtatt atatataata 60 tatattatat attattatat attatatatt atatattatt atttatataa igtattatat 120 attatatagt atatatagta tatataatgt attatatatt atatagtata tatagtatat 180 ataatgtatt atatatagta tatataatgt attatatagt atatatacta tataatgtat 240 tacatattat gtatagtata tgtaatgtat tatatattat atagtatatg taatgtatta 300 tatgtattat atagtatata ttatatatga tgtattattt agtatatata atatatatga 360 tgtatiatat aacatatata atatatatga tgtattatat agcatgtata gtatatatga 420 tgtattatat agcatgtata gtatatatga tgtattatat atagcatgta tagtatatat 480 gatgtattat atatagcatg tatagtatat atgatgtatt atatatagca tgtatagtat 540 atatgatgta ttatatatag catgtatagt atatatgatg tattatatat agcatgtata 600 gtatatatga tgtaitatat atagcatgia tagtatatat gatgtattat atatagcatg 660

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SEL PCT 012.8T25 tatagtatat atgatgtatt atatatagca tgtatagtat atatgatgta ttatatatag 720 catgtatagt atatatgatg tattatatat agcatgtata gtatatatga tgtattatat 780 attatatatg gtataiatga tgtattatat aitatatatg gtatatatga tgtatiatat 840 attatatatg giatatatga tgtattatat attatatata atatatatga fgtattatat 900 aftatatata afatatatga tgtattatat atgatgtatt atatataata tatatgatgt 960 attatatata ttattatcta ttatatacga tgtattatat gcaagttatt atgtataata 1020 tataatgtat tatatattat ataatgtata atatataaat atataaatat ataattatgt 1080 ataaatatag aaatatafac attatacatt atatacatta taatgtataa tatataaata 1140 tattatatat aaatgtatac attatatata aatatattat atacattata tataaaatat 1200 gtatatagit attatacctt atatatacta aacagt 1236 <210> 85 <211> 309 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1}..(309) <223> MAR of chromosome 1 genomic contig; 1925173..1925481 <400> 85 atataittat ataaatatat tttatataaa tatatattat ataatattat aatatatgtt 60 atattatata tatittatac aatatataat atatattata tatattttat acaatatata 120 atatatatta tatatatitt atataatata taatatatat tatatatatt ttatacaata 180 tataatatat attatatatt atataatata tattatatat atittatata atatataata 240

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SEL PCT 012.8725 tatattttat acaatatata atgtatatca ttatattata taatgtatat catattatat 300 aatgtatat 309 <210> 66 <211> 312 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(312) <223> MAR of chromosome 1 genomic contig; 4396756..4397067 <400> 86 cacagtgiat atatagtata tatactgtat atatactgtg tatatacact gtatatacac 60 agtgtatata cagtatatat actatatata cactgtgtat atatagtata tataaaftct 120 aggaatatat atactatata tatactatat atataaattc taggaatata tacacactat 180 atatacacta {atatacaca tatatacact atatatatta tacacatata ttatatatat 240 acactatata tacacgagat atataacata tacactatat actatacata acatatatac 300 tatatatact at 312 <210> 87 <211> 398 <212> DNA <213> Homo sapiens <220>

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SEL PCT 012.5725 <221> misc binding <222> (1)..(398) <223> MAR of chromosome 1 genomic contig; 56057..56454 <400> 87 atatatatta catattatat atataatata tattatataa tatatattat attatataat 60 atataatata aatataatat aaattatatt atataatata taatataaat ataatataaa 120 ttatataaat ataatatata ttitattata taatataata tatattatat aaatataata 180 tataaattat ataatataat atatattata taatataata tattttatta tataaatata 240 tattatatta tataatatat attttattat ataatatata ttatatattt atagaatata 300 atatatattt tattatataa tatatattat ataatatata ttatatttat atataacata 360 tattattata taaaataigt ataatatata itatataa 398 <210> 88 <211> 391 212 DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(391) <223> MAR of chromosome 1 genomic contig; 56984..57374 <400> 88 tactataata catattatat ataatattat atactatata ttactatatt attatattat 80 atataattaa actatattat agtatataat atataatata tactatatgt aatattacta 120

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SEL PCT 012.8725 tgatactgat attatattat atataattaa attatattat attaatatat aaattatata 180 taatacataa tatataaatt atattatait atttatatat aatgtatgcc atataattta 240 tatataatgc atiatatata atitatatat aatgcattaa atataaatta tatataatge 300 altatatata attatatata atgcatiata tataaittat atttaatata taaatttata 360 titaatatat ttatatatta fatataataa a 391 <210> 89 <211> 309 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(309) <223> MAR of chromosome 1 genomic contig; 469547..469855 <400> 89 atatatatgt aatatatatg ttatatatgt aatatatatg ttatgttata tatgttatat 60 atatgttata tataatatat atgitatata tacgttatat gitatatata fgttatatat 120 aatatatgtt atatatacgt tatatgttat atatgttata tataatatat gttatatata 180 atatatgita tatatgttat atataatata tgttatatat attatatata atatatgtta 240 tatatattat atataatata taatatatgt gatatataat ataaaatata tgtgatatat 300 aitatatat 309 <210> 90 <211> 444 : <212> DNA

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SEL PCT 012.5725 <213> Homo sapiens <220> <221> misc_binding <222> (1)..(441) <223> MAR of chromosome 1 genomic contig; 546190..546630 <400> 90 atacacaaca tatgtgtata tatatagtat atatacacaa cataigtgta fatatatagt 60 atatatacac aatatatgtg tatatatata gtatatatac acaatatatg tgtatatata 120 giataaatat atactatata tagtatatat agtataaata tatactatat atagtatata 180 catagtataa atatatacta tatatagtat atacatagta taaatatata ctatatatag 240 fatatacata gltataaatat atactatata tagtatatac atagtataaa tatatactat 300 atatagtata tacatagtat aaatatatac tatatatagt atatacatag tataaatata 380 tactatatat agtatataca tagtataaat atatactata tatagtatat acatagtata 420 aatatatact atatatagta t 441 <210> 91 <211> 1367 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1367) <223> MAR of chromosome 1 genomic contig; 124643..126009

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SEL PCT 012.8725 <400> 91 atatttatat gatatataat atatataata ttatatataa tattatatat gatatataac 60 attatataat attatatatg atatatatta tatatattat atatgatata taatatatat 120 aatattatat atgatattat atatcatata taatatataa aatattatat atgatatata 180 atatatataa tattatatat attatatata ttatatatca tatataatat tctaaatata 240 faatattata tgatatataa gattatatac attatatata atatataata ttatatatga 300 tatataatat tatatacatt atatataata tataafgtat ataatattat atattatata 360 titatattat atacaatgta tataatatta tatatcatat atatttatat tatatacaat 420 gtatataata {tatatatca tatataatat tatatacaat gtatataata tatattatat 480 atatttatat tatatacaat gtatataata tatatiatat atatttatat tatatacaat 540 gtatataata tatattatat atatttatat tatatacaat gtatacaata ttatatatta 600 tatattatat atttatatta tatacaatgt atatatiata tattatatat ttatattata 660 tacaatgtat atatitatata ttatataitt atattatata caatgtatat attatatatt 720 atatatttat attatataca atgtatatat tatatattat atatttatat tatatacaat 780 gtatatatta tatattatat atitatatta tatataatgt atgtaatatt afatattata 840 tatttatatt atatataatg tatgtaatat tatatattat atatttatat tatatataat 900 gtatgtaata ttatatatta tatatttata {tatatataa tgtatgtaat attatatatt 960 atatattiat attatatata atgtatgtaa tattatatat tatatattta tattatatat 1020 aafgtatgta atattatata tiatataitt atattatata taatgtatgt aatattatat 1080 attatatatt tatattatat ataatgtatg taatattata tattatatat ttatattata 1140 tataatgtat gtaatattat atattatata tttatattat atataatgta tgtaatatta 1200 tatattatat atitatatta tatataatgt atataatatt atatattata tatitatatt 1260 gtatataata ttatatatia tatatitata tigtatataa tatatattat atatttatat 1320 tgtatataat attatatatt atatatitat attatatata atgtata 1367

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SEL PCT 012.8725 <210> 92 <211> 458 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(458) <223> MAR of chromosome 1 genomic contig; 58908..59365 <400> 92 tatatgatat atatgatata tatgggatat atatgatata tatgatatat atggtatata 60 tatgatatat agtatatatg atatatatgg tatatatatg atatatagta tatatgatat 120 atatggiata tatgatatat agtatatatg atatatatgg tatatatggt atatatatga 180 tatatgatat atatgatata tatgalatat gatatatatg atatatatga tatatatggt 240 atatatgata tatatggtat atatggtata tatatgatat atatgatata tatggtatat 300 atatgatata tatgatatat atggtatata tatgatatat atgatatata tggtatatat 360 atgatatata tgatatatat ggtatatata tgatatatat gatatatatc atatatatgg 420 tatatatatg atatatatga tatatatcat atatatgg 458 <210> 93 <211> 330 <212> DNA } <213> Homo sapiens <220>

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SEL PCT 012.8725 <221> misc_binding <222> (1}..(330) <223> MAR of chromosome 1 genomic contig; 306867..307196 <400> 93 ataatatata aatatatatg atatatatct atatatatca tatataaata tatatgatat 60 atatctatat atatcatata taaatatata tgatatataa atatatatga tatatatcta 120 iatataicat atataaatat atatgatata taaatatata tgatatatat ctatatatat 180 catatataaa tatatatgat atatatctat atatcatata taaatatata tgatatatat 240 ctatatatat catatataaa tatatatgat atctatctat atatatcata tataaatata 300 tatgatatct atctatatat atcatatata 330 <210> 94 <211> 353 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(353) <223> MAR of chromosome 1 genomic contig; 636899..637251 <4(0> 94 tatgtataca tatacacata tacgtatata tatacatata tacacatata cgtatatata 60 tacgtataca tacatatgta tatgtatacg tatacacaca tatgtatatg tatacgtata 120 cacacatata cgtatatatg tatacgtata cacacatata cgtatatgta tacatatata 180

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SEL PCT 012.8725 tgtgtacata tacgtatata cgtatatgta tacatatata cgtttatgta tatatacgta 240 tatacgtata tatgtatatg tatacatata tacatatatg tgtatatacg tatatacgta 300 tatgtgtata tatacaatat acatacatgc acatatatgt gtatatgcac ata 353 <210> 95 <211> 345 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(345) <223> MAR of chromosome 1 genomic contig; 1435510.,1435854 <400> 95 atcatatata ttatatatca tatatatgat atataaaaat tatatatcat atatatgata 60 tataaaaalt atatatafca tatataatat atataatata ttatatatat aaattatata 120 taatatatat aaattatata tatcatatat atgatatata atitatatat catatatatg 180 atatatataa tatattattt atatataata tattatatat tatataatat gtaatatata 240 ttatatatta catattatat tafitataaa taatatttta taatatatat aatattatat 300 aatatagaat axttatatatt atatattaca tattatataa tatat 345 <210> 96 <211> 521 <212> DNA <213> Homo sapiens

Seite 88

SEL PCT 012.8T25 <220> <221> misc_binding <222> (1)..(521) <223> MAR of chromosome 1 genomic contig; 39695..40215 <400> 96 tatatatata atagatatia tatatctatt atatatctat tatatataia atagatatta 60 tatatctatt atatatataa tagatattat atatctatta tatatataat agatattata 120 tatctattat atataatata tafctattat atattatata tctattatat ataatatata 180 tctattatat atattatata tctattatat atataataga tattatatat ctattatata 240 taatatatat ctattatata ttatatatct attatatata tgtatctatt atatatatta 300 tgtatctatt atatataata tatatctatt atatatatat tatatataat atatattata 360 tataftatat atctattata tataatatat alctattata tatattatat atctattata 420 tatattatat atctattata tataatatat atctattata tatattatat atctattata 480 tataatatat attatatata tattatatat tgtatatcta t 521 <210> 97 <211> 484 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(484) <223> MAR of chromosome 1 genomic contig; 1286007..1286490

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SEL PCT 012.8725 <400> 97 atatcatata tattatatat catatatatg atatataaaa atfatatatc atatatatga 60 latatataaa ttatatatat catatataat atatataata tattatatat ataaattata 120 tataatatta tatataaatt atatatcaca tatatgacat ataaattata fatcacatat 180 atgatatata atttatatat cacatatatg atafataatt tatatatcat atatatgata 240 tataatttat atatcatata taigatatat aatttaiata tcatatatat gatatatata 300 atatattait tatatataat atattatata ttatataata igtaatatat attatatatt 360 atataatatg taatatatat tatatatiac atattatatt atttataaat aatattitat 420 aatatatata atattatata atatagaata ttatatatta tatattacat attatataat 480 atat 484 <210> 98 <211> 244 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(244) <223> MAR of chromosome 1 genomic contig; 73556..73879 <400> 98 attatatatt atattatata atatataata atattatata attatatatt acattatata 60 atatataata atattatata ataatatata attatataat atataataat attatataat 120 altatataat attatataat atataaatat ataataatat atattatatt atataatagt 180 atatattata ttatalaata tatgttatia tattatataa tataaactat tatataatat 240

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SEL PCT 012.5725 aata 244 <210> 99 <211> 463 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(463) <223> MAR of chromosome 1 genomic contig; 179038..179500 <400> 99 tacaatatat titctattat atatatttlg tattatatat aatatacaat atattttcta 60 ttatatataa tatattttgt attatatata ttacaatata tittgtatta tataatatat 120 aatacaafat aatatattgt attatataat atataatact atataatata ttgtattata 180 tattatatat aatactatat aatatatttt attatatalt atatataata ctatataata 240 : tatitatta tatattatat ataatacaat atataatata tigtattata atacaatgta 300 ttataatgla ttatatataa {atataatac aatatataat attatatata tttatatata 360 tatatatttt gtatiaiata tittgtatta tatatattit gtattatata titatatttt 420 ataftataat tatgttitgc attatatatt tcatattata tat 463 <210> 100 <211> 390 <212> DNA <213> Homo sapiens

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SEL PCT 012.8T25 <220> <221> misc_binding <222> (1)..(390) <223> MAR of chromosome 1 genomic contig; §5617..56006 <400> 100 totataatat atatactita tatataatat atatacttta tatatatact atatactaat 60 atatatzata tatactatat ataatatata ctaatatata taatatatac actatatata 120 atatatacta atatatatta tatatacttt atataatata tactaatata tataatatat 180 atacitiata tataatatat actaatatat ataatgtata tactttatat ataatatata 240 ctagtatata atatatatac titatatata atatatacta atatatatta tatatacttt 300 atatatataa {atatactta tatatiatat atgcttatat ataatatata cactaatata 360 taatatatat acittatata ttatattita 390 <210> 101 <211> 582 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(582) <223> MAR of chromosome 2 genomic contig; 1157405..1157986 <400> 101 tgtatatgta tatatacaca tacgcacata tatgtatatg tatatataca catacgcaca 60

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SEL PCT 012.8725 tatatgtata tgtatatata cacatacgca catatatgta tatgtatatg tatatgtata 120 tatacacata tacacatata tgtatatgta tatatacaca tatacacata tatgtatatg 180 tatatataca catatacaca {atatgtata tgtatatata cacatacaca tatatgtata 240 tgtatatgta tatatacaca tacacatata tgtatatgta tatgtatata tacacatata 300 cacatatata catatatgta tacatatatg tgtatatata tacacatata tatacatata 360 tgtatacata tatgtgtata tatacacata tatatacata tatacatata catatatatg 420 tgtatgtata tatacacata tacatatata tgtatatgtg tatatatatt agacagatat 480 atatgtacat atacatatat atgtatatgt atatgtatat gtatatgtat atgtatatgt 540 atatgcatat ataatataca tatacatata igtatatgta ta 582 <210> 102 <211> 322 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(322) <223> MAR of chromosome 2 genomic contig; 1858638..1858858 <400> 102 acaccatata tacaccatat atatacatac catatatata ccatatatat acataccata 60 tatataccat atatatacat accatatata caccatatat atacatacca tatatataca 120 ccatatatat acataccata tatataccat atatatacat accatatata taccatatat 180 atacatacca tatatataca ccatatatat acataccata tatatacacc atatatatac 240 ataccatata tataccatat atacaccata tatatacacc atatatacac accatatata 300

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SEL PCT 012.5725 ccatatatat acaccatata ta 322 <210> 103 <211> 914 <212> DNA <213> Homo sapiens : <220> <221> misc_binding <222> (1)..(914) <223> MAR of chromosome 2 genomic contig; 5712196..5713108 <400> 103 aaatatatat tctatatata gaaaatatat attctatata tatagaatat atatagaata 60 tatattctat atataticta tatatataga atatatatat aaaacatata ttctatatat 120 aaaatatata tictatatat ataaaatata tatictatat atatagaatg tatataaaat 180 atatattcta tatatataga atgtatataa aatatatatt ctatatatat agaatgtata 240 taaaatatat attctatata tatagaatgt atataaaata tatattctat atatatagaa 300 tatatataac atatatatga aatatatata aaatatatat aaatacatat ttctatatat 360 aaatatatat aaatacatat ttctatatat aaatatatat caatacatat tictatatat 420 aaatatatat aaatatatat tcatatatat aaaaatatat aaatatatat tcatatatat 480 aaaatatata fgaatataia tictctatat ataaaatata tataatatat attatatata 540 taaaatatat ataatatata ttatatatat aaaatatata taatatatat tcatatatat 600 aaattatata taaatatata ttcatatata taatatatat aaatatttat ttcatatata 660 aaatatattt aaatatatat ttctatatag aatatatatt ctatatataa aatatatata 720 taaatatatt tictatatag aaatatatat gaaatatata gaatatatat agatatatat 780

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SEL PCT 012.8725 tatatatact atatatacaa tatatattat atataaaata tatatacaat atatattcta 840 tatattaata tatagaatat atattaacat atatttcaat atattaatat atgaaatata 900 tataaatalt tcat 914 <210> 104 <211> 370 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(370} <223> MAR of chromosome 2 genomic contig; 5713613..5713982 <400> 104 tatttcatat ataatatata tataaaatat atatttcata tacataatat atataatata 60 aataaaatat atatttcata tatataatat atataaatata tataaaacat atatttcata 120 tataatatat ataaactata tatttcatat ataatatata taaactatat atticatata 180 cataatatat ataatatata titcattiat attatatata taatatatat ticatatata 240 taatalataa aatagatata aatatatata aatatatatt tcatatataa tatatataaa 300 atatatatta atatatatit tatatataat atatatatit catatataaa tataaaaaaa 360 tatatattic 370 <210> 105 <211> 442 <212> DNA <213> Homo sapiens :

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SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(442) <223> MAR of chromosome 2 genomic contig; 7481647..7482088 <400> 105 atataaatta tataatatgt taiataatat ataaatatat tatataacat gttatataat 60 : atataacatg ttatataata tataacatgt tatataatat ataacatgtt atataatata 120 taacatgtta tataatatat tatgtaatat gttatataat atataatata ttatataaca 180 tgttatataa tatataacat gttatataat atgttatata atatataaat atattatatt 240 atatgttata taatatataa atatatiata ttatatgita tataatatat aaatatatta 300 tattatatgt tatataatat ataaatatat tatattgtat gitatataat atataaatat 360 attatattgt atgitatata atatataaat atattatatt gtatgttata taatatataa 420 atatattata ftatatatgt ta 442 <210> 106 <211> 338 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{338) <223> MAR of chromosome 2 genomic contig; 9594557..9594894

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SEL PCT 012.8725 <400> 106 tatataaata tataccatat atataaatat atataticca tatataaata tatatattcc 60 atatatataa atatatatat tccatatata aatatatata ttccatatat ataaatatat 120 : atataaatat atatattcca tatatataaa tatatatata aatatatata ttcatatata 180 aatatatata taticcatat ataaaaatat atatataitc catatataaa aatatatata 240 taticcatat atataaatat atatatattc catatatata aatatatata tattccatat 300 atataaatat atatatattc catatatata aatatata 338 <210> 107 <211> 364 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(364) <223> MAR of chromosome 2 genomic contig; 10519720..10520083 <400> 107 ttatatatat ttataataat atatataagc tatatatatt tatatataat atattatata 60 tattagctat atatatitat ataataatat attatatatt agcetatatat atttatatat 120 aataatatat ataagctata tatttatata tattatatat tagctatata tatttatata 180 taatatatta tatattagct atatatttat atataataaa taataiatat attagctata 240 tatatttata tataatzata tatataagct atatatttat atataatata ttatatatta 300 gcotatatata titatatata ataatatatt atatattagc tatatatatt tatatataat 360 atat 264

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SEL PCT 012.8725 <210> 108 <211> 342 <212> DNA <213> Homo sapiens «220» <221> misc_binding <222> (1)..(342) <223> MAR of chromosome 2 genomic contig; 11481943..11482284 <400> 108 tacatataat atataatiat atataatata tattatatat tacatatata atatatatat 60 tacatatgta atataiatat tatatatgta atatatatta tatatgtaat atatatatta 120 tatatgtaat atatattata tatatgtaat atatatatta tatatgtaat atatatatta 180 tatgtaatat atatatgtaa tatatatata atatataigt aatatatata taatatatat 240 gtaatatata tataatatat atgtaatata tatattatat atatgtaata tatatcatat 300 atatgiaata tataicatat atatgtaata tatatcatat at 342 <210> 109 <211> 415 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(415)

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SELPCT 012.8725 <223> MAR of chromosome 2 genomic contig; 134989598..13500012 <400> 109 tatatatata tatatatata atataatata atatatatat aaatatatat aatataaatt 60 tatatatata taittatata tacatatata aatatatatt tatatttata tataaatata 120 tataaatata tataaatata tatftatata tacatatata aatatatatg ttcatataaa 180 tatatatgta tatatacata tataaatata tattatatat gtatatatat aatataatat 240 ataataataa tataatatat attatataaa tataatatat tatatataat atatataata 300 tataatatat aatatataat atataatata tattatatat tatataatat ataaaatata 360 tattatataa tatatataca taatatatat aaataaatat atataaagat ataaa 415 <210> 110 <211> 330 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(330) <223> MAR of chromosome 2 genomic contig; 16370976..16371305 <400> 110 catttacata tgtatgtata agtatgtata ttacatactt atacatacat acttataaat 60 atataagtat aatacataca tacttataaa tatataagta taatacatac atacttatac 120 atatataagt ataatacata catacttata catatataag tataatacat acatacttat 180 acatatataa gtataataca tacatactta tacatataag tataatacat acatacttat 240

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SEL PCT 012.8725 acatatataa gtataataca tacatactta tacatatata agtataatac atacttatta 300 catatgtata taagtatatt acatactiat 330 <210> 111 <211> 702 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(702) <223> MAR of chromosome 2 genomic contig; 626641..627342 <400> 111 tatatataca catatacata tataatatat atacatatac atatatatta tatatacata 60 tatattacat atatcatata tacaiatata ttatatatac atatatatta tatatatcat 120 atatacatat atatattata tattatatat aicatatata catatatatt atatatatta 180 tatatatcat atatacatat atat{atata tattatatat acatatatat tatatatatc 240 atalaaacat atataitata tatatcatat atacatatat attatatata tiatatatat 300 catatataca tatatattat atatatcata tataatatat attatataia ttatatataa 360 tatatattat alatacatat atattatata tacatatata ttatatatac atatatatta 420 tatatacata tataitatat atacatatat atiatatata tacatatata ttatatatac 480 atatatatta tatatacata tattatatat acatatatat tatatataca tatattatat 540 atatacatat atattatata tacatatatt atatatatac atatatatta tatatacata 600 tattatatat atacatatat attatatata catatattat atatacatat atattatata 660 tacatatata ttttatatat atataatata tattttatat at 702

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SEL PCT 012.5725 <210> 112 - <211> 679 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(679) <223> MAR of chromosome 2 genomic contig; 3186047..3196725 <400> 112 atatattata taftcatata tcataaatat atatattata tattcatata ttatatatct 60 atatatitat atattcatat attatatatc tatatattia tataftcata tattatatat 120 clattiatat aticatatat tatatatcta tatatittat atattcgtat attatatatc 180 tatataltat ataticgtat attatatatc tatatattat gtattcatat atatctatat 240 attatatata ttcatatata ttataaatia taticatata gtatatatct attataaatg 300 tatattcata tagtatatat ctatatatta taaatataca tatattatat atttatatat 360 tatatatica tatagaicta tatatiatat ataticatat atgaatatat atattatatg 420 tatatatatt ataaatatat ttatatagta tagatattat atagtatatqg catatitata 480 ttataaataa tttacatagt atalgtatat ttataaatta tatatattta catattacat 540 gtatatttat atattataaa tacatatita catattataa atatatttat atattatgaa 600 tataatttat atattatiac ataittacat atatgcatag ttatatatta taaatatgca 660 tttatgtaaa tatatattt 679 <210> 113 <211> 728

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SEL PCT 012.8725 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(728) <223> MAR of chromosome 2 genomic contig; 3196778..3197505 <400> 113 tacataaata tatatttaca atatgtaaat aictgatatg taaatatgta tttataatat 60 ataaatatac atataatatg taaatatata aatatacata factatgtaa atatatgtta 120 tatatacata tactatataa atatagaata tataaatata catatactat ataaatatgt 180 aatatataaa tatatactat ataaatatac atatactata taaatgtatt tataatatat 240 aaatatacat atactatata aaticatata tgaatatata atatataaat atatataata 300 tatgaataia tacicatata taaatatata tgaatatata tttataatat atagatataa 360 : tatgaatata {atttataat atatagatat atattatatg aatatatatt tataatatat 420 agatafatac catalgaata tatattatac actataigaa tatafattta taatatataa 480 atagatatat actatatgaa tatataatat atatactcta tgaatatata atatatatac 540 tatatgaata tatiatatac tgtatgaata {ataatatat agatgtatac tatatgaata 600 tataatatat agatatatat actatatgaa tatatataat atatagatat atactatatg 660 aatatatatg atatatagat atatactata tgaatatata atatatagat atatatitat 720 gatatatg 728 <210> 114 <211> 413 <212> DNA

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SEL PCT 012.5725 <213> Homo sapiens <220> <221> misc_binding <222> (1)..{413) <223> MAR of chromosome 2 genomic contig; 2560638..2561050 <400> 114 atataaatat atatttatat attttatata aatatatata titatatatt tttatataaa 60 tatatatati tatatatatt {tatataaata tatatattta tatatatita tataaatata 120 {aaatatata {atttatata aatatataaa atatataaat atatitatat aaatatataa 180 aatatataaa tatatttata taaatatata aaatatataa atatatttat atataaatat 240 ataaaatata taaatatctt talatalaaa tatataaaat atataaatat ctitatatat 300 azatatataa aatatataaa tatatttata tataaatata taaaatatat aaatatatff 360 atatacaaat atataaaata tataaatata titatatata aatataiaaa ata 413 <210> 115 <211> 361 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(361) <223> MAR of chromosome 2 genomic contig; 4965309. 4965669

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SEL PCT 012.8T25 <400> 115 tatacgtata tatacatata tatacgtata tatatacata tatatacgta tatatacata 60 tgtatatatg tgtgtacatg tatatatata catatgtaca tatatatgta cacatatata 120 tatacatata tatgtacaca tatacatata tatgtacaca tatacatata catatatatg 180 tacacatata tatacatata tatgtacaca catatatata catatatatg tacacacata 240 tatacgtata tatgtacaca catatatacg tatatatatg tacacacata tatacgtata 300 tatatgtaca cacatatata tacgtatata tatgtacaca tatatatata cgtatatata 360 t 361 <210> 116 <211> 325 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(325) <223> MAR of chromosome 2 genomic contig; 5258150,.5258474 <400> 118 tacacacaca tatacatata tacatatata cgtgtatacg tatacgtata tacgtatata 60 ~ tacatatatg tatacgtata cgtatatacg tatatataca tatatgtata cgtatacgta 120 fatacgtata tatacatatla tgtatacgta tacgtatata cgtatatata catatatgta 180 tacgtatacg tatatacgta tatatacata catatgtata cgtatacgta tatatgtata 240 tatacgtata tgtatacgta tacatatata cgtatatata cgtatatgta tatgtatata 300 cgtatatgia tatatgtaca tatac 325

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SEL PCT 012.5725 <210> 117 vo <211> 1508 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1508) <223> MAR of chromosome 2 genomic contig; 6057499. 6059006 <400> 117 atataatata tataaattat ataatatata aaaattaata tataatatat ataaattata 60 taatatataa attaattata taatatatat aaattatata atatataaat taattatata 120 atatatataa attatataat acatataaat taattatata atatataaat tatataatat 180 atacaaatta tatactaiat taattatata ttatataatt aattatataa tatatataaa 240 ttatatatta ttaaatiaat tatataatat ataaattata taatatataa attaattata 300 taatatataa attatataat atataaatta attatataat atataaatia tataatatat 360 aaattaattg tataatatat aaattaatta tataatatat aatatataat taataaataa 420 itatatatta attatataat taataaataa ataataaata tatataatta atatataata 480 tacatcatat atatcacata tagattatat aatagttata tattatataa taaattatat 540 ataatataia ataaacatat ataacatatg ttatatatta cataatatag tataatatat 600 aacatatgtt atatattaca taatatagta taatatataa catgttatat aitacataat 660 atagtataat atataacata tgttatatat tacataatat agtataatat ataacatatg 720 ttatatatta cataatatag tataatatat aacatatgit atatattaca taatatagta 780 taatatataa catatgttat atattacata atatagtata atatataaca tatgttatat 840

Seite 105

SEL PCT 012.8725 attacataat atagtataat atataacata tgitatatat tacataatat agtataatat 900 ataacatatg ttatatatta cataatatag tataatatat aacatatgit atatattaca 960 taatatagta taatatataa catatgttat atattacaia atatagtata atatataaca 1020 tatgttataf attacataat atagtataat atataacata {gttatatat tacataatat 1080 agtataatat ataacatatg ttatatatta cataatatag tataatatat aacatatgtt 1140 atatattaca taatatagta taatatataa cafgttatat attacataat atagtataat 1200 atataacata tgctatatat tacataatat agtataatat atatgttata tattacataa 1260 tatagtataa tatataacat atgttatata ttacatatia tagtataata tatatgttat 1320 atattatata atatagiata atatataatg tatgttatat attafataat atagtataat 1380 atataacatg tiatatatta tataatatag tataatatat atgttatata ttatataata 1440 tagtataata tataatatat gttatatatt atataatata gtataatata tatgttatat 1500 attatata 1508 <210> 118 <211> 415 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(415) <223> MAR of chromosome 2 genomic contig; 7996866..7997280 <400> 118 caattatata atatacatat tatataattg tataaattat acaatcatat aattatatta 60 tatataatat acatataata taattatata taattatata attttataat ataattatat 120

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SEL PCT 012.8725 ataattatat aattatatat aatatatatt ataattatat atataatata tatattatat 180 atattatata taatatataa ataatatata taatatatat ataattatat ataataatat 240 atgtaatata tataatatat atataatata ttatttataa ttatatatta tatatatatt 300 ataatatata taattataaa taatatatat tataatatat ataataatat atatataatt 360 atatataata atatatafta taattatata taataatata tataattiat ataat 415 <210> 119 <211> 526 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(526) <223> MAR of chromoscme 2 genomic contig; 8300930..8301455 <400> 119 tatatcatat gatatattat acaatatatc atataatatg atatattata tgatatatty 60 tacaatatat catatgatat atgatatatt atacaatata tcatataagg tatatattat 120 atcatatata atatataata taatatafga fataatatat gatatatgat atataatata 180 tgatatatga tatatgatat ataatatatg atatatgata tatgatatat aatatatgat 240 atatgatata igatatataa tatatgatat atgatatatg atatgatata tgatatatga 300 tataatatat gatataatat atgatatata ttatatgata tataatatat gatataattt 360 atatgatata taatatatga tatataatat ataatatatg atatgatata tattatatca 420 tatataatat ataatataat atatgatata tattatatat itttatacat tatatatata 480 aactatataa caatataaca tattatgtgt ataatatata ttacat 526

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SEL PCT 012.8T25 <210> 120 <211> 402 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{402) <223> MAR of chromosome 2 genomic contig; 8576553..8576954 <400> 120 atgtatatta tatacaatat agtatatcat atatagtata tattatatag taatgtatta 60 tatataaigt ataatgtata aatatataat atatactaca tactatacta ttatatatac 120 tatatattat atatgafaca tatactatat aatatgctat atattatact atataatatg 180 ctatatatta tactatataa tatgctatat atiatactat ataatatgct atatattata 240 ctatataata tgctatatat tatactatat aatatactat ataatatgct atatattata 300 ctatataata tactatatat tatactatat aatatactat ataacatact atatattata 360 tatgatacat atactatatt acatatataa tatatatata ta 402 <210> 121 <211> 477 <212> DNA <213> Homo sapiens <220> <221> misc_binding

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SEL PCT 012.8725 <222> (N).{477) <223> MAR of chromosome 2 genomic contig; 8785649..8786125 <400> 121 tatttatata tafatttata tatataitta tatatatita tatatatatt tatatatata 60 ittatatata tatttatata tttatatata {ataftttta tatatitata tatatatita 120 tatatttata tatatttata tttatatata tatttatata tatitatafa tatttatata 180 tatatattta tatatattta tatatatata tttatatata ittatatata tttatatata 240 tatttatata tatatitata tatatattca tatatattta tatatatatt catatatatt 300 tatatatata ttcatatata tttatatata tatttatata tatatttata tatatttata 360 tatatttata tatatattta tatatatatt tatatatata tatttatata tatatttata 420 tatatatatt tatatatata tttatatata tatatitata tatatatifa tatatat 477 <210> 122 <211> 773 <212> DONA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(773) <223> MAR of chromosome 2 genomic contig; 10064737..10065509 <400> 122 ataltatata tattacatat atattatatt gtatataata tatatattat attgtatata 60 atatatatat tatattgtat ataatatata tattatattg tatataatat atatattata 120:

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SEL PCT 012.8T25 tiglatataa tatattatat tgtatatatt atatigtata tattatattg tatacaatat 180 atattatatt gtatacaata tatattatat tgtatataat atattatait gtatataata 240 : tattatattg tatatattat atigtatata atatattata ttgtatataa tatattatat 300 tgtatatatt atattgtata taatatatta tatgtatata atatagtgta tactatatta 360 tataatatat attatataca atatataata tattgtatat catatatgat atattgtata 420 taatatataa tataigatat atigtatata atatattata tatgatatat tgtatattat 480 atattatata tgatafattg tatattatat attatatatt gtatatigta tattatatat 540 tatatatigt atataatatg ttatatattg tatataatat gitatatatt atatattgta 600 tatatgttat atattatgta tigtatataa tatgttatat attatatatt gtatataatg 660 tattatatat tatatatatt atatattgta tataatgtat tatatattgt atattatata 720 ttatatattg tatataatat attatataca ttatattata tattatatat tgt 773 <210> 123 <211> 1554 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(1554) <223> MAR of chromosome 2 genomic contig; 1039775..1041328 <400> 123 ataatatatt aaatgtatat ataatatait aaatataaat atatttataa tatataaata 80 titatataaa tataaaatat atattaaata taaatatata taaaatatat attaaatata 120 taaaatataa atatatatta aatatatatt aaatatataa aatataaata tatattaaat 180

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SEL PCT 012.8725 atattttaaa tatataaaat ataaatatat attaaatata tittaaatat attaaatata 240 aatatatatt aaatatattt taaatatait aaatataaat acatatatta aatatatatt 300 : atatatataa aatatataaa atataaatat atattaaata tatataaaat atatatgtta 360 aatatataaa agatatataa aatataaata tataitaaat atatataaaa tatatatata 420 ttaaatatat atattaaata taaatatata taaaatataa atatatgtat taaatatata 480 tattaaatat aaatatatgt attaaatata tattaaatat gaatatatgt attaaatata 540 tattaaatat aaatatatgt attatatata tagaatataa atataigtat taaatatagt 600 atattaaata taaatatata taaaatatat attaaatatg aatatatata agatatatat 660 attaaaaata tatataatat aaatatatal aaaatatata tattaaaaat atatataata 720 taaatatata taaaatatat atattaaaaa tatatataaa alatatatat taaaaatata 780 tataaaatat atatattaaa aatatatata aaatatatat attaaaaata tatattaaat 840 ataaatatat atattaaaaa tatatattaa atataactat atattaaata tatattaaat 900 ataactatat altaaatata tattaaatat aactatatat taaatatata ttaaatataa 960 ctatatatta aatatatat! aaatataact atatatiaaa tatatattaa atataactat 1020 atattaaata tatattaaat ataactatat attaaatata tattaaatat aactatatat 1080 taaatatata tgaaatataa ctatatatta aatatatatt aaatataact atatgtatta 1140 aatataaata tatgicitaa atatatatta aatataaata tatgtattaa atatatatta 1200 aatataaata tgigtattaa atatatatta aatataaata tgtgtattaa atatatafta 1260 aatataaata tgigtatiaa atatatatta aatataaata igigtattaa atatctatat 1320 taaatataaa tataigtatt aaatatatat taaatataaa tatatattaa atatatatat 1380 taaatataaa tatatattaa atataaatat atatattaaa tatatataft aaatataaat 1440 atatataaaa tatatatatt aaatataaat ataaatataa aatatatatt aaatataaat 1500 acatatatta aatatatgia ttaaatatat atataaaata tatgtattaa atat 1554 <210> 124 <211> 650

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SEL PCT 012.8T25 <212> DNA : <213> Homo sapiens <220> <221> misc_binding <222> (1)..(650) <223> MAR of chromosome 2 genomic contig; 3944813..3945462 <400> 124 catgatatat tatgtataat atatattata gattacatat aaattatata tataatatat 60 aattatataa tatataatat tatataatat attatatata ttatacaatt atataatata 120 tataatatac aattatataa tatataatat acaattatat aatatataat acaatataat 180 atatatttaa tatatiatat aatacatatt taatatatta tatattatat gttatatact 240 aaatatataa tatgtatita atatatacta itatatatgt aatatattat ataatttatg 300 taacatatta tatattatat atgcaatata ttacatgita catatatatt acatataata 360 tatgtaatat ataatataca ctatattatt atagtatata atatactata ttatgtaatt 420 atataatata gtatattata cactatatta tattatcata taattatata ttatatacta 480 tattacatat atattatgta atataatatg caatatgtta catatataat atatatigtat 540 tatatagtat atatactata giatatataa aatatatgct ataatatata ttttatatat 600 tatataatac atataatgta tcatatatta tatataatat attttataat 650 <210> 125 <211> 441 <212> DNA <213> Homo sapiens

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SEL PCT 012.5T25 <220> <221> misc_binding <222> (1)..(441) <223> MAR of chromosome 2 genomic contig; 5314265..5314705 <400> 125 tataaatata tatgaaatat atataaatta tatataattt atatatacat atataaatta G0 tatataaatt atatataaat tatatataca tatataaatt atatattata tataaaattg 120 tatatattta tatataaatt gtatatataa tttatatata aatigtatat ataatttata 180 tatacaatgt atataitaat ttatatatac atlgtatata taatttatat atacattgta 240 tatacaatit atatatacat igtatataca attiatatat acatigtata tacaatttat 300 atataaatta fattatttat atatagtata tataaatata tatactatat ataaatiata 360 tatitattta tatatiatat tatttatata taaattatat attatttata tatacattat 420 atataaatta tatattattt a 441 <210> 126 <211> 1169 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1169) <223> MAR of chromosome 2 genomic contig; 5953971..5955139 <400> 126

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SEL PCT 012.8725 atgiaticat attatatatt tatatataaa taatatacat tcatattata tatttatata 60 taaataatat ataticatat tatatattia tatataaata tataatatat ttatgtataa 120 ataatatata tattcatait atatattict atataaataa tatatatatt catattatat 180 atttatatat aaatatataa tatatttata tataaatata taatatattt atatataata 240 tatatatica tattatatat ttatatataa atatataata tatttatata taaataatat 300 atatattcat attatatat! tatatataaa taatatatat tcatattata tatttatata 360 taaataatat atattcatat tatatactia tatataaata atatatatic atattatata 420 cttatatata aataatatat attcatatta tatatttata taaaaataat atataticat 480 attatatatt tatatataat atatatatic atattatata tttatatatt ctatatattc 540 atattatata tttatatata aataatgiat attcatatia tatatttata tataaataat 600 glataticat aftatatatt tatatataaa tatatatica tattatatat tfatatataa 660 atatatattc atattatata tttatatata aatatatatt catattatat atttatataa 720 aatatatata ticatattat atitatatat aaatatatat attcatatat atatttatat 780 ataatatata tattcatatt atatatitat atataatata tatattcata ttatatattt 840 atatataaat aatatatata ftcatattat afatttatat ataaataatg tatattcata 900 ttatatatit atatataaat aatgtatatt catattatat atitatatat aaatatatat 960 attcatatta tatatttgta tataaatata tattcatait atatattigt atatatattc 1020 atatatattt atatataaat atataatatt catattatat ataaatatat ataticatat 1080 tatatattia tatatataaa taatatatat tcatattatt tatatatata aataatatat 1140 attcatatta tttatatata taaataata 1169 <210> 127 : <211> 653 <212> DNA <213> Homo sapiens

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SEL PCT 012.8725 <220> <221> misc_hinding <222> (1)..(653) «223> MAR of chromosome 2 genomic contig; 6427669..6428321 <400> 127 tatatatgta tacatatatg tatataigtg tatatatgta tacatatatg tatatatgtg 60 tatataigta tacatatatg tatatatgtg tatatatgta tacatatatg tatatatgtg 120 tatatatgta tacatatatg tatatatgtg taiatatgta tacatatatg tatatatgtg 180 tatatatgta tacatatatg tatatatgtg tatatatgia tacatatatg tatacatgtg 240 tacatgtgia tacatatatg tatacatgtg tacatgigta tacatatatg tatacatgty 300 tacatgtgta tacatatatg tatatatgig tatacatata tgtatatatg tgtatataty 360 tatacatata tgtatataag tgtatatatg tgtataigta tataagtgta tatatgtgta 420 tatgtatata agtgtatata tgtgtatatg tatataagtg tatatatgtg tatatatgia 480 tacatatatg tatatatgtg tatatatgtg tatatgtata taagtgtata tatgtgtata 540 tatgtataca tatatatgtg tatatatgta tacatatatg tatatatgig tatatatgta 8600 tacatatatg taaataigtg tatatatgtg tatatgtata taagigtata tat 6563 <210> 128 <211> 414 <212> DNA <213> Homo sapiens : <220> <221> misc_binding <222> (1)..(414)

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SEL PCT 012.8725 <223> MAR cof chromosome 2 genomic contig; 10890453. 10890866 <400> 128 tatattttgt aaatatatat atagtaaata tatgtaaata tatatattit gtaaatatat 60 atatatittg taaatatatg taaatatata tatttigtaa atatatgtaa atatatatat 120 titgtaaata tatgtaaata tatatatttt gtaaatatat gtaaatatat atatittgta 180 aatataigta aatatatata tttigtaaat ttatgtaaat atatatattt tgtaaatata 240 tgtaaatata tatatatttt gtaaatatat atacatatat atttigtaaa tatataaaca 300 tatatattit ataaatatat tfataaatat atatattgta aatatattta taaatatatt 360 tataatatat atattgtaaa tatgtttata aatatatata ttgtatatat aaat 414 <210> 129 <211> 406 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(496) <223> MAR of chromosome 2 genomic contig; 13952568.,13953063 <400> 129 taatatacat attatatatt atatatigta tatataatat acatattata tattatatat 60 tgtatatata atatacatat tatatattat atattgtata tataatatac atattatata 120 ttatatattg tatatataat atacatatta tatattatat attgtatata taatatacat 180 attatatatt atatattgta tatataatat acatattata tattatatat tgtatatata 240

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SEL PCT 012.8725 atatacatat {atatattat atattgtata tataatatac atattatata ttatatatty 300 tatatataat atacatatta tataitatat attgtatata taatatacat attatatatt 360 atatattgta tatataatat acatatiata fattatatat tgtatatata atatacatat 420 tatatattat atatigtata tataatatac atattatata ttatatatig tatatataat 480 atacatatta tatatt 496 <210> 130 <211> 317 <212> DNA <213> Homo sapiens <220> <221> mis¢_hinding <222> (1)..(317) <223> MAR of chromosome 2 genomic contig; 16942865..16843181 <400> 130 toteetagta gitatatata tatatatgty tatatatata tatcctagta gatatatata 60 tatatatatc ctagtagata tatatatata tatatcctag tagatatata tatatatata 120 tectagtagt tatatatata tafatatcet aacagttata tatatatata tectagtagt 180 tatatatata tatatcctag tagttatata tatatatata toctagtagt tatatatata 240 tatatcctag tagttatata tatatatate ctagtagtta tatatatata ttatatatta 300 tataatatat atataat 317 <210> 131 <211> 464 <212> DNA

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SEL PCT 012.8725 <213> Homo sapiens <220> <221> misc_binding <222> {1)..(4B4)} <223> MAR of chromosome 2 genomic contig; 17217049..17217512 <400> 131 acatactata tatatacaca tactatatat actatataca gtatatagta tacatatact 60 atacatatac atatactata catatacata tacatatact aagtatacgt atatacagta 120 catagtatat glatactata {agtatgtat atatagcata tagtatgcgt atactctata 180 tagcatatag tatgcatata cgctatatag catatagtat gcatatacta tatatagtat 240 agagtatgcg tatactatat atatagtata gagtatgegt atactatata tatagtatag 300 agtatgcgta tactatatat atagtataga gtatgcgtat actatatata tagtatagag 360 tatgcgtata ctatatatat agtatagagt atgcgtatac tatatatata gtatagagta 420 tgcgtatact atatatatag tatagagtat gtatatatat agta 464 <210> 132 <211> 430 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(430) <223> MAR of chromosome 2 genomic contig; 19647266..196476385

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SEL PCT 012.8725 <400> 132 tgtaaatata tgtaaatata tatttatatt atatattata taaaaatata atatataata 60 tataatatat aaactatata ftaatataat atatataaac tattatataa atacatatta 120 aatatattat atttttaata ttiatatatt aaatataata tatatttaat atttatatat 180 taaatatata atatatttaa tatttatata atatatagca tattttatat ttatattata 240 tataacaitt {atatitata ttiafatita tatatattta atftatattt atattatatt 300 tatattiata tlatatataa cataattata tatattitca tattgtatat aataaagaaa 360 tgtatatttg ttatatataa tatatattat ataatitatt atatattata taatatatat 420 tatataatat 430 <210> 133 <211> 2131 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(2131) <223> MAR of chromosome 2 genomic contig; 20481223..20483353 <400> 133 tatatataaa tatatttata tttaatatat atttatataa atataititt atataaatat 60 atatttaata taaataictt tatatitaat atatatttaa tataaatatc tttatatita 120 atatafattt atatataaat atatatttat atttaatata tattaatatt taatatacgt 180 ttatatttaa tatatatttc tatataaata tatttatatt aacatatatt tatatataaa 240

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SEL PCT 012.8T25 tatatttata titaatatat ttacatataa atatatttat atgtaatata tttacatata 300 aatatattta tatttaatat atatgcatat gtaaatatat ttatatttaa taatatttat 360 atataaatat atttatattt aataatattt atatataaat atatttatat ttaatatata 420 ttaaatatat atttatattt aatatatatt aataittaat atatatttat atttaatata 480 tattatatat aaacatatat ttatatitaa tatatattat atataaacat atatttatat 540 ttaatatata ttatatataa acatatailt ataittaata tatatttata tttaatatat 600 tatatataaa catataitta tatttaatat atatttatat taaatatata ttatatataa 660 acatatatit atatttaata tatatttata ttaaatatat aftiatattt aatatatata 720 tattaaatat atatitatat ttaatatata tttatattaa atatatattt atattaaata 780 tatttatatt taatatatat ttatattaaa iatatattaa atatttaata tatatttata 840 tftaatatat acatatatat ttatatttaa tatatacata tatatttata tttaatatat 900 acatatatat ttatatttaa tatatacata tatatttata taatatat aaatttatat 960 titatatata taaaaatata taittatatt taatatatat aaatatatat ttatatttaa 1020 tatatatatt tatattgaat atatacataa atatatattt atatttaaia tataaacata 1080 {attiatatt tatatatiaa atatatattt atatttaata tataaatata tatttatatt 1140 tantatatlt atatatacta atatatitat atitaatata ittatatata gatatattta 1200 — atttatgtgt attaatatat ttatalttaa tatatttata tattaatata 1260 tttatatitt atatttatat attaatatat tatatttta tatttatatt ttatatattt 1320 atatattaat atatttatat ttatatatat tttatataf taataaattt atattttata 1380 tatitatata ttaataaatt tatattttat acagttatat aaatatattt atattttata 1440 cagttatata aatatatita tatittatag ttaiataaat atatttatat titatacagt 1500 tatataaata tatttatatt ttatacagtt atataaatat alttatattt tatacagtta 1560 tataaatata titatatitt atacagttat ataaatatat ttatattita tacagttata 1620 taaatatatt tatatittat acagttatat aaatatattt atattttata cagttatata 1680 aatatattta tattttatac agttatataa atatatitat attttataca gttatataaa 1740

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SEL PCT 012.8725 tatatttatg ttttatacat ttatataaat atattiatat tttatacatt tgtatttaat 1800 atatatttat atataaatat aftttatatt taatatattt atatataaat atatatigat 1860 atttaatata tatttatata taaatatata ttgatattta atatgfttat atataaatat 1820 atatttatat ttaatatata tgttiatata tcaatatata tttatattta atatatattt 1980 acatataaat atatatftat atttgatata tatttatait tgatatatat titatatata 2040 ttaatatatt tacattigat atatatitta tatatattaa tatatttaca tttgatatat 2100 : attttatata tattaatata tftacattig a 2131 <210> 134 <211> 842 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(842) <223> MAR of chromosome 2 genomic contig; 20483478..20484319 <400> 134 tatatattta tgtttaatat atatttatag ataaatatat atttacgttt aatatatatt 60 tatagataaa tatatattta cgtttaatat atatttatct ataaatatat ttacgtttaa 120 tatatattta tatattaata tatttatgtt taatatatat ttatatatat taatatattt 180 atgtttaata tatatitata tattaatata tttatgtita atatatttat atatattaat 240 atatttatgt ttaatatata ttiatatgtt aatatattta ggtatatata tatttatatg 300 ttaatatata tttatattaa tatattatat ttatatataa aagtatatat aatatataaa 360 tattatataa attattatat agtattitta tatatatita tatataaatt tiatatattt 420

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SEL PCT 012.8T25 taiatatata aatatatatt tatatataca tittatatat aaatatatat ttatatatac 480 atiatatata taaatatata tatitatatt ttatatataa atatatatat ttatatatac 540 attttatata tittatatat gtaaatatat atataaattt tatatattgt atatatattt 600 ataaatttta tafatatatt {atatatata atatatataa tatatataaa itttatatat 660 attatatata tttatattt! atataitata talttattta tatatatita tafgttatat 720 atatttatat ttatatitat tttitattta tatattttat atatatatit atatatgtat 780 attatatata ttatatatta tataatatat {atatatatt atattatata tittataftat 840 at 842 <210> 135 <211> 645 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(645) <223> MAR of chromosome 2 genomic contig; 20897566..20898210 <400> 135 giatatttat attatatait atataatata tattatatat taataaatta tatataatat 60 aatatatatg tatatifata tttatgtiat aatatacata taattatata tgtatgtata 120 catgtataca tatacgtaia tgtgtafatlg tatacatata ggtatatgig tacatgtata 180 catataggta tatgtatatg tatacatgta tacatataat ataattacat atgtatgtat 240 acatacatat glaattatat tatafatgta tatgtatatt tatataatat ataatatgta 300 tiatatatta tacatgcata ttatatgta tattatatat acacatataa tataattata 360

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SEL PCT 012.8725 tatgtatgta tatatacaca tatatatita tattatatat gtatattata tacatatatt 420 tatattatat atgtatatat afttatcata tttatatgta atatgcatgt gtaataaata 480 atatacacat ttatatatgt atattatata catatatila tatigtatat gtatatatat 540 ttatatatat tigtatatca tatatttata tattgtatat tiatgtatat tatatatita 600 tatattatat atgtattata taatatatat gtaaatatat attat 645 <210> 136 <211> 722 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(722) <223> MAR of chromosome 2 genomic contig; 21664541..21665262 <400> 136 tataatatat attatatict atataatatg taaaatatat attatattct atataatgta 60 ttatatatag aatataatat attctatgta tictataatc tatataatac atattatata 120 ttatatagaa tattataaat aatatattct atattatata tagaatatat tctatatgtt 180 tatattctat atattatata tgaaatagta tataaaatat atataatata tataaaatat 240 gatatataat atatataaaa taatatataa tgtataatat ataaaataat atataatgta 300 taatatataa aataatatat aatgtataat atataaaata atatataatg tatattatat 360 aaaataatat ataatgtata ttatatataa aataatatat aaigtatatt atatataaaa 420 taatatataa tgtatataaa ataatatata atatatiaia tataaaataa tatataatat 480 aftatatata aaataatata tattatatat aaaataatat ataatatatt atatataaaa 540

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SEL PCT 012.8725 taatatatat tatatataaa ataatatata atatattata tataaaataa tatatattat 800 atataaaata atatatatta tatataaaat aatataatat atattatata taaaataata 860 tataatatat tatataaaaa tataaatata ttatataaaa atataaaata taaaatatta 720 ca 722 <210> 137 <211> 305 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(305) <223> MAR of chromosome 2 genomic contig; 22834991..22835295 <400> 137 : aatataaaat atatgatata taatacgtat tatataigta taatacgtat tatatattaa 60 tatataatat ataatacata ttatatatgt atataatata tactaatata tataatgtat 120 acattatata {itacataat atataataca taatatagaa ttataattat atataataca 180 taatatataa ttatatatat tattatatat gtatttatat tatatataat atattatata 240 taatatatat tatataatta tataagtata taattatgit atatacataa taatatataa 300 tatat 305 <210> 138 <211> 352 <212> DNA <213> Homo sapiens :

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SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(352) <223> MAR of chromosome 2 genomic contig; 25277762..25278113 <400> 138 taatatatat aatatattat atattatata taatatattt tataatatat aaaatatatt 60 atatataata tataatatat tfiataatat atataatata ttatatataa tatataatat 120 attitataat atatataata taitatatat attatatatlt tatatitatt tatatattca 180 taaatatata tttatatata atatattita taatatatia tatataatat ataatatatt 240 ttataatata ttataatata taatatataa tatattitat aatatatata atatataata 300 tattatatat ttatatttat ttatatatic ataaatatat atatitatat ta 352 <210> 139 <211> 342 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(342) <223> MAR of chromosome 2 genomic contig; 25378452..25378793 <400> 139 tatgtacata tataitttat atattatata taatatatat tatatgatat atataatata 60

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SEL PCT 012.5725 ttatataata taatatataa aatatatata atatatatta tattatataa attatattat 120 atatatcata taatatattt tatatattat ataatatata tiatattata tatattttat 180 atattatatt atatattata tataicatat aatatatatt atattatata tittatatat 240 tatataatat atattatata {ttttatata ttatataata fatattatat attttatata 300 ftatataata catatattat atataatata atatatatta ta 342 <210> 140 <211> 663 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(663) <223> MAR of chromosome 2 genomic contig; 30209437..3021009% <400> 140 aatatatatt acatatigta tatatagtat atgtaatgta tataatatag tatattctat 60 attgtataat agiaatatat agtatatgat atactatata ttacttatca tatatacaat 120 atatattata tcgtatattg tatattatat attgtatata tgtaatatat gataigtaca 180 tatgttatat atgiatataa tatactatat tatatatigt atattatata catatataac 240 actattatac aatatataat atagcatatt atatacaata tagcatatac aatatataat 300 atagcalatt atatataata tagtatatta tatacaatat ataatatagc atattatata 360 taatataata tagtatatta tatacaatat ataatatagc atatacaata tagtatacaa 420 tatataatat agcatataca atatagtata itatatataa tatataatat agcatgtaca 480 atatagtatg ttatatacaa tatataatat agcatataca atatagtata ttatatacaa 6540

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SEL PCT 012.8725 tatataatat agcatataca atatattata ttatatacaa tatataatat agcatataca 600 atatagtata ttatatacaa tatataatac agcatataca atatagtata ttacatacag 660 tat 663 <210> 141 <211> 1200 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1200) <223> MAR of chromosome 2 genomic contig; 31725089..31726288 <400> 141 tgtacttata tattataatg tatatataaa gtatatactt tatatatact tatatattat 60 aatgtatatt attgtatata agtatatatc ataatatata cttacatatg ctcacatata 120 ttataatgta tattgtatat attatataca tattatatat gtataatgta fatatacatt 180 atatatgtat aatgtatata tacattatat atgtataatg tatatataca ttatatatgt 240 ataatgtata taatatatac aatatatgta taatatataa tatatacaat atatgtataa 300 tatacaatat atgtataata tacaatatat gtatagtata taatatatat tatatatgta 360 tagtatatta tatattatat atgtatagta tataatatgt ataatgtata tattataata 420 tattatatat aatatctata acaatataat atatigiata tattatatat aatatatatt 480 tatataatat atattataia taatatatta igtatitatt {atatiatat ataatataaa 540 {atatataat ataaataata tttaftatat at{aatataa atatttatat taatatataf 600 ttattatata taaataatat ctatgatata aataatatat aatatacatg tatatgttat 660

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SEL PCT 012.8725 aatatataca tataatatac atgtgtatat atactataca tgtatatata acatgtatat 720 atatacatgt atatatatta tgtatacatg tatagtatat atacatgtat atatatacat 780 atatactata caigtatata tacatgtata tatatacata tatactatac atgtatatat 840 acatgtatat atacacatat atactataca tgtatatata catgtatata tatacatgta 900 tgttatatac attattataa tatacatata tagtatacat tatatacatt atataataty 960 cattattata atataatata cattattata atatacatta ttataatata atatacatta 1020 ttataatata cattattata atatacaftta taataatata cattattata atatacatta 1080 taatatigaa gtatatatac tataatatat gtatatatta taatgtatat aatatacatt 1140 attatatata agtatgtatt atatataagt atatattata atatatgtat atacatatat 1200 <210> 142 <211> 325 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(325) <223> MAR of chromosome 2 genomic contig; 32147252..32147576 <400> 142 aaatacaaat afttatttat atataatata taatataata tatttattta tatataatat 60 ataatttata attatataaa tatataatat atttatatat aatatataat titattatat 120 attaattata tatataataa atatatataa tatataattt tattatatat taattatata 180 tataataaat atatataata tataataata ttatatacat tatatataaa tataaatatt 240 tatataatat ataatataat atatttatit atatataaat atataatata taattatata 300 :

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SEL PCT 012.8725 aatatataat atatttatat ataac 325 <210> 143 <211> 507 <212> DNA <213> Homo sapiens <220> «21> misc_ binding <222> (1)..(507) <223> MAR of chromosome 2 genomic contig; 32312662..32313168 <400> 143 attatttata taaatattat atttatatta ittatataaa taftatattt atattattta 60 tataaatatt atatttatat tatttatata aatattatat ttatattatt tatataaata 120 ttatatitat attatttata taaatattat attiatatta tttatataaa tattatattt 180 atattattta tataaatatt atatttatat tatttatata aatattatat ttatattait 240 tatataasata ttatatitat attatttata taaatattta tttatattat ttatataaat 300 attatatita {atiatttat ataaatattt atitatatta tttatataaa tatttaitta 360 tatitatata aataatatat aaataaatat tttataigta tataaatatt atttatatia 420 titatttaaa taaataatat aaattaatat aaatattaat attatitatt ttattataaa 480 taatataaat attatattta tatttat 507 <210> 144 <211> 339 <212> DNA <213> Homo sapiens

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SEL PCT 012.8725 <220> <221> misc_binding <222> {1}..{339) <223> MAR of chromosome 2 genomic contig; 33651118..33851456 <400> 144 aaatataata tattatttat atataatata aatgatatat tatgtatata taaaatataa 60 ataatatatt atgtatatat aaaatataaa tattatttat atataaaata taaataatat 120 itatatataa aatataaata ttatatiatt tatatataaa atataaataa tatattattt 180 atatataaaa tataaataat atattattta tatataaata atatataaaa tataaatata 240 tattatatat aaataaaata tatatattat atatataaat ttatatataa tatataaaat 300 ataatatata tatttaatat ttattatata atatataat 339 <210> 145 <211> 461 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(461) <223> MAR of chromosome 2 genomic contig; 45073053..45073513 <400> 145 tgtgtataca tatatacgtyg tacatataca tatatacatg tgtatatata tacgtgtaca 60

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SEL PCT 012.85T25 tatacatata tacatgtgia tatatatgta catatacata tatacatgtg tatacataca 120 tatatacatg tacatataca tatatacatg tgtatacata catatataca igtacatata 180 catatataca tgigtatact tacatatata catgtacata tacatatata catgtgtata 240 fatacatata tacacgtaca tatacatata tacaigtaca tatatacatg tatacatata 300 tacatgtaca tatgtacata tatacatgta tacatatata catgtacata tgtacatata 360 tacatgtata catatataca tgtacatatg tacatatata catgtataca tatatacata 420 tgtacatacg cacagataga catatataca tatgtacata c 461 <210> 146 21 1> 1162 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(1162) <223> MAR of chromosome 2 genomic contig; 45487691..45488852 <400> 146 attatattat ctatataaat ctattatatc tattatatta tctatataat atctattata 60 tatattatat tatctatata aatctattat atatatiata ttatctatat aaatctatta 120 tatatattat attatctata tatctatiat atattatatt atattatatt atatataata 180 tctattatat atattatatt atattatatt atatataata {ctattatat atattatatt 240 atctatataa tatctattat atattatata ttatatfata tataatatct aftatatata 300 ttatattata tiatatataa tatctattat aiclatiata tatattatat atatctaita 360 tatctattat atatattata tataatafct attatatcta ttatatatat tatatataat 420

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SEL PCT 012.8725 atctattata tctattatat tatattatat ataatatcta tiatatctat tatatatatt 480 atatatatct atiatatcta ttatatatat tatatataat atctattata tctattatat 540 atattatata taatatciat tatatctatt atatattata tatataatat ctattatatc 600 tattatatat tatatatata atatctatta tatctattat atctattata tatatatcta 660 ttatatctat tatatatatt atatacataa tatctattat atctattata tatattatat 720 atataatatc tattatatct attatatata tactatctat tatatctatt atatatatta 780 tatatgtact aictattata tctattatat ctattatata tatactatct attatatcta 840 ttatatatat tatatatata ctatctatta tatctattat atatattata tatatactat 900 ctatiataia tctattatat atattattit atattatata tagtatctat tacatatait 960 atattatatt atatataata tctattatat atattatatt atattataaa taatatatat 1020 aatatctglt atatataata gatattatat ataatatata atatatataa tagatatiat 1080 atatattata ttatataata tataatatat aatataatta atataaaata tatataatat 1140 ataattaata taatatgtaa ta 1162 <210> 147 <211> 562 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(562) <223> MAR of chromosome 2 genomic contig; 45516233..45516794 <400> 147 acatattata tatattatat ataatatata ttatatatac atattatata tattatatat 60

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SEL PCT 012.8725 aatatatatt atatatacat aitatatata ttatatatac atatatatat tgtatataat 120 atatacatat tatatatatt atatatacat attatatatt atatatasta tatacatatt 180 atatattata tataaatait atatatiata tataaatatt atatatataa atattatata 240 ttataiataa atattatata icttatatat aaatataata tataatatat ataatattta 300 tatattatat ataaatatta tatatattat ataatattat atataatata taaatatata 360 tattatataa atattgtata tattatataa atattatata tattatatat aaatattata 420 tatattatat aaatatatat aaatatataa aatatataaa tatgtaaaat ttataittat 480 aaatatataa tataaatata taaatataaa tataaattat atataatata taatatatta 540 tacataatat atactatata ta 562 <210> 148 <211> 801 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(801) <223> MAR of chromosome 2 genomic contig; 45727251..45728051 <400> 148 atatatatat ataatatata catatataga atatatatat tattatatic tatatataga 60 atatatatat agaatatata tatatagaat atatatatag aatatatata tagaatatat 120 atatagaata tatatataga atatatatat atagaatata tatatagaat atatatatat 180 agaatatata tatatagaat atatatatat agaatataia {atatagaat atatatatag 240 aatatatata tagaatatat atatatagaa tatatatata gaatatatat atatagaata 300

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SEL PCT 012.8725 tatatataga atatatatat atagaatata tatatagaat atatatatat agaatatata 360 tatagaatat atatatatag aatatatata tagaatatat atatatagaa tatatatata 420 gaatatatat atatagaata tatatataga atatatatat atagaatata tatatagaat 480 atatatatat agaatatata tatagaatat atatatatag aatatatata tagaatatat 540 atatatagaa tatatatata gaatatatat atatagaata tatatataga atatatatat 600 atagaatata tatatagaat atatatatat agtatatata gaatatatat atatagtata 660 tatagaatat atatatatag aatatatata tagaatatat atatatagaa tatatatata 720 gaatatatat atatagaata tatatataga atatatatat atatagaata tatatataga 780 ataiatatat atatatagaa t 801 <210> 149 <211> 348 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(346) <223> MAR of chromosome 2 genomic contig; 50937238..50937583 <400> 149 taaaattata tatattatat ataatatata atatattata {ataatatat attataatat 60 atataatata tatiatataa aatatalict atagaatata tatictaita tataatatat 120 attctattat aatatatait atatataata tatattctat tataatatat attatatata 180 atataticta ttalgatata tattatatat aataacatat attatatata atatatattc 240 tattatataa aatatatatt atataaaata tatattctat tatataaaat atatattata 300

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SEL PCT 012.8T25 taaaatatat attatattat ataaaatata tattatacta tatata 346 <210> 150 <211> 482 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(462) <223> MAR of chromosome 2 genomic contig; 55672627..55673088 <400> 150 taaatatata ttatataita tattatatat aatatatita tatttatata tactataatt 60 tatatataat atatattata tatataatat atttataata tatatcatat agataatata 120 tatttataat atatatcata taaataatat atatttataa tagatatcat ataaataata 180 tatattiata atagatatca tataaataat atatattiat aatagatatc atataaataa 240 tatatatita taatagatat catataaata atatatatti ataatatata tcatataaat 300 aatatatatt tataatatat atcatataaa taatatatat ttataatata tatcatataa 360 ataatatata titataatag atatcatata aataatatat atttataata gatatcatat 420 aaataatata tatitataat agatatcata taaataatat at 462 <210> 151 <211> 401 <212> DNA <213> Homo sapiens

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SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(401) <223> MAR of chromosome 2 genomic contig; 56081352..56081752 <400> 151 tatacatgta tgtattcgta tatgtatgtt atatatgtat atgtgttata tacatataca 60 tatatacatg tatatgtgtt atatacatat acatatatac atgtatatgt gttatataca 120 tatacatata tacatgtata tgigitatat acatatacat atatacatgt atatgtgtta 180 tatacatgtg tatgtgtata tgtatatata catatatgtg tatgtgcatg tgtatatata 240 catatatgta tatgitgiata tgtatatata catatatgta tatgtgtatg tgtatacgta 300 tatatacata tatgtgtatg tgtatgtgta tacgtatata tatacatata tgtgtatgtg 360 tatacgtaca tatacatata tgtgtatgtg tatacgtaca t 401 <210> 152 <211> 765 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(765) <223> MAR of chromosome 2 genomic contig; 56404208..56404972 <400> 152 tatattatat anagaatata tattatataa tatgtaaaga atatatatta tataatatgt 60

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SEL PCT 012.8725 aaagaatata tattatatat tatgtaaaga atatatatta tatataatat ataaagaata 120 tatattatat aatatataaa gaatatatat tatatatiat ataaagaata tatattatat 180 ataatatata aagaatatat aatatataat atataaagaa tatatattat atataatata 240 taaagaatat ataitatata taatatataa agaatatata ttatatatta tataaagaat 300 acatatatat aatatataaa gaatatatat tatatataat atataaagaa tatatattat 360 atataatata taaagaatat atattatata taatatataa agaatatata ttatatataa 420 tatataaaga atatatatta tatataatat ataaagaata tatattatat atattatata 480 aagaatatta taiatiatat aaagaatata {attatatat aatatataaa gaataaacat 540 atatactata {atazagaat atacattata tatactatat ataaagaata tacattatat 600 atactatata taaagaatat atataatata taaagaatat acattatata taatatataa 660 agaatatatt atatattata taaagaatac attataatat aaagaataca ttatatataa 720 tataaagaat acattataat atataaagaa tatatataat atata 765 <210> 153 <211> 443 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(443) <223> MAR of chromosome 2 genomic contig; 61953416. 61953858 <400> 153 fttatatatt atagataaaa ttataitata ttacaigtaa tatataatat gtaaaatata 60 ttatatiaca tatataatat ataatatgta aaatatatta tattacatat ataatatata 120

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SEL PCT 012.5T25 ataigtaaaa tataitatat tacatatata atataaaata ttacatataa tatatittac 180 ataaatatat attatctatt acatatitat tatatgtaat aatatgtaca tatgtataaa 240 tatgtatata fitatacata igtatatatt atatatacat atatatgtat atattatata 300 tacatatata tgtatatait atattatata tacatatata tgtatatatt atattatata 360 tacatatata tgtatatait atattatata tacatatata {giatatata ttataaatat 420 gtataataaa gatttatatg taa 443 <210> 154 <211> 372 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(372) <223> MAR of chromosome 2 genomic contig; 62076211..62076582 <400> 154 tatatataat tatatatgta attatatatc agtatatata attatatata attatcaata 60 tatataatta tatataatita tcaatatata taattatcaa tagatafata taaitatata 120 tataattata tataatata tatcagtata tatacitata taattatata tatgtatata 180 taaitatatg tataaattat ctataagtat atataactat aatatatatc aattatatat 240 acttatgtat aattatatat actgatatat aattatacat aattatatat atcaattata 300 tataattatg tataattata tatacatata tataattata tatataaatt atatgtaatt 360 atataattac ac 372 <210> 155

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SEL PCT 012.8T25 <211> 484 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(484) <223> MAR of chromosome 2 genomic contig; 62158581..62159064 <400> 155 attatatata atataaaaat tatacatatt attttattat atattatata cataatatat 60 atatttcata tataatatat attatatata atataaaata tatattatgt ataattatat 120 ataaaatata ttatataatt atatataaca taaaatatat ataatatata attatatata 180 atataaaata tatatataat ataaaatata tatfatatgt aattataiat aatataaaat 240 atatatataa tataaaatat atattatata taattataat ataaaatata tattatatag 300 tatatattat ataaaatata tattatatat aatiatatat tatataaaat atatattata 360 tataattata taatataaaa tafatattgt atataattat atataatata aaatatatat 420 aatatatgaa ataagatata tactatatat aatatatata atttacatat aagatatata 480 feat 484 <210> 156 <211> 6844 <212> DNA <213> Homo sapiens <220>

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SEL PCT 012.8725 <221> misc_binding <222> (1)..(B44) <223> MAR of chromosome 2 genomic contig, 68145036..68145679 <400> 156 tatatatatg ctaatatatg taatatatat tatatatatg ctaatatata tatgctaata 60 tataatatat attatatata aatatataat atatatitat ataaatatat aatatattat 120 atataaatat ataatataaa tatatataat atatactata tatatatia tgtataacat 180 ataatacata tigttatat ataatatata tat{atatgt tatatattat ataftatata 240 taatataaca atatafttta tatattatat gttatatatt atatatiata tataatataa 300 cataatatat aatatatatt atattatata ttacatatat tagcaatatt atatataaaa 360 tatatataat atatataaaa tatatataaa aatataaaai atatatcaaa atataaacta 420 tataatatat asaaatatat tatatataat atataaaaat ataaactata taatatataa 480 aaatatatta tatataatat ataaaaatat attatatatt atatataaaa atatattata 540 tataatatat aaaaatatat ataaaatata aaaaatatat ataaaatata aaaaatatat 600 aaaataatat aaaatatata atatataata atataatata taat 644 <210> 157 <211> 530 <212> DNA <213> Homo sapiens <220> <221> misc_binding «2225 (1)..(530) <223> MAR of chromosome 2 genomic contig; 71257289..71257818

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SEL PCT 012.5725 <400> 157 atatctatta tatttatata ctitatataa attatatcta ttataittat atacittata 60 {aaattatat ctattatatt tatatactit atataaatta tatctattat atttatatac 120 tttatataaa ttatatctat tatatttata tacittatat aaattatatc tattatattt 180 atatacttta tataaatata taattatat! tatatactit atataaatat aattataaat 240 atatitatat actttatata aatataatta taaatatatt tatatacttt atataaatat 300 aattataaat atatttatat actttatata aatataatta taaatatatt tatatacttt 360 ataattatat gtiatatita taattatatt tatataattc ataattatat acattaigtt 420 tatagttata taatttataa tiatatacat tatatitata iftataiaat ttataattat 480 : ataaattata taaattatat aaattatctt taatttatat tatataatct 530 <210> 158 <211> 337 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(337) <223> MAR of chromosome 2 genomic contig; 73413615..73413951 <400> 158 acttatatta tatataacta tatiaiigta tattaatata aattaatgat atataatata 60 ttaattatat attattatat gtgatataaa atacttatat ttatactgta tatatgtata 120 tacacacata tatgtatata tgtatatata cacatatgta tatatgtata tgtatatatg 180

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SEL PCT 012.8725 tatactgtat atatgtatat acacacatat atgtatatat gtatatgtat atatgtatac 240 tgtatatatg tatatacata tatacatata tgatatatat cacatatatg tgatatataa 300 atatattiat ataaatataa tattaatatt tatatta 337 <210> 159 <211> 1340 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(1340) <223> MAR of chromosome 2 genomic contig, 77011049..77012388 <400> 159 afgtatitta tatagtatat attaigtatt atattgatat aatiatataa caattatita 60 tatatgaaat aacaaataaa tatataaaat aataaatata tatiiattat taaataataa 120 atatatattt attattaaat aataaatata taaagtaata aatatatatt tatatattaa 180 ataattcata tatatttata taltaaataa ttcatatata tttaaataat taatacatat 240 ttaaataatt aatatatatt tatataatat atatttatat attaaataat taatatatat 300 ttatagatta aattaatata tattiatata ttaaattaaa tttaatatat tatatattta 360 tataatitaa atttaataat ttatataat! taatiiaatt taatataatt aaaatatatt 420 aaacatiata taatatataa tatatitaat atataatata tatttaatat ataatatatt 480 taatatataa tatatttaat atataatata tatttaatat ataatatatt taatatataa 540 tatatitaat alataatata tatttaatat ataatatatt taatatatag tatatatita 600 atatataata tatttaatat ataatatata tttaatatat aatatattta atatataata 660

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SEL PCT 012.8725 tatatttaat gtataatata titaatatat aatatatatf taatgtataa tatatttaat 720 atataatata tatttgatgt ataatatatt taatatatat ttgatgtata atatatttaa 780 tatataalat atatitgatg tataatatat ttaatatata atatatatit gatgtataat 840 atatttaata {ataatatat atttgatgia taatatattt aatatataat atatatttga 900 totataatat atitaatata taatatatat tigatgtata atataittaa tatataatat 960 atattigatg tataatatat ttaatataia atatatattt gatgtataat atafttaata 1020 tataatatat attigatata taatatattt aatatataat atatattiga tatatatfta 1080 atatataata tatalttgat atataatata titaatatat aatatatatt tgatatataa 1140 tatatttaat atataatata tatttgatat ataatatatt taatatataa tatatatitg 1200 atatataata tatitaatat ataatatata ttigatatat aatatatita atatataata 1260 tatatttgat atataatata tittcttatt aattatttat atataatata taaatatata 1320 ftaattaatt atatattaaa 1340 <210> 160 <211> 937 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{937) <223> MAR of chromosome 2 genomic contig; 78226855..78227791 <4Q00> 160 tgtgtatata tacatatatg tgtatciatfg tgtatatata cataigtgta tatatacata 60 tatgtgtata tatacatatg tgtatatatg tgtatatatg tgtatatata catatatgig 120

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SEL PCT 012.8T25 tatatatgtg tatatatgtg tatatataca tatatgtgta tatatgtgta tatatacata 180 tgigtatata tgtgtatata tacatatatg tgtatatatg totatatata catatatgty 240 tatatatgty tatatataca tatatgtgta tatatgtgta tatatgtgta tatatacata 300 tatgtgtata tatgtgtata tatacatata tgtgiatata tgigtatata tacatataty 360 tgtatatatg igtatatgtg tgtatatata catatatgtg tatatacaca catatatgtg 420 tatatatgtg tatatataca tatatgtata tatacatata tgtgtatata tgtgtatata 480 tacatataig tgiatatatg tgtatatata catatatgtg tatacataca tataigtgta 540 tatatgigta tatatacata tatgtgtata catacatata tgfgtatata tgtgtataca 600 tacatalatg fgtatacata catataigig tgtatatgtg tatacataca tatatgtgtg 660 tatatatgtg tatacatatg tgigtataig igtatatata catatatgig tgtatatatg 720 tgtatatata catatatgtg tgtatatatg tgtatatata catatatgtg tgtatatatg 780 {gtatatata catatatgtg tgtatatatg tgtatatata catataigtg tgtatatatg 840 tgtatatata catatatgtg tgtatatatg tgtatatata catatatgtg tgtatatatg 900 tgtatatata catatatgtg tgtatatatg tgtatat 937 <210> 161 <211> 1350 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1350) <223> MAR of chromosome 2 genomic contig; 79287748..79289007 <400> 161

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SEL PCT 012.8725 tatatatatt atatatatag taactgtict attatatata tattatatat attictgttc 60 tattatatat tatatatatt atattatata ttatatgtaa tatattatat atattataag 120 : taatatatta tatatattat atgtaatata ttatatatat tatatgtaat atattatata 180 tattatatgc aatatgttat atatattata tgcaatatgt tatatatatt atatgcaata 240 tattatatat attatatgca atatattata tataatatat gtaatatatt atattatata 300 ttatatgtaa tatcttatat attatatgia atatattata tatattatat gtaatatctt 360 atatatatta tatgtaatat attatatatt atatgiaata {attatcita tatatattat 420 atgtaatata ttatattata tattatatgt aatatatatt atatgtaata tattacatat 480 tatatgtaat atatattata tgtaatatat tacatattat atgtaatata tattatatgt 540 aatatattac atattatatg taatatatta catattatat gtaatatatt atatgtatta 600 tatgtaatat attatatgta tiatatgiaa tatattatat gtattatatg tattatatgt 660 aatatattat atgtattata tgtaatatat tatatattat atgiaattat attatatgta 720 atatattata ttatatatta tatatattat atgtaatata ttatattata tattatatat 780 attatatgta atatattata ttatatatta tatatattat atgtaatata ttatattata 840 tattatatat attatatgta atatattata {tatatatta tatatattat atgtaatata 900 ttatattata tattatatat atiatatgta atatattata ttatatatta tatatattat 960 atgtaatata ttatattata tattatatat attatatgta atatattata ttatatatta 1020 tatatattat atgtaafata ttatatiata tattatatat attatatgta atatattata 1080 ttatatatta tatatattat atgtaatata ttatattata tattatatat attatatgta 1140 atatattata ttatatatta tatatattat algtaatata tittatatta tatatattat 1200 attatatatt atatgtaata tattatatta tttattatat attatatatt atatgtaata 1260 tattatatta titattatat atattatatt atttattata tataatatat tatattatat 1320 atattatatt atatatattt ctgttctaat 1350 <210> 162 <211> 332

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SEL PCT 012.8725 <212> DNA <213> Homo sapiens <220> <221> misc_difference <222> (1)..(332) <223> MAR of chromosome 2 genomic contig, 81142998..81143329 <400> 162 : ctatgiatat aactatatat aactattata taacttaata agatatataa ctattatata 60 acttaataaq ftatatataa ctatiatata taactiaata agitatatat aactatiata 120 taacttaata agttatatat aactattata taacitatta agttatatat aactatatat 180 aacttaataa gttatatata actatiatat aacttaataa gttatatata actattatat 240 aacttaataa gitatatata actattatat aacttaataa gttatatata actatatata 300 actiatatac aacttaftaa gctatatata ta 332 <210> 163 <211> 327 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(327) <223> MAR of chromosome 2 genomic contig; 84019536..84019862

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SEL PCT 012.5725 <400> 163 actgacagta facatactgt atatatatac agtatgtata catatacagt atgtatacta 80 tatacagtat gtatactgia tatatatata cagtatgtat actgtatata tatacagtat 120 gtatacgtat gtatactgta tatatgtatt atagtgtata tatgtattat agigtatata 180 igtattatat atattatagt gtatgtatta tatgtgtata tacatataat atattataca 240 tatacatatg cacaatatgt atatgtatta tatgtattca tatacatata tgtatatgta 300 taatatatgt atacatataa tacacat 327 <210> 164 <211> 407 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(407) <223> MAR of chromosome 2 genomic contig; 1448030..1448436 <400> 164 tatataatat atattacata tatattatat ctatattatt tatattacat atgtaatata 60 tattatattt atattattia tataatatat tatatatatt atattattta tatgtaatat 120 atttatattg tttatatata ttatatttat attattiata tataatacat attatattita 180 tattattiat atataatata tataataaat atataatata tataaaaaia tatatattta 240 atatatctat aatatatatt atatatatta tatataataf atataaitgt acatatattt 300 attatatata ttatatatat aatatatatt ataaatataa tatataaata tatttataaa 360 tatatataaa tattatattt atacattata tttatataca tattata 407

Seite 147

SEL PCT 012.8725 <210> 185 <211> 1959 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1959) <223> MAR of chromosome 2 genomic contig; 2117630..2119588 <400> 165 tatacatgtt atagtgtata tagtatacta atatataatg tatgtatgig tatacatata 60 cacatataat atacacatat ataatatata tagtatataa taatgtataa tatataatat 120 aiaatalaaa aigtatagia tactacatat tiatatatag tatatagtat gcatagtaca 180 tatatactat atatgiagta tactatagig tatatatagt acaccatata tagtataaat 240 atactatata gtatatgtac tatatatata ctatatagia tatacagtat acatatatag 300 tatacctata ctatatagta tatatagtgt gegtatacta tatagtatat atagtgigcg 360 tatactatat agtatatata gtgtgcgtat actatatagt atatatagtg tgegtatact 420 atatagtata tatagigtgc gtatactata tagtatatat agtatacata taiagtgtgc 480 gtatactata tagtatatat agtatacata tatagtatgc gtatactata tatagtatac 540 atatatagta tatctagagt atatgtagta tgtatagtat atatagtcta catactgtat 600 atacagtata {atatactct atagtatact atacagtata gtatactata tagtatacaa 660 tatatgtata ctatagaaac acactatata tagtatacta tatatactat atactatata 720 ctatatatag tatactatat atactacata ctatatatag igtatgiata gtatatataa 780 actatatata gtgtatatag tatatatalt atatataata tatattatat tatattatac 840

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SEL PCT 012.8T25 tatatattat atgtatatta tagtatatta tactattata tattatatat tatattatat 900 attatataat ataatataat tatatattat aaaatatata tititatatt atatattttt 960 aaatatiita taatatatat ttiataatat atatattata attatittat atataatata 1020 aaatataata aatattttat aatatatatt tttaaaatat aatattiata tattataaaa 1080 atataaatat ataatatatt atatattata tatagtataa tatataatat gttatatagt 1140 atcttatact attatactat atatattata tagtgtatat atagtatact atatatagtg 1200 tatatagtgt atactatagt gtatatagtg tatactatag tgtatatagt gtatactata 1260 tacactgtat atagtagtgt atactatata cacigtatat agtagtgtat actatataca 1320 ctgtatatag tagigtatac tatatacact gtatatagta gtgtatacta tatacactgt 1380 atatagtagt giatactata tacactgtat atagtagtgt atactatata cactgtatat 1440 agtagigtat actatataca ctgtatatag tagtgtatac fatatacact gtatatagta 1500 gtgtatacta tatacactgt atatatagta tattatatat actatatatg tatatatagt 1560 atacatatat aitatatata cagtatatat agtatatata ctatgtagta tatatagtat 1620 atatactata tagtatgtat agtatactat atagtatata tagtatatta tatagtatat 1680 atactatata gtatatatag tatattgtat atatagtata tatactatat agtatatata 1740 gtatatigta tatatagtat attgtatata tagtatacat agtatgtata tatagtatat 1800 atagtataca tatatagtat gtacacagta tatatagict atatgtatac tacatatagt 1860 atacatgtat actatactac atatagtata catgtatact atactacata tagtatacat 1920 gtatagtata ctacatatac tatacatgta tagaatact 1959 «<210> 166 <211> 520 <212> DNA <213> Homo sapiens <220>

Seite 149

SEL PCT 012.5725 <221> misc_binding : <222> {1}..(520) <223> MAR of chromosome 2 genomic contig; 2119984,.2120503 <400> 166 tatgtatgca tcgtatacat atatagtata tatatgtatg catcgtatac atatatacag 60 tatatatagt atgcatcgta tacatacagt atactatata tacagtatat acagtatact 120 atatatacag tatatacagt atactatata tacagtatat acagtatact gtatatacag 180 tatatacagt atatatagta tactatafat acagtatata tactatgtat tctatatata 240 gtatagtgia catagtaiac atatagtata cactatacta tatatagiat actatatata 300 cictatatag latatatagt atactatata tagtatatat gtatactata fatagtgtat 360 atatatacta tatatagtgt atatatatac tatatatagt atatatatac actatatatt 420 gtatagtata gtgtatatat agtatagtat atgtatatat acacaigtat acatgtatat 480 atgtatacia atatatacta atatatgtat aaatatatat 520 <210> 167 <211> 954 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(954) <223> MAR of chromosome 2 genomic contig; 2578285..2579238 <400> 167

Seite 150

SEL PCT 012.8T25 tattatatat aactttataa tatataatat atattatata taactttata atatataata 60 tatatiatat ataactttat aatatataat atatattata tataacttta taatatataa 120 tatatattat atataactit ataatatata atatatatta tatataactt tataatatat 180 aatatatatt atatataact ttataatata taatatatat tatatataac tttataatat 240 ataatatata ttatatataa ctttataata tataatatat attatatata acttiataat 300 atataatata tattatatat aactitataa tatataatat ataftatata taactttata 360 atatataata tatattatat actatatata atatataact ttataatata taatatatat 420 fatatactat atataactit ataatatata atatatatta tatattatat ataactttat 480 aatatataat atataitata tataacttia taatatataa tgtatattat atattatata 540 ttatatatta tatataactt tataatatat aatgtatatt atataitata tataacttta 600 taatatataa tatataatat aatatataac tttataatat atatatcata tattatatat 660 aactttataa tatatatcat atattatata taactataat atatatatca tatattatat 720 ataactataa tatatatatc atatattata tataacttta taatatatat aicatatatt 780 atatataact t{ataatata tatcatatat tatatataac tttataatat atatcatata 840 ttatatataa cittataata tatattatat ataactttat aatatatatc atatattata 900 tataacttta taatatatat catatattat atataactit ataatatata tcat 954 <210> 168 <211> 452 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(452) <223> MAR of chromosome 2 genomic contig; 3836217..3836668

Seite 151

SEL PCT 012.5T25 <400> 168 {ttatatata aatatatatc ttatatatat ttatatataa tacatatata tcttatatat 60 ataaaatata tatacatati tatatataaa atacatatgt atiatataca tttatatata 120 atacatatgt attatataca attatataat acatatgtat tatatacaat tatataatac 180 atatitataa atatatatat ttatatitat atatatitat atataaataa atatatattt 240 atagatttat ttatataaat atatatitat ataaatatat atitatatat atttatataa 300 atatataftt atatatatit ctatatatat atataaatat atgtataaat atatatattt 360 atacatatat tcatataaat atatatatit atacatgtat ttatatgaat atatatttat 420 acatgtaatt atatgaatat atatttatac at 452 <210> 169 <211> 417 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(417) «2235 MAR of chromosome 2 genomic contig; 3837666..3838082 <400> 169 gatatatata ittatataza tatatatata aagagatata tttatatatt tatifatata 60 aatataittc tttatataaa gatataigta aatatattta titatataaa tatatttata 120 tatgtaaata tatattiata tatttatata tttatatatt tatttatata aatatatata 180 tttatatatt tatitatata tataaaaata tataaatata aatatatata aatatatata 240

Seite 152 :

SEL PCT 012.8T25 attataaata tagaaataaa tataaatata aatatataaa tatatataaa tataaatata 300 (ataaatata aatatatata aatataaata tataaatgta taaatatata aatataaata 360 tatataaata tgtataaata tataaatata taaatatata aaaatatata taaatac 417 <210> 170 <211> 1197 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1197) <223> MAR of chromosome 2 genomic contig; 6294846..6256042 <400> 170 tatatactaa taigtatata taaatatata aatatatata cacgigtata tataaatata 80 tatgtatata taaatatata tacatatatg tatataaaaa tatatacgta tatacgtata 120 tacgtatata tagatatata cgtatatacg tatatacgta tatatagata tatacgtata 180 tacgtatata tagatatata cgtatatacg tatatacgta tacatgigta tatacgtata 240 tacacatata cgiatacatg tgtatatacg tataigtata cattatatat acgtatatat 300 acatatatgt atacatgtat atataaatat atacatatat gtatatatta tacatatatg 380 tatatataat atatalatia {atataatat atatattata tataataiat atattatata 420 taatafatat attatatata atatattata tattatatat aatatataca tatataatat 480 attatatatg tacatatgta cataatgtat atatgtatat atataatata tatgcacatg 540 tatatataat atatgtatat tatatataca tatgtatata tgtacatatt atataigtat 600 atatgtacct attatatata catatgtata taigtaccta t{atatatac atatgtatat 660

Seite 153

SEL PCT 012.8725 atgtacatat {atatataca tatgtatata tgtacatatt atatatacat atgtatatat 720 gtgcatgcat atataatata taatatatta tagattataa tattatatac atatcatata 780 ttatatactt atatatacat gtatatatta tatacatatt atatattata tacatataat 840 atatgtatat aatatataca tatattatat attatatata atacattatg ttatatatta 900 tgitatataa tatatattat ataatataca iatattatat ataatatata catatataat 9860 aaataatata taattatata tataatatat gcatataaat atgtaatata ttttatatta 1020 tatatgatca tatataatat gacatattat atatgattat atatatgata tattatatat 1080 gattatatat attatatata aatatatgat tatatataat catatatata aatatatgat 1140 tatatgatta tatataaata tatatatatg attatatgat tatatataat fgattat 1197 <210> 171 <211> 382 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(362) <223> MAR of chromosome 2 genomic contig; 8506971..6507332 <400> 171 tatatatagt gtatactata tatacgctat atgcacacat aaactatata tacagtatat 60 aatatgcgta tactatatac acagtatata ctacatgtat actatatata gtatataaga 120 tatatactat gtatataata tatatactag gtatatatat ccatatatat actatatact 180 atagtatata catatatatg tacgtatata tgtatatgta catatatatg tagtatgtat 240 atatatacat atatacacac tatagtatat acatatatat actatatata ccctatatag 300

Seite 154

SEL PCT 012.5725 agtataitat atacagtata ctatatatac tatatatacc ctatatagag catgtctaiy 360 ct | 362 <210> 172 <211> 2578 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(2578) <223> MAR of chromoscme 2 genomic contig; 6507395..6509972 <400> 172 ggtatactat atatactata gagtatactt tatagtatat atacctatat tatatatata 60 tacatacact gtatagtata tatggtatat atactatata tggcatatat agtitatata 120 tatactatat afggtatata tagtitatat atatactata tatggtatat atagtttata 180 tataccatat atggtatata tagtttatat agtacatata gtatatatac acactgtata 240 gtatatatta tgtagtatat atactatata tactgtatat atagtataaa tactatatat 300 agtatacact atatactata cactatatat actatatact atatactata tatagtatac 360 tatatagtat atagtatact ctatatgtac tatagagtat actatatata ctatacataa 420 aatattitta tatatagtac agcgtatact atatactata tatagtatac tctatatgta 480 ctatagagty tagtatatac tatacagtat actciatata tactatacag tacactatat 540 atactatata tagtatattt tatatatagt acagtatata cagtatatat attatactat 600 atgiagtaca tatatagttt agtatatata gtatatatac tatactatat gtactacata 660 tataatagta tatatagtat atatactata ctatatgtag tacatatata gtttagtata 720

Seite 155

SEL PCT 012.8726 tatactagta tatagatata tagttatata gatatataat agtatatata gtatatatag 780 catatatagt atatatgcta tataiactat atagcatata ctatatacta tatatacagt 840 atatatagca tatatagcat atataatata tatactittg atatacatac tatatacagt 900 atatatagta tatatactgt ataaatatac tatatatacc gtatatgcac actatatgct $60 atatatacta tatacactat atacagtata tatagtacac tatactatat aaagtatata 1020 tagtatacag tacactatac tatatacatt atatatagta tatattatac atagtatata 1080 gtatataaat agtatatata gtatatacag tatatatata gcatactita tatagtatac 1140 acagtatata gatactatat atgctatata tagtatctat atactgtata ftatatatac 1200 taatatagta tatatgtata tatatactgt atatataata tatacatata tagtatatat 1260 actatacata cacactatac atatgtatat atactataca tactatatac tatatatcct 1320 atatatacta tatagtatat tatatatcct atatatacta tatagtatat tatatatcet 1380 atatatacta tatagtatat tatatatact atataccata tatactatat atactgtata 1440 gtatactata tatactatat agtatactgt atatactata tagtatactg tatatactat 1500 atagtatact gtatatacta tatagtatac tgtatatact atatagtata ctgtatatac 1560 tatatagtat actgtatata ctatatatac tatatagiat actgtatata ctatatagta 1620 tactatatat actatatacc atatatacta tgtatatact atatatagta tatactatgt 1680 atatgctata tatagtatat atagtatata igctatatat agtatatata giatatatgc 1740 tatatataca gtctatatat agtatatata ctatatagac tatatatata gcatatatac 1800 tatatatact atatataata tatatggtat atacatagta tctatatgta gtatctatat 1860 atagtaccta tatatactat atataggtac tatatatagt atatatactt tatatagata 1920 ctatatatag tatatatact ttatatagta tatatagtat aigtagcata tatagtatat 1580 atagtatata tagtatatag tatgtatagt atatatagat tatatigtat atacagtata 2040 tatactgtat atactatata aatagtacat acagtatata cagtatatat gtactatata 2100 tagtatatac agtatataca gtatatatgt accatatata gtatatacag tatatacagt 2160 atatatgcac tatatgttat atacagtata tacagtatat atgtactata taaatagaat 2220

Seite 156

SEL PCT 012.8T25 atactctata tacagtatat atgtactata taaatatata cactatgtac agtatatatg 2280 tactatataa atagtatata cactatatac agtatatatg tactatatag tgtatacagt 2340 atatacagta tataggtact atatatggta tatacagtat atatgcacta tatggtatat 2400 acagtatata tgractatat aiggtatata cagtatatat gtactatata tggtatatac 2460 agtatatatg tactatatat ggtatataca gtatatatgt actatatatg gtatatacag 2520 tttatacagt atatatgcac tatatatggt atatacagta tacatgtact atatatgg 2578 <210> 173 <211> 598 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(598) <223> MAR of chromosome 2 genomic contig; 7770400..7770997 <400> 173 gtgtattgta tatacatata cgtatctacg tatatacata tatgtattgt atatacatat 60 : atglaitgta tatacatata tgtatatacg tatatacata tatgtattgt atatacatat 120 atgtatatac gtatatacat atatgtatat acgtatatag atatacatat atatgtattg 180 tatatacata tatgtatata catatataca tatatattga tatacatata tatgtattgt 240 atatacatat acaatatatg tatatataca tatacatata caatatatgt atatacatat 300 atatgtattg tatatacata tatatgtatt gtatatacat atattgatat acatatatgt 360 atatatacat atatgcatat atgtatatat acatatatgc atatatgtat atatacatat 420 atacatatgt acatatatac atatatacat atatgtatat atacatatat acatatgtac 480

Seite 157

SEL PCT 012.5T25 atatatacat atatacatat gtacatatat acatatatac atatgtacat atatacatat 540 atagatatat atacacatat atagatatac ttatatgtat atatacatac atacatat 598 <210> 174 <211> 1048 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1048) <223> MAR of chromosome 2 genomic contig; 8332422..8333469 <400> 174 cattatatat aatatataat atattattat atataatata tataacatta tatatagtat 60 atatgacata tataacatat attatatata acatatataa aatataacat attatatata 120 acatatataa aatataacat atattatata taacatatat aaaatataac atatattata 180 tataacatgt ataaaatata acatatatta tatataacat gtataaaata taacatatat 240 tatataacat gtataaacta taacatatat tatatataaa atatattata fgitatatat 300 tataaataaa atatattata tgttatatat tataacatat tatataaata atatataata 360 tataacatat attatataaa taatatataa catataitat ataaataata tataacataa 420 catatattat ataacatata acatataaca tatattatat ataacatata acatataaca 480 tatattatat ataacatata acatataaca tatattatat ataacatata acatatatta 540 tattatatat aacatataac atatattata ttatatataa catataacat atattatatt 600 atatataaca tataacatat atiatattat atataacata taacatatat tatattatat 660 ataatatata acatatatat tatatataat atataacata taacatatat tatatataat 720

Seite 158

SEL PCT 012.8T25 ataatatata acatatatta tatataatat aatatataac atatattata tataatataa 780 tatataacat atattatata taatataata tataacatat attatatata atataatata 840 taacatatat tatatataat ataatatatia acatatatta tatataatat aatatataac 900 atatattata tataatataa tatataacat atataatata taacatatag catatataat 960 atataacata taacatatat tatatataac atataacata tattatatat aacatataac 1020 atatataata tgtaacatta tatataac 1048 <210> 175 <211> 375 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(375} <223> MAR of chromosome 2 genomic contig; 8908678..8810052 <400> 175 tatatacaca tatatacgta tgaatatata tacacatata cgtatgaata tatataccca 60 tatacgtatg aatatacaca iatatatacg tacgtatata tatacacata tatacgtacg 120 tatatatata cacatatata cgtacgtaia tatatacaca tatatacgta cgaatatata 180 tacacatata tacgtacgaa tatatataca catatatacg tacgaatata tatacacata 240 tatacgtacg aatatatata cacatatata cgtacgaata tatatacaca tatatacgta 300 cgaatatata tacacatata tacgtacgaa tatatataca catatatacg tacgaatata 360 tatacacata tatac 375 <210> 176

Seite 159

SEL PCT 012.8725 <211> 563 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(663) <223> MAR of chromosome 2 genomic contig: 10572503..10573065 <400> 176 atttataata tatatgtata aatatatgta tatatttata tttaaatata tgtatatata 60 titatattta aatatacgta tatatattia tatttaaata tacgigtata tatttatatt 120 taaatatacg tgtatatatt tatafttaaa tatacgigta tatatttata tttagatata 180 cgtgtatata titatattta aatatacgtg tatatattta tatttaaata tacgtgtata 240 tatttatatt taaatatacg tgtatatatt tatatttaaa tatacgtgta tatttatatt 300 taaatatacg tgtatattta tatttaaata tatgtatgta tttataaata tatatttaaa 360 gtatatatit ataaatgtat acatgtatat ataaatatat atattttaaa tatatatita 420 tatatatatt tatatatita tataagtata tatatattta aatatatgta tatatttata 480 tatttatata agtatatata tttaaatata tgtatatatt tataatatat attttaaata 540 tatatttata tatttattat ata 263 <210= 177 <211> 595 <212> DNA <213> Homo sapiens

Seite 160

SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(595) <223> MAR of chromosome 2 genomic contig; 11609694..11610288 <400> 177 tataaatact atatatagta tatataatat tatatatact atatataaat atatgtagta 60 taaataatat ataatataga tatataatat aatataatat gttataaata taaatatatt 120 tatataatit aatttataat atataatata taatatataa tttaatttta taatatataa 180 tatataattt aatittataa tatataatat ataatatgta aattatatat aatttaatat 240 atctaaatta tataatttaa atataaatat aatataaata tatctaacat aatatacata 300 acataaatat atatagtata tatagtacat ataaatatat atagtacata tagtatatat 360 aaatatatag tatatataaa tatagtatat ataaatatat agtatatata tagtatatat 420 aaatatatag {atatataaa tatatatagt atatataaat aatatatagt atataaataa 480 tatatatiat taaatataat aataatttat tatatatact atatattatt atgtattata 540 ttatatatat tattitatat ttaatatata ttattttata tattatattt aatat 505 <210> 178 <211> 662 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..(662) <223> MAR of chromosome 2 genomic contig; 12699804,,12700465

Seite 161

SEL PCT 012.8T25 <400> 178 gtatatatat atatatatat atggtgtata tatatatata tatatatggt gtatatatat 60 atatatatat atggtgtata tatatatata tggtgtatat atatatatgc {gtatatata 120 tatggtatat atataiggia tatatatatt tgctatatat atagcagatc tgctatatat 180 atatatttgc tatatatata gcagatcetge tatatatatt igctatatat atgetatata 240 tatgctacat atatgctata tatatgctat atatatgcta tatataiget atatatatgc 300 tatatatatg ctacatatat gctatatata tgctacatat atgctatata tatgctatat 360 atataigcta tatatatgct atatatatat gctatatata tgctatatat atatgctata 420 tatatgctat atatatatgc tatatatatg ctatatatat gctatatata tagcatatat 480 atatagctat atataigcta tatatatage Htatatatat gctatatalg ctatatatat 540 gctatatata {agctatata tatgctatat atagctatat atatgctaca tatatgctat 600 atatatgcca tatgtatgct atatatatge tatatatata tgctatatat atgctatata 660 ta 662 <210> 179 <211> 649 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(649) <223> MAR of chromosome 2 genomic contig; 12821904..12822552 <4D00> 179

Seite 162

SEL PCT 012.8725 tatgtaatat tatatatata aattatatat tatacataty taatattata tatatataaa 60 ttatatatta tacatatgta atattatata tatataaatt atatattata cataigtaat 120 attatatata tataaatiat atattataca tatgtaatat tatatatata taaattatat 180 attatacata igtattatat atataaaita tatattatac atatataata tatatataaa 240 ttatatatta tacatgtata atatatataa attatatatt atacatatat aatatatata 300 aattatatat tatacalata taatatatat aaatiatata ttatacatat ataatatata 360 taaattatat attatacata tataatatat ataaattata tattatacat atataatata 420 tataaatiat atattataca tatataatat atataaatia tatattatac atatataata 480 tatataaatt atatattata catatataat atatataaat tatatattat acatatataa 540 tatatataaa ttatatatta tacatatata atatatataa attatatatt atacatatat 600 aatatatata aattatatat tatacatata taatatatat aaattatat 649 <210> 180 <211> 3191 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(3191) <223> MAR of chromosome 2 genomic contig; 15356889..15360079 <400> 180 tacaattata tataactata aatataatat aatatatatt atctatatta catattaata 60 tataatatat attacctatt aatatataat ataatatata taatatatat tacctattaa 120 tatataatat aatatatata atatatatta cctattaata lataataaaa tatatataat 180

Seite 163

SEL PCT 012.8T25 atatattaca tattattata taatatatat tatataacat atataacata tactatatat 240 tatataacat atataattgt atatgtatta tatatattat atatacttat acataatata 300 tanataatta aatatatgtt ataaatataa caaatatata acaiatataa catatataac 360 atatatataa ttacataaaa tatataatac ataatatata ttatgcaaca tattatataa 420 tatataacat ataatgtata ttatattata tcatatataa tacataatat ataatatatg 480 atataatata atatattata tatgatataa tataatatat tatatatgtt ataatataat 540 atatattata tataggatat attataacat aftacatatg atataataaa tittatctta 600 tatataggat atattataat atatcacata tagcatatat taaaatatat tacatatagt 660 atattatata tactatatgt atatatacat atagtatatt atagtatatt atacagtata 720 tatiatatat actatatata gtagtataca gtatatatta {atatactat atatagtagt 780 atacagtata tattatacag tatatattat atacactata ttatatatta tgtataatat 840 atactatata tagtatatta tgtagtatat attaaacata atagatatat agtatatact 900 atagataata gatattatat agtatatagt atatattata tataatatat ataatatata 960 ttatatacat atatgatata tgatatatta tatataatat atataatata taatatatgt 1020 aatataatac atattatata taatatatgt aatataatat aatatataat atatgtaata 1080 taataatata tattatataa tataacatat ataaatataa taatatatat tatatgatat 1140 aacatacata aatataataa catatataat atatattata tattatattg tatatatgat 1200 atactatata ttacacatta tacattattt ataatatata attaatatat aacatatatt 1260 agataacata taattatatc tgtaacatat ataagatata attacatata taacatatat 1320 aattatatat atatttatct aattatatat gaaattatat atgacatata aaattatata 1380 ttatatatgt tatatgtatt atatattata {atgttatat atgttatata taacatatat 1440 aacatatata acacacacat ataacatata taacatatat tacatatata acatatataa 1500 cacatatata attaictaac atagataata tatataatat ataatataac atatatatta 1560 tatattatac actctattat attatatata ttatacataa tatataatat atatgatata 1620 atataataca ttgtatatac gatataatat atattgtaca tagtataata tacatatata 1680

Seite 164

SEL PCT 012.5725 gtatattatg tataacataa tatatagtat attatgtata acataatata tagtatatta 1740 \gtataacat aatatatagt atatiatgta taacataata tatagtatat tatgtataac 1800 ataatatata gtatattatg tataacataa tatatagtat attatgtata acataatata 1860 tagtatatta tgtataacat aatatatagt atattatgta taacataata tatagtatat 1920 tatgtataac ataatatata gtataliatg tataacataa tatatagiat attatgtata 1980 tataatatac atattatata gtatattatg tatatataat atacatatta tatagtatat 2040 tatgiatata taatatacat attatatagt atattatgta tatataatat acataitata 2100 tagtatatta tglatatata atatacatat tatatagtat attatgtata tataatatac 2160 atattatata gtatattatg tatatataat atacatatta tatagtatat tatgtatata 2220 taatatacat altatatagt atatiatgta tatataatat acatattata tagtatatta 2280 tgtatatata atatacatat tatatagtat attatgtata tataatatac atatiatata 2340 gtatattatg tatatataat atacatgita tgtagtatat tatgtatata taatatacat 2400 gttatgtagt atatiatgta tatataatat acatgttatg tagtatatta tgtatatata 2460 atatatataa ggtgtatata tattatgtat atataatata taaggtatat atattaigta 2520 tatataatat atataaggtg tttatataat gtatatataa tatataaggt atgtatatta 258C tgtatatata atatgtatat tatatataat atatattatt tatatacatt atgtatctat 2640 ataatatata ttatgtatat attaggtatc tatataatat atattatgta tatatattat 2700 gtatctatat aatatatata ttatgtatat atattatgia tctatataat atatatatta 2760 tatgtatatt aigtaictat ataatatata taatgtatat agatatatta tatattatgt 2820 atatatatta tgtatctatt ttatatataa tgtatataga tatacaatat atattatgta 2880 tatattatgt atctatataa tatatattat ttatatagat atatatatta tgtatatata 2940 cataatatat tacatattat gtatatatac ataatatata atatattatg tatatataca 3000 taatatataa tatatfatat attacatata ttatatataa tatattatat tatgtatata 3060 tattatgtat atataatgta tatataatat ataaagigta tatatatigt gtatatataa 312C tgtatatata ttacatatat tatgtgtata tatattatac ataatatata tactacatta 318C

Seite 165

SEL PCT 012.8725 tacataatat g 3191 <210> 181 <g11> 314 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(314) <223> MAR of chromosome 2 genomic contig; 728676..728989 <400> 181 tgtgtatata tgtatatata atatatatia tataatatgc ataigtataa aatatgtata 60 ttatatatgt atattttata tatatgtata fattatatgt ataitttata tatgtatatt 120 ttatatatat gtatatatta tatatgtata ttttatatat atgtatatat tatatgtata 180 tittatatat atgtatatat tatatatgta tatittatat atatgtatat aftatatatg 240 tatattitat atatatgtat attttatata tatgtatatc atatatatgt atatattata 300 tatatgtata tctt 314 <210> 182 <211> 423 <212> DNA <213> Homo sapiens <220> <221> misc_binding

Seite 168

SEL PCT 012.5T25 <222> (1)..(423) <223> MAR of chromosome 2 genomic contig; 737493..737915 <400> 182 ataatatata gigicittta tattatctaa tatgtaatat aatgtatttt atattatgta 60 ttitatatta tataatatat aatataatgt attttatatt atatgitata taatatatag 120 tgcattatat attatgttat attatatata ttitatitat ataaattata tattatatgt 180 tatittatat atattatata acatataata taacaatgca ttatatatta taaaatatat 240 aatacattac atatatiata taatatataa tacattacat atattatata atatataata 300 caltatcata tattacaaat attacattag tataatagta attataatat aatatattat 360 atattacata tattatatta atgtaatagt aattataata taatatatat tatattitat 420 att 423 <210> 183 <211> 724 <212> DNA <213> Homo sapiens <220> <Z221> misc_binding <222> (1)..(724) <223> MAR of chromosome 2 genomic contig; 1069556..1070279 <400> 183 tattataata tattatatac attatatigt atatatacta tatatggtat atatagtata 60 cataatataa aafgtatatt gtaatataca ttatatatat acatagtgta cattatataa 120

Seite 167

SEL PCT 012.8T25 tataatataa tgtatattat aatatacatt ataatataat agtgtactat gtatatagta 180 tatataatgt atattataat gtattatata gtataatata atataatata cattatatag 240 tattgcatta tatatgctat ataatatata atatattatg tatatataca ttatatatac 300 tatattatat agtacatata atgtatatta tatagtatat ataatataat acattataca 360 tacaatatat aatgtatatt atatagtatg tataatgtaa tacattatac atagtacata 420 aagiatatta taatatatta taatatataa tatacattat atattataat gtatataata 480 tattgtatat atactatata taatgtatat acaattatat ataattgtat atatacatgt 540 atatgtatat gtatatatac atgtatatgt atgtgtatat atacatatat gtatatgtat 600 gtgtatatat gtatatgtat atatgtatat gtatacgtat atatgtatat acaatgtata 660 tataatgtat ataaaaatat ataatatata caatatgtat ataatgtata taattatata 720 atat 724 <210> 184 <211> 383 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(383) <223> MAR of chromosome 2 genomic contig; 2719818..2720300 <400> 184 gtatttatat titatatatt atitatatat agatatatat ttatatitta tatattatit 60 atatataaat atatatttat attttatata ttatftatat ataaatatat atttatattt 120 tatatatiat ttatatataa atatatattt atatittata tattatttat atataaatat 180

Seite 168

SEL PCT 012.8725 atatttatat tttatatatt atttatatat aaatatatat ttatattita tatattattt 240 atatataaat atatatitat aftttatata ttatatattt atatattata tatatttata 300 ttaattigty tataatatat attattaaat ataataaata tafttatit! tatatattat 360 ataaaaatat ataatatata aaa 383 <210> 185 <214> 309 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{309) <223> MAR of chromosome 2 genomic contig; 4994249, 4994557 <400> 185 tataatatat aattgttata acattataac aattatatat tatatataat acaattatat 60 aatatatatt atataattgt aatatataat ataattatat aatatatatt atataatata 120 atatataata tatcatatat gttatatatt tiattatata atatatatta tatataatat 180 tatatataat atatattata tataatatta tatataatat atattatata taatatattt 240 atatatatta tatataatat atattatata ttaaatatta tatatataat atatataaca 300 ttattgtta 309 <210> 186 <211> 740 <212> DNA <213> Homo sapiens

Seite 169

SEL PCT 012.8T25 <220> <221> misc_binding <222> (1)..(740) <223> MAR of chromosome 2 genomic contig; 5034916..5035655 <400> 186 tttatatata aaatattata tataatatta tatataatat ttictatata aaatgtgtat 860 ataattatat ataattatat aaaatataat atagaatatc taataatgta taatatataa 120 catataaaaa taatattatt taatatataa tattttatat ataatattt! tatatataat 180 ataatatata tttatatat a attattaat tatataatta atatataata tatatittat 240 acataattat taattatata taattaatat ataatatatc ttatacataa ttatcaatta 300 tatataatta atatataata tatattttat acataattat taattatata taattaatat 360 ataatatatc ttatacataa tatatataaa tatattatat ataatatata ttatatataa 420 tattatatat aatatatatt atatatataa aatttatata taatattata tataatatta 480 tatattttat atacaatatg atatataata taatttatat attatatata tttatatata 540 attattatat aaaitatata aatataaatt atatatttat atataattat tatataaatc 600 atiatataat tattataatt ataatatata atataatata atattatata taatatatag 660 tatictatat aaataatata acatatatit tatatagaat attatatata atataatata 720 tatittatat agaatattat 740 <210> 187 <211> 847 <212> DNA <213> Homo sapiens

Seite 170

SEL PCT 012.8725 <220> <221> misc binding <222> (1)..(847) <223> MAR of chromosome 2 genomic contig; 6074678..6075524 <400> 187 aatatagaca taaatatata tgcataaata tatatatgca taaatatata taaaaatata 60 tataaatata tacataaata tatataaata tatacaaaaa tatatataaa tatataaaaa 120 aatatataaa tatatataca catatataaa tatatataca tacatatata aacatatata 180 cataaatata tatgtataaa tatatataca cataaatata tgtatgaata tatatacata 240 aatatatatg tataaatata tatacataaa tatataaaga tatatacata aatatatata 300 aatatatata cataaatata tataaatata tataaataga tatataaata tatatataaa 360 t{atataaata tatatataaa tatataaata tataaaaata gatatataaa tatatatata 420 : aaiatataaa tatatatata aatatatata aatataiaaa tatatatata aatatatata 480 aatatataaa tatatataaa tatataaata tatatataaa tatatataaa tatataaata 540 tatataaata tatataaata tataaatata tatataaata tatataaata tataaatata 600 tatataaata tataaatata taaatatata tataaatata taaatatata taaatatata 660 taaatatata aatatatata aatatatata aatatataaa tatatataaa tatatataaa 720 tatatataaa tatataaata tatataaata tatataaata tatataaata tatataaata 780 tataaatata tatataaata taaatatata taaatatata aatatatata taaatatata 840 taaatat 847 <210> 188 <211> 784 <212> DNA <213> Homo sapiens

Seite 171

SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(784) <223> MAR of chromosome 2 genomic contig; 6108986..6109769 <400> 188 atttatitat atalttaata tataaaatat atatttaata tataaaatgt atatatatac 60 tatatiata tataatacaa tatatattat atataatata tattatatat aatattatat 120 attatattat aatataatat atattatata taatataata tatattatat attattatat 180 ataatataat atatattata tattattata tataatataa tatatattat atattattat 240 atataatata atatatatta tatattatta tatataatat aatatatatt atatatatat 300 tttatatata taatatataa fatatatati atatatatat ittatatata taatatataa 360 tatatataft atatatatat titatatata taatatataa tatatatatt atatatatat 420 tttatatgta taatatataa tatatatatt atatatatat tatatatata taatatgtaa 480 tatatatait atatatatat tatatatata atatatatta tacataaaat atatattata 540 tataatatat ataatatata ttatatataa a atafatttt atgtataata tatattatat 600 ataatatata atgtatattt atatataaaa tatatatita tatacaatgt atatttatat 660 ataaaatata tatttatata caatgtatat ttatataaat aigigtttaa tatatgaaat 720 atatatttat atataatata tatttaatct ataaaatata tatiaaatat atatitatat 780 ttaa 784 <210> 189 <211> 381 <212> DNA <213> Homo sapiens

Seite 172

SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(381) <223> MAR of chromosome 2 genomic contig; 10389032..10389412 <400> 189 tatacacata tagagtatat agagtatata tagagtatat ctatagagta tatatgtata 60 : tagagtatat aatacagcct accatatata tagtatacat atatatatac tctatatact 120 atatatatag tgtgtatata tatagtatag accctaccat atatatatat aggagtatat 180 atatatacac acicctacta tatatagtat gtatatagag agtatataga gtatatatac 240 agtatatata cacagtatat atatgccata tatagtatct atatactiat atatagtatg 300 tatctatata cttatatata gtatgtatct atatactata tatagtatgt aictatatac 360 tatatagagt atatatgtat a 381 <210> 190 <211> 507 <212> DNA <213> Homo sapiens <220> <221> misc_difference <222> (1)..(507} <223> MAR of chromosome 2 genomic contig; 11097807..11098313 <400> 190

Seite 173

SEL PCT 012.8725 aaftatatat aatttattat atataafttt atattiataa tattittata tacatatttt 60 atatatcttt ataattatat attacatata taatattata taatatatat aatatatata 120 atatatatta tatattatat aatatatatt atatatafta tatataatat atataatata 180 tataatatat ataatatata taatatataa tatatattat ataatatata ttatatataa 240 tatatattat atataatata tattatatat aatatataat atatataata tatataacat 300 ataataatat attatacata atttatatat aaittttata taattatata tatttatata 360 tititatata attatatata tttatatatt titatataat tatatatatt tatatatitt 420 tatataatta tatatataat ttitatataa atatatataa tittatataa tittatataa 480 ttataaaata tataattata tataatt 307 <210> 191 <21t> 329 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(329) <223> MAR of chromosome 2 genomic contig; 11234628..11234956 <400> 191 ttatagttaa atatataaat ataaaatata cagttttata cagtatatat aaaatataca 60 atatataata cataatacat tagttatata tactatatat actatatata ctacacgtat 120 agtatatata tgaaactata tatatactat acgtgtagta tatatatgaa actatatata 180 tactatacgt glagtatata tatgaaacta tatactatac gtatagtata tatatgaaac 240 tatatatact atatatactt aactataatt gtatatagtt aaaaatataa atataaaata 300

Seite 174

SEL PCT 012.8T25 tacagttaaa tatattaata tataatagt 329 <210> 192 <211> 584 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(584) <223> MAR of chromosome 2 genomic contig, 797844 ..798427 <400> 192 tattaittta igitataaat agataaaaat atatactaat atatatgtac ttatatatac GO atcaatatat aatgtattat tttatactaa cgtatattat atatactagt atataatcta 120 tattalttta tatgttataa atatataata aaatatataa atattitatg catataitaa 180 tatataatat atactaacat gctaatitat atatacttat atataattta tatagtatat 240 aatatataaa tgtatataat acataattta tatatitata tattaatagt ttatatatta 300 gtatatatac taatittata tactaataaa taaattatat aatatataaa ttatatatta 360 tagtacataa tatatattat atagttaaat aactatgtaa ctataatata taactatata 420 tgatatacag tlatatataa tataaatttt acatacagta tataaattat atactataca 480 titatataca tatggtatat aaattatata ctatacatit atatacatat ggtatataaa 540 ttgtatacta tataatgtgt attagtatat atactaatat atac 584 <210> 193 <211> 363 <212> DNA

Seite 175

SEL PCT 012.8T25 <213> Homo sapiens <220> <221> misc_binding <222> (1)..(363) <223> MAR of chromosome 2 genomic contig; 1093824,.1094 186 <400> 193 tatacacaca catatatata cacatatata tacacatata tatatacaca tatatataca 60 catatatata cacgtatata tgtatacaca tatatalgla tatatataca catatataca 120 cacatatata cgigtatata cgtatatacg tacatatata cgtgtatata cgtatatigcg 180 tacatatata cgigtatata cgtatatgcg tacatatata cgtatatata cgtatatgcg 240 tacatatata cgtgtatata cgtatatgcg tacatatata cgtgtatata cgtatatgeg 300 tacatatata cgtgtalata cgtatatgcg tacatatata cgtgtatata cotatatocg 360 tac 363 <210> 194 <211> 545 <212> DNA 13> Homo sapiens <220> <221> misc_binding <222> (1)..(545) <223> MAR of chromosome 2 genomic contig; 3456187..3456731

Seite 176

SEL PCT 012.8725 <400> 194 tattataata tatatttata tattataata tatattatat tatatatiia tatattataa 60 tatatattat attatatatt tatatattat aatatatatt atattataat atatatttat 120 attataatat aitatattat aatatatatt atattattat atattataat ataatatata 180 itataatata tattatatia taattiatat attatatata ttataatata tattatatta 240 tatatatatt tatattataa tatatattat tatatattat atattataat ttatattata 300 ttacaatata tattataaat atatataita tattataaat atatatttit atattacaat 360 atatattata aatatatatt ttatattaca atatatatta taaatatata tattatatta 420 caatatatat tataaatata tattatatta caatatatat tatattataa tatatattta 480 tatatgatat attatattia atatattata taacataata tataatatat aatatattaa 540 tataa 545 <210> 195 <211> 356 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1}..(356) <223> MAR of chromosome 2 genomic contig, 5001567..5001922 <400> 195 tataaaatat atgttatata {ataatatat atiatataat atatastata tataatatat 60 aaaatatata aaatatataa tatataatat aatatataat atatataata tataaaatat 120 atataatata aaatatatat aatatataat atatataata tataatacat ataatatata 180

Seite 177

SEL PCT 012.8725 atatataata tataatatat ataatatata atatataata tataatatat ataatatata 240 atatataata tatataatat ataatatata alatataata tataaatata taaatatata 300 tacacacata cacacacata tatgcatata tatacatata catgtgtaca tagata 356 <210> 196 <211> 321 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> {1)..(321) <223> MAR of chromosome 2 genomic contig; 5457 330..5457650 <400> 196 tatacaatat attataaatt atatataatt tatatataat atatattata tataaattat 60 atataattta tataatatat aaattatata taatataaat tatatataat ttatataata 120 tataaattat atattatata aattaaatat aattiatatt atatataaat tatatttaat 180 ttatataata tataaattat atttaattta tatataatat aaattatatt tttatatatt 240 atgtataatt tatatattta tacatatata cattataata taftgtatag tatatataat 300 atatagtata tataaagcat a 321 <210> 197 <211> 361 <212> DNA <213> Homg sapiens

Seite 178

SEL PCT 012.8725

<220>

<221> misc_binding <222> (1)..(381) <223> MAR of chromosome 2 genomic contig; 8124469..8124829 <400> 197 tatatataat atatattata tatattatat aaattatata taatatgtaa tataaafttit 60 gtaatataaa ttatatatat aaattatata taatatatat taatatatat aatataaatt 120 aatatatata atatataatt atatataatt {ataigatat atataaatat atattatata 180 taaattatat atatcataaa ttatatatca tataaattat atataatata cattatgtac 240 ataatatatg atatataata tataatatat attatatata attatatata tataattata 300 taatatatat aaattataat atataatata tataaattat aatatataat atatataaat 360 t 361 <210> 198 <21 1> 418 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(418) <223> MAR of chromosome 2 genomic contig; 11151485..11151902 <400> 198 atgtaactat atatatagta tatatagtat atatatacta tatagigigt atatatagta 60

. Seite 179

SEL PCT 012.8725 tatatatact atatagtgtg tatatatagt atatatatag tgtatatatc gtatatacac 120 tatatactat atagtgtata tatagtatat gtagtatata tagtatatat agtatagtat 180 atatagtata tatagtgtat atatactgta tatatagigt acatagtata ctatatagia 240 tacatatagt acactgtata gtatatatag tatagtatat atagtataca fagtatacta 300 tatatagtat agtatacata gtatactata tagiatatag agtatatata cagtatacta 360 tatagtatat agagtatata tacagtatac tatatcgtgt gtatagagta tatataca 418 <210> 199 <211> 394 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..{394) <223> MAR of chromosome 2 genomic contig; 13591477..13591870 <400> 199 ttatatatat titatatata ttatatataf tttatatata tiatatatat attatatata 60 tattatatat aattatatat aatatatatt atatatatta tatataatta tatataatat 120 atattatata tattatatat ataatatata tataatatat atatttiata tatgtattat 180 atataittta tatatattat atatattata tatatattit atatatatta tattttatat 240 atataatata acatatataa tatataatia tatattatat atatattata ttatatataa 300 tatatattat atataatata atatataatt atatatatta tatattitat atatttatat 380 aaaaattatt ttatattatt ttatatataa atat 394 <210> 200

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SEL PCT 012.8725 <211> 1194 <212> DNA <213> Homo sapiens <220> <221> misc_bkinding <222> {1)..(1194) <223> MAR of chromosome 2 genomic contig; 14996824..14998017 <400> 200 taatatttat atatacatat aaaatttata tataatatat aatatttata tatacatata 60 aaatitatat atatatataa tatttatata tacatataaa alftatatat aatatataat 120 atttatatat acatataaaa tttatatata atatataata {ttatatata catataaaat 180 ttatatataa taaatattta tatatacata taaaatttat atataattta tatataacat 240 ataatattta tatataaaat ttatatataa catatattta tatataatit atatataaca 300 tataataltt atatataata tatatttatt tatacaatit atatataata tataatactt 360 atatatacat acataattta tatgatatat attatatata taatitatat gatatataat 420 ataictaata tatattatat atattatata tattatatat aatttatata atatatatta 480 tatatataat ttatataata tatatattat atatataatt tatataatat atatattata 540 tatataattt atataatata tattatatat ataatttata taatatatat tatatatata 800 atttatataa tatatattat atataattia tatataacat atittatata catatataat 660 ftatatataa tatatattta catatacata tataatttit atataatata aaatatitct 720 atatacatat ataatttita tataatataa aatatticta tatacatata taatttttat 780 ataatatata {tictatata catgictaat ttttatataa tatatattic tatatacata 840 tataattttt atataatala taatattttt atatacataa tttttatata atatatattt 900

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SEL PCT 012.8725 acatatacat atataatttt tatataatat atatttatat atacatatat aatitttaca 960 taatatatat tatatataca tatataattt atatacaaca tataatatat acatatataa 1020 tttatataca acatataata tttatgtata catatataat gtatacacaa tatataatat 1080 ttatatatac atatataatt tatatgtaat atatacatat ataatttata tgtaatatat 1140 atacatgtat aattiatatg tagtatatat acatgtataa tttatatgta gtat 1194 <210> 201 <211> 487 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(487) <223> MAR of chromosome 2 genomic contig; 14998429..14998915 <400> 201 tagtatacat ttacacatac atgtataait atatgtaata tataatattt acatatataa 60 ttatagataa tatatatita catatacata tataattata tataatatat aatgtttaca 120 tatacataca taattatata taatatatat ttaaatatac atatacaatt atatataata 180 tatatitaca tatgcatata taattataga taatatatat ttacatatac atatataatt 240 atatataata tataatgttt acatatacat atataatiat atataatata tatttaaata 300 tacatataca altatatata atatatatit acatatgcat atataattat agataatata 360 tatttacata tacatatata attatatata atatataata tttacatata catatataat 420 gtatatataa tatataatat ttacatatac atatataatt tatatataat atatattata 480 tatatta 487

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SEL PCT 012.8725 <210> 202 : <211> 421 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(421) <223> MAR of chromosome 2 genomic contig; 16562490..16562910 <400> 202 tatatgaata tatatatgaa tatatacgta tatatgaata tatacatgta tgtatatatg 60 aatatatgta tatatatgaa tatatatgta tatatgaata tatatatata tatgaatata 120 tatgtatata tgtatatata tgaatatata tgtatataty tatatataig aatatatatg 180 tatatatgta tatatgtata tatatgaata tatatgtata tatgaatata tatgaatata 240 tatgtatata tatgaatata tatgaatata tgigtatata tatgaatata fatgtatata 300 tatgaatata tglatatata tatgaatata tatgtatata tgtatatalg aatatatatg 360 tgtatatgaa tatatatatg aatatatatg tgtatatgaa tatatatgaa tatatatgty 420 t 421 <210> 203 <211> 479 <212> DNA <213> Homo sapiens <220>

Seite 183

SEL PCT 012.8725 <221> misc_binding <222> (1)..(479) <223> MAR of chromecsome 2 genomic contig; 21582301..21592779 <400> 203 tatatgtata cgtatataat atattatata ttatatacgt gtacgtatat atgtaatata 60 taatgtatat gtacacgtat ataatatata atatattata tacgtatacg tatacattat 120 atattacata tatacgtata tacgtatata aaafatatgt atatattata tatacgtata 180 taatatatat fatataatat ataatatata cgtatacata taatatatta tatatacata 240 ttatatatta tatatttaaa ttatatatta tatcatatat aatatatatg atataatata 300 taatatacat atattacata atatatatta tatacatata catatataat atataatata 360 itatatacat atacatatat aatatataat atattatata catatacata tataatatat 420 aatatattat atacatatac atatataata tataatatat tatatataca tattatata 479 <210> 204 <211> 870 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(870) <223> MAR of chromosome 2 genomic contig; 22557584..22558453 <400> 204 tataatatat aatatacata atatgtatat iftatacaca atataaataa tatacataac 60

Seite 184

: | SEL PCT 012.8T25 atatatgtat attttatata tgtatatttt atatatatit {atataittt atatatatgt 120 ataitttata tataatatat atattgtata taataatata taatatatta tattatatat 180 aatatatata atatalatat aaatatatat tatatataat atgtataata tataaiattt 240 tatatataat atgtataata tatattitat atataataat atgtacaata tataitttat 300 atataataat atglacaata tatattiiat atataataat atgtacaata tatattitat 360 glataatatg tataatatat attftatgta faatatatat titatgtata atatatattt 420 tacgtatatt itatatataa tatataatat tttatatata atatataaca itttatatat 480 aatatataat attatatata ttatatatit tatatataat atatataaat atatatattt 540 tatatataat atattttata tataatatat ataaatatat atattatata taatatattt 600 tatatataat atattttata tataatatat aatatatttt atatattata tataatatat 660 tatatattat atataatata ttatatataa tatataatat ataatatatt atatataata 720 tataatatat aatatatiat atataatata taatatataa tatataatat attatatata 780 atatataata tgtaatatat aatatttiat atataatata taatataata tataatattt 840 tatatataat atataatata taatatataa 870 <210> 205 <211> 10886 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1086) <223> MAR of chromosome 2 genomic contig; 30591960..30593045 <400> 205

Seite 185

SEL PCT 012.8T25 gtatatataa tatatattat attatgttat atattatgta gactatgtat taaatatatg 60 tatatattat atataaatat ataatatata titataattt ataattataa atatatttat 120 aatatatttt tclaaatatt tatatattat atattatatc taatgatata taataaatat 180 atttctaata tatittatat ttataaatat titatatata ttatatattt tatatatact 240 atatattata taitatatat tttatatata ctatatatta tatagtatat atittatata 300 tactatatat tatatattat atattttata tatactatat attatatatt atatatttta 360 tatatactat atactattta ttatatattt tatatatact atatactait tattatatat 420 tttatatata ctatatacta tttattatat atttiatata tactatatat tatatattat 480 atattttata tataatatat atttattata tattitatat attatatata ttatatatta 540 tatatttata tattatataa tatatattat atatagaata tataatatat attatatata 600 atataatata atatatatta tataaaatat atataatata taaaatatat aatatatgat 660 atatataata tatattctat atttatacat atatatttaa tattatatta atatataatt 720 atatattatc atatgtaata atagatataa tatgtaatat ataaattata attatatatt 780 aaftattatat attatttaat atgtatattt acacatatat taattattaa atatatatat 840 ttaatatatt aaatattatg tattaaatat atataatata tttataaata ttttatatat 900 aatatataca tatattaaca tataigtata {aigtatata ttatatataa cattatatat 960 attatgtiac atatactata ttttatatgt tacatatact atatattata tgttacatat 1020 aatatatata acatatatta taatatgtaa catattatat ataacatata atatatagta 1080 tatata 1086 <210> 208 <211> 406 <212> DNA <213> Homo sapiens <220>

Seite 186

SEL PCT 012.8725 <221> misc_binding <222> {1)..(406) <223> MAR of chromosome 2 genomic contig; 36233909..36234314 <400> 206 attataaata tatattatag atattagata ttatagatat aatatatata atatatatta 60 tagatattat agatatagat ataatagata ttatagatat tatagatata atatatatta 120 tagatattat agatataata tatattatag ataitataga tataatatat attatagata 180 ttatagatat aatatatatt atagatataa tatatattat agatattata gatatagata 240 ttatagatat tatatatatt atagatataa tatatatiat agatattata gatatagata 300 ttatagatat aatatatatt atagatatta tagatataat atatattata gatattatag 360 atataatata tattatagat ataagatata ttatagatat tacaga 406 <210> 207 <211> 797 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(797) <223> MAR of chromosome 2 genomic contig; 36271745..36272541 : <400> 207 atataaacat atacgiatat acacatatat acaaatacat atatacatat attatatata 60 totatatata ttatatiata catatattat atatatatia tattatacat atatacatac 120

Seite 187

SEL PCT 012.8725 acacataaac atattacata catatacaaa ttatacacat atacatatat acatatatgt 180 atatacatac attatatata aatatatgta tataaaatgt acattatata tacatatata 240 ttatgtataa ataatatata aaataaacat aatatatatt tatagatatg atatatataa 300 tatatatgta tacatatata catatatgta t{atataatgt acattataca tacataaaca 360 : tcatatataa atgtitatata tataatataa atatatataa tatataatat atactttata 420 tactatatat aatatatata atatgatata acatatacta tatataciat atataatata 480 tactatatat actgtatata atatataata taatatatac tatatatact aaatataata 540 facataatat aatatatact atatataata tataatatat aatatagtat atatactata 600 tataataatt acatattata tattatacat tatatattat ataattatta tatataatta 660 tatattacat acttigtata taatgtaaat atacattaga atatataatg tatatatatg 720 tacatatata atgtatatat gtatacatta tataaactat atataaacat tatattatat 780 aaacattata tataaac 797 <210> 208 <211> 423 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(423) <223> MAR of chromosome 2 genomic contig, 36498521..36498943 : <400> 208 taitatatta tatatttaat attatatatt taatatatta tatatttaat attatatatt 60 taatatatta tatatttaat attatatatt taatatatta tatatttaat attatatata 120

Seite 188

SEL PCT 012.8725 taatatatta tatatttaat attatatata taatattata tatataatat tatatattta 180 atattatata tataatatta tatatataat atattatata tttagtatta tgtatttaat 240 afattatata tttagtatia tgtatitaat atattattta tttagtatta tatatttaat 300 atattattta tttagtatta tatatttaat atattatata tttaatatat tatatattta 360 ttatatattg tatatitaat atattatata tttattatat attatatata attatatatt 420 taa 423 <210> 209 2115 304 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1}..(304) <223> MAR of chromosome 2 genomic contig; 37179891..37180194 <400> 209 gigtatatat atcatatata ttatatcata tatatgigta tatatatcat atattatatc 60 atatatatgt gtatatatat catatatata tcatataigt gtatatatca tatatattat 120 atatcatata igtgtatata tatcatatat tatatatcat atatatgtgt afatatcata 180 tatattatat atatctcata tgtgtatata tatcatatat aatatatatg igtatatatc 240 atatatcata tataacatat atatgigtat atatcatata tataacatat atcatatatg 300 tgta 304 <210> 210 <211> 693

Seite 189 :

SEL PCT 012.8725 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(693) <223> MAR of chromosome 2 genomic contig, 38440448..38441140 <400> 210 tatatattct tttatatatt atatataata tatattcttt tatatattat atatagtata 60 faticttita tatattatat atagtatata ttctittata tattatatat agtatatatt 120 citttatata ttatatatag tatatattct titatatait atatatagta tatattcttt 180 tatatattat atatagtata tattctttta tatattatat atataatata tattctttta 240 tatatcatat ataatatata ticttttata tattatatat aatatatatt cttttatata 300 ttatatatca tgtatatata atatacaaaa tatatataga tittatatat agattattac 360 ataatagaat atattatata {tatatataa tatatacata atatataata ttatatatga 420 tataatatat atcatatata tcatataata tatattatat atcatatatt atatataata 480 atatatagat tatatataat tatatatata atatatataa ttatatatat tatctatata 540 tagataatat atafaattat atataatata ttatatagat tatatataat tatattatat 8600 acaaaatcta tatataatat atattatatt atatataata tacataacta tatacaaaat 660 ataatatata atatatataa tatataatat ata 693 <210> 211 <211> 471 <212> DNA <213> Homo sapiens

Seite 190

SEL PCT 012.5725 <220> <221> misc_binding <222> (1)..(471) <223> MAR of chromosome 2 genomic contig; 38887582..38888052 <400> 211 aacatatata ctatatatat tatatactat attatatatt atatatataa acatatatac 60 taatataat atataaacat attatattat acatgatata gataaacata tatattatat 120 ataatataga taaaatatgt tatatataat ataatgtata gacatatait atatatacat 180 atatictaca tatattatat atatattcta cacatattat attatatata catatattct 240 acatatatta tatatacata tatictacat atattatata tacatatatt ctacatatac 300 atatatacat atattatata tacatatatt atagatatat aatatataaa catatataat 360 attattatat ataatatata taataatatt atataatata taataataft atatcttata 420 tataaataat atatatattt tatatatata atattatata tatataatat a 471 <210> 212 <211> 1221 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1221) <223> MAR of chromosome 2 genomic contig; 43885944, 43887164

Seite 191

SELPCT 012.8T25 <400> 212 catataaaca tatattatat gtaacatata aacatattat atgtaacata taatatataa 60 tatataaaca {atattttat atattatatg ttacatataa tatataatat ataaacatat 120 attatatatt atatgtaaca tataatatat aatatataaa catatattit atatataata 180 tataaacata tittatatat aatatataaa cafatittat atataatata taaacatata 240 ttttatatat aatatataaa catattttat atataatata taaacatata ttttatataa 300 tatataaaca tataatatat ataatatata aaagtatata atataaatat atataatata 360 aacatatata atataaatat atataaaata taaacatatg taatatataa acatatatta 420 tatataatat ataaacatat attatacgta caatatataa acatatattg tacgtacaat 480 atataaacat ataitatacg tacaatatat aaacatatat tatacgtaca atatataaac 540 atatattata cgtacaatat ataaacatat attatacgta caatatataa acatatatta 600 tacgtacaat atataaacat atattatacg tacaatatat aaacatatat tatacgtaca 660 atatataaac atatattata cgtacaatat ataaacatat attatacgta caataaacat 720 atattatacg tacaatatat aaacatatat tatacgtaca atatataaac atatattata 780 cgtacaatat ataaacatat atigtacgta caatatataa acatatatta tatgtataat 840 atataaacat ataatatata atatatatta {atataigtt tattatatat gtttatatat 900 tatatataac atatattatt atattatata tgtttatata tiatatatta tataatatat 960 atgtitatat attatatait atataatata tatgtttata tattatatat tatataatat 1020 atatgtitat ataltatata ttatataata tatatgttta tatattatat attatataat 1080 atatatgitt atatattata tattatataa tatatatgtt tatatattat atattatata 1140 atatatatgt {tatatatta tatattatat aatatatatg tttatatati atataaataa 1200 : taaacttaca tattttatta a 1221 <210> 213 <211> 543 <212> DNA

Seite 192

SEL PCT 012.8T25 <213> Homo sapiens <220> <221> misc_binding <222> (1)..(543) <223> MAR of chromosome 2 genomic contig; 45818200..45818742 <400> 213 tatgtatata tacatatata titatacalg tatatatgta tatatacata tatatttata 60 catgtatata tatacatata tatttataca tgtatatata tacatatata tttatacatg 120 tatatatata catatatatt tatacatgta tgtatatata catatatatt tatacatgta 180 totatatata catatatatt tatacatgta igtatatata catatatatt tatacaigta 240 totatatata catatatatt tatacatgta tgtatatata catatatatt tatacatgta 300 tgtatatata catatatatt tatacatgta tgtatatata catatatatt tatacatgta 360 tgtatatata catatatatt tatacatgta igtatatata catatatatt tatacatgta 420 tgtatatata catgtatatt tatacatgia tgtatatata catgtatatt tatacatgta 480 igtatatata catgtatatt tatacatgta tgtatatata catgtatatt tatacatgta 540 tac - 543 <210> 214 <211> 463 <212> DNA <213> Homo sapiens <220> <221> misc_binding : Seite 193

SEL PCT 012.8725 <222> (1)..(463) <223> MAR of chromosome 2 genomic contig; 47055478..47055940 <400> 214 atacatacat atatacatat atacacatat atacatataa tacacacata tttacatata 60 tacacacata tatacatata tacatatata cacatatata catgcataca catatataca 120 tatatacaca catatacaca catatataca tatatacaca tatatacaca tatacacata 180 tatacacaca tatacatata tacacatata tacatatata catatataca cacatataca 240 catatataca tatacacata tatacacata tacatatata cacatatata cacatatata 300 catatataca catatataca tatatacaca tatatacaca catatacaca tatatacata 360 tatacatatg tatacacata tatacatatg tatacacata tatacacata tacatatata 420 catacacata tatacgtata tatgtgtata tatacacata tac 463 <210> 215 <211> 2482 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(2482) <223> MAR of chromosome 2 genomic contig; 47492698..47495177 <400> 215 aatatatata aaatatatia tattctatgt aatatataga atatataaaa tatattctat 60 atattatata gaatatatat tttataatat afattatita tatatitita tatatttata 120

Seite 194

SEL PCT 012.8725 ttatttatat atttatatat aatttatata atttatacat ataatttata tataatttat 180 ataaattata tatataattt atatataatt tatatataat ttatataaat tatatatata 240 atttatatat aatttatatg atttttatat ataatttata tataatttat ataattttta 300 tatataaltt atatataatf tatataattt ftatatataa titatataat atatatatat 360 aatttatata taatitatat aatttatata tataatitat atataattta tataatttat 420 atatataatt tatatataat ttatataatt tatatatata atttatatat aatttatata 480 atttatatat ataatitata cataatttat ataatttata tatataattt atataattta 540 tatatataat ttatatatat aatttatata atitatatat atgatttata taaittatat 600 atataatita tataattiat atatataaat tatatatata atitttatat aatttatata 660 tttataattt atatatitat ataatitata tatttataat ttatatatit atataattta 720 tatatttata atitatatat itatataatt tatatataat tattcatata tttatataat 780 ttacatataa ttatitatat aticatatat aatttatata titatatata atitatatat 840 aattatttac atatttatat atttatatat aatitatata {atttatata taatttataa 900 ataaaatata taatatataa tatataatat tataatagat aaaatatata ctatatatta $60 tatattttac attatattta atatiatatg tataatttta tatcatatat aatatatatg 1020 atatatataa tittatatca fatataatat atatggtata tataatttta tatcatatat 1080 aatatatatg gtatatataa itttatatca tatataatat atgatatata attttatatc 1140 atataatata tattatatat aatittatat ctacatatta tatattatat atacaatittt 1200 atatctatct ataatatata tiatatatac aattitatat ctatataata tatattatat 1260 atactittat attatatata aaatgtatat tatatatact tttatattat atataaaatg 1320 tatat{atat ataaitttat tttatatata aaaigtatat tatatataat titattttat 1380 atataaaatg tatattatat ataattitat tttatatata aaatgtatat tatatataat 1440 titatittat atataaaatg tatattatat ataatittat tttatataaa aaatgtatat 1500 tatatataat titatattat atataatatg tatattatat ataattttat attatatata 1560 ataigtatat tatatataat tttatattat atataatatg tatattatat ataattttat 1620

Seite 185

SEL PCT 012.8725 attatatata atatgtatat tatatataat titgtattat atataatatg {atattatat 1680 ataattttat attatatata atatgtatat tatatataat titatatiat atataatatg 1740 tatattatat ataatittat attatatata atafgtatat {atatataat tttatattat 1800 : atataatatg tatattatat ataattitat attatatata aaatgtatat tatatataat 1860 ttiatattat atataatatg {atattatat ataattttat attatatata atatgtatat 1920 tatafataat {{atattat atataaaatg tatattatat ataattitat attatatata 1980 aaatgtatat tatatatatt atatataaaa tgtatattat atatattata tataaaatgt 2040 atattatata tatfatatat aaaatgtata ttatatatat tatatataaa atgtatatta 2100 tgtatattat atataatgta tattatgtat atiatatata atgtatatta tatataatat 2160 atattatata taaigtatat tatataatat atattatata ttataatata taatatacat 2220 tatatattac atattatata taatatatta tatattatat attacatatt atatataata 2280 tattatatat tatattaaat atatatitta tatattatat attatatatt atataaaata 2340 tatatattat atattatata aaatatatat afatiatatt atatattata ttaaatatat 2400 attitatata taatatatat aatatataat atataaaata tatattatat attatatata 2460 aattatatat attatatata aa 2482 <210> 216 <211> 539 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(539) <223> MAR of chromosome 2 genomic contig; 47561069..47561607

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SEL PCT 012.8T25 <400> 216 = aacagtaata tatcactaat atataataat ataiaacagt aatatatcat taatatataa 60 tatatcatta gtatataata ttaatatata ttaatatata atatatcata tacaatatta 120 : atatataita atatataata atatattatt aatgtataat agtaatataa tatattatca 180 atatatatta ctaatatata ataatatatc gitaatatat aatagatcat taatatataa 240 : tgttaatata ttatgaatag ataatatatc agtatataat attaatatat taatatatta 300 tatattattt aataatatat aatatattaa taaataatta tatattaata tagecaatata 360 ttaatataty actgtattat attattaata tataacaata tatiatatat tatataataa 420 titattatat aatatataat aatatattat atattatata acatattaat aatacataat 480 aacattaata atatataata atgttaatat attattatat tatatatiaa tatataata 539 <210> 217 <211> 336 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(336) <223> MAR of chromosome 2 genomic contig; 52853648..52853983 <400> 217 tatatacata aaatatatat attitatata tatacataat atatatatgt atattttaty 60 tatatatcta taatatatat aatataataa aatatacata tatatittat atatatataa 120 tatacatata aaatatacat acataaaata tacatgtata tiftatgtat atataatata 180 tatataaaat atacatgtat attttatata tataatatac atgtataatt aatatacatg 240

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SEL PCT 012.8725 tatgttatat atattacatg tatattalat ataatataca tataaatitt aaatftagty 300 tatattacat gtatattata tataatatat gtatat 336 <210> 218 <211> 406 <212> DNA <213> Homo sapiens <220> <221> misc _binding <222> (1)..(406) <223> MAR of chromosome 2 genomic contig; 54866263..54866668 <400> 218 tacgtatata aaaatgtata ittacatata taaaataaat atittatata cgtatataaa 60 atatatattt attttatata cgtatataaa atatttattt tatatatgta tataaaatat 120 ttattitata tacatgtata ttaaatatat atttatatat gtatataaaa atatatatta 180 tatacatgta tataaaatat atattatata tgtatataaa aatatatatg tatataaaat 240 atatatatta tatagatata taaaatatat attatataga tatatazaat atatatatta 300 tatagatata taaaatatat atatlatata gatatataaa atatatatat tatatagata 360 tataaaatat atatattata tagatatata aaatatatat attata 406 «210> 219 <211> 1452 <212> DNA : <213> Homo sapiens

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SEL PCT 012.8T25 <220> <221> misc_binding <222> (1)..(1452) <223> MAR of chromosome 2 genomic contig; 55113305..55114758 <400> 219 ataatatata atatatattg tatattatat {attatatat tatatattat taaatatata 60 tattatatta tatattatat aatatatatt atatataata atatagaata tataattata 120 tattatatta tatattatat aatatatatt atataiaata atatagaata tataattata 180 tattatacta tatatiatat aatatatatt atatataata atatagaata tataattata 240 tattatataa tatgtgaata atgtaatata taattatatt atttacatat tatataatat 300 ataatiatat tatataatat ataatiatat tattigtata ttatatataa catatacatt 360 atattatata taatataatt atatataatt aattataaat taattatata taattatata 420 atataatata taatatacat aatatataal atataataca {aatatacat aatataatat 480 atattatata taatataata tatataatat aatataatat aatgtataat ataattatat 540 attatatata atatataatg tiatataatt atattatatt atataattaa tiataigtaa 600 ttaatataat ataattatta tatataattt ittatataat ataatatata attatataat 660 ataatataat tatattatat tatataatat atatatatta tataatataa tataattata 720 {tatataatt atataatata atataatiat atattatait atataataaa tataattata 780 taatataata tgattatata atatattatg tatattatat attatatatt gtattatgta 840 tattatatat tatatattat gtatattata tattatgtat attatatatt atgtatatta 900 tatattatat attatattat gtataatata ttatgtatgt tatatataat ataaattata 960 ttatatatta tgtatattat atataaatta tattatatat tatgtatatt atatataata 1020 taaagiatat attatgtata ttatatataa tataaagtat atattatgta tattatatat 1080 aatataaagt atatattatg tatattatat ataatataaa gtatatatta tgtatattat 1140

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SEL PCT 012.8725 atataatata aagtatatat tatgtatatt atatataata taaagtatat attatgtata 1200 ttatatataa tataaagtat ataitatgta tattatatat aatataaagt atatattatg 1260 tatattatat ataatataaa gtatatatta tgtatattat atataatata aagtatatat 1320 tatgtatatt atatataata taaagtatat attatgtata ttatatataa tataaagtat 1380 atattatgta tattatatat aatataaagt atatattata tgttataaat tatatattgt 1440 tatatattat at 1452 <210> 220 <211> 502 <212> DNA <213> Homo sapiens <220> <221> misc _binding <222> (1)..(502) <223> MAR of chromosome 2 genomic contig; 56350637..56351138 <400> 220 atatattata gaaatataaa tatatagata tatctatata ttatagaaat ataaatatat 60 agatatatct atataitata gaaatataaa tatatagata tatctatata ttatagaaat 120 ataaatatat agatatacct atatattata gaaatataaa tatatagata tacctatata 180 : ttatagaaat ataaatatat agatatacct atatattata gaaatataaa tatatagata 240 tatctatata ttatagaaat ataaatatat agatatatct atatattata gaaatataaa 300 tatatagata taictatata ttatagaaat ataaatatat agatatatct atatattata 360 gaaatataaa tatatagata tatctatata ttatagaaat ataaatatat agatatatac 420 aacatatatg ttacatatta tatattatat atctatatat ctatataaca ttatatatct 480

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SEL PCT 012.8T25 atatatctat ataacatata ta 502 <210> 221 <211> 794 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..{794) <223> MAR of chromosome 2 genomic contig; 57051633..57052426 <400> 221 : aactatatat actatattat atagttatac tatatatact atattatata gttatataac 60 tattatataa cigtattata tagttatata actattatat aactgtatta tatagttata 120 taactattat ataactgtat tatatagtta tataactata ttatataact gtgtiatata 180 gttatatatt atataactat attatataac tgtattatat agttatatat tatataacta 240 tattatatas ctgtattata tagttatata ttatataact atattatata actgtattat 300 atagttatat attatataac tgtattatat agttataaaa ctatattata taactgtatt 360 atatagitat aaaactacta tataactgta ttatataatt ataaaattat actatataac 420 tgtattatat agttataaaa ctatactata taactgtait atatagttat aaaactatac 480 tatataactg tattatatag ttataaagct atactatata actgtattat atagttatat 540 aactatacta tataactgta ttatatagtt ataaaactat actatataac tgtattatat 600 agttataaaa ttatattata taactgtatt atatagitat ataactatat tatataactg 660 tattatatag ttatataact atattatata agtgtatiat atagttatat aactatatta 720 tataactgta ttatacagit atataactat attatataac tgtattatat acttatataa 780

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SEL PCT 012.8725 ctatattata taac 794 <210> 222 <211> 300 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..(300) <223> MAR of chromosome 2 genomic contig; 57089272..57069571 <400> 222 acacatacat atatgtatat atgcacacac atatatatgt atatatacac atacatatat 60 gtataiatac atatatgtat atacgcacat acatatatgt atatatacac gtacatatat 120 gtctctatat atacacatac acatafgtat atacatatat gtgtatatat acacaatcat 180 atatgtatat acatatatac acatatacac aaacatatat gtatatacat atatgtatat 240 acatatatac acatatacac aaacatatat gtatatacat atatgtatat acatacacaa 300 <210> 223 <211> 370 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(370)

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SEL PCT 012.8725 <223> MAR of chromosome 2 genomic contig; 57235143..57235512 <400> 223 tatttttata tataactata tatattttat atataaatta fatatatgat catatatata 60 atcatatata taafcatata igattatata tgatcatata tatatttata tatataatta 120 tatatactta tatataatta tatatatait tatatatata attatgtata cttatatata 180 tttatatata taattatata tacaatttat atatataatt atatataatt tatatataat 240 tatatatata aattatatat aagtatatat aattatatat atgtttatat ataattatat 300 atataaatga taigtataat atataactat atataattat atataaatat atatatagat 360 tttatatata 370 <210> 224 <211> 306 <212> DNA <213> Homo sapiens <220> <221> misc binding <222> (1)..{306) <223> MAR of chromosome 2 genomic contig; 57693125..57693430 . <400> 224 tacgtatata cacgtataaa tataaatata tacatgtata tacgtatata catgtataaa 60 tataaatata tatatgtata tacgtatata catgtataaa tatatatatg tatatacgta 120 tatacatgta taaatatata tatatgtata tacgtatata catgtataaa tatatataca 180 tgtatatacg tatgttgtgt atacatacaa atctgtacat atatacatat atgttgtgty 240

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SEL PCT 012.5725 tatatataca tctatacatg tgtatgcgta tatatgtata tgtatatata gtatatataa 300 tacatg 306 <210> 225 <211> 500 <212> DNA <213> Homo sapiens <220> <221> misc _binding <222> (1)..(500) <223> MAR of chromosome 2 genomic contig; 59810331..59810830 <400> 225 titattatat gtaatatata tigtattatt atatatatta tatataatat atatigtatt 60 attatatata ttatatataa tatatattgt attattatat atattatata taatatatat 120 tgtattatta tatatattat atataatata tattgtatat tatatatatt atatattata 180 ttattatata ttatatatat tatattatta tatattatat attatatata ttatattata 240 tattatatat tatattatat atattatatt atatattata tattatatta tatatattat 300 attatatatt atatattata ttatatatat tatattatat atattatata ttatatatta 360 tatatattat atattatata ttatatatat tatatattat atataatata tattatatta 420 ttatataata ttatatatta tatatattat atattatata taatatatat tatattatta 480 (ataatatta tatattatat 500 : <210> 226 <211> bh65 <212> DNA

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SEL PCT 012.8T25

<213> Homo sapiens <220> <221> misc_binding <222> (1)..(565) <223> MAR of chromosome 2 genomic contig; 59974589..59975153 <400> 226 atatatgtat aatatgtata tatgtatata ttatgtatat gttatatatg taatatatgt 60 atgtatatat tatatatcat atataatata taatgigtat atatgtatat atgtatgtat 120 acatglatat actatgtata tatigtatat attatatatg tatatataca tatacatata 180 taatatatac atatattata tacaatatat acaigtatat tatatacgat atatacatat 240 atattatata caatatatac atagtatata aatgtataca tacatacata tatacatatt 300 atatatgtat atatgtatac ataaatgtat atataatata tatacatata taaatgtata 360 catacgtaca tatacgtata tgtatatgca tatatgtata tatgtgcata catatatatg 420 tatatacata tatgtacata tgtacatata cgtatatatg tacatatgta catatacgta 480 tatatgtaca tatgtacata tacgtatata tgtacatatg tacatatacg tatatatgta 540 cafatgiaca tatatacata tatat 565 <210> 227 <211> 427 <212> DNA <213> Homo sapiens 2205 <221> misc_binding

: | Seite 205

SEL PCT 012.8725 <222> (1)..4427) <223> MAR of chromosome 2 genomic contig; 60605573..60605999 <400> 227 tatataatgt atataatgga tatagatata gatatagata tatattttat ataatatata 60 ttatatalta tatataatat atgttatata tatiatatat tttatataat atatatatta 120 tataaattat atatatataa tatataatat atatattata tatattttat ataatatata 180 ttitaatatta {ctattatat attttatata atatatatit tatataatat ataatatata 240 atatataltt tacataatat ataatatata atacgtatta tatataatat ataatacgta 300 ttitatataa tatataatac gtattatata taatacgtat tatatattat ataatatata 360 atacgiatia tataatatac giaattatat titatlataa tacgtattat atattatata 420 atatata 427 <210> 228 <211> 1199 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..{1199) <223> MAR of chromosome 2 genomic contig; 61223949..61231147 <400> 228 glatacatat ataaagtgta fatataatgt atatacatat atacatatat aaagtatata 60 tataatatat acatatataa agtatatata taatatatac atatataaag tatatataat 120

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SEL PCT 012.8725 atatacatat ataaagtata tataatatat acatatataa agtatatata tcatatatac 180 atatataaag tatatatata atatatacat atatacatat ataaagtata tataacatat 240 atacatatat aaagtatata taacatatat acatatataa agtatatata taatatatac 300 atatatacat atataaagta tatataacat atatacatat atacagtata tataacatat 360 atacatatat acagtatata taacatatat acatatatac agtatatata acatatatac 420 atatatacag tatatataac atatatacat atatacatga agtatatata acatatatac 480 atatatacat gaagtatata taacatatat acatatatac atgaagtata tataacatat 540 atacatatat acatgaagta tatataacat atatacatat atacatatat aaagtatata 600 {aacatatac atatatacat atataaagta taacatatac atatatacat atataaagta 660 tatataatat ataacatata catatataaa gtatatataa {atataacat atacatatat 720 aaagtatata taatatataa catatacata tataaagtat atataatata tacatatata 780 catatataaa gfatatataa iatatatata catatataaa gtatatataa tatatataca 840 tatatacata tataaagtat atataatata tatacatata taaagtatat ataatatata 900 tacatatata catatataaa gtatatataa tatatataca tatatacata tataaagtat 960 atataatata tatacatata tacatatata aagtatatat aatatatata catatataca 1020 tatataaagt atatataata tatatacata tatacatata taaagtatat ataatatata 1080 tacatatata catatataaa gtataiataa tatgtataca tatatacata tataaagtat 1140 atataatatg {atacatata tacatatata aagtatatat ataatatgta tacatatat 1199 <210> 229 <211> 454 <212> DNA <Z13> Homo sapiens <220> <221> misc _hinding

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SEL PCT 012.8725 <222> (1)..(454) <223> MAR of chromosome 2 genomic contig; 62181058..62181511 <400> 229 tatatatcat atattatata tgatatatat tatgtatata atacatatta tatataataa 60 atattatta tatatgatat atattatgta tataatacat attatatata ataaatatat 120 attatattat atataataaa tatatattat attatatata atatatattt atatataaat 180 atattatata taaatatata ttatatataa aatatitata tattatatat aaatatatat 240 tatatataaa fatttatata Hatatataa atatttatat attatatata aatatttata 300 tattatatat aaaatatatt atatatatta tatatattat atattatata taatatattt 360 aatatataat atataaacat atattatata taatatataa acatatataa atatatttat 420 atataataga taaaaatata tataatatat ataa 454 <210> 230 <211> 658 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(658) <223> MAR of chromosome 2 genomic contig; 62190919..62181576 <400> 230 tatatacaca actatatata taactatata tatacaacta tatatacaac tatatatata 60 actatatata taactatata taactatata tataactata tataactata tatataacta 120

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SEL PCT 012.8725 tatatataac tatatataac tatatatata actatatata actatatata actatatata 180 taactatata tataactata tatataacta tatatataac tatatatact atatatataa 240 ctatatatat ataactatat atataactat atatatataa ctatatataa ctatatatat 300 ataactatat atataactat atatatataa ctatatatat aactatatat atataactat 360 atatataact atatatatat aactatatat aactatatat atataactat atatataact 420 atatatatat aactatatat ataactataf atatataact atatatataa ctatatatat 480 ataactatat atataactat atatataact atatatataa ctatatatat ataactatat 540 atataactat atatatataa ctatatatat aactatatat ataactatat atataactat 600 atatatataa ctatatatat aactatatat atataactat atatataact atatatat 658 <210> 231 <211> 1486 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(1486) <223> MAR of chromosome 2 genomic contig; 62384127..62385612 <400> 231 attatatcta atctattata tattatatct aatacatatt atatctaatc tattgtatat 60 tatatctaat atataatata ttatatataa tataftatat attatatatt atatacaata 120 tattatatat tatataatat ataatatatt atatataata tattatatct aatatattac 180 atattatatc taatctatta tagatataat atgtaatata ttatatatta tatctaatag 240 atattagata taatatataa tatattatta atataatata ttagatataa tatataatat 300

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SEL PCT 012.8125 aataatatat aatatatatt attggtaata tataatatat aattaataat atatattata 360 tataattatt atgaataata tatcatatat aatatctagt atattatata ttaataacat 420 ataaatatta tattaataat aaataacata ttaatattat attaataata tataatatac 480 taatattata ttaataatat ataatatact aatattatat taataatata taatatacta 540 atattatatt aataatatat aataiactaa tattatatta ataatatata atatactaat 600 attatattaa taatatataa tatactaata tattaagaat atataatata ctaatatatt 660 aagaatatat aatatactaa tattatatta ataatatata tttatattaa taatatatta 720 attattatta attaatiatt aataattata taatattgat tatattaata ttatcaatit 780 aataatattg attatatalt atatattata tattatatat tatatattat atattatata 840 ttatatatta ataatatata ftagatataa tataatatat iaataatata taagatataa 900 tataatatat taataatata tattagatat aatataatat attaataata fatattagat 960 ataatataat atattaataa tatatattag atataatata atatattaat aatatatatt 1020 agatgtaata taatatatta ataatatata ttagatgtaa tataatatat taataatata 1080 tattagatgt aatataatat attaataata tatattagat gtaatataat atattaataa 1140 tatatattag atgtaatata atatattaat aatatatatt agatgtaata taatatatta 1200 ataatatata ttagatgtaa tataatatat taatatatat tagatgtaat ataatatatt 1260 aataatatat attagatata atataatata ttaataatat attagatata atataaiata 1320 ttaataatat ataagatata atataatata ttaataatat ataagatata atataatata 1380 ttaataatat ataagatata atataatata ttaataatat atattagata tataatatat 1440 taataatata tattagatat ctaatatcta ttagatatct aataga 1486 <210> 232 <211> 333 <212> DNA <213> Homo sapiens

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: SEL PCT 012.8725 <220> <221> misc_binding <222> (1)..(333) <223> MAR of chromosome 2 genomic contig; 62538649..62538981 <400> 232 tiatatatat tatatatata tattitatat atatattata tatatatitt atatatatat 60 tatatatata tittatatat atattatata tatatittat atatatatta tatatatatt 120 itatatatat tatatatata tittatatat attatatata tatittatat atataftata 180 tatatatttt atatatatat tatatatata ttttatatat atattatata tatattttat 240 atatatatta tatatatatt ttatatatat aitatatata tattttatat atatattata 300 tatatattit atatatatat tatatatata ttt 333 <210> 233 <211> 480 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..{(480) <223> MAR of chromosome 2 genomic contig; 63240325..63240804 <400> 233 tatatataaa atatatattt tttaaatata aaatatatat atattttaat attaatatat 60 atatattita atatataata tatatattat atattttata tataaaatat atatattata 120

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SEL PCT 012.8725 tatittatat ataaaatata tataitatat attttatata ttaaaatata tattttatat 180 : attttaatta ttaaaatata tatattatat attitaaata taaaatatat atattatata 240 tittaatata taaaatatat atattatata ttitaatata taaaatatat atattttata 300 tttatatata taaatatata tattatatat titaatatat aaaatatata tattatatat 360 titaatatat aaaatatata tattatatat titaatatat aaaatatata tattatatat 420 titaatatat ataaaatata tatattatat attitatata tattaaatat atattttata 480 <210> 234 <211> 302 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(302) <223> MAR of chromosome 2 genomic contig; 63935480.,63935781 <400> 234 atatatataa atatatatat aattatatat agatatatat aattatatat agatatatat 60 atictatatt ctatatatat ataatatata atatataaat tatatataga atatatatta 120 tatataatat attatatata ttatatataa tatatatatt atatatatta tatataatat 180 atatattata tatattatat ataatttata tatatiatat atagaatata tattatatat 240 agaatataga atatatataa tatatataga atacagaata tatatagaat atagaatata 300 ta 302 <210> 235 <211> 407

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SEL PCT 012.8725 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(407) <223> MAR of chromosome 2 genomic contig; 63935888..63936294 <400> 235 tataatatat taatataata tatagacagt atataatata atatacagac agtatataat 60 atacagacag tatataatat ataatatiat atataatatt atatataata ttatataata 120 tattatatta tatatattat ataatatatt atattatata taatatatgt aatattatat 180 attatattat acataatata tiatatataa tatattatat ataatattat atatattata 240 tataatatat ataataataa tattataata tataatatat aatagtacag tatatattat 300 atatataatt ctatatataa tatatagaat tctatctatt tataatatat atagaattct 360 atatataata tataatatac agaatictat atatattata tatagaa 407 <210> 236 <211> 302 <212> DNA <213> Homo sapiens <220> <221> misc_hinding <222> (1)..{302) <223> MAR of chromosome 2 genomic contig, 66958350..866558651

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SEL PCT 012.5725 <400> 236 tattatatat attgtatata tatgtatatt atatatattg tatatataat gtatattata 60 tatattatat atatatgtat attatatata tigtatatat atgtatatta tatatattgt 120 atatatgtat atgtatatat gtatgtgtat atatatacac atatacacat atatgtgtat 180 gtatatatat gtgtgtatat acgtatatat acatatatac aatitttgta tatatacata 240 fatacacata tatatgtgta tgtgtatata tatacacata tatgtgtgtg tatatacaca 300 ta 302 : <210> 237 <211> 651 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(851) <223> MAR of chromosome 2 genomic contig; 68307125..68307775 <400> 237 gatattatat attgtatata ttatatatgt atataatata ctattatata ttatatatgt 60 atataatftt attaatatat atattatatt afattatata ttatattata ttatattata 120 tatataatat taatattata tattattata tattatatta tattaatatt atatatatat 180 aatatatata atatatataa {agtattata tataatatat ataatagtat tatatattat 240 alatatataa tactattata tatattatat ataatagtat tatatatatt atatatataa 300 tactattata tataatatat actattatat aatatatata atactatiat atatattata 360

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SEL PCT 012.8T25 tataatacta Htatatataa tatatataat actattatat ataatatata taatactatt 420 atatataata tatataatac taitatatat aatatatata atactattat atataatata 480 tataatacta ttatatataa tatatatatt atatataatt atattaatat ataatagtat 540 catatataat aatagtatat ataatatata atatatatat tatatatatt ataatagtat 600 atataacata taatatagta tatatattat atattatata taaaataitt a 651 <210> 238 <211> 367 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(367) <223> MAR of chromosome 2 genomic contig; 68308243..68308609 <400> 238 atatatatat atgagicaac catacacata tatatatata atgtttatat atataatgta 60 tatatataat gittatatat aatgtatata tataafgtit atatatataa tgtatatata 120 : taatgtttat atatataaty tatatatata atgtttatat atataatgtg tatatataat 180 gtitatatat ataatgigta tatataatgt ttatatataa tgtgtatata taatgtttat 240 atatataatg tgtatatata atgtttatat atataatgtg tatatataat gtttatatat 300 ataatgigta tatatataat gtttatatat ataatgtgta tatatataat gtttatatat 360 ataatgt 367 <210> 239 <211> 499

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SEL PCT 012.8725 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(499) <223> MAR of chromosome 2 genomic contig; 410241..410739 <400> 239 ataalatgta tatatattat attatatatt atattacata ttatatatta tattacatat 80 tatatatita tatattacat attatatatt atatittata ttatatatta tatcatatat 120 afgttatgca ttatataata cataatatat tatatatgat ataatatata ttatatatta 180 itatatataa tataattaat atattatgta tiatataata tatattatgt tataatatat 240 aatafatatt atataatiat ataatatatt atgtattata taatatatat tatgttataa 300 tatattatat tatatatatt atatatatat tatatatata atgtatatta tatataatac 360 ataatatatt atatattata tattattita tataatatat tatataatgt gatatattat 420 ataatatatt atataacata gtatattata taatatatta tataatgtaa tatattatat 480 attatataat atattgtat 499 <210=> 240 <211> 402 <212> DNA <213> Homo sapiens <220> : <221> misc binding

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SEL PCT 012.8725 <222> (1)..(402) <223> MAR of chromosome 2 genomic contig; 31531..31932 <400> 240 cacattatat atataaacat tatatatata cacattatat atataaacat tatatatata 60 cacattatat atataaacat tatatataca cattatatat ataaacatta tatatacaca 120 ttatatatat aaacattata tatacaaatt atatatataa acattatata tacaaattat 180 atatataaac attatatata tacattatat atataaacat tatatatata cattatatat 240 ataaacatta tatalataca ttatatatat aaacattata tatatacatt atatatataa 300 acattatata tatacatiat atatataaac gttatatata tacattatat atataaacat 360 tatatgtata cattatatat ataaacatta tatatatatg tg 402 <210> 241 <211> 421 <212> DNA <213> Homo sapiens <220> <221> misc_binding <222> (1)..(421) <223> MAR of chromosome 2 genomic contig; 32415..32835 <400> 241 ataaatattt tatatataat atataatata tatactatat tatatgttat atatactatt 60 ataatatata taatatatat attatatatt atatatacta ttattatata tgatactatt 120 atataliaat ataattatat ataatatata tattatataa tatactatta tatattatat 180

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SEL PCT 012.8725 ataatagtat attatataat atatataita tatataatag tattatatat actaitatat 240 attatatata ttatatatat ataaaatata atataatata tataatatat aatattaata 300 tiatatatat aaiataatat aatatataat ataatataat atatatatta ataaaatiat 360 attaatatat aatatataat agtatattat atacatatat aatatataca atatataata 420 t 421

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Claims (25)

1. A purified and isolated DNA sequence having protein production increasing activity, characterized in that said DNA sequence comprises a) at least one bent DNA element, wherein the bent DNA element contains at least 33% of dinucleotide TA and/or at least 33% of dinucleotide AT on a stretch of 100 contiguous base pairs, b) at least one binding site for a DNA binding protein, ¢) and that it is a MAR nucleotide sequence with the sequence SEQ IDS No 24, 26 and 27, or a sequence complimentary thereof, or ) : a sequence having at least 90% identity with said sequence SEQ IDS No 24,26 and 27. .

2. The purified and isolated sequence of claims 1, characterized in that said DNA binding protein is a transcription factor.

3. The purified and isolated sequence of claim 2, characterized in that the transcription factor is selected from the group comprising the polyQpolyP domain proteins.

4. The purified and isolated sequence of claim 2, characterized in that the transcription factor is selected from the group comprising SATB1, NMP4, MEF2, 58, + DLX1, FREAC7, BRN2, GATA 1/3, TATA, Bright, MSX, AP1, C/EBP, CREBP1, FOX, Freac7, HFH1, HNF3alpha, Nkx25, POU3F2, Pit1, TTF1, XFD1, AR, C/EBPgamma, Cdc5, FOXD3, HFH3, HNF3 beta, MRF2, Oct1, POUGF1, SRF, V$MTATA_B, XFD2, Bach2, CDP CRS, Cdx2, FOXJ2, HFL, HP1, Myc, PBX, Pax3, TEF, VBP, XFD3, Brn2, COMP1, Evil, FOXP3, GATA4, HFN1, Lhx3, NKX3A, POU1F1, Pax6, TFIIA and Vmw85 or a combination of two or more of these transcription factors.

5. The use of a purified and isolated DNA sequence comprising a first isolated matrix attachment region (MAR) nucleotide sequence which is a MAR nucleotide sequence selected from the group comprising: - a purified and isolated DNA sequence of any of claims 1 to 4, - the sequence SEQ IDS No 24, 26 and 27,

or a sequence complementary thereof, for increasing protein production activity in a eukaryotic host cell.

6. The use of the purified and isolated DNA sequence of claim 5, characterized in that said purified and isolated DNA sequence further comprises a promoter operably linked to a gene of interest.

7. The use of the purified and isolated DNA sequence of claims 5 or 6, characterized in that said purified and isolated DNA sequence further comprises at least a second isolated matrix attachment region (MAR) nucleotide sequence which is a MAR nucleotide sequence selected from the group comprising: - a purified and isolated DNA sequence of any of claims 1 to 4, - the sequence SEQ IDS No 24, 26 and 27, or a sequence complementary thereof, for increasing protein production activity in a eukaryotic host cell.

8. The use of the purified and isolated DNA sequence of claim 7, characterized in that said first and at least second MAR sequences are located at both the 5’ and the 3' ends of the sequence containing the promoter and the gene of interest.

9. The use of the purified and isolated DNA sequence of claim 7, characterized in that said first and/or at least second MAR sequences are located on a sequence distinct from the one containing the promoter and the gene of interest.

10. The use of the purified and isolated DNA sequence of any of claims 5to 9, characterized in that said purified and isolated DNA sequence is in the form of a linear DNA sequence as vector.

11. A method for transfecting a eukaryotic host cell, said method comprising a)introducing into said eukaryotic host cell at least one purified DNA sequence comprising at least one purified and isolated DNA sequence consisting of a MAR nucleotide sequence of any of claims 1 to 4, b) subjecting within a defined time said transfected eukaryotic host cell to at least one additional transfection step with at least one purified DNA sequence comprising at least one DNA sequence of interest and/or with at least one purified and isolated DNA sequence consisting of a MAR nucleotide sequence or other chromatin modifying elements, and c) selecting said transfected eukaryotic host cell.

12 The method of claim 11, characterized in that said DNA sequence of interest is a gene of interest coding for a protein operably linked to a promoter.

13. The method of claims 11 or 12, characterized in that the selected transfected eukaryotic host cells are high protein producer cells with a production rate of at least 10 pg per cell per day.

14. The method of any of claims 11 to 13, characterized in that the MAR nucleotide sequence is selected from the group comprising: - a purified and isolated DNA sequence of any of claims 1 to 4, - the sequence SEQ IDS No 24, 26 and 27, or a sequence complementary thereof.

15. The method of any of claims 11 to 14, characterized in that the MAR nucleotide is a purified and isolated sequence according to any of claims 1 to 4, or a sequence complementary thereof.

16. The method of any of claims 11 to 15, characterized in that the defined time corresponds to intervals related to the cell division cycle.

17. The method of claim 16, characterized in that the defined time is the moment the host cell just has entered into a second cell division cycle.

18. A method for transfecting a eukaryotic host cell, said method comprising co- transfecting into said eukaryotic host cell at least one first purified and isolated DNA sequence comprising at least one DNA sequence of interest, and a second and isolated purified DNA comprising at least one MAR nucleotide selected from the group comprising:

- a purified and isolated DNA sequence of any of claims 1 {o 4, - the sequence SEQ IDS No 24, 26 and 27, or a sequence complementary thereof.

19. A process for the production of a protein wherein a) a eukaryotic host cell transfected according to any of claims 11 to 18 is cultured in a culture medium under conditions suitable for expression of said protein and b) said protein is recovered.

20. A eukaryotic host cell transfected according to any one of claims 11 to 18.

21. A cell transfection mixture or kit comprising at least one DNA sequence according to any of claims 1 to 4.

22. Atransgenic non-human organism characterized in that at least some of its cells have stably incorporated at least one DNA sequence of any of claims 1 to 4.

23. A transgenic non-human organism characterized in that its genome has stably incorporated at least one DNA sequence of any of claims 1 to 4.

24. The transgenic non-human organism of claims 22 or 23 characterized in that some of its cells have been transfected according to the method of any of claims 11 to 18.

25. A eukaryotic host cell transfected with at least one DNA sequence according to any of claims 1 to 4.