AU2012200570A1 - Ungulates with genetically modified immune systems - Google Patents

Abstract

The present invention provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which lack expression of functional endogenous immunoglobulin loci. The present invention also provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which express xenogenous, such as human, immunoglobulin loci. The present invention further provides ungulate, such as porcine genomic DNA sequence of porcine heavy and light chain immunogobulins. Such animals, tissues, organs and cells can be used in research and medical therapy. In addition, methods are provided to prepare such animals, organs, tissues, and cells.

Description

Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Ungulates with genetically modified immune systems The following statement is a full description of this invention, including the best method of performing it known to us: UNGULATES WITH GENETICALLY MODIFIED IMMUNE SYSTEMS This application claims priority to U.S. provisional application No. 60/621,433 filed on October 22, 2004, which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which lack expression of functional. endogenous immunoglobulin loci. The present invention also provides ungulate animals, tissue and organs as well as cells and cell lines derived from such animals, tissue and organs, which express xenogenous, such as human, immunoglobulin loci. The present invention further provides ungulate, such as porcine genomic DNA sequence of porcine heavy and light chain immunogobulins. Such animals, tissues, organs and cells can be used in research and medical therapy. In addition, methods are provided to prepare such animals, organs, tissues, and cells. BACKGROUND OF THE INVENTION An antigen is an agent or substance that can be recognized by the body as 'foreign'. Often it is only one relatively small chemical group of a larger foreign substance which acts as the antigen, for example a component of the cell wall of a bacterium. Most antigens are proteins, though carbohydrates can act as weak antigens. Bacteria, viruses and other microorganisms commonly contain many antigens, as do pollens, dust mites, molds, foods, and other substances. The body reacts to antigens by making antibodies. Antibodies (also called immunoglobulins (Igs)) are proteins that are manufactured by cells of the immune system that bind to an antigen or foreign protein. Antibodies circulate in the serum of blood to detect foreign antigens and constitute the gamma globulin part of the blood proteins. These antibodies interact chemically with the antigen in a highly specific manner, like two pieces of a jigsaw puzzle, forming an antigen/antibody complex, or immune complex. This binding neutralises or brings about the destruction of the antigen. When a vertebrate first encounters an antigen, it exhibits a primary humoral immune response. If the animal encounters the same antigen after a few days the immune resonse is more rapid and has a greater magnitude. The initial encounter causes specific immune cell (B-cell) clones to proliferate and differentiate. The progeny lymphocytes include not only effector cells (antibody producing cells) but also clones of memory cells, which retain the capacity to -produce both effector and memory cells upon subsequent stimulation by the original antigen. The effector cells live for only a few days. The memory cells live for a lifetime and can be reactivated by a second stirnuation with the same antigen. Thus, when an antigen is encountered a second time, its memory cells quickly produce effector cells which rapidly produce massive quantities of antibodies. By exploiting the unique ability of antibodies to interact with antigens in a highly specific manner, antibodies have been developed as molecules that can be manufactured and used for both diagnostic and therapeutic applications. Because of their unique ability to bind to antigenic epitopes, polyclonal and monoclonal antibodies can be used to identify molecules carrying that epitope or can be directed, by themselves or in conjunction with another moiety, to a specific site for -diagnosis._ r-therapy.__Polycnatand r.rmonrlonal. antibodies can be generated against practically any pathogen or biological target. The term polyclonal antibody refers to immune sera that usually contain pathogen-specific antibodies of various isotypes and specificities. In contrast, monoclonal antibodies consist of a single immunoglobulin type, representing one isotype with one specificity. In 1890, Shibasaburo Kitazato and Emil Behring conducted the fundamental experiment that demonstrated immunity can be transmitted from one animal to another by transferring the serum from an immune animal to a non-immune animal. This landmark experiment laid the foundation for the introduction of passive immunization into clinical practice. However, wide scale serum therapy was largely abandoned in the 1940s because of the toxicity associated with the administration of heterologous sera and the introduction of effective antimicrobial chemotherapy. Currently, such polyclonal antibody therapy is indicated to treat infectious diseases in relatively few situations, such as replacement therapy in immunoglobulin-deficient patients, post-exposure prophylaxis against several viruses (e.g., rabies, measles, hepatitis A and B, varicella), and toxin neutralization (diphtheria, tetanus, and botulism). Despite the limited use of serum therapy, in the United States, more than 16 metric tons of human antibody are required each year for intravenous antibody therapy. Comparable levels of use exist in the economies of most highly industrialized countries, and the demand can be expected to grow rapidly in 2 developing countries. Currently, human antibody for passive immunization is obtained from the pooled serum of donors. Thus, there is an inherent limitation in the amount of human antibody available for therapeutic and prophylactic therapies. The use of antibodies for passive immunization against biological warfare agents represents a very promising defense strategy. The final line of defense against such agents is the immune system of the exposed individual. Current defense strategies against biological weapons include such measures as enhanced epidemiologic surveillance, vaccination, and use of antimicrobial agents. Since the potential threat of biological warfare and bioterrorism is. inversely proportional to the number of immune persons in the targeted population, biological agents are potential weapons only against populations with a substantial proportion of susceptible persons. Vaccination can reduce the susceptibility of a population against specific threats, provided that a safe vaccine exists that can induce a protective response. Unfortunately, inducing .a protective response by.yaccination may take longer than.the time between exposure and onset of disease. Moreover, many vaccines require multiple doses to achieve a protective immune response, which would limit their usefulness in an emergency to provide rapid prophylaxis after an attack. In addition, not all vaccine recipients mount a protective response, even after receiving the recommended immunization schedule. Drugs can provide protection when administered after exposure to certain agents, but none are available against many potential agents of biological warfare. Currently, no small molecule drugs are available that prevent disease following exposure to preformed toxins. The only currently available intervention that could provide a state of immediate immunity is passive immunization with protective antibody (Arturo Casadevall "Passive Antibody Administration (Immediate Immunity) as a Specific Defense Against Biological Weapons" from Emerging Infectious Diseases, Posted 09/12/2002). In addition to providing protective immunity, modern antibody-based therapies constitute a potentially useful option against newly emergent pathogenic bacteria, fungi, virus and parasites (A. Casadevall and M. D. Scharff, Clinical Infectious Diseases 1995; 150). Therapies of patients with malignancies and cancer (C. Botti et al, Leukemia 1997; Suppl 2:S55-59; B. Bodey, S.E. Siegel, and H.E. Kaiser, Anticancer Res 1996; 16(2):661), therapy of steroid resistant rejection of transplanted organs as well as autoimmune diseases can also be achieved through the use of 3 monoclonal or polyclonal antibody preparations (N. Bonnefoy-Berard and J.P. Revillard, J Heart Lung Transplant 1996; 15(5):435-442; C. Colby, et al Ann Pharmacother 1996; 30(10):1164 .1174; M.J. Dugan, et al, Ann Hematol 1997; 75(1-2):41 2; W. Cendrowski, Boll Ist-Sieroter Milan 1997; 58(4):339-343; L.K. Kastrukoff, et al Can J Neurol Sci 1978; 5(2):175178; J.E. Walker et al J Neurol Sci 1976; 29(2-4):303309). Recent advances in the technology of antibody production provide the means to generate human antibody reagents, while avoiding the toxicities associated with human serum therapy. The advantages of antibody-based therapies include versatility, low toxicity, pathogen specificity, enhancement of immune function, and favorable pharmacokinetics. The clinical use of monoclonal antibody therapeutics has just recently emerged. Monoclonal antibodies have now been approved as therapies in transplantation, cancer, infectious disease, cardiovascular disease and inflammation. In. many more monoclonal antibodies are in late stage clinical trials to treat a broad range of disease indications. As a result, monoclonal antibodies represent one of the largest classes of drugs currently in development. Despite the recent popularity of monoclonal antibodies as therapeutics, there are some obstacles for their use. For example, many therapeutic applications for monoclonal antibodies require repeated administrations, especially for chronic diseases such as autoimmunity or cancer. Because mice are convenient for immunization and recognize most human antigens as foreign, monoclonal antibodies against human targets with therapeutic potential have typically been of murine origin. However, murine monoclonal antibodies have inherent disadvantages as human therapeutics. For example, they require more frequent dosing to maintain a therapeutic level of monoclonal antibodies because of a shorter circulating half-life in humans than human antibodies. More . critically, repeated administration of murine immunoglobulin creates the likelihood that the human immune system will recognize the mouse protein as foreign, generating a human anti-mouse antibody response, which can cause a severe allergic reaction. This possibility of reduced efficacy and safety has lead to the development of a number of technologies for reducing the immunogenicity of murine monoclonal antibodies. Polyclonal antibodies are highly potent against multiple antigenic targets. They have the unique ability to target and kill a plurality of "evolving targets" linked with complex diseases. Also, of all drug classes, polyclonals have the highest probability of retaining activity in the event of antigen mutation. In addition, while monoclonals have limited therapeutic activity 4 against infectious agents, polyclonals can both neutralize toxins and direct immune responses to eliminate pathogens, as well as biological warfare agents. The development of polyclonal and monoclonal antibody production platforms to meet future demand for production capacity represents a promising area that is currently the subject of much research. One especially promising strategy is the introduction of human immunoglobulin genes into mice or large domestic animals. An extension of this technology would include inactivation of their endogenous irmunoglobulin genes. Large animals, such as sheep, pigs and cattle, are all currently used in the production of plasma derived products, such as hyperimmune serum and clotting factors, for human use. This would support the use of human polyclonal antibodies from such species on the grounds of safety and ethics. Each of these species naturally produces considerable quantities of antibody in both serum and milk. Arrangement of Genes Encoding Immunoglobulins --Antibody molecules are assembled from- combinations of variable gene elements, and the possibilities resulting from combining the many variable gene elements in the germline enable the host to synthesize antibodies to an extraordinarily large number of antigens. Each antibody molecule consists of two classes of polypeptide chains, light (L) chains (that can be either kappa (K) L-chain or lambda (I) L-chain) and heavy (H) chains. The heavy and light chains join together to define a binding region for the epitope. A single antibody molecule has two identical copies of the L chain and two of the H chain. Each of the chains is comprised of a variable region (V) and a constant region (C). The variable region constitutes the antigen-binding site of the molecule. To achieve diverse antigen recognition, the DNA that encodes the variable region undergoes gene rearrangement. The constant region amino acid sequence is specific for a particular isotype of the antibody, as well as the host which produces the antibody, and thus does not undergo rearrangement. The mechanism of DNA rearrangement is similar for the variable region of both the heavy- and light-chain loci, although only one joining event is needed to generate a light-chain gene whereas two are needed to generate a complete heavy-chain gene. The most common mode of rearrangement involves the looping-out and deletion of the DNA between two gene segments. This occurs when the coding sequences of the two gene segments are in the same orientation in the DNA. A second mode of recombination can occur between two gene segments that have 5 opposite transcriptional orientations. This mode of recombination is less common, although such rearrangements can account for up to half of all V, to J, joins; the transcriptional orientation of -half of the human V. gene segments is opposite to that of the J, gene segments. The DNA sequence encoding a complete V region is generated by the somatic recombination of separate gene segments. The V region, or V domain, of an immunoglobulin heavy or light chain is encoded by more than one gene segment. For the light chain, the V domain is encoded by two separate DNA segments. The first segment encodes the first 95-101 amino acids of the light chain and is termed a V gene segment because it encodes most of the V domain. The second segment encodes the remainder of the V domain (up to 13 amino acids) and is termed a joining or J gene segment. The joining of a V and a J gene segment creates a continuous exon that encodes the whole of the light-chain V region. To make a complete immunoglobulin light-chain messenger RNA, the V-region exon is joined to the C-region sequence by RNA splicing after transcription. - A heavy-chain-V region -is encoded -in-three-gene segments. In addition--to the V and J gene segments (denoted VH and JH to distinguish them from the light-chain VL and JL), there is a third gene segment called the diversity or DH gene segment, which lies between the VH and JH gene segments. The process of recombination that generates a complete heavy-chain V region occurs in two separate stages. In the first, a DH gene segment is joined to a JH gene segment; then a VH gene segment rearranges to DJH to make a complete VH-region exon. As with the light chain genes, RNA splicing joins the assembled V-region sequence to the neighboring C-region gene. Diversification of the antibody repertoire occurs in two stages: primarily by rearrangement ("V(D)J recombination") of Ig V, D and J gene segments in precursor B cells resident in the bone marrow, and then by somatic mutation and class switch recombination of these rearranged Ig genes when mature B cells are activated. Immunoglobulin somatic mutation and class switching are central to the maturation of the immune response and the generation of a "memory" response. The genomic loci of antibodies are very large and they are located on different chromosomes. The immunoglobulin gene segments are organized into three clusters or genetic loci: the K, X, and heavy-chain loci. Each is organized slightly differently. For example, in humans, immunoglobulin genes are organized as follows. The X light-chain locus is located on 6 chromosome 22 and a cluster of Vi gene segments is followed by four sets of J)L gene segments each linked to a single C gene. The K light-chain locus is on chromosome 2 and the cluster of V, gene segments is followed by a cluster of J, gene segments, and then by a single C, gene. The organization of the heavy-chain locus, on chromosome 14, resembles that of the K locus, with separate clusters of VH, DH, and JH gene segments and of CH genes. The heavy-chain locus differs in one important way: instead of -a single C-region, it contains a series of C regions arrayed one after the other, each of which corresponds to a different isotype. There are five immunoglobulin heavy chain isotypes: IgM, IgG, IgA, IgE and IgD. Generally, a cell expresses only one at a time, beginning with IgM. The expression of other isotypes, such as IgG, can occur through isotype switching. The joining of various V, D and J genes is an entirely random event that results in approximately 50,000 different possible combinations for VDJ(H) and approximately 1,000 for VJ(L). Subsequent random pairing of H and L chains brings the total number of antibody specificities to about 10-possibilities--Diversity -is-further- increased by the imprecise joining of different genetic segments. Rearrangements occur on both DNA strands, but only one strand is transcribed (due to allelic exclusion). Only one rearrangement occurs in the life of a B cell because of irreversible deletions in DNA. Consequently, each mature B cell maintains one. immunologic specificity and is maintained in the progeny or clone. This constitutes the molecular basis of the clonal selection; i.e., each antigenic determinant triggers the response of the pre-existing clone of B lymphocytes bearing the specific receptor molecule. The primary repertoire of B cells, which is established by V(D)J recombination, is primarily controlled by two closely linked genes, recombination activating gene (RAG)-1 and RAG-2. Over the last decade, considerable diversity among vertebrates in both Ig gene diversity and antibody repertoire development has been revealed. Rodents and humans have five heavy chain classes, IgM, IgD, IgG, IgE and IgA, and each have four subclasses of IgG and one or two subclasses of IgA, while rabbits have a single IgG heavy chain gene but 13 genes for different IgA subclasses (Burnett, R.C et al. EMBO J 8:4047; Honjo, In Honjo, T, Alt. F.W. T.H. eds, Immunoglobulin Genes p. 123 Academic Press, New York). Swine have at least six IgG subclasses (Kacskovics, I et al. 1994 Jlmmunol 153:3565), but no IgD (Butler et al. 1996 Inter. Immunol 8:1897-1904). A gene encoding IgD has only been described in rodents and primates. Diversity in the mechanism of repertoire development is exemplified by contrasting the pattern 7 seen in rodents and primates with that reported for chickens, rabbits, swine and the domesticated Bovidae. Whereas the former group have a large number of VH genes belonging to seven to 10 families (Rathbun, G. In Hongo, T. Alt. F.W. and Rabbitts, T.H., eds, Immunoglobulin Genes, p. 63, Academic press New York), the VH genes of each member of the latter group belong to. a single VH gene family (Sun, J. et al. 1994 J. Immunol. 1553:56118; Dufour, V et al.1996, J Imiunol. 156:2163). With the exception of the rabbit, this family is composed of less than 25 genes. Whereas rodents and primates can utilize four to six JH segments, only a single JH is available for repertoire development in the chicken (Reynaud et al. - 1989 Adv. Immunol. 57:353). Similarly, Butler et al. (1996 Inter. Immunol 8:1897-1904) hypothesized that swine may resemble the chicken in having only a single JH gene. These species generally have fewer V, D and J genes; in the pig and cow a single VH gene family exists, consisting of less.than 20 gene segments (Butler et al, Advances in Swine in Biomedical Research, eds: Tumbleson and Schook, 1996; Sinclair et al, J. Immunol. 159: 3883, 1997). Together with lower numbers of J and D...gene. .segments, this results in- significantly less diversity.being generated by gene rearrangement. However, there does appear to be greater numbers of light chain genes in these species. Similar to humans and mice, these species express a single K light chain but multiple X light chain genes.. However, these do not seem to affect the restricted diversity that is achieved by rearrangement. Since combinatorial joining of more than 100 VH, 20-30 DH and four to six JH gene segments is a major mechanism of generating the antibody repertoire in humans, species with fewer VH, DH or JH segments must either generate a smaller repertoire or use alternative mechanisms for repertoire development. Ruminants, pigs, rabbits and chickens, utilize several mechanisms to generate antibody diversity. In these species there appears to be an important secondary repertoire development, which occurs in highly specialized lymphoid tissue such as ileal Peyer's patches (Binns and Licence, Adv. Exp. Med. Biol. 186: 661, 1985). Secondary repertoire development occurs in these species by a process of somatic mutation which is a random and not fully understood process. The mechanism for this repertoire diversification appears to be templated mutation, or gene conversion (Sun et al, J. Inimunol. 153: 5618, 1994) and somatic hypermutation. Gene conversion is important for antibody diversification in some higher vertebrates, such as chickens, rabbits and cows. In mice, however, conversion events appear to be infrequent 8 among endogenous antibody genes. Gene conversion is a distinct diversifying mechanism characterized by transfers of homologous sequences from a donor antibody V gene segment to an acceptor V gene segment. If donor and acceptor segments have numerous sequence differences then gene conversion can introduce a set of sequence changes into a V region by a single event. Depending on the species, gene conversion events can occur before and/or after antigen exposure during B cell differentiation (Tsai et al. International Immunology, Vol. 14, No. 1, 55-64, January 2002). Somatic hypermutation achieves diversification of antibody genes in all higher vertebrate. species. It is typified by the introduction of single point mutations into antibody V(D)J segments. Generally, hypermutation appears to be activated in B cells by antigenic stimulation. Production of Animals with Humanized Immune Systems In order to reduce the immunogenicity .of antibodies generated in mice for human therapeutics, various attempts h-ave-been made to replace.murine protein sequences with human protein sequences in a process now known as humanization. Transgenic mice have been constructed which have had their own immunoglobulin genes functionally replaced with human immunoglobulin genes so that they produce human antibodies upon immunization. Elimination of mouse antibody production was achieved by inactivation of mouse Ig genes in embryonic stem (ES) cells by using gene-targeting technology to delete crucial cis-acting sequences involved in the process of mouse Ig gene rearrangement and expression. B cell development in these mutant mice could be restored by the introduction of megabase-sized YACs containing a human germline-configuration H- and K L-chain minilocus transgene. The expression of fully human antibody in these transgenic mice was predominant, at a level of several 100 pg/l of blood. This level of expression is several hundred-fold higher than that detected in wild-type mice expressing the human Ig gene, indicating the importance of inactivating the endogenous mouse Ig genes in order to enhance human antibody production by mice. The first humanization attempts utilized molecular biology techniques to construct recombinant antibodies. For example, the complementarity determining regions (CDR) from a mouse antibody specific for a hapten were grafted onto a human antibody framework, effecting a CDR replacement. The new antibody retained the binding specificity conveyed by the CDR sequences (P. T. Jones et al. Nature 321: 522-525 (1986)). The next level of humanization 9 involved combining an entire mouse VH region with a human constant region such as gamma, (S. L. Morrison et al., Proc. NatI. Acad. Sci., 81, pp. 6851-6855 (1984)). However, these chimeric antibodies, which still contain greater than 30% xenogeneic sequences, are sometimes only marginally less immunogenic than totally xenogeneic antibodies (M. Bruggemann et al., J. Exp. Med., 170, pp. 2153-2157 (1989)). Subsequently, attempts were carried out to introduce human immunoglobulin genes into the mouse, thus creating transgenic mice capable of responding to antigens with antibodies having human sequences (Bruggemann et al. Proc. Nat'l. Acad. Sci. USA.86:6709-6713 (1989)). Due to the large size of human.immunoglobulin genomic loci, these attempts were thought to be limited by the amount of DNA, which could be stably maintained by available cloning vehicles. As a result, many investigators concentrated on producing mini-loci containing limited numbers of V region genes and having altered spatial distances between genes as compared to the natural or germline configuration (See, for example, U.S. Pat. No. 5,569,825). These studies indicated -that.producing.human sequence antib.odies-in-.mice.was possible,_but-serious obstacles remained regarding obtaining sufficient diversity of binding specificities and effector functions (isotypes) from these transgenic animals to meet the growing demand for antibody therapeutics. In order to provide additional diversity, work has been conducted to add large germline fragments of the human Ig locus into transgenic mammals. For example, a majority of the human V, D, and J region genes arranged with the same spacing found in the unrearranged germline of the human genome and the human Cp and CS constant regions was introduced into mice using yeast artificial chromosome (YAC) cloning vectors (See, for example, WO 94/02602). A 22 kb DNA fragment comprising sequences encoding a human gamma-2 constant region and the upstream sequences required for class-switch-recombination was latter appended to the -foregoing transgene. In addition, a portion of a human kappa locus comprising VK, JK and CK region genes, also arranged with substantially the same spacing found in the unrearranged germline of the human genome, was introduced into mice using YACS. Gene targeting was used to inactivate the murine IgH & kappa light chain immunoglobulin gene loci and such knockout strains were bred with the above transgenic strains to generate a line of mice having the human V, D, J, Cp, CS. and C7 2 constant regions as well as the human VK, JR and Cic region genes all on an inactivated murine immunoglobulin background (See, for example, PCT patent application WO 94/02602 to Kucherlapati et al.; see also Mendez et al., Nature Genetics 15:146-156 (1997)). 10 Yeast artificial chromosomes as cloning vectors in combination with gene targeting of endogenous loci and breeding of transgenic mouse strains provided one solution to the problem of antibody diversity. Several advantages were obtained by this approach. One advantage was that YACs can be used to transfer hundreds of kilobases of DNA into a host cell. Therefore, use of YAC cloning vehicles allows inclusion of substantial portions of the entire human Ig heavy and light chain regions into a transgenic mouse thus approaching the level of potential diversity available in the human. Another advantage of this approach is that the large number of V genes has been shown to restore full B cell development in mice deficient in murine immunoglobulin production. This ensures that these reconstituted mice are provided with the requisite cells for mounting a robust human antibody response to any given immunogen. (See, for example, WO 94/02602.; L. Green and A. Jakobovits, J. Exp. Med. 188:483495 (1998)). A further advantage is that sequences can be deleted or inserted onto the YAC by utilizing high frequency homologous recombination in yeast. This provides for facile engineering of the YAC transgenes. In addition,Green et al. NatureGenetics 7.:13-21 (1994)_describe the generation of YACs containing 245 kb and 190 kb-sized germline configuration fragments of the human heavy chain locus and kappa light chain locus, respectively, which contained core variable and constant region sequences. The work of Green et al. was recently extended to the introduction of greater than approximately 80% of the human antibody repertoire through introduction of megabase sized, germline configuration YAC fragments of the human heavy chain loci and kappa light chain loci, respectively, to produce XenoMouse'm mice. See, for example, Mendez et al. Nature Genetics 15:146-156 (1997), Green and Jakobovits J. Exp. Med. 188:483-495 (1998), European Patent No. EP 0 463 151 BI, PCT Publication Nos. WO 94/02602, WO 96/34096 and WO 98/24893. Several strategies exist for the generation of mammals that produce human antibodies. In particular, there is the "minilocus" approach that is typified by work of GenPharm International, Inc. and the Medical Research Council, YAC introduction of large and substantially germline fragments of the Ig loci that is typified by work of Abgenix, Inc. (formerly Cell Genesys). The introduction of entire or substantially entire loci through the use microcell fusion as typified by work of Kirin Beer Kabushiki Kaisha. In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus. Thus, one or more VH genes, one or more DH genes, 11 one or more JH genes, a mu constant region, and a second constant region (such as a gamma constant region) are formed into a construct for insertion into an animal. See, for example, U.S. Patent Nos. 5,545,807, 5,545,806, 5,625,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, 5,789,650, 5,814,318, 5,591,669, 5,612,205, 5,721,367, 5,789,215, 5,643,763; European Patent No. 0 546 073; PCT Publication Nos. WO 92/03918, WO 92/22645, WO 92/22647, WO 92/22670, WO 93/12227, WO 94/00569, WO 94/25585, WO 96/14436, WO 97/13852, and WO 98/24884; Taylor et al. Nucleic Acids Research 20:6287-6295 (1992), Chen et al. International Immunology 5:647-656 (1993), Tuaillon et al. J. Immunol. 154:6453-6465 (1995), Choi et al. Nature Genetics 4:117-123 (1993), Lonberg et al. Nature 368:856-859 (1994), Taylor et al. International Immunology 6:579-591 (1994), Tuaillon et al. J. Immunol. 154:6453-6465 (1995), and Fishwild et al. Nature Biotech. 14:845-851 (1996). In the microcell fusion approach, portions or whole human chromosomes can be introduced into mice (see, for example, European Patent Application No. EP 0 843 961 Al). _M'ige_ gengated.ig .thisappoach_and.oatainingjhe .human Igjeavy .chain locus will generally possess more than one, and potentially all, of the human constant region genes. Such mice will produce, therefore, antibodies that bind to particular antigens having a number of different constant regions. While mice remain the most developed animal for the expression of human immunoglobulins in humans, recent technological advances have allowed for progress to begin in applying these techniques to other animals, such as cows. The general approach in mice has been to genetically modify embryonic stem cells of mice to knock-out murine inununoglobulins and then insert YACs containing human immunoglobulins into the ES cells. However, ES cells are not available for cows or other large animals such as sheep and pigs. Thus, several fundamental developments had to occur before even the possibility existed to generate large animals with immunoglobulin genes knocked-out and that express human antibody. The alternative to ES cell manipulation to create genetically modified animals is cloning using somatic cells that have been genetically modified. Cloning using genetically modified somatic cells for nuclear transfer has only recently been accomplished. Since the announcement of Dolly's (a cloned sheep) birth from an adult somatic cell in 1997 (Wilmut, I., et al (1997) Nature 385: 810-813), ungulates, including cattle (Cibelli, J et al 1998 Science 280: 1266-1258; Kubota, C. et al.2000 Proc. Natl. Acad. Sci 97: 990-995), goats 12 (Baguisi, A. et al., (1999) Nat. Biotechnology 17: 456-461), and pigs (Polejaeva, I.A., et al. 2000 Nature 407: 86-90; Betthauser, J. et al. 2000 Nat. Biotechnology 18: 1055-1059) have been cloned. The next technological advance was the development of the technique to genetically modify the cells prior to nuclear transfer to produce genetically modified animals. PCT publication No. WO 00/51424 to PPL Therapeutics describes the targetted genetic modification of somatic cells for nuclear transfer. Subsequent to these fundamental developments, single and double allele knockouts of genes and the birth of live animals with these modifications have been reported. Between 2002 and 2004, three independent groups, Immerge Biotherapeutics, Inc. in collaboration with the University of Missouri (Lai et al. (Science (2002) 295: 1089-1092) & Kolber-Simonds et al. (PNAS. (2004) 101(19):7335-40)), Alexion Pharmaceuticals (Ramsoondar et al. (Biol Reprod (2003)69: 437-445) and Revivicor, Inc. (Dai et al. (Nature Biotechnology (2002) 20: 251-255) & . Phelps. et al. (Science (2003) Jan 17;299(56.05):411-4)) produced pigs that lacked one allele or both alleles of the alpha-1,3-GT gene via nuclear transfer from somatic cells with targeted genetic deletions. In 2003, Sedai et al. (Transplantation (2003) 76:900-902) reported the targeted disruption of one allele of the alpha-1,3-GT gene in cattle, followed by the successful nuclear transfer of the nucleus of the genetically modified cell and production of transgenic fetuses. Thus, the feasibility of knocking-out immunoglobulin genes in large animals and inserting human immunoglobulin loci into their cells is just now beginning to be explored. However, due to the complexity and species differences of immunoglobulin genes, the genomic sequences and arrangement of Ig kappa, lambda and heavy chains remain poorly understood in most species. For example, in pigs, partial genomic sequence and organization has only been described for heavy chain constant alpha, heavy chain constant mu and heavy chain constant delta (Brown and Butler Mol Immunol. 1994 Jun;31(8):633-42, Butler et al Vet Immunol Immunopathol. 1994 Oct;43(1-3):5-12, and Zhao et al J Immunol. 2003 Aug 1;171(3):1312-8). In cows, the immunoglobulin heavy chain locus has been mapped (Zhao et al. 2003 J. Biol. Chem. 278:35024-32) and the cDNA sequence for the bovine kappa gene is known (See, for example, U.S. Patent Publication No. 2003/0037347). Further, approximately 4.6kb of the bovine mu heavy chain locus has been sequenced and transgenic calves with decreased expression of heavy chain immunoglobulins have been created by disrupting one or both alleles 13 of the bovine mu heavy chain. In addition, a mammalian artificial chromosome (MAC) vector containing the entire unarranged sequences of the human Ig H-chain and K L-chain has been introduced into cows (TC cows) with the technology of microcell-mediated chromosome transfer and nuclear transfer of bovine fetal fibroblast cells (see, for example, Kuroiwa et al. 2002 Nature Biotechnology 20:889, Kuroiwa et al. 2004 Nat Genet. Jun 6 Epub, U.S. Patent Publication Nos. 2003/0037347, 2003/0056237, 2004/0068760 and PCT Publication No. WO 02/07648). While significant progress has been made in the production of bovine that express human imnmunoglobulin, little has been accomplished in other large animals, such as sheep, goats and . pigs. Although cDNA sequence information for immunoglobulin genes of sheeps, goats and pigs is readily available in Genbank, the unique nature of immunoglobulin loci, which undergo massive rearrangements, creates the need to characterize beyond sequences known to be present in mRNAs (or cDNAs). Since immunoglobulin loci are modular and the coding regions are redundant, deletion of a known coding region does not ensure altered function of the locus. For example, if-one were to delete the coding region of a heavy-chain variable region, the function of the locus would not be significantly altered because hundreds of other function variable genes remain in the locus. Therefore, one must first characterize the locus to identify a potential "Achilles heel". Despite some advancements in expressing human antibodies in cattle, greater challenges remain for inactivation of the endogenous bovine Ig genes, increasing expression levels of the human antibodies and creating human antibody expression in other large animals, such as porcine, for which the sequence and arrangement of immunoglobulin genes are largely unknown. It is therefore an object of the present invention to provide the arrangement of ungulate immunoglobin .germline gene sequence. It is another object of the presenst invention to provide novel ungulate immunoglobulin genomic sequences. It is a further object of the present invention to provide cells, tissues and animals lacking at least one allele of a heavy and/or light chain immunoglobulin gene. It is another object of the present invention to provide ungulates that express human immunoglobulins. 14 It is a still further object of the present invention to provide methods to generate cells, tissues and animals lacking at least'one allele of novel ungulate immunoglobulin gene sequences and/ or express human immunoglobulins. SUMMARY OF THE INVENTION The present invention provides for the first time ungulate immunoglobin germline gene sequence arrangement as well as novel genomic sequences thereof. In addition, novel ungulate cells, tissues and animals that lack at least one allele of a heavy or light chain immunoglobulin gene are provided. Based on this discovery, ungulates can be produced that completely lack at least one allele of a heavy and/or light chain immunoglobulin gene. In addition, these ungulates can be further modified to express xenoogenous, such as human, immunoglobulin loci or fragments thereof. . In one aspect pf the present invention,. a transgenic ungulate. that lacks any expression of functional endogenous immunoglobulins is provided. In one embodiment, the ungulate can lack any expression of endogenous heavy and/ or light chain immunoglobulins. The light chain immunoglobulin can be a kappa and/ or lambda immunoglobulin. In additional embodiments, transgenic ungulates are provided that lack expression of at least one allele of an endogenous inimunoglobulin wherein the immunoglobulin is selected from the group consisting of heavy chain, kappa light chain and lambda light chain or any combination thereof. In one embodiment, the expression of functional endogenous immunoglobulins can be accomplished by genetic targeting of the endogenous immunoglobulin loci to prevent expression of the endogenous immunoglobulin. In one embodiment, the genetic targeting -can be accomplished via homologous recombination. In another embodiment, the transgenic ungulate can be produced via nuclear transfer. In other embodiments, the transgenic ungulate that lacks any expression of functional endogenous immunoglobulins can be further genetically modified to express an xenogenous immunoglobulin loci. In an alternative embodiment, porcine animals are provided that contain an xenogeous immunoglobulin locus. In one embodiment, the xenogeous immunoglobulin loci can be a heavy and/ or light chain immunoglobulin or fragment thereof. In another embodiment, the xenogenous immunoglobulin loci can be a kappa chain locus or fragment thereof and/ or a 15 lambda chain locus or fragment thereof. In still further embodiments, an artificial chromosome (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human immunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof. In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement.- In a further embodiment, the human immunoglobulin loci can include any fragment of a human immunoglobulin heavy chain and a human immunoglobulin light chain that can undergo rearrangement. In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens. In another. aspeptof_ the presenj_invenion, transgenic uingulates are provided that expresses a xenogenous immunoglobulin loci or fragment thereof, wherein the immunoglobulin can be expressed from an immunoglobulin locus that is integrated within an endogenous ungulate chromosome. In one embodiment, ungulate cells derived from the transgenic animals are provided. In one embodiment, the xenogenous immunoglobulin locus can be inherited by offspring. In another embodiment, the xenogenous immunoglobulin locus can be inherited through the male germ line by offspring. In still further embodiments, an artificial chromosome (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human immunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement. In a further embodiment, the human immunoglobulin loci can include any fragment of a human immunoglobulin heavy chain and a human immunoglobulin light chain that can undergo rearrangement. In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular 16 embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens. In another aspect of the present invention, novel genomic sequences encoding the heavy chain locus of ungulate immunoglobulin are provided. In one embodiment, an isolated nucleotide sequence encoding porcine heavy chain is provided that includes at least one variable region, two diversity regions, at least four joining regions and at least one constant region, such as the mu constant region, for example, as represented in Seq ID No. 29. In another embodiment, an isolated nucleotide sequence is provided that includes at least four joining regions and at least one constant region, such as as the mu constant region, of the porcine heavy chain genomic sequence, for example, as represented in Seq ID No. 4. In a further embodiment, nucleotide sequence is provided that includes 5' flanking sequence to the first joining region of the porcine heavy chain genomic sequence, for example, as represented in Seq ID No 1. Still further, nucleotide sequence is provided that includes 3' flanking sequence to the first joining region of the porcine heavy chain.genomic sequepce,for example, as represented in the 3'*region .of Seq ID No 4. In further embodiments, isolated nucleotide sequences as depicted in Seq ID Nos 1, 4 or 29 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous to Seq ID Nos 1, 4 or 29 are also provided. In addition, nucleotide sequences that contain at least 10, 15, 17, 20, 25 or 30 contiguous nucleotides of Seq ID Nos 1, 4 or 29 are provided. In one embodiment, the nucleotide sequence contains at least 17, 20, 25 or 30 contiguous nucleotides of Seq ID No 4 or residues.1- 9,070 of Seq ID No 29. In another embodiment, the nucleotide sequence contains residues 9,070-11039 of Seq ID No 29. Further provided are nucleotide sequences that hybridizes, optionally under stringent conditions, to Seq ID Nos 1, 4 or 29, as well as, nucleotides homologous thereto. In another embodiment, novel genomic sequences encoding the kappa light chain locus of ungulate immunoglobulin are provided. The present invention provides the first reported genomic sequence of ungulate kappa light chain regions. In one embodiment, nucleic acid sequence is provided that encodes the porcine kappa light chain locus. In another embodiment, the nucleic acid sequence can contain at least one joining region, one constant region and/or one enhancer region of kappa light chain. In a further embodiment, the nucleotide sequence can include at least five joining regions, one constant region and one enhancer region, for example, as represented in Seq ID No. 30. In a further embodiment, an isolated nucleotide sequence is 17 provided that contains at least one, at least two, at least three, at least four or five joining regions and 3' flanking sequence to the joining region of porcine genomic kappa light chain, for example, as represented in Seq ID No 12. In another embodiment, an isolated nucleotide sequence of porcine genomic kappa light chain is provided that contains 5' flanking sequence to the first joining region, for example, as represented in Seq ID) No 25. In a further embodiment, an isolated nucleotide sequence is provided that contains 3' flanking sequence to the constant region and, optionally, the 5' portion of the enhancer region, of porcine genomic kappa light chain, for example, as represented in Seq ID Nos. 15, 16 and/or 19. In further embodiments, isolated nucleotide sequences as depicted in Seq ID Nos 30, 12, 25, 15, 16 or 19 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous -to Seq ID Nos 30, 12, 25, 15, 16 or 19 are also provided. In addition, nucleotide sequences that contain at least 10, 15, 17, 20, 25 or 30 contiguous nucleotides of Seq ID) Nos 30, 12, 25, 15, 16 or 19 are provided. Further provided are nucleotide sequences that hybridizes, optionally under-stringent.-conditions, to -SeqID .Nos 30, 12, 25, 15,. 16 or 19, as well as, nucleotides homologous thereto. In another embodiment, novel genomic sequences encoding the lambda light chain locus of ungulate immunoglobulin are provided. The present invention provides the first reported genomic sequence of ungulate lambda light chain regions. In one embodiment, the porcine lambda light chain nucleotides include a concatamer of J to C units. In a specific embodiment, an isolated porcine lambda nucleotide sequence is provided, such as that depicted in Seq ID) No. 28. . In one embodiment, nucleotide sequence is provided that includes 5' flanking sequence to the first lambda J/C region of the porcine lambda light chain genomic sequence, for example, as represented by -Seq ID No 32. Still further, nucleotide sequence is provided that includes 3' flanking sequence to the J/C cluster region of the porcine lambda light chain genomic sequence, for example, approximately 200 base pairs downstream of lambda J/C, such as that represented by Seq ID No 33. Alternatively, nucleotide sequence is provided that includes 3' flanking sequence to the J/C cluster region of the porcine lambda light chain genomic sequence, for example, as represented by Seq ID No 34, 35, 36, 37, 38, and/or 39. In a further embodiment, nucleic acid sequences are provided that encode bovine lambda light chain locus, which can include at least one joining region-constant region pair and/or at least one variable region, for example, as represented by Seq ID No. 31. In further embodiments, isolated nucleotide 18 sequences as depicted in Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous to Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39 are also provided. In addition, nucleotide sequences that contain at least 10, 15, 17, 20, 25 or 30 contiguous nucleotides of Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39 are provided. Further provided are nucleotide sequences that hybridizes, optionally under stringent conditions, to Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39, as well as, nucleotides homologous thereto. In another embodiment, nucleic acid targeting vector constructs are also provided. The targeting vectors can be designed to accomplish homologous recombination in cells. These targeting vectors can be transformed into mammalian cells to target the ungulate heavy chain, kappa light chain or lambda -light chain genes via homologous recombination. In one embodiment, the targeting vectors can contain a 3' recombination arm and a 5' recombination arm (i.e. flanking sequence) that is homologous to the genomic sequence of ungulate heavy chain, kappa light chain or lambda_ lightchain genomic sequence, for example, sequence represented by Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. The homologous DNA sequence can include at least 15 bp, 20 bp, 25 bp, 50 bp, 100 bp, 500 bp, lkbp, 2 kbp, 4 kbp, 5 kbp, 10 kbp, 15 kbp, 20 kbp, or 50 kbp of sequence homologous to the genomic sequence. The.3' and 5' recombination arms can be designed such that they flank the 3' and 5' ends of at least one functional variable, joining, diversity, and/or constant region of the genomic sequence. The targeting of a functional region can render it inactive, which results in the inability of the cell to produce functional immunoglobulin molecules. In another embodiment, the homologous DNA sequence can include one or more intron and/or exon sequences. In addition to the nucleic acid sequences, the expression vector can contain selectable marker sequences, such as, for example, enhanced Green Fluorescent Protein (eGFP) gene sequences, initiation and/or enhancer sequences, poly A-tail sequences, and/or nucleic acid sequences that provide for the expression of the construct in prokaryotic and/or eukaryotic host cells. The selectable marker can be located between the 5' and 3' recombination arm sequence. In one particular embodiment, the targeting vector can contain 5' and 3' recombination arms that contain homologous sequence to the 3' and 5' flanking sequence of the J6 region of the porcine immunoglobulin heavy chain locus. Since the J6 region is the only functional joining region of the porcine immunoglobulin heavy chain locus, this will prevent the exression of a 19 functional porcine heavy chain immunoglobulin. In a specific embodiment, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the J6 region, including Jl-4, and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the J6 region, including the mu constant region (a "J6 targeting construct"), see for example, Figure 1. Further, this J6 targeting construct can also contain a selectable marker gene that is located between the 5' and 3' recombination arms, see for example, Seq ID No 5 and Figure 1. In other embodiments, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the diversity region, and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the diversity.region of the porcine heavy chain locus. In a further embodiment, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the mu constant region and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the mu constant region of the porcine heavy chain locus. . In ..another .particular. embodiment,.. the targeting vector can contain 5' and 3' recombination arms that contain homologous sequence to the 3' and 5' flanking sequence of the constant region of the porcine immunoglobulin heavy chain locus. Since the present invention discovered that there is only one constant region of the porcine immunoglobulin kappa light chain locus, this will prevent the expression of a functional porcine kappa light chain immunoglobulin. In a specific embodiment, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the constant region, optionally including the joining region, and a* 3' recombination arm that contains sequence homologous to genomic sequence 3' of the constant region, optionally including at least part of the enhancer region (a "Kappa constant targeting construct"), see for example, Figure 2. Further, this kappa constant targeting construct can also contain a selectable marker gene that is located between the 5' and 3' recombination arms, see for example, Seq ID No 20 and Figure 2. In other embodiments, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the joining region, and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the joining region of the porcine kappa light chain locus. In another embodiment, primers are provided to generate 3' and 5' sequences of a targeting vector. The oligonucleotide primers can be capable of hybridizing to porcine 20 immunoglobulin genomic sequence, such as Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. In a particular embodiment, the primers hybridize under stringent conditions to Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. Another embodiment provides oligonucleotide probes capable of hybridizing to porcine heavy chain, kappa light chain or lambda light chain nucleic acid sequences, such as Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. The polynucleotide primers or probes can have at least 14 bases, 20 bases, 30 bases, or 50 bases which hybridize to a polynucleotide of the present invention. The probe or primer can be at least 14 nucleotides in length, and in a. particular embodiment, are at least 15, 20, 25, 28, or 30 nucleotides in length. In one embodiment, primers are provided to amplify a fragment of porcine Ig heavy chain that includes the functional joining region (the J6 region). In one non-limiting embodiment, the amplified fragment of heavy chain can be represented by Seq ID No 4 and the primers used to amplify this fragment can be complementary to a portion of the J-region, such as, but not limited. to.Seq ID No 2, to produce .the 5'. recombination arm.and complementary to a portion of Ig heavy-chain mu constant region, such as, but not limited to Seq ID No 3,-to produce the 3' recombination arm. In another embodiment, regions of the porcine Ig heavy chain (such as, but not limited to Seq ID No 4) can be subcloned and assembled into a targeting vector. In other embodiments, primers are provided to amplify a fragment of porcine Ig kappa light-chain that includes the constant region. In another embodiment, primers are provided to amplify a fragment of porcine Ig kappa light-chain that includes the J region. In one non limiting embodiment, the primers used to amplify this fragment can be complementary to a portion of the J-region, such as, but not limited to Seq ID) No 21 or 10, to produce the 5' recombination arm and complementary to genomic sequence 3' of the constant region, such as, but not limited to Seq ID No 14, 24 or 18, to produce the 3' recombination arm. In another embodiment, regions of the porcine Ig heavy chain (such as, but not limited to Seq ID No 20) can be subcloned and assembled into a targeting vector. In another aspect of the present invention, ungulate cells lacking at least one allele of a functional region of an ungulate heavy chain, kappa light chain and/or lambda light chain locus produced according to the process, sequences and/or constructs described .herein are provided. These cells can be obtained as a result of homologous recombination. Particularly, by inactivating at least one allele of an ungulate heavy chain, kappa light chain or lambda light 21 chain gene, cells can be produced which have reduced capability for expression of ungulate antibodies. In other embodiments, mammalian cells lacking both alleles of an ungulate heavy chain, kappa light chain and/or lambda light chain gene can be produced according to the process, sequences and/or constructs described herein. In a further embodiment, porcine animals are provided in which at least one allele of an ungulate heavy chain, kappa light chain and/or lambda light chain gene is inactivated via a genetic targeting event produced according to the process, sequences and/or constructs described herein. In another aspect of the present invention, porcine animals are provided in which both alleles of an ungulate heavy chain, kappa light chain and/or lambda light chain gene are inactivated via a genetic targeting event. The gene can be targeted via homologous recombination. In other embodiments, the gene can be disrupted, i.e. a portion of the genetic code can be altered, thereby affecting transcription and/or translation of that segment of the gene. For example, disruption of a gene can occur through substitution, deletion ("knock-out") or insertion ("knoc-in)_techniques. Additional genes for a desired- protein or regulaory sequence that modulate transcription of an existing sequence can be inserted. To achieve multiple genetic modifications of ungulate immunoglobulin genes, in one embodiment, cells can be modified sequentially to contain multiple genentic modifications. In other embodiments, animals can be bred together to produce animals that contain multiple genetic modifications of immunoglobulin genes. . As an illustrative example, animals that lack expression of at least one allele of an ungulate heavy chain gene can be further genetically modified or bred with animals lacking at least one allele of a kappa light chain gene. In embodiments of the present invention, alleles of ungulate heavy chain, kappa light chain. or-lambda light chain gene are rendered inactive according to the process, sequences and/or constructs described herein, such that functional ungulate immunoglobulins can no longer be produced. In one embodiment, the targeted immunoglobulin gene can be transcribed into RNA, but not translated into protein. In another embodiment, the targeted immunoglobulin gene can be transcribed in an inactive truncated form. Such a truncated RNA may either not be translated or can be translated into a nonfunctional protein. In an alternative embodiment, the targeted immunoglobulin gene can be inactivated in such a way that no transcription of the gene occurs. In a further embodiment, the targeted immunoglobulin gene can be transcribed and then translated into a nonfunctional protein. 22 In a further aspect of the present invention, ungulate, such as porcine or bovine, cells lacking one allele, optionally both alleles of an ungulate heavy chain, kappa light chain and/or lambda light chain gene can be used as donor cells for nuclear transfer into recipient cells to produce cloned, transgenic animals. Alternatively, ungulate heavy chain, kappa light chain and/or lambda light chain gene knockouts can be created in embryonic stem cells, which are then used to produce offspring. Offspring lacking a single allele of a functional ungulate heavy chain, kappa light chain and/or lambda light chain gene produced according to the process, sequences and/or constructs described herein can be breed to further produce offspring lacking functionality in both alleles through mendelian type inheritance. In one aspect of the present invention, a method is provided to disrupt the expression of an ungulate immunoglobulin gene by (i) analyzing the germline configuration of the ungulate heavy chain, kappa light chain or lambda light chain genomic locus; (ii) determining the location of nucleotide sequences that flank the 5' end and the 3' end of at least one functional region of .the.lqys; and (iii) transfecting a tageing.gQnstruct containingnthe Ranking sequence into a cell wherein, upon successful homologous recombination, at least one functional region of the immunoglobulin locus is disrupted thereby reducing or preventing the expression of the inimunoglobulin gene. In one embodiment, the germline configuration of the porcine heavy chain locus is provided. The porcine heavy chain locus contains at least four variable regions, two diversity regions, six joining regions and five constant regions, for example, as illustrated in Figure 1. In a specific embodiment, only one of the six joining regions, J6, is functional. In another embodiment, the germline configuration of the porcine kappa light chain locus is provided. The porcine kappa light chain locus contains at least six variable regions, six joining regions, one constant region and one enhancer region, for example, as illustrated in Figure 2. In a further embodiment, the germline configuration of the porcine lambda light chain locus is provided. In further aspects of the present invention provides ungulates and ungulate cells that lack at least one allele of a functional region of an ungulate heavy chain, kappa light chain and/or lambda light chain locus produced according to the processes, sequences and/or constructs described herein, which are further modified to express at least part of a human antibody (i.e. immunoglobulin (Ig)) locus. In additional embodiments, porcine animals are provided that express xenogenous immunoglobulin. This human locus can undergoe rearrangement and 23 express a diverse population of human antibody molecules in the ungulate. These cloned, transgenic ungulates provide a replenishable, theoretically infinite supply of human antibodies (such as polyclonal antibodies), which can be used for therapeutic, diagnostic, purification, and other clinically relevant purposes. In one particular embodiment, artificial chromosomes (ACs), such as yeast or mammalian artificial chromosomes (YACS or MACS) can be used to allow expression of human immunoglobulin genes into ungulate cells and animals. All or part of human inimunoglobulin genes, such as the Ig heavy chain gene (human chromosome 414), Ig kappa chain gene (human chromosome #2) and/or the Ig lambda chain gene (chromosome #22) . can be inserted into the artificial chromosomes, which can then be inserted into ungulate cells. In further embodiments, ungulates and ungulate cells are provided that contain either part or all of at least one human antibody gene locus, which undergoes rearrangement and expresses a diverse population of human antibody molecules. In additional embodiments, methods of producing xenogenous antibodies are provided, wherein the method can -include:_(a). administering one_ or more antigens of interest to an ungulate whose cells comprise one or more artificial chromosomes and lack any expression of functional endogenous immunoglobulin, each artificial chromosome comprising one or more xenogenous immunoglobulin loci that undergo rearrangement, resulting in production of xenogenous antibodies against the one or more antigens; and/ or (b) recovering the xenogenous antibodies from the ungulate. In one embodiment, the immunoglobulin loci can undergo rearrangement in a B cell. In one aspect of the present invention, an ungulate, such as a pig or a cow, can be prepared by a method in accordance with any aspect of the present invention. These cloned, transgenic ungulates (e.g., porcine and bovine .animals) provide a replenishable, theoretically infinite supply of human polyclonal antibodies, which can be used as therapeutics, diagnostics and for purification purposes. For example, transgenic animals produced according to the process, sequences and/or constructs described herein that produce polyclonal human antibodies in the bloodstream can be used to produce an array of different antibodies which are specific to a desired antigen. The availability of large quantities of polyclonal antibodies can also be used for treatment and prophylaxis of infectious disease, vaccination against biological warfare agents, modulation of the immune system, removal of undesired human cells such as cancer cells, and modulation of specific human molecules. 24 In other embodiments, animals or cells lacking expression of functional immunoglobulin, produced according to the process, sequences and/or constructs described herein, can contain additional genetic modifications to eliminate the expression of xenoantigens. Such animals can be modified to elimate the expression of at least one allele of the alpha-1,3-galactosyltransferase gene, the CMP-Neu5Ac hydroxylase gene (see, for example, USSN 10/863,116), the iGb3 synthase gene (see, for example, U.S. Patent Application 60/517,524), and/or the Forssman synthase gene (see, for example, U.S. Patent Application 60/568,922). In additional embodiments, the animals discloses herein can also contain genetic modifications to expresss fucosyltransferase and/ or sialyltransferase. To achieve these additional genetic modifications, in one embodiment, cells can be modified to contain multiple genentic modifications. In other embodiments, animals can be bred together to achieve multiple genetic modifications. In one specific embodiment, animals, such as pigs, lacking expression of functional immunoglobulin, produced according to the process, sequences and/or constructs described herein, can be bred with animals, such as pigs, lacking expression of alpha-1,3-galactosyl transferase (for example, as described in WO 04/028243). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the design of a targeting vector that disrupts the expression of the joining region of the porcine heavy chain immunoglobulin gene. Figure 2 illustrates the design of a targeting vector that disrupts the expression of the constant region of the porcine kappa light chain immunoglobulin gene. Figure 3 illustrates the genomic organization of the porcine lambda immunoglobulin locus, including a concatamer of J-C sequences as well as flanking regions that include the variable region 5' to the JC region. Bacterial artificial chromosomes (BAC1 and BAC2) represent fragments of the porcine immunoglobulin genome that can be obtained from BAC libraries. Figure 4 represents the design of a targeting vector that disrupts the expression of the JC clusterregion of the porcine lambda light chain immunoglobulin gene. "SM" stands for a selectable marker gene, which can be used in the targeting vector. 25 Figure 5 illustrates a targeting strategy to insert a site specific recombinase target or recognition site into the region 5' of the JC cluster region of the porcine lambda immunoglobulin locus. "SM" stands for a selectable marker gene, which can be used in the targeting vector. "S SRRS" stands for a specific recombinase target or recognition site. Figure 6 illustrates a targeting strategy to insert a site specific recombinase target or recognition site into the region 3' of the JC cluster region of the porcine lambda immunoglobulin locus. "SM" stands for a selectable marker gene, which can be used in the targeting vector. "SSRRS" stands for a specific recombinase target or recognition site. Figure 7 illustrates the site specific recombinase mediated transfer of a YAC into a host genome. "SSRRS" stands for a specific recombinase target or recognition site. DETAILED DESCRIPTION The present invention provides for the first time ungulate immunoglobin germline gene sequence arrangement as well as novel genomic sequences thereof. In addition, novel ungulate cells, tissues and animals that lack at least one allele of a heavy or light chain immunoglobulin gene are provided. Based on this discovery, ungulates can be produced that completely lack at least one allele of a heavy and/or light chain immunoglobulin gene. In addition, these ungulates can be further modified to express xenoogenous, such as human, immunoglobulin loci or fragments thereof. In one aspect of the present invention, a transgenic ungulate that lacks any expression of functional endogenous immunoglobulins is provided. In one embodiment, the ungulate can lack -any expression of endogenous heavy and/ or light chain immunoglobulins. The light chain immunoglobulin can be a kappa and/ or lambda immunoglobulin. In additional embodiments, transgenic ungulates are provided that lack expression of at least one allele of an endogenous immunoglobulin wherein the immunoglobulin is selected from the group consisting of heavy chain, kappa light chain and lambda light chain or any combination thereof. In one embodiment, the expression of functional endogenous immunoglobulins can be accomplished by genetic targeting of the endogenous immunoglobulin loci to prevent expression of the endogenous immunoglobulin. In one embodiment, the genetic targeting can be accomplished via 26 homologous recombination. In another embodiment, the transgenic ungulate can be produced via nuclear transfer. In other embodiments, the transgenic ungulate that lacks any expression of functional endogenous immunoglobulins can be further genetically modified to express an xenogenous immunoglobulin loci. In an alternative embodiment, porcine animals are provided that contain an xenogeous immunoglobulin locus. In one embodiment, the xenogeous immunoglobulin loci can be a heavy and/ or light chain immunoglobulin or fragment thereof. In another embodiment, the xenogenous immunoglobulin loci can be a kappa chain locus or fragment thereof and/ or a. lambda chain locus or fragment thereof. In still further embodiments, an artificial chromosome (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human immunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof. In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement In a further embodiment, the human immunoglobulin loci can include any fragment of a human immunoglobulin heavy chain and a human immunoglobulin light chain that can undergo rearrangement In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens. In another aspect of the present invention, transgenic ungulates are provided that expresses a xenogenous immunoglobulin loci or fragment thereof, wherein the immunoglobulin can be expressed from an immunoglobulin locus that is integrated within an endogenous ungulate chromosome. In one embodiment, ungulate cells derived from the transgenic animals are provided. In one embodiment, the xenogenous immunoglobulin locus can be inherited by offspring. In another embodiment, the xenogenous immunoglobulin locus can be inherited through the male germ line by offspring. In still further embodiments, an artificial chromosome (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human immunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin 27 locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof. In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement. In a further embodiment, the human immunoglobulin loci can include any fragment of a human immunoglobulin heavy chain and a human immunoglobulin light chain that can undergo rearrangement. In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens. Definitions The terms "recombinant DNA technology," "DNA cloning," "molecular cloning," or "gene cloning" refer to the process of transferring a DNA sequence into a cell or orgaism. The transfer of a DNA fragment can be from one organism to a self-replicating genetic element (e.g., bacterial plasmid) that permits a copy of any specific part of a DNA (or RNA) sequence to be selected among many others and produced in an unlimited amount. Plasmids and other types of cloning vectors such as artificial chromosomes can be used to copy genes and other pieces of chromosomes to generate enough identical material for further study. In addition to bacterial plasmids, which can carry up to 20 kb of foreign DNA, other cloning vectors include viruses, cosmids, and artificial chromosomes (e.g., bacteria artificial chromosomes (BACs) or yeast artificial chromosomes (YACs)). When the fragment of chromosomal DNA is ultimately joined with its cloning vector in the lab, it is called a "recombinant DNA molecule." Shortly after the recombinant plasmid is introduced into. suitable -host cells, the newly inserted segment will be reproduced along with the host cell DNA. "Cosmids" are artificially constructed cloning vectors that carry up to 45 kb of foreign DNA. They can be packaged in lambda phage particles for infection into E. coli cells. As used herein, the term "mammal" (as in "genetically modified (or altered) mammal") is meant to include any non-human mammal, including but not limited to pigs, sheep, goats, cattle (bovine), deer, mules, horses, monkeys, dogs, cats, rats, mice, birds, chickens, reptiles, fish, and insects. In one embodiment of the invention, genetically altered pigs and methods of production thereof are provided. 28 The term "ungulate" refers to hoofed mammals. Artiodactyls are even-toed (cloven hooved) ungulates, including antelopes, camels, cows, deer, goats, pigs, and sheep. Perissodactyls are odd toes ungulates, which. include horses, zebras, rhinoceroses, and tapirs. The term ungulate as used herein refers to an adult, embryonic or fetal ungulate animal. As used herein, the terms "porcine", "porcine animal", "pig" and "swine" are generic terms referring to the same type of animal without regard to gender, size, or breed. A "homologous DNA sequence or homologous DNA" is a DNA sequence that is at least about 80%, 85%, 90%, 95%, 98% or 99% identical with a reference DNA sequence. A. homologous sequence hybridizes under stringent conditions to the target sequence, stringent hybridization conditions include those that will allow hybridization occur if there is at least 85, at least 95% or 98% identity between the sequences. An "isogenic or substantially isogenic DNA sequence" is a DNA sequence that is identical to or nearly identical to a reference DNA sequence. The term "substantially isogenic" .refers to DNA that is at least about 97-99% identical with the reference DNA sequence, or at least about 99.5-99.9% identical with the reference DNA sequence, and in certain-uses 100% identical with the reference DNA sequence. "Homologous recombination" refers to the process of DNA recombination based on sequence homology. "Gene targeting" refers to homologous recombination between two DNA sequences, one of which is located on a chromosome and the other of which is not. "Non-homologous or random integration" refers to any process by which DNA is integrated into the genome that does not involve homologous recombination. A "selectable marker gene" is a gene, the expression of which allows cells containing the gene to be identified. A selectable marker can be one that allows a cell to proliferate on a medium that prevents or slows the growth of cells without the gene. Examples include antibiotic resistance genes and genes which allow an organism to grow on a selected metabolite. Alternatively, the gene can facilitate visual screening of transformants by conferring on cells a phenotype that is easily identified. Such an identifiable phenotype can be, for example, the production of luminescence or the production of a colored compound, or the production of a detectable change in the medium surrounding the cell. 29 The term "contiguous" is used herein in its standard meaning, i.e., without interruption, or uninterrupted. "Stringent conditions" refers to conditions that (1) employ low ionic strength and high temperature for washing, for example, 0.015 M NaCI/0.0015 M sodium citrate/0.1% SDS at 50*C, or (2) employ during hybridization a denaturing agent such as, for example, formamide. One skilled in the art can determine and vary the stringency conditions appropriately to obtain a clear and detectable hybridization signal. For example, stringency can generally be reduced by increasing the salt content present during hybridization and washing, reducing the temperature, or a combination thereof. See, for example, Sambrook et aL, Molecular Cloning: A Laboratory Manual, Cold Spring Harbour Laboratory Press, Cold Spring Harbour, New York, (1989). I. Immunoglobulin Genes In one aspect of the present invention, a transgenic ungulate that lacks any expression of functional endogenous immunoglobulins is provided._In one embodiment, the ungulate can lack any expression of endogenous heavy and/ or light chain immunoglobulins. The light chain immunoglobulin can be a kappa and/ or lambda immunoglobulin. In additional embodiments, transgenic ungulates are provided that lack expression of at least one allele of an endogenous immunoglobulin wherein the immunoglobulin is selected from the group consisting of heavy chain, kappa light chain and lambda light chain or any combination thereof. In one embodiment, the expression of functional endogenous immunoglobulins can be accomplished by genetic targeting of the endogenous immunoglobulin loci to prevent expression of the endogenous immunoglobulin. In one embodiment, the genetic targeting can be accomplished via homologous recombination. In another embodiment, the transgenic ungulate can be produced via nuclear transfer. In another aspect of the present invention, a method is provided to disrupt the expression of an ungulate immunoglobulin gene by (i) analyzing the germline configuration of the ungulate heavy chain, kappa light chain or lambda light chain genomic locus; (ii) determining the location of nucleotide sequences that flank the 5' end and the 3' end of at least one functional region of the locus; and (iii) transfecting a targeting construct containing the flanking sequence into a cell wherein, upon successful homologous recombination, at least one functional region of the 30 immunoglobulin locus is disrupted thereby reducing or preventing the expression of the immunoglobulin gene. In one embodiment, the germline configuration of the porcine heavy chain locus is provided. The porcine heavy chain locus contains at least four variable regions, two diversity regions, six joining regions and five constant regions, for example, as illustrated in Figure 1. In a specific embodiment, only one of the six joining regions, J6, is functional. In another embodiment, the germline configuration of the porcine kappa light chain locus is provided. The porcine kappa light chain locus contains at least six variable regions, six joining regions, one constant region and one enhancer region, for example, as illustrated in Figure 2. In a further embodiment, the germline configuration of the porcine lambda light chain locus is provided. Isolated nucleotide sequences as depicted in Seq ID Nos 1-39 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous to any one of Seq ID Nos 1-39 are also provided. In addition, nucleotide.sequenc.es that contain at least. 10, 15, 17, 20, 25 or 30 contiguous nucleotides of any one of Seq ID Nos 1- 39 are provided. Further provided are nucleotide sequences that hybridizes, optionally under stringent conditions, to Seq ID Nos 1-39, as well as, nucleotides homologous thereto. Homology or identity at the nucleotide or amino acid sequence level can be determined by BLAST (Basic Local Alignment Search Tool) analysis using the algorithm employed by the programs blastp, blastn, blastx, tblastn and tblastx (see, for example, Altschul, S.F. et al (1 997) Nucleic Acids Res 25:3389-3402 and Karlin et al , (1 900) Proc. Natl. Acad. Sci. USA 87, 2264 2268) which are tailored for sequence similarity searching. The approach used by the BLAST program is to first consider similar-segments, with and without gaps, between a-query sequence and a database sequence, then to evaluate the statistical significance of all matches that are identified and finally to summarize only those matches which satisfy a preselected threshold of significance. See, for example, Altschul et aL, (1994) (Nature Genetics 6, 119-129). The search parameters for histogram, descriptions, alignments, expect (ie. , the statistical significance threshold for reporting matches against database sequences), cutoff, matrix and filter (low co M'plexity) are at the default settings. The default scoring matrix used by blastp, blastx, tblastn, and tblastx is the BLOSUM62 matrix (Henikoff et aL, (1 992) Proc. Natl. Acad. Sci. USA 89, 31 10915-10919), which is recommended for query sequences over 85 in length (nucleotide bases or amino acids). Porcine Heavy Chain In another aspect of the present invention, novel genomic sequences encoding the heavy chain locus of ungulate immunoglobulin are provided. In one embodiment, an isolated nucleotide sequence encoding porcine heavy chain is provided that includes at least one variable region, two diversity regions, at least four joining regions and at least one constant region, such as the mu constant region, for example, as represented in Seq ID No. 29. In another embodiment, an isolated nucleotide sequence is provided that includes at least four joining regions and at least one constant region, such as as the mu constant region, of the porcine heavy chain genomic sequence, for example, as represented in Seq ID. No. 4. In a further embodiment, nucleotide sequence is provided that includes 5' flanking sequence to the first joining region of the-porcine heavy-chain genomic sequence, for example, as represented in Seq ID No 1. Still further, nucleotide sequence is provided that includes 3' flanking sequence to the first joining region of the porcine heavy chain genomic sequence, for example, as represented in the 3' region of Seq ID No 4. In further embodiments, isolated nucleotide sequences as depicted in Seq ID Nos 1, 4 or 29 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous to .Seq ID Nos 1, 4 or 29 are also provided. Further provided are nucleotide sequences that hybridizes, optionally under stringent conditions, to Seq ID Nos 1, 4 or 29, as well as, nucleotides homologous thereto. In addition, nucleotide sequences that contain at least 10, 15, 17, 20, 25 or 30 contiguous nucleotides of Seq ID Nos 1, 4 or 29 are provided. In one embodiment, the nucleotide sequence contains at least 17, 20, 25 or 30 contiguous nucleotides of Seq ID No 4 or residues 1- 9,070 of Seq ID No 29. In other embodiments, nucleotide sequences that contain at least 50, 100, 1,000, 2,500, 4,000, 4,500, 5,000, 7,000, 8,000, 8,500, 9,000, 10,000 or 15,000 contiguous nucleotides of Seq ID No. 29 are provided. In another embodiment, the nucleotide sequence contains residues 9,070-11039 of Seq ID No 29. In further embodiments, isolated nucleotide sequences as depicted in Seq ID Nos 1, 4 or 29 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous to Seq ID Nos 1, 4 or 29 are also provided. In addition, nucleotide sequences that contain at least 10, 32 15, 17, 20, 25 or 30 contiguous nucleotides of Seq ID Nos 1, 4 or 29 are provided. Further provided are nucleotide sequences that hybridizes, optionally under stringent conditions, to Seq ID Nos 1, 4 or 29, as well as, nucleotides homologous thereto. In one embodiment, an isolated nucleotide sequence encoding porcine heavy chain is provided that includes at least one variable region, two diversity regions, at least four joining regions and at least one constant region, such as the mu constant region, for example, as represented in Seq ID No. 29. In Seq ID No. 29, the Diversity region of heavy chain is represented, for example, by residues 1089-1099 (D(pseudo)), the Joining region of heavy chain is represented, for example, by residues 1887-3352 (for example: J(psuedo): 1887-1931, J(psuedo): 2364-2411, J(psuedo): 2756-2804, J (functional J): 3296-3352), the recombination signals are represented, for example, by residues 3001-3261 (Nonamer), 3292-3298 (Heptamer), the Constant Region is represented by the following residues: 3353-9070 (J to C mu intron), _5522-8700 (Switch region), 9071-9388 (Mu Exon 1), 9389-9469 (Mu Intron A), 9470-9802 (Mu Exon 2), 9830- 10069 (Mu Intron B), 10070-10387 (Mu Exon 3), 10388-10517 (Mu Intron C), 10815-11052 (Mu Exon 4), 11034-11039 (Poly(A) signal). Seq ID No. 29 tctagaagacgtggagagaggccagacttcectcggaacagcteaaagag ctctgtcaaagccagatccatcacacgtgggcaccaataggccatgcca gcctccaagggccgaactgggttctccacggcgcacatgaagcctgcagc ctggcttatcctcttccgtggtgaagaggcaggcccgggactggacgagg ggctagcagggtggtaggcaccttgcgccccccaccccggcaggaacc agagaccctggggctgagagtgagcctccaaacaggatgccccaccett aggccacctttcaatccagctacactccacctgccattctectctgggca cagggcccagcccctggatcttggccttggctcgacttgcacccacgcgc acacacacacttcctaacgtgctgtccgctcacccctccccagcgtggtc catgggcagcacggcagtgcgcgtccggcggtagtgagtgcagaggtccc ttcccctcccccaggagccccaggggtgtgtgcagatctgggggctcctg tcccttacaccttcatgcccetcccctcatacccaccctccaggcgggag gcagcgagacctttgcccagggactcagccaacgggcacacgggaggcca gccctcageagctggcteccaaagaggaggtgggaggtaggtccacagct gccacagagagaaaccctgacggaccccacaggggccacgccagccggaa ccagctccctcgtgggtgagcaatggccagggccccgccggccaccacgg ctggccttgcgccagctgagaactcacgtccagtgcagggagactcaaga cagcctgtgcacacagcctcggatctgctcccatttcaagcagaaaaagg aaaccgtgcaggcagccctcagcatttcaaggattgtagcagcggccaac tattcgtcggcagtggccgattagaatgaccgtggagaagggcggaaggg tctctcgtgggctctgcggccaacaggccctggctccacctgcccgctgc cagcccgaggggcttgggccgagccaggaaccacagtgctcaccgggacc acagtgactgaccaaactcccggccagagcagccccaggccagccgggct ctcgccctggaggactcaccatcagatgcacaagggggcgagtgtggaag agacgtgtcgcccgggccatttgggaaggcgaagggaccttccaggtgga caggaggtgggacgcactccaggcaagggactgggtccccaaggcctggg 33 gaaggggtactggcttgggggttagcctggccagggaacggggagcgggg cggggggctgagcagggaggacctgacctcgtgggagcgaggcaagtcag gcttcaggcagcagccgcacatcccagaccaggaggctgaggcaggaggg gcttgcagcggggcgggggcctgcctggctccgggggctcctgggggacg ctggctcttgtttccgtgtcccgcagcacagggccagctcgctgggccta tgcttaccttgatgtctggggccggggcgtcagggtcgtcgtctcctcag gggagagtcccctgaggctacgctgggg*ggggactatggcagctccacc aggggcctggggaccaggggcctggaccaggctgcagcccggaggacggg cagggctctggctctccageatctggccctcggaaatggcagaacccctg gcgggtgagcgagCtgagagcgggtcagacagacaggggccggCCggaaa ggagaagttgggggcagagcccgccaggggccaggcccaaggttctgtgt .gccagggcctgggtgggcacattggtgtggccatggctacttagattcgt ggggccagggcatcctggtcaccgtctcctcaggtgagcctggtgtctga tgtccagctaggcgctggtgggccgcgggtgggcclgtctcaggctaggg caggggctgggatgtgtatttgtcaaggaggggcaacagggtgcagactg tgcccctggaaacttgaccactggggcaggggcgtcctggcacgtctcc tcaggtaagacggccctgtgcccctctctcgcgggactggaaaaggaatt ttccaagattccttggtctgtgtgggg crctctggggcccccgggggtgg ctcccctcctgcccagatggggcctcggcctgtggagcacgggctgggca cacagctcgagtctagggcc' acagaggcccgggctcagggctctgtgtgg cccggcgactggcagggggctcgggtt~ggacaccccctaatgggc cacagcactgtgaccatcttcacagctggggccgaggagtcgaggtcacc gtctcctraggtgagtcctcgtcagccctctctcactctctggggggttt tgctgcatmtgtgggggaaagaggatgcctgggtctcaggtctaaaggt -ctagggccagcgc-cggggcccaggaaggggccgaggggccaggctcggct cggccaggagcagagcttccagacatctcgcctcctggcggctgcagtca ggcctttggccgggggggtctcagcaccaccaggcctcttggctcccg gtccccggcrcccggctgcctc~acc-aggc-accgtgcgcggtgggcccgggc tcftggtcggcr-accctttcttaactgggatccgggcttagttgtcgcaa tgtgacaacgggctcgaaagctggggccaggggaccctagtctacgacgc ctcgggtgggtgtcccgcacccctccccactttcacggc-actcggcgaga cctggggagtcaggtgttggggar-actttggaggtcaggaacgggagctg gggagagggctctgtcagcggggtcc-agagatgggccgccctccaaggac gccctgcgcggggacaagggcttcttggcctggcctggccgcttcacttg ggcglcagggggggcttcccggggcaggcggtcagtcgaggcgggttgga attctgagtctgggttcggggttcggggttcggccttcatgaacagacag cccaggcgggccgttgtttggcccctgggggcctggttggaatgcgaggt ctcgggaagtcaggagggagcctggccagcagagggttcccagccctgcg gccgagggacctggagacgggcagggcattggccgtcgcagggccaggcc acaccccccaGGTTfGTggggcgagcctggagattgcacCACrGTGAT TArATGCTATGGATrCrCGGGGCCCAGGCGrrGAAGTCGTCGTGTCC'rC AGgtaagaacggccctccagggcctttaatttctgctctcgtctgtgggc ttttctgactctgatcctcgggaggcgtctgtgccccccccggggatgag gccggcttgccaggaggggtcagggaccaggagcctgtgggaagttctga cgggggctgcaggcgggaagggccccaccggggggcgagccccaggccgc tgggcggcaggagacccgtgagagtgcgccttgaggagggtgtctgcgga accacgaacgcccgccgggaagggcttgctgcaatgcggtcttcagacgg gaggcgtcttctgccctcaccgtctucaagcccttgtgggtctgaaaga gccatgtcggagagagaagggacaggcctgtcccgacctggccgagagcg ggcagccccgggggagagcggggcgatcggcctgggctctgtgaggccag gtccaagggaggacgtgtggtcctcgtgacagggcacttgcgaaacctt agaagacggggtatgttggaagcggctcctgatgtttaagaaaagggaga ctgtaaagtgagcagagtcctcaagtgtgtaggttttaaaggtcaaag tgtttaaacctttgtgactgcagttagcaagcgtgcggggagtgaatgg ggtgccagggtggccgagaggcagtacgagggccgtgccgtcctctaatt ____________________cagggcttagttttgrcagaataaaglcggcctgttctaaaagcattgg 34 tggtgctgagctggtggaggaggccgcgggcagccctggccacctgcagc aggtggcaggaagcaggtcggccaagaggctattttaggaagccagaaaa cacggtcgatgaatttatagcttctggtttccaggaggtggttgggcatg gctttgcgcagcgccacagaaccgaaagtgcccactgagaaaaaacaact cctgcttaatttgcatttctaaaagaagaaacagaggctgacggaaac tggaaagttcctgttttaactactcgaattgagttttcggtcttagctta I tcaactgctcacttagattcattttcaaagtaaacgtttaagagccgagg cattcctatcctcttctaaggcgttattcctggaggctcattcaccgcca gcacctccgctgcctgcaggcattgctgtcaccgtcaccgtgacggcgcg cacgattttcagttggcccgcttcccctcgtgattaggacagacgcgggc actctggcccagccgtcttggctcagtatctgcaggcgtccgtctcggga cggagctcaggggaagagcgtgactccagttgaacgtgatagtcggtgcg ttgagaggagacccagtcgggtgtcgagtcagaaggggcccggggcccga ggccctgggcaggacggcccgtgccctgcatcacgggcccagcgtcctag aggcaggactctggtggagagtgtgagggtgcctggggcccctccggagc tggggccgtgcggtgcaggttgggctctcggcgcggtgttggctgtttct gcgggatttggaggaattcttccagtgatgggagtcgcc-agtgaccgggc accaggctggtaagagggaggccgccgtcgtggccagagcagctgggagg gttcggtaaaaggctcgcccgtttcctttaatgaggacttttcctggagg gcatttagtctagtcgggaccgttttcgactcgggaagagggatgcggg gagggcatgtgcccaggagccgaaggcgccgcggggagaagcccagggct ctcctgtccccacagaggcgacgccactgccgcagacagacagggccttt ccctctgatgacggcaaaggcgcctcggctcttgcggggtgctggggggg agtcgccccgaagccgctcacccagaggcctgaggggtgagactgaccga - tgcctcttggccgggcctggggccggaccgagggggactccgtggaggca gggcgatggtggctgcgggagggaaccgaccctgggccgagcccggcttg gcgattcccgggcgagggccctcagccgaggcgagtgggtccggcggaac caccctttctggccagcgccac-agggctctcgggactgtccggggcgacg ctgggctgcccgtggcaggccTGGGCrGACCTGGAC1TCACCAGACAGAA CAGGGC11CAGGGCTGAGCrGAGCCAGG1TAGCGAGGCCAAGTGGGGC TGAACCAGGCrCAACTGGCCrGAGCrGGGTrGAGCrGCGGCTGACCrGGGC TGAGCTGAGCrGGGCTGGGGGCrGGGCTGGGCrGGCrGGGCrGGAC TGG~GAGC1TGAGOrGGGTTGAGCrGAGCTGAGCrrGGCCrGGGnfGAGCr GGGCTGGG1TGAGCrGAGCrGGGTrGAGCrGGGTTGAGCGGGGITGATCT GAGCTGAGCrGGGCTGAGCrGAGCTAGGCTGGGGTGAGCrGGGCIGAGCr GGTrrGAG1TGGGTTGAGL-rGAGCrGAGCrGGGCTrGTGCrGGCrGAGCrA GGCrGAG~rAGGCTAGGTGAGarGGGGGGCFGAGCrGAGCAGGCTG GGCTGAMrGGGCrGAGCrGAGCTGAGCrAGGCrGCG7rGAGCTGGCTGG GCrGGA7rGAGCTGGCrGAGCrGGCrGAGCrGGGCGAGCrGGCCTGGGT TGAGcTGAGCrGGACTGGTrGAGCrGGGTCGATCTGGGnrGAGCTGTCC TGGGTGAGCTGGGCTGGGTTGAGcITGAGCrGGGTrGAGCrGGGCFCAGC AGAGCrGGGTrGGGCTGAGCrGGG~rGAGCTGAGCrGGGCrGAGCrGGCC TGGGTGACGGGrGAGCGAGrGCrGAGCGGCCTGTGTTGAGC TGGGCrGGGTrGAGCTGGGCTGAGCrGGATrGAGCTGGGTTGAGCTGAGC TGGGCrGGGCFGTGCTGACrGAGCrGGGCrGAGCTAGGCTGGGGTGAGCr GGGCGAGCGATCCGAGCrAGGCGGGCTGG1TGGGCTGAGCrGAGcr GAGCTAGGCTGGATrGATCrGGCrGAGCTGGGTTGAGCTGAGL-rGGGCrG AG~rGGTCrGAGCrGGCCTGGGTCGAGCTGAGCrGGACTGG'TrrGAGCrG GGTCGATCTGGGCTGAGCTGGCCTGGGTGAGCGGGCGGG1trGAGCTG AGCTGGGTUGAGCGGGCTGAGcGAGGGcGGGGTGAGCTGGcJCTGAAC TAGCCTAGCrAGG~rGGGCrGAGCTGGGCrGGIMGGGCrGAGCGAGC2 GAGCrAGGCrGCA1-rGAGCAGGCTGAGCTGciGCrGAGCAGGCCTGGGGTG AGCTGGGCTAGc3TGGAGCTGAGCTGGGTCGAGCrGAGTrGGGCTGAGCTG GCCITGGGTTGAGGTAGGCrGAGCTGAGCTGAGCTAGGCTGGGTTGAGCTG GCrGGGCrGGTITGCGCGGGTCAAGCGGGCCGAGCTGGCCTGGGTrGA GTGGGCCGGTGAGCGGG~rGAGCGAGCCGAC~rAGGCTrGGGATGA 35 GCTGGGCTGArrGGGCTGAGCTGAGCTGAGCTAGGCrGCATrGAGCAGG CrGAGCTGGGCCTGGAGCCTGGCCTGGGGTGAGCTGGGCTGAGCTGCGCT GAGCTAGGCTGGGTTGAGCTGGCTGGGCTGGITGCGCTGGGTCAAGCTG GGCCGAGCTGGCCTGGGATGAGCTGGGCCGGTITGGGCTGAGCTGAGCTG AG~AGGCGCAGAGCAGGCGAGCTGGG~TIGAGCTrGCCrGGGGTGA GCGGGCrGAGCAAGCTGAGGGGGCTGGTGGGCTGAGCTGGCrGAG CTGGGTCarGCrGAGCTGGGCTGAGCTGACCAGG3GGTGAGCTGGGCrGAG TAGGCrGGG~rCAGCAGGCGGGTGAT~rGGCAGGGCTGGTITGCGC TGGGTCAAGCICCCGGGAGATGGCCTGGGATGAGCrGGGCrGGmrGGGC TGAGrGAGCrGAGCTGAGCTAGGCTGCATrGAGCAGGCrGAGCTGGGCT GAGCrTGQCCTGGGGTGAGCTGGGCTGGGTGGAGCTGAGcrGGGcrGAAcr GGGCTAAGCTGGCTGAGCTGGATCGAGCr.GAGCrGGGCTGAGCrGGCCTG GGGOTAGCTGGGCGAGCGAGCTGAGCrAGGCTGGGTrGAGCGGCTGG GCrGGTTGCGCI'GGGTCAAGCTGGGCCGAGCrGGCCTGGG~rrGAGCTGG GCTGGGCTGAGCTGAGCTAGGCrGGGITGAGCTGGGCrGGGCrGAGCTGA GCTAGGCTGCATGAGCTrGGCTGGGATGGAUrGAGCrGGCTGAGCTGGCr GAGCrGGCrGAGCTGGGCrGAGCTGGCCrGGGTrGAGCTGGGCrGGGITG AGCTGAGCI'GGGCTGAGCTGGGCTCAGCAGAGCrGGG7TGAGCTGAGCrG GGTEGAGCrGGGGTGAGCTGGGCTGAGCAGAGCI'GGOTGAGCTGAGCTG GGnTGAGCrGGGCTCGAGCAGAGCrGGGTrGAGCTGAGCTGGGTrGAGCT GGGCTCAGCAGAGCTGGGTTGAGcrGAGcTGGGTrGAGCTGGGcrGAGCT AGCrGCGCCAGCAGGCTGGGT'GAGCGAGCTGGGCTGAACrGGGCTG AGCTGGGCTGAACrGGGCrGAGCTGGGCTGAGCrGGGCrGAGCAGAGCTG GGrGAGCAGAGCrGGGTrGGTCrGAGCrGGGTGAGCTGGGCrGAGCrG GGCrGAGCAGAGTrGGGrrGAGCTGAGCrGGGTrCAGCrGGGCTGAGCrA GGCTGGGTrGAGCrGGGTrGAG1TGGGCrGAGCrGGGCTGGG7TGAGCGG AGCTGGGCrGAACTGGGCTGAGCrGGGCTGAGCGGAACrGGciTrrGATCrG AATrGAGCTGGGCrGAGCCGGGCrGAGCCGGGCrGAGCTGGCrAGGTrG AGC]TGGGTGAGCrrGCCTCAGCrGGTCTGAGCrAG1TrGGGTGGAGCTA GGCTGGATTGAGCTGGGrGAGCrGAGCrGATCrGGCrCAGCrGGGCTG AGGTAGGCTGAACrGGGCrGTGCrGGGCTGAGCTGAGCrGAGCCAGT'ITG AGCrGGGTrGAGCTGGGCrGAGCTGGGCrGTGrrGATCTITCTGAACTG GGCrGAGCTGGGCTGAGCTGGCCTAGCTGGAUTGAACGGGQGTAAGCTGG GCCAGGCTGGACTGGGCTGAGCrGACrAGGCTGACrGAGITGAATTGG GTTAAGCrGGGCrGAGATGGGCTGAGCTGGGCTGAGCTGGG1FGAGCCAG GTCGGA~rGGGTrACCCTGGGCCACACTGGG~rGAGCrGGGCGGAGCrCG attaacctggtcaggctgagtcgggtccagcagacatgcgctggccaggc tggcttgacctggacacgttcgatgagctgccttgggatggttcacctca gctgagccaWglgctccagctgggctgagctggtgaccctgggtgacct cggtgaccaggttgtcctgagtccgggccaagccgaggctgcatcagact cgccagacccaaggcctgggccccggctggcaagccaggggcggtgaagg ctgggctggcaggactgtcccggaaggaggtgcacgtggagccgcccgga ccccgaccggcaggacctggaaagacgcctctcactcccctttctcttct gtcccctctcgggtcctcagAGAGCCAGTCTGCCCCGAATCfrACCCCC. TCGTCTC0X3CGTCAGCCCCCCGTCCGATGAGAGCCTGGTGGCCCTGGGC TGCCTGGCCCGGGACTrCCTGCCCAGCTCCGTCACCrrCrCCGGAACTA CAAGAACAGCAGCAAGGTCAGCAGCCAGAACATCCAGGACTCCCGTCC G TCCTGAGAGGCGGCAAGTACnrGGCCTCCrCCCGGGTGCTCUFACCCTCT GTGAGCATCCCCCAGOACCCAGAGGCCrrCCrGGTGTGCGAGGTCCAGCA CCCCAGTGGCACCAAGTCCGTGTCCATCUIrGGGCCAGgtgagctgggct ccccctgtggctgtggcgggggcggggccgggtgccgccggcacagtgac gccccgttcctgcctgcagTCGTAGAGGAGCAGCCCCCCGTCITGAACAT CTTCGTCCCCACCCGGGAGTCCTrCTCCAGTA~rCCCCAGCGCACGTCCA AGCTCATCTGCCAGGCCTCAGACITCAGCCCCAAGCAGATCTCCATGGcCC TGGTrCCGTGATGGGAAACGGGTGGTGTCTGGCGTCAGCACAGGCCCCGT 36 GGAGACCCTACAGTCCAGTCCGGTGACCTACAGGCTCCACAGCATGCrGA CCGTCACGGAGTCCGAGTGGCTCAGCCAGAGCGTCTTCACCTGCCAGGTG GAGCACAAAGGGCTGAACTACGAGAAGAACGCGTCCTCCrGTGCACCTC CAgtgagtgcagcccctcgggccgggcggcggggcggcgggagccacaca cacaccagctgctccctgagccttggcttccgggagtggccaaggcgggg aggggctgtgc-agggcagctggagggcactgtcagctggggcccagcacc ccctcaccccggcagggcccgggctccgaggggccccgcagtcgcaggcc ctgctcttgggggaagccctacttggccccttcagggcgctgacgctccc cccacccacccccgcctagATCCCAACTCTCCCATCACCGTCFI'CGCCAT CGCCCCCrCCITCGCrGGCATCrrCCTCACCAAGTCGGCCAAGCrrrCCr GCCTGGTCACGGGCCTCGTCACCAGGGAGAGCCTCAACATCTCCrGGACC CGCCAGGACGGCGAGGTCrGAAGACCAGTATCGTCITCrCrGAGATCrA CGCCAACGGCACCrrCGGCGCCAGGGGCGAAGCCTCCGTCTGCGTGGAGG ACrGGGAGTCGGGCGACAGGTrCACGTGCACGGTGACCCACACGGACCrG CC~17CGCCGCrGAAGCAGAGCGTCrCCAAGCCCAGAGgtaggccctgccc tgcccctgcctccgcccggcctgtgccttggccgccggggcgggagccga gcctggccgaggagcgccctcggccccccgcggtcccgaccc-acacccct cctgctctcctccccagGGATCGCCAGGCACATGCCGTCCGTGTACGTGC TGCCGCCGGcCCCGGAGGAGCTGAGCCTGCAGGAGTGGGCCTCGGTCACC TGCCrGGTGAAGGGCTI'CrCCCCGGCGGACGTGTrCGTGCAGTGGCTGCA* GAAGGGGciAGCCCGTGTCCGCCGACAAGTACGTGACCAGCGCGCCGGT G CI CCGAGCCCGAGCCCAAGGCCCCCGCCTCCTACrCGTGCAGAGCGTCCrG ACGGTGAGCGCCAOACAGCGACGGGAGACCACACCTGCGTCG T GGGCCAcGAGGCCCrGcccACACGGTQACCGAGAGGACCGTGGACAAG T CCACCGGTAAACCCACCCrGTACAACGTCTCCCrGGTCCrGTCCGACACG GCCAGCACCTGCrACrGACCCCCTGGCTGCCCGCCGCGGCCGGGGCCAGA GCCCCCGGCTGACCATCGCrCTGTGTGGGCCTGTGTrGCAACCCGACC~rG TCGGOGTGAGCGGTCGCA1TCrGAAAATAGAaataaaAGATCrCGTGC CG Seq ID No.1 TCrAAGACGCGGAGAGAGGCCaAClCCTCGGAACAGCTCAAAGAG CTCTGTCAAAGCCAGATCCCATCACACGTGGGCACCAATAGGCCATGCCA GCCrCCAAGGGCCGAACrGGGTrCTCCACGGCGCACATGAAGCCTGCAGC CTGGCTTATC~rCTCCGTGGTGAAGAGGCAGGCCCGGGACfGGACGAGG GGCrAGCAGOGTGTGGTAGGCACCrTGCGCCCCCCACCCCGGCAGGAACC AGAGACCCTGGGGCTrGAGAGTGAGCCrCCAAACAGGATGCCCCACCCrrC AGGCCACC1TCAATCCAGCTACACTCCACCrGCCA17rCCrCGGGCA CAGGGCCCAGCCCCrGGATCTrGGCcMGGrCTGACTGCACCCACGCGC ACACACAcAcrccAACGTGcGTCCGCTCACCCCTCCCCAGCGTGGTC CATGGGCAGCACGGCAGTGCGCGTCCGGCGGTAGTGAGTGCAGAGGTCCC TrCCCCTCCCCCAGGAGCCCCAGGGGTGTGTGCAGATCrGGGGOCrCCTG TCCCTTACACCrrCATGCCCCCCCCTCATACCCACCCrCCAGGCGGGAG GCAGCGAGACCIMGCCCAGGGACTCAGCCAACGGGCACACGGGAGGCC A GCCCTCAGCAGCTGGG Seq ID No.4 GGCCAGACITCCrCGGAACAGCrCAAAGAGCTCrGTCAAAGCCAGATCCC ATCACACGTGGGCACCAATAGGCCATGCCAGCCCCAAGGGCCGAACrCGG GTrCrCCACGGCGCACATGAAGCCrGcAGCCTGCTrATCCrCrrCcGTG GTGAAGAGGCAGGCCCGGGACTGGACGAGGGGCrAGCAGGGTGTGGTAG GCACCITGCGCCCCCCACCCCGGCAGGAACCAGAGACCCTGGGGCT'GAGA IG 37 TGAGCCTCCAAACAGGATGCCCCACCC1TCAGGCCACC1TCAATCCAGC TACACCCACCGCCAlCTCCTCTGGGCACAGGGCCCAGCCCCTGGATC TrGGCCTrGGCTCGAC~rGCACCCACGCGCACACACACACTCCTAACGT GCTGTCCGCTCACCCCTCCCCAGCGTGGTCCATGGGCAGCACGGCAGTGC GCGTCCGGCGGTAGTGAGTGCAGAGGTCCCTrCCCCTCCCCCAGGAGCCC CAGGGGTGTGTGCAGATCTGGGGGCTCCTGTCCCrrACACMrCATGCCC CrCCCCTCATACCCACCCTCCAGGCGGGAGGCAGCGAGACC T"cCCAG GGAarCAGCCAACGGGCACACGGGAGGCCAGCCCTCAGCAGCrGGC7cCCC AAAGAGGAGGTGGGAGGTAGGTCCACAGCrGCCACAGAGAGAkACCTG ACGGACCCCACAGGGGCCACGCCAGCCGGAACCAGCTCCCTCGTGGGTGA GCAATGGCCAGGGCCCCGCCGGCCACCACGGCTGGCC17GCGCCAGCTGA AACTCACGTCCAGTGCAGGAGACrCAAGACAGCCGTGCACACAGC~CT GGATCTGCrCCCATMCAAGCAGAAAAAGGAAACCGTGCAGGCAGCCC AGCATIMCAAGGATrGTAGCAGCGGCCAACrATrCGTCGGCAGTGGCCGA TrAGAATGACCGTGGAGAAGGGGAGGGTCrCGTGGGCrGGG CAACAGGCCCGG~CTCACCTGCCCGCrGCCAGCCCGAGGG~rGGJCC GAGCCAGGAACCACAGTGCTCACCGGGACCACAGTGACTGACCAAACrCC * CGGCCAGAGCAGCCCCAGGCCAGCCGGCCrCGCCCTGGAGGACTCACC ATCAGATGCACAAGGGGGCGAGTGTGOAAGAGACGTGTCGcCC3CGGCCA *T TUGGGAAGGCGAAGGGACCYFCCAGGTGGACAGGAGGTGGGACGCAC C AGGCAAGGGACrGGGTCCCCAAGGCCTGGGGAAGGGGTA~rGGCrrG3cJ GUrAGCCGGCCAGGGAACGGGGAGCGGGGCGGGGCrGAGCAGXJGAG G * ACCTGACCrCGTGGGAGCGAGGCAAGTCAGGCTCAGGCAGCAGCCGCAC ATCCCAGACCAGAGCTGAGGCAGGAGGGOMGCAGCGOGCGGGG c * CrGCCGGCCCGGGGGCTCCTGGGGGACGCTGGCrCITGT[CCGTGTC CCGCAGCACAGGGCCAGTCGarGGGCCrATGCaTACCUTGATGTCGGG4 GCCGGGGCGTCAGGGTCGTCGTaCrrCAGGGGAGAGTCCCCTGAGGCrA CGCrGGGG*G6GGACTATGGCAGCrCCACCAGOG6CCrGGGGACCAGGcJ G CCTGGACCAGGrGCAGCCCGGAGGACGGGCAGGGrCrGGCTCrCAGCY ATCTGGCCCTCGGAAATGGCAGAACCCCrGGCGGGTGAGCGAG~JrGAGA G *CGGGTCAGACAGACAGGGGCCGGCCGGAAAGGAGAAGTrGGGGGCAGAG C CCGCCAGGGGCCAGGCCCAAGGTTCTGTGTGCCAGGGCCrGGGTGGGCAC ATTGGTGTGGCCATGGCTACTrAGATrCGTGGGGCCAGGGCATC~rGGTC ACCGTCrCCrCAGGTGAGC~rGGTGTCTGATGTCCAGCAGGCGCTGG GGCCGCGGGTGGGCCTGTCrCAGGCTAGGGCAGGGGCrGOATGTAn TGTCAAGGAGGGGCAACAGGGTGCAGA~rGTGCCCCTGGAAACTGACCA CrGGGGCAGGGGCGTCCTGGTCACGTCFCCTCAGGTAAGACGGCCCTJG CCCCTCrCGCGGGACTGGAAAAGGAArTCCAAGATrCCI-TGGT~rG TGTGGGCCGGGCCCCCGGGOTG G.CCCCCrCCrGCCCAGATGG GG~CGCGGACCGCGGCCCGTGGCAGC ACAGAGCCCGGOTCAGG6GTGTGGCCCGGCGACGGCAGQQCG C TCGGGTITIGGACACCCCCrAATGGGGGCCACAGCACTGTGACCAT~rr CACAGCrGGGCCGAGGAGTCGAGGTCACCGTCrCCTCAGGTGAGTCrC GTCAGCCCrCTCCACTCTCrGGGGGOmGCrGCA1TIGTGGGGGAA AGAGGATGCCGGGTCrCAGGTCrAAGGTCTAGGGCCAGCGCCGGGGCC _____________CAGGAGGGGCCGAGGGGCCAGGTCGGCTCGGCCAGGAGCAGAGMC 38 C AGACATCTCGCCTCCTGGCGGCTGCAGTCAGGCCI1GGCCGOGGGGGTC. TCAGCACCACCAGGCCrCTGGCCCCGAGGTCCCCGGCCCCGGCTGCCr CACCAGGCACCGTGCGCGGTGGGCCCGGGCCTGGTCGGCCACCCITC TrAACTGGGATCCGGGCITAGITGTCGCAATGTGACAACGGGC-TCGAAAG CTGGGGCCAGGGGACCCTAGT*TACGACGCCTCGGGTGGGTGTCCCGCAC CCCrCCCCA=CACGGCACTCGGCGAGACCTGGGGAGTCAGGTGTI'GG GGACAL~rI IGGAGGTCAGGAACGGGAGCrGGGGAGAGGGcCTCGTCAGC G GGGTCCAGAGATGGGCCGCC~CCAAGACGCCCrGCGCGGGGACAAGG G CrrTGGCCTGCCGGCCGCrCACTGGGCGTCAGGGGGGCITCCC GGGGCAGGCGGTCAGTCGAGGCGGGTrGGATCrGAGTCTGGG'rrCGGG GTrCGGGGTrCGGCC1'rCATGAACAGACAGCCCAGGCGGGCCGTITrGG GCCCCTGGGGGCCTGG'TrGGAATGCGAGGTCTCGGGAAGTCAGGAGGGA G * CCTGCCAGCAGAGGGTCCCAGCCC'GCGGCCGAGGGACCTGGAGACG GCAGGGCAT17GGCCGTCGCAGGGCCAGGCACACCCCCCAGGTITIGTG GGCGACGOAGATGCACCACGTGAA~ATGCATGGATCCrG GGGCCCAGGCGTTGAAGTCGTCGTGTCCTCAGGTAAGAACGGCCCrCCAG GGCCT1TAAmrCrGCrCrCGTCrGTGGGCTGACUTGATCCrCG GGAGCGCGTCTGTGCCCCCCCCGGGGATGAGGCCGGCTGCCAGGAGGGGT CAGGGACCAGGAGCCrGTGGGAAGTTCTGACGGGGGCrGCAGGCGGGAA G GGCCCCACCGGGGGGCGAGCcCCAGGCCGCTGGGCGGCAGGAGACCCGT G AGAGTGCGCCTlGAGGAGGGTGTCI'GCGGAACCACGAACGCCCGCCGG A AGGGC1TGCrGCAATGCGGTCrrCAGACGGGAGGCGTC11'CIGCCCI'CAC CGTC=rCAAGCCCTrGTGGGTCGAAAGAG~rxATGTCGGAGAGAGAAGG GACAGGCCTGTCCCGACCTGGCCGAGAGCGGGCAGCCCCGGGGGAGAGC G GGGCGATCGG3CCTGGCTCrGTGAGGCCAGGTCCAAGGAG3ACGTGTG G 'rCCrCGTGACAGGOCACTGCGAAACCTrAGAAGACGGGGTATGITGGA AGCGGCrCCrGATGTTTAAGAAAAGGGAGACTGTAA.AGTGAGCAGAGTCC TCAAGTGTGTI'AAGG1TIAAAGGTCAAAGTG IIAAACCnTGTGACr GCAGTTAGCAAGCGTGCGGGc3AGTGAATGGGGTGCCAGGGTGGCCGAGA G CGCAGTACGAGGGCCGTGCCGTCCrCTAATCAGCn7AGTM~GCAGAA TAAAGTCGGCCJTGTAAAAGCATGGTGGTGCrGAGCrGGTGGAGG AGGCCGCGGGCAGCCCJrGGCCACCrGCAGCAGGTGGCAGGAAGCAGGTC G GCCAAGAGGCrTTAGGAAGCCAGAAAACACGGTCGATGAATITATAG CTTCTGGTITCCAGGAGGTGGTTGGGCATGGCTIGCGCAGCGCCACAGA ACCGAAAGTGCCCAC]GAGAAAAAACAACXXGCflAATflGCATITI CTAAAAGAAGAAACAGAGGCTGACGGAAACrGGAAAGTTCGTIAAC TACTCGAATrGAGT=CGGTCAGCATCAACGCCACITAGAI1C Am=CAAAGTAAACGmrAAGAGCCGAGGCATrCCTATCcIC'ITCAAG GCGTTATTCCTGGAGGCrCA1TCACCGCCAGCACCrCCGCTGCCrGCAGG CATTGCTGTCACCGTCACCGTGACGGCGCGCACGA=mCAGTrGGCCCG CrTCCCCTCGTGATrAGGACAGACGCGGGCACTCTGGCCCAGCCGTCMG GCTCAGTATCrGCAGGCGTCCGTCTCGGGACGGAGCTCAGGGGAAGAGCG TGACrCCAGTTGAACGTGATAGTCGGTGCGTrGAGAGGAGACCCAGTCGG GTGTCGAGTCAGAAGGGGCCCGGGGCCCGAGGCCCTGGGCAGGACGGCC 39 GTGCCCTGCATCACGGGCCCAGCGTCCrAGAGGCAGGACTCTGGTGGAGA GTGTGAGGGTGCCTGGGGCCCCrCCGGAGCTGG3GGCCGTGCGGTGCAGGT TGGGCTCTCGGCGCGGTG FrGGCGTTCTGCGGGArrrGGAGGAATrCr TCCAGTGATGGGAGTCGCCAGTGACCGGGCACCAGGCrGGTAAGAGG3A G GCCGCCGTCGTGGCCAGAGCAGCTGGGAGGGTrCGGTAAAAGGCTCGCCC G1TrCCIAATGAGGACTTCCTGGAGGGCATITAGTCrAGTCGGGAC CG=rICGAC'CGGGAAGAGGGATGCGGAGGAGGGCATGTGCCCAGGAG c CGAAGGCGCCGCGGGGAGAAGCCCAGGGCTCTCCTGTCCCCACAGAGGC G ACGCCACrGCCGCAGACAGACAGGGCC'IMCCCTCTGATGACGGCAAAGG CGCCTCGGCTCITGCGGGGTGCTGGOGOOAGTCGCCCCGAAGCCGCrCA CCCAGAGGCCrGAGGGGTGAGACTGACCGATGCCTCITGGCCGGGCCrGG GGCCGGACCGAGGGGGACTCCGTGGAGGCAGGGCGATGGTGGCTGCGGG A GGGAACCGACCCTGGGCCGAGCCCGGCrrGGCGATTCCCGGGCGAGGGCC CrCAGCCGAGGCGAGTGGGTCCGGCGGAACCACCC'IrGGCCAGCGCC ACAGGGCTCTCGGGACrGTCCGGGGCGACGCrGGGCrGCCCGTGGCAGGC crGGGcrGAccTGGAcrrcACCAGACAGAACAGGGrTcAGGGcrGAGC TGAGCCAGGTrrAGCGAGGCCAAGTGGGGCTGAACCAGGCFCAACrGGCC TGAGCTGGGTrGAGCTGGGCrGACCrGGGCrGAG~rGAGCI'GGGCrGGGC TGGGCrGGGrGGGCGGGCGGGCGGACGGCGAGCrGAGCGGGT2 GAG rGAGCTGAGCrGGCCrGGG FrGAGCrGGGCrGGG1-rGAGCrGAGCT~ *GGGTGAGCrGGGTrGAGCrGGGTrGATCrGAGCrGAG~rGGGCrGAGCr GAGCTAGGCrGGGGTGAGCTGGGCTGAGCTGGTIGAGTFGGG1TGAGCr GAGCrGAGCTGGGCTGTGCrGGCTGAGCrAGGCTGAGCTAGGCrAGGTrG AGCTGGGCrGGGCTGAGCTGAGCrAGGCrGGGCrGATIGGGCrGAGCTG AGCrGAGCrAGGCTGCGTGAGCrGGCGGGCrGGATrGAGCrGGCrGAG CrGGCTGAGCrGGGCrGAGCrGGCCrGGGT'rGAGCTGAGCrGGACrGG1T TGAGCrGGGTCGATCTGGGTrGAGCrGTCCrGGGrrGAGCrGGGCTGGGT TGAGCTGAGCrGGGTrGAGCrGGGCCAGCAGAGCTGGGITGGGCTGAGC TGGGTTGAGCrGAGCTGGGCTGAGCrTGGCCrGGGTrGAGCTGGGCrGAGC TGAGCFGGCrGAGCrGGCCrGTGTTGAGCrGGGCTGGGTrGAGCTGGGC TGAG~rciGATTGAGCrGGGTrGAGCrGAGCTGGGCrGGGCTGTGCrGACr GAGCJrGGGCGAGCTAGGCrGGGGTGAGCTGGGCTGAGCrGATCCGAGCr AGGCrGGGCrGGT'1GGGCTGAGCrGAGCTGAGCTAGGCrGGA1TGATCr G GCTGAGCTGGGTrGAGCTGAGCTGGGCrGAGCIGGTCrGAGCrGGCCTG GGTCGAGCrGAGCTGGACIGGTrGAGCrGGGTCGATCTGGGCrGAGCrG GCCTGG1GAGCTGGGCTGGGTrGAGCrGAGCrGGGTrGAGCrGGGCTG AGCrGAGGGCTGGGGTGAGCGGGCTGAA~rAGCCrAGCrAGGTGGGar GAGCTGGGCTGGTT1-GGGCTGAGCTGAGCTGAGCTAGGCTGCAr'rGAGCA GGCrGAGCTGGGCTGAGCAGGCCTGGGGTGAGCrGGGCrAGGTGGAGCT G AGCrGGGTCGAGCTGAGTrGGGCrGAGCTGGCCTGGGTGAGGTAGGCrG AGCrGAGCrGAGCTAGGCTGGGflGAGCrGGCTGGGCTGGT1GCGCrGG GTCAAGCTGGGCCGAGCTGGCCrGGG -rGAGCrGGGCrCGGrrGAGCrGG GCrGAGCTGAGCCGACCTAGGCTGGGATGAGCrGGGCTGATI-rGGGCTGA GFGAGCrGAGCAGGCGCATGAGCAGCGAGCTGGGCCrGGAGCCT GGCCrGGGGTGAGCTGGGCTGAGCETGCG~rGAGCTAGGCTGGcrGAGCTC GGC1'GGG~rGGTIrrGCGCTGGGTCAAGCrGGGCCGAGCTGGC~rGGGATG AGCTGGGCCGGTrrGGGCrGAGCITGAGCrGAGCTAGG~rGCA1TGAGCAG GCrGAGCTGGGCTGAGCTGGCCrGGGGTGAGCrGGGCGAGCTA4GCTGA GCTGGGCTGGMrGGGCrGAGCrGGCTGAGCrGGGTCCTGCrGAGCrGGG CrGAGCTGACCAGGGGTGAGCrGGGCrGAGTrAGGCTGGGCTCAGCTAGG 40 CrGGGTTGATCTGGCAGGGCTGGTTrGCGCTGGGTCAAGCTCCCGGGAGA TGGCCTGGGATGAGCrGGGCTGGMGGGCTGAGCTGAGCrGAGCTGAGC. TAGGCTGCATTGAGCAGGCTGAGCTGGGCTGAGCTGGCCTGGGGTGAGCT GGGCTGGGTGGAGCTGAGCGGGCTGAACTGGGCTAAGCrGGCTGAGCrG GATCGAGCTGAGCrGGGCTGAGCTGGCCTGGGGTTAGCTGGGCrGAGCTG AGCTGAGCAGGCTGGGTTGAGCGGCTGGGCTGGTTTGCGCTGGGTCAA GCTGGGCCGAGCTGGCCTGGGTrGAGCTGGGCTGGGCrGAGCTGAGCrAG GCTGGGTTGAGCTGGGCrGGGCTGAGCTGAGCTAGGCTGCATGAGCTGG CrGGGATGGATTGAGCTGGCrGAGCTGGCTGAGCTGGCrGAGCTGGGCTG AGCTGGCCTGGGTrGAGCTGGGCTGGGTGAGCTGAGCTGGGCrGAGCTG GGCTCAGCAGAGCTGGGTTGAGCrGAGCrGGGTrGAGCTGGGGTGAGCTG GGCTGAGCAGAGCTGGGTTGAGCGAGCGGGTrGAGCTGGGCrCGAGCA GAGCTGGGTrGAGCrGAGCrGGGTrGAGCTGGGCrCAGCAGAGCTGGGTT GAGCTGAGCTGGGTTGAGCGGGCTGAGCTAGCrGGGCrCAGCTAGGCrG GGTrGAGCTGAGCTGGGCTGAACTGGGCTGAGCTGGGCrGAACTGGGCTG AGCTGGGCrGAGCrGGGCTGAGCAGAGCTGGGCrGAGCAGAGCTGGGTT G GTCTGAGCTGGGTTGAGCTGGGCTGAGCTGGGCTGAGCAGAGTUGGTG AGCTGAGCrGGGTrCAGCTGGGCGAGCTAGGCrGGGTrGAGCrGGGTTG AGTTGGGCTGAGCGGGCTGGGTGAGCGGAGCTGGGCTGAACTGGGCTG AGCTGGGCrGAGCGGAACTGGGTrGATCTGAATrGAGCGGGCTGAGCCG GGCTGAGCCGGGCrGAGCTGGGCTAGGTrGAGCITGGGTGAGCITGCCTC AGCTGGTCrGAGCrAGGTTGGGTGGAGCAGGCTGGATTGAGCrGGGCrG AGCTGAGCrGATCTGGCCTCAGCTGGGCTGAGGTAGGCrGAACTGGGCTG TGCrGGGCTGAGCTGAGCTGAGCCAGmGAGCGGGTGAGCrGGGCrG AGCTGGGCrGTGTGATCTACCG GGGCGAGCTGGGCGAGCrG GCCrAGCrGGATTGAACGGGGGTAAGCTGGGCCAGGCTGGACGGGCTGA GCTGAGCFAGGCrGAGCTGAGTrGAATTGGGTTAAGCrGGGCTGAGATGG GCTGAGCTGGGCrGAGCTGGGTfGAGCCAGGTCGGACTGGGTTACCCTGG GCCACACTGGGCrGAGCTGGGCGGAGCCGATTAACCGGTCAGGCTGAG TCGGGTCCAGCAGACATGCGCTGGCCAGGCTGGCTTGACCrGGACACGTT CGATGAGCTGCCrTGGGATGGTrCACCrCAGCTGAGCCAGGTGGCTCCAG CTGGGCTGAGCrGGTGACCCTGGGTGACCrCGGTGACCAGGTrGTCCFGA GTCCGGGCCAAGCCGAGGCrGCATCAGAC1CGCCAGACCCAAGGCCrGGG CCCCGGCGGCAAGCCAGGGGCGGTGAAGGCTGGGCGGCAGGACTGTC CCGGAAGGAGGTGCACGTGGAGCCGCCCGGACCCCGACCGGCAGGACCT GGAAAGACGCCTCTCACTCCCCTTTCTCGTCCCCrCrCGGGTCCFCA GAGAGCCAGTCrGCCCCGAATCTCTACCCCCTCGTCTCCTGCGTCAGCCCC CCGTCCGATGAGAGCCTGGTGGCCCTGGGCTGCCTGGCCCGGGACTCCr GCCCAGCTCCGTCACCTTCrCCrGGAA Porcine Kappa Light Chain In another embodiment, novel genomic sequences encoding the kappa light chain locus of ungulate immunoglobulin are provided. The present invention provides the first reported genomic sequence of ungulate kappa light chain regions. In one embodiment, nucleic acid sequence is pTovided that encodes the porcine kappa light chain locus. In another embodiment, the nucleic acid sequence can contain at least one joining region, one constant region and/or one enhancer region of kappa light chain. In a further embodiment, the nucleotide sequence can 41 include at least five joining regions, one constant region and one enhancer region, for example, as represented in Seq ID No. 30. In a further embodiment, an isolated nucleotide sequence is provided that contains at least one, at least two, at least three, at least four or five joining regions and 3' flanking sequence to the joining region of porcine genomic kappa light chain, for example, as represented in Seq ID No 12. In another embodiment, an isolated nucleotide sequence of porcine genomic kappa light chain is provided that contains 5' flanking sequence to the first joining region, for example, as represented in Seq ID No. 25. In a further embodiment, an isolated nucleotide sequence is provided that contains 3' flanking sequence to the constant region and, optionally, the 5' portion of the enhancer region, of porcine genomic kappa light chain, for example, as represented in Seq ID Nos. 15, 16 and/or 19. In further embodiments, isolated nucleotide sequences as depicted in Seq ID Nos 30, 12, 25, 15, 16 or 19 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous to Seq ID Nos 30, 12, 25, 15, 16 or 19 are also provided. In addition, nucleotide sequences that contain at least 10, 15, 17, 20, 25 or 30 contiguous nucleotides of Seq ID Nos 30, 12, 25, 15, 16 or 19 are provided. In addition, nucleotide sequences that contain at least 10, 15, 17, 20, 25 or 30 contiguous nucleotides of Seq ID Nos 1, 4 or 29 are provided. In other embodiments, nucleotide sequences that contain at least 50, 100, 1,000, 2,500, 5,000, 7,000, 8,000, 8,500, 9,000, 10,000 or 15,000 contiguous nucleotides of Seq ID No. 30 are provided. Further provided are nucleotide sequences that hybridizes, optionally under stringent conditions, to Seq ID Nos 30, 12, 25, 15, 16 or 19, as well as, nucleotides homologous thereto. In one embodiment, an isolated nucleotide sequence encoding kappa light chain is provided that includes at least five joining regions, one constant region and one enhancer region, for example, as represented in Seq ID No. 30. In Seq ID No. 30, the coding region of kappa light chain is represented, for example by residues 1-549 and 10026-10549, whereas the intronic sequence is represented, for example, by residues 550-10025, the Joining region of kappa light chain is represented, for example, by residues 5822- 7207 (for example, Ji:5822-5859, J2:6180 6218, J3:6486-6523, J4:6826-6863, J5:7170-7207), the Constant Region is represented by the following residues: 10026- 10549 (C exon) and 10026-10354 (C coding), 10524-10529 (Poly(A) signal) and 11160-11264 (SINE element). 42 Seq lID No 30 GCGTCCGAAGTCAAAAATATCTGCAGCCTICATGTA3TCATAGAAACAAG GAATGTCTACA1TICCAAAGT3GGACCAGAATCTGGGTCATGTCTAAG GCATGTGCA1TGCACATGGTAGGCAAAGGAC'TGCnrCTCCCAGCACA TCITCGCAGAGATCCATGGAAACAAGACrCAACTCCAAAGCAGCAAAG AAGCAGCAAGTrCAAGTGATCrCCrCGACTCCCrCCCCCAGGCrAA TGAAGCCATGTTGCCCCTGGGGGATI'AAGGGCAGGTGTCCA'ITGTGGCAC CCAGCCCGAAGACAAGCAATrGATCAGGTCrGAGCACrCCrGAATGTG GACTCTGGAATITTrCCrCACCnGTGGCATATCAGCrTAAGTCAAGTA CAAGTGACAAACAACATAATCCTAAGAAGAGAGGAATCAAGCrGAAGTC A AAQGATCACTGCCTrGGA1TrCACTGTGAATGATGACCrGGAAAATATCC TGAACAACAGCrlCAGGGTGATCATCAGAGACAAAAGITCCAGAGCCAGg tagggaaaccctcaagccttgcaaagagcaaaatcatgccattgggttct taacctgctgagtgatttactatatgttactgtgggaggcaagcgctca aatagcctgggtaagtatgtcaaataaaaagcaaaagtggtgtttettga aatgttagacctgaggaaggaatattgataacttaccaataattaga atgatttatagatgtgcacttagtcagtgtctdtccccccgcacctgac aagcagtttagaatttattctaagaatctaggtttgctgggggctacatg ggaatcagcttcagtgaagagttgtggaatgattcactaaatttcta tttccagcataaatccaagaacctctcagactagtttattgacactgctt ttcctccataatccatctcatctccgtccatcatggacactttgtagaat gacaggtcctggcagagactcacagatgcttctgaaacatcctttgcctt caaagaatgaacagcacacatactaaggatctcagtgatccacaaattag ttmgccacaatggttcataaagtctattaacagcaaatt gMtffatagttgttctgctttataataattgcatgcttcacttct tcttttctttttttttgcutttgtgccgcaggtgcagca tatgaaatttcccaggctaggggtcaaatcagaactacacctactggcct acgccacagccacagcaactcaggatctaagccatgtcggtgacctacac tacagctcatggcaatgccagatccttaacccaatgpgcgaggccaggga tcgaacccatgtcctcatggatactagtcaggctcattatccgctgagcc ataacaggaactcccgagtttgctttttatcaaaattggtacagccttat tgtttctgaaaaccacaaaatgaatgtattcacataatttaaaaggtta aataatttatgatatacaagacaatagaaagagaaaacgtcafgectct ttcttccacgacaacacgcctccttaattgatttgaagaantaactactg agcatggtagtgtactttttagcaattagcctgtttcatagccat acatattcaattaaaatgagatcatgatatc-acacaatacataccat=c gcctaagggataatcatcttccacatgactaataasaaccta cctakaaaaaaaaaaaaccctacttcatcctcctattggctgctttgtgc tccattaaagctctatcataattaggttatgatgaggatttccatttt ctacctttcaagcaac~atttcaatgcacagtcttatatac-acatttgagc ggtcttttgtcttttctaaggctgcatatggaggttcccaggctagctg tctatcagaactatagctgctggcctacgccacatccacagcaatacaa gatctgagccatgtctgcaacttacaccacagctcacagcaacggtggat ccttaaaccactgagcaaggcc-agggatc-aaacccataacttcatggctc ctagttggatttgttaaccactgagccatgatggcaactcctgagcctac ttttctaatcatttccaaccctaggacactttttagtttcantttt ccccccaccccctgttttctgaagtgtgtttgcttccactgggtgacttc actcccaggatctcatctgcaggatactgcagctaagtgtatgagctrtg aatttgaatcccaactctgccactcaaagggataggagtttccgatgtgg cccaatgggatcagtggcatctctgcagtgccaggacgcaggttcctcc ctggcccagcacagtgggttaagaatctggcattgctgcagctgaggcat agatttcaattgtgcctragatctgptccttggcccaaggactgcatatg cctcagggcaaccaaaaaagagaaaaggggggtgatagcattagtttcta gatttgggggataattaaataaagtgatccatgtacaatgtatggrcamt _____________________tgtaaatgctcaacaaatttcaactattatggagttcccatcatggctca 43 gtggaagggaatctgattagcatccatgaggacacaggtccaaccccgac cttgctcagtgggcattgctgtgagctgtggcatgggttacagacgaage tcggatctggcattgctgtggctgtggtgtaagccagcaactacagctct cattcagcccctagcctgggaacctccatatgcctaaaagacaaaaaata aaatttaaattaaaaataaagaaatgttaactattatgattggtactgct tgcattactgcaaagaaagtcactttctatactctttatatcttagttg actgtgtgctcagtgaactattttggacacttaatttecactctcttcta tctccaacttgacaactctetttcctctcttctggtgagatrCcactgctg actttgctctttaaggcaactagaaaagtgctcagtgacaaaatcaaaga aagtaccttaatcttcagaattacaatcttaagttctcttgtaaagctt actatttcagtggttagtattattccttggtcccttacaacttatcagct ctgatctgctgattttcactatttattgttggagtuttctttt ttccctgttcattctgcaaatgtttgctgagcatttgtcaagtgaagata ctggactgggccflccaaatataagacaatgaaacatcgggaguctcat tatggtgcagcagaaacgaatccaactaggaaatgtgaggttgcaggttc gatccctgcccttgctcagtgggttaaggatccagcattaccgtgagctg tggtgtaggttgcagacgtggctcagatcctgcgttgctgtggctgtggc ataggctggcagctctagctctgattcgaccgctagcctgggaacctcca tgcgccccgagtgcagcccttaaaagcaaaaaaaaaagaaagaaagaaa aagacaatgaaacatcaaacagctaacaatccagtagggtagaaagaatc *tggcaacagataagagcgattaaatgttctaggtcr-agtgaccttgcctc tgtgctctacacagtcgtgccacttgctgagggagaaggtctctcttgag ttgagtcctgaaagacattagttgttcacaaactaatgccagtgagtgaa ggtgtttccaagcagagggagagtttggtaaagctggaagtcacagaa agactctaaagagtttaggatggtgggagrcaacatacgctgagatggggc tggaaggttaagagggaaaca actatagtaagtgaagctggactcacagc aaagtgaggacctcagcatccttgatggggttaccatggaaacaccaagg cacaccttgatttccaaaacagcaggcacctgattc-agcccaatgtgaca tggtgggtacccctctagctctacctgttctgtgacaactgacaaccaac gaagtaagtctgamcacttgctatccttgttgtttcaca cgtcatctatagcttcatgccaaaatagagttcaaggtaagacgcgggcc ttggtttgaacatgtgtatettgtgagacaatatggtggcaa ggaagaggttcaaacaggaaaatactctcta~agattaactgagaaa agctaaagtccataatgacactgaatgaagtteatrcattgcaaaag ccttcccccCcccaggagactataaaaaagtgcaatttatgaa cttamacaaaacagaaatagacteacagatggaacgaar-agatg gttaccaagggtgaaagggagtaggaigggataaataaggagtctggggtt agcagatacac~cccagtgtacacaaaataaacaacagggacctactatat agcacagggaactatatgcagtagcttacaataacctataatggaaaaga atgtgaaaaagaatatatgtatgcgtgtgtgtgtaactgaatcactttgc tgtaacctgaatctaacataacattgtaatcaactacagMtUttt ttttagtgcagggtmtggtgtttttttttttcatttttgttgtt tttgttttttgctttttgggccacacccagacatatgggggttcccagg ctaggggtctaattagagctacagttgccggcttgcaccacagccacagc aacatcagatccgagccgcacttgcgacttacaccacagctcatggcaat accagatccttaacccactgagcaaggcccagggatcgtacccgcaacct catggttcctagtcagattcattctgctgcgctacaatgggaactccaa gtgcagttttttgtaatgtgcttgtctttcttgtaattcatattcatcc taettcccaataaataaataaatacataaataataaacataccatgtaa atcaactacaatttttttaatgcagggtttttgttttttgtttttgt Mtgtctttttgcctttctagggccgctcccatggcatatggaggttcc caggctaggggtcgaatcggagctgtagccaccggcctacgccagagcca cagcaacgcgggatccgagccgcgtctgcaacctar-accacagctcacgg caacgccggatcgttaacccactgagcaagggcagggatcgaacctgcaa cctcatggttcctagtcagattcgttaactactgagcc-acaacggaaact cctaaagtgcagtttttaaatgtgcttgtcttcttgtaatttacactc 44 aacctacttcccaataaataaataaataaacaaataaatcatagacatgg ttgaattctaaaggaagggaccatcaggccttagacagaaatacgtcatc ttctagtattttaaaacacactaaagaagacaaacatgctctgccagaga agcccagggcctccacagctgcttgcaaagggagttaggcttCagtagct gacccaaggetctgttcctctcagggaaaagggtttttgttcagtgaga cagcagacagctgacgtgGTGGACGTrCGGCCAAGGAACCAAGCTGG AACTCAAACgtaagtcatcaaacgttccttccttggctgtctgtgtct tacggtctctgtggctctgaaatgattcatgtgctgactctctgaaacca gactgacattctccagggcaaaactaaagcctgtcatcaaactggaaaac tgagggcacattttctgggcagaactaagagtcaggcactgggtgaggaa aaacttgttagaatgatagtttcagaaacttactgggaagcaaagccat gttctgaacagagctctgctnaagggtrcaggaggggaaccagtttttgta r-aggagggaagttgagacgaacccctgtgTATATGGMlCGOCGCGGGGA CCAAGCTGGAGCTCAAACgtaagtggctttttccgactgattctttgctg tttctaattgttggttggctttttgtccatttagtgttttcatcgaa ttagttgtcagggaccaaacaaattgccttcccagattaggtaccaggga ggggacattgctgcatgggagaccagaggggctaatttacgtttc caagccaaaataactggggaagggpgcttgctgtcctgtgagggtaggtt tttatagaagtggaagtaaggggaaatcgctatgrrCACTITGCrC GGGGACCAAAGTGGAGCCCAAAAttgagtac-atmtccatcaattatttg tgagattttttctgttgtgtcatttgtgcaagtttgacattttggt tgaatgagccanccagggaccaaaaggatgagaccgaaaagtagaaa agagccaacttttaagctgagcagacagaccgaattgttgagtttgtgag gagagtagggtttgtagggagaaaggggaacagatcgctggctttttc *-tgaattagcctttctcatgggactggcttcagagggggtttugatgagg gaagtgttctagagccttaactgtgGGflGTGTXCGGTAGCGGGACCAAG * CTGGAAATCAAACgtaagtgcacttttctactcctttctttcttatac ggtgtaattgggcttttcatgtttggagtatgagttgaggtcagt tctgaagagagtgggactcatccaaaaatctgaggagtaagggtcagaac agagttgtctcatggaagaacaaagacctagttagttgatgaggcagcta aatgagtcagttgacttgggatccaaatggccagacttcgtctgtaacca acaatctaatgagatgtagcagcaaaaagagattccattgaggggaaag taaaattgttaatattgtgGATCACCTflTGGTGAAGGGACATCCGTGGAG ATlGAACgtaagtaMttctctaacttctgaaatttgtctaaatg ccagtgttgactttagggcttaagtgtcagttttgtgaaaaatgggta aacaagagcattcatatttattatcagttcaaaagttaaactcagctc caaaaatgaatttgtagacaaaaagattaatttaagccaaattgaatgat tcaaaggaaaaaaaaattagtgtagatgaaaggaattcttacagctcc aaagagcaaaagcgaattaattttctttgaacttgccaaatcttgtana tgatttttgttctttacaatttaaaaaggttagaaatgtattcttag tctgttttctctcttctgtctgataaattattatatgagatanaatgaa aattaataggatgtgctaaaaasatrcagtaagaagttagaaaaatatatgt ttatgttaaagttgccacttaattgagaatcagaagcaatgttatttt aagtctaaaatgagagatauctgtcaatacttaaattctgcagagattc tatatcttgacagatatctccttcaaaaatccaatctatggtaga ctaaatttgaaatgatcttectcataatggagggaaaagatggactgacc ccaaaagctcagatttaaagaaatctgtttaagtgaaagaaaataaaaga actgcatttttt aaggeCCatgaatttagaaaataggaaatatt aataagtgtatctttcatctgttattacttgaggtgttttata ccgccaaggaggccgtggcaccgtcagtgtgatctgtagaccccatggcg gcctttttcgcgattgaatgaccttggcggtgggtccccagggctctgg tggcagcgcaccagccgctaaaagccgctatiaactgccgctaaaggcca cagcaaccccgcgaccgcccgttcaactgtgctgacacagtgatacagat aatgtcgctaacagaggagaatagaaatatgacgggcacacgctaatgtg gggaaaagagggagaagcctgattttatttttagagatctagagata _____________________ aattcccagtattatatcctttataaaaaatttctattaggagatta 45 taaagaatttaaagctattttttagtggggtgtaattctttcagtagt ctcttgtcaaatggatttaagtaatagaggcttaatrcaaatgagagaa tagacgcataaccctttcaaggcaaaagctacaagagcaaaaattgaaca cagcagccagccatctagccactcagattttgatcagttttactgagttt gaagtaaatatcatgaaggtfltaattgctgataaaaaaataagatacagg tgtgacacatctttagtttcagaaattaatggcttcagtaggattata Mtcacgtatacaaagtatctaagcagataaaatatgccattaatggaauc ttaatagaaatatatttaattccttcattctgtgacagaaattttct aatctgggtcttttaatcacctaccctttgaaagagtttagtaatttgct atttgccatcgctgtttctcagctaatcaaagtgatacttgagaa agattatttttggttgcaaccacctggrcaggactattttagggccattt taaaactcttttcaaactaagtatttaaactgttctaaaccatttaggg ccttttaaatctttteatgfatttcaflacttcgttaaaagttattaag gtgtctggcaagaacttccttatcaaatatgctaatagtttaatctgtta atgcaggatataaaattaaagtgatcaaggcttgacccaaacaggagtat cttcatagcatatttcccctccttctagaatteatatgattgc tgccaaggctattttatataatctctggaaaaaaaatagtEaatgaaggtt aaaagagaagaaata tcagaacattaagaattcggtattttactaactg cttggttaacatgaaggttattttattaaggtttctatctttataaa aatctgttcccttttctgctgatttctccaagcaaaagattcttgatttg ttttttaactcttactctcccacccaagggcctgaatgcccacaaagggg acttccaggaggccatctggcagctgctcaccgtcagaagtgaagcragc cagttcctcctgggcaggtggccaaaattacagttgacccctcctggtct ggctgaaccttgccccatatggtgacagcc-atctggccagggcccaggtc - tccctctgaagcctttgggaggagagggagagtggctggc-ccgatcacag atgcggaaggggctgactcctcaaccggggtgcagactctgcagggtggg tctgggcccaacacacccaaagcacgcccaggaaggaaaggcagcttggt atcactgcccagagctaggagaggcaccgggaaatgatctgtccaagac ccgttcttgcttctaaactccgagggggtcagatgaagtggttttgtttc ttggcctgaagcatcgtgttccctgcaagaagcggggaacacagaggaag gagagagatgaactgaacaaagcatgcaaggcaaaaaaggrcttagg atggctgcaggaagttagttcttctgcattggctccttactggctcgtc atcgccc~acaaacaacgcacccagtggagaacttccctgttacttaaaca ccattctctgtgcttgcttcctrcagGGGCrGATGCCAAGCCATCCGTCIT CATCrTCOCGCCATCGAAGGAGCAGTrAGCGACCCCAACTGTCTCTGTGG TGTGCTGATCAATAAC1TCrCCCCAGAGAAATCAGTGTCAAGTGGAAA GTGGATGGGGTGGTCCAAAGCAGTGGTCATCCGGATAGTGTCACAGAGCA GGACAGCAAGGACAGCACCrACAGCCTCAGCAGCACCCr~rCGCrGCCCA CGTCACAGTACCTAAGTCATAATT7ATATFCCTGTGAGGTCACCCACAAG ACCCrGGCCrCCCCrCGGTCACAAGCrCAACAGGAACGAGTGTGAGGC TtagAGGCCCACAGGCCCCTGGC~rGCCCCCAGCCCCAGCCCCCrCCC ACCrCAAGCC[CAGGCCCJGCCCCAGAGGATCCrTGGCAATCCCCCAGC CCCT=CCCTcCCCATCCCCrCCCCCrCIMGGCI=AACCGTG1TAAT ACrGGGGGGTGGGGGAATGAATAaataaaGTGAACCI=GCACCrGTGAt ttctctctcctgtctgatttaaggttgttaaatgttgtttcccstta tagttaatctttaaggaactacatactgagttgctaaaaactacaccat cacttataaaattcacgccttctcagttctccc-ctcccctcctgtcctcc * gtaagacaggcctccgtgaaacccataagcacttctctttacaccctctc ctgggccggggtaggagactttttgatgtcccctcttcagcaagcctcag aaccattttgagggggacagttcttacagtcacattcctgtgatctaat gacttagttaccgaaaagccagtctctcaaaaagaagggaacggctaga aaccaagtcatagaaatatatatgtataaaatatatatatatccatatat gtaaaataacaaaataatgataacagcataggtcaacaggcaacagggaa tgttgaagtccattctggcacttcaatttaagggaataggatgccttcat tacamttaaatacaatacacatggagagcttcctatctgccaaagacca _____________________tcctgaatgccttccacactcactacaaggttaaageattcatacaat 46 gtgatcgaggagttcccgttgtggctcagcaggttaagaacgtgactgg tatccaggaggatgcgggtttggtccccagcctcgctcagtggattaagg atccagtgttgctgcaagatcacgggctcagatcccgtgttctatggcta tggtgtaggctggtagctgcatgcagccctaattgacccctagcctggg aactgccatatgccacatgtgaggcccttaaaacctaaaagaaaaaaaa gaaaagaaatatcttacacccaatttatagataagagagaagctaaggtg gcaggcccaggatcaaagccctacctgcctatcttgacavctgatacaaa ttctgtcttctagggtttccaacactgcatagaacagagggtcaaacatg ctaccctcccagggactectcccttcaaatgacataaattttgttgccca tctctgggggcaaaactcaacaatcaatggcatctctagtaccaagcaag gctcttctcatgaagcaaaactctgaagccagatccatcatgacccaagg aagtaaagacaggtgttactggttgaactgtatccttcaattcaatatgc tcaatttccaactcccagtccccgtaaatacaaccccctttgggaagaa gtccttgcagatgtagccacgtb.aagagattatacagaaaggctagt gaggatgcagtgaaacgggatctttcatacattgctggtggaaatgtaaa atgctgcaggcactctagaaaataatttgccagttttttgsaaaagctaaa caaaatagtttagttgcattctgggttatttatcccccagaaattaaaa ttatgtccgcacaaaaacgtgtacataatcattcataacagccttgtac Seq W) No. 12 caaggaaccaagctggaactcaaacgaagtcaaccaaacgu~ctc ttggctgtctgtgtcttacggtrtctgggctctgaaatgattcatgtgc tgactctctgaaaccagactgacattctccagggcnaaactaaagcctgt catcaaactggaaaactgagggcacattttctgggc-agaactaagagtca ggcactgggtgaggaaaaacttgttagaatgatagttagaaacttaict gggaagcaagc-ccatgttctgaacagagctctgctc-aagggcaggagg ggaaccagtttgtacaggagggaagttgagacgaacccctgtgtatat ggtttcggcgcggggaccaagctggagctcaaacgtaagtggcttttc gactgattttgctgttctaattgtggttggcttgtccattttt cagtgtmcatcgaattagttgtcagggaccaaiacaaattgccttccca gattaggtaccagggaggggacattgctgcatgggagaccagagggtggc taattttaacgtttccaagccaaaataactggggaagggggcttgctgt cctgtgagggtaggtttttagaagtggaagttaggggaaatcgctat ggttcacttttggctcggggaccaaagtgagcc-caaaattgagtacat ttccaktcaattatttgtgagatttttgtcctgttgtgtcattgtgcaag tttttgacattttggttgaatgagccattcccagggacccaaaaggatga gaccgaaaagtagaaaagagccaaclttuaagctgagcagacagaccgaa ttgttgagtttgtgaggagagtagggtttgtagggagaaaggggaacaga -tcgctggctttttctctgaattagcctttctcatgggactggcttcagag ggggtttttgatgagggaagtgttctagagccttaactgtgggttgtgtt cggtagcgggaccaagctggaaatcaaacgtaagtgcactttttactcc ttttctttcttatacgggtgtgaaattggggacttttcatgtttggagt atgagttgaggtcagttctgaagagagtgggactcatccaaaaatctgag gagtaagggtcagaacagagttgtctcatggaagaacaaagacctagtta gttgatgaggcagctaaatgagtcagttgacttgggatccaaatggccag acttcgtctgtaaccaacaatctaatgagatgtagcagcaaaaagagatt tccattgaggggaaagtaaaaftgttaatattgggatcacctttggtga agggacatccgtggagattgaacgtaagtattttttctctactaccttct gaaatttgtctaaatgccagtgttgacttttagaggcttaagtgtcagtt ttgtgaaaaatgggtaaacaagagcatttcatatttattatcagttca aagttaaactcagctccaaaaatgaatttgtagacaaaaagattaatta agccaaattgaatgatcaaaggaaaaaaaaattagtgtagatgaaaaag _______________________1 gaattcttacagctccaaagagcaaaagcgaattaattttcttgaactt 47 tgccaaatcttgtaaatgatttttgttctttacaatttaaaaaggttaga gaaatgtatttcttagtctgttttctctcttctgtctgataaattattat atgagataaaaatgaaaattaataggatgtgctaaaaaatrcagtaagaag ttagaaaaatatatgtttatgttaaagttgccacttaattgagaatcaga agcaatgttattttaagtctaaaatgagagataaactgtcaa;tactta aattctgcagagattctatatcttgacagatatctcctttcaaaaatr, caatttctatggagactaaatgaatgatcttcctcataatggaggg aaaagatggactgaccccaagctcagatt*aagaaaacctgtttaag *gaaagaaaataaaagaactgcatttttaaaggcccatgaatttgtaga aaaataggaaattaataagtgtattctattlctgttattac ttgatggtgtttttataccgccaaggaggccgtggrcarcgtcagtgtgat ctgtagaccccatggcggccttttttgcgattgaatgaccttggcggtg ggtccccagggctctggtggcagcgcaccagccgctaaaagccgctaaaa actgccgctaaaggccacagcaaccccgcgaccgcccgttcaactgtgct gacacagtgatac-agataatgtcgctaacagaggagaatagaaatatgac gggcacacgctaatgtggggaaaagagggagaagcctgatttttttt tagagattctagagataaaattcccagtattatatectttaaaa tttctattaggagattataaagaatttaaagctatttaagtggggt gtaattcttcagtagtctcttgtrcaaatggatttaagtaatagaggctt aatccaaatgagagaaatagacgcataaccctttcaaggcaaaagctaca agagcaaaaattgaacacagcagccagccatctagccactcagattttga tc-agtttctgagtttgaaglaaatatcatgaaggtataattgctgata aaaaaataagatacaggtgtgacacatctttaagtttcagaaatttaatg gcttcagtaggattatatttcacgtatacaaagtatctaagcagataaa - -atgccattaatggaaacttaatagaaatatatttttaaattcctteattc tgtgacagaaattttctaatrctgggtctttaatcacctac-cctttgaaa gagtttagtaatttgctatttgccatcgctgtttactccgctaatttea aaagtgatacttgagaaagattatttttggtttgcaaccacctggcagga ctattttagggccattttaaaactcttttcaaactaagtattaaactg ttctaaaccatttagggccttaaaaatcttttcatgaatttcaaactt cgttaaaagttattaaggtgtctggcaagaactteettatcaaatatgct aatagtttatctgttaatgcaggatataaaattaaagtgatcaaggctt gacccaaacaggagtatcttcatagcatatttcccctcctttttctag aattcatatgattttgctgccaaggctattttatataatctctggaaaa aaatagtaatgaaggttaaaappgagaaaatatcagaacattaagaatt cggtattttactaactgcttggttaacatgaaggttttttattaag gttctatctttataaautctgttcctttctgctgatttctccaagc aaaagattcttgatttgtttaactcttactctccracccaagggcct gaatgcccacaaaggggacttccaggaggccatctggcagctgctcaccg tcagaagtgaagccagccagttcctcctgggcaggtggccaaaattacag ttgacccctcctggtctggctgaaccttgcccatatggtgacagcc-atc tggccagggcccaggtctccctctgaagcctttgggaggagagggagagt ggctggcccgatcacagatgcggaaggggctgactcctcaaccggggtgc agactctgcagggtgggtctgggcccaacacacccaaagrcacgcccagga aggaaaggcagcttggtatcactgcccagagctaggagaggcaccgggaa aatgatctgtccaagacccgttcttgcttctaaactccgagggggtcaga tgaagtggttttgttncttggcctgaagcatcgtgttccctgcaagaagc ggggaacacagaggaaggagagaaaagatgaactgaacaaagcatgcaag gcAaaaaaggccttaggatggctgcaggaagttagttcttctgcattggc tccttactggctcgtcgatcgcccacaaacaacgcacccagtggagaact tccctgtacttaaacaccattctctgtgcttgcttcctcaggggctgat gccaagccatccgtcttcatcttcccgccatcgaaggagrcagttagcgac ________________________cccaactgtctctgtggtgtgcftgatca Seq ID No.15 gatgccaagccatccgtcttcatcttcccgccatcgaaggagcagttagc 48 gaccccaactgtctctgtggtgtgcttgatcaataacttcttccccagag aaatcagtgtcaagtggaaagtggatggggtggtccaaagcagtggcat ccggatagtgtcacagagcaggacagcaaggacagcacctacagcctcag cagcaccctctcgctgcccacgtrcacagtacctaagtcataatttatatt. cctgtgaggtcacccacaagaccctggcctcccctctggtcacAAGCTTC AACAGGAACGAGTGTGAGGcrrAGAGGCCCACAGGCcCTGGCCTGCCCC CAGCCCCAGCCCCCCTCCCCACCTCAAGCCTCAGGCCMrGCCCCAGAGG ATCCfl'GGCAATCCCCCAGCCCCJZITCCCTCCTCATCCCCTCCCCCrCr 'TrGGCI=AACCGTGTAATACTGGGGGGTGGOGGGAATGAATAAATAAAG TGAACCITGCACCTGTGA1TrCCrCCrGTCrGATI=AAGQTGTr AAATGTTGTM~CCCCATTATAGTrAATCr'AAGGAAC'rACATACrGA GTGCTAAAAACrACACCATCACTrATAAAACAcgCMfCrCAG I I CCCCrCCCCTCCGTCCrCCGTAAGACAGGCCTCCGTGAAACCCATAAGC ACTrCTC'lACACCCTCTCCTGGGCCGGGGTAGGAGACITI=GATGTC CCCrTrICAGCAAGCCTCAGAACCATI=GAGGGGGACAGrCrrACAGT CACAT*TcMGtGATCrAATGACrIAGTraCCGAAAAGCCAGTCrCTCA AAAAGAAGGGAACGGCTAGAAACCAAGTCATAGAAATATATATGTATAAA ATATATATATATCCATATATGTAAAATAACAAAATAATGATAACAGCATA GGTCAACAGGCAACAGGGAATGrrGAAGTCCArrCrGGCACrrCALIA. AGGGAATAGQ3ATGCC1TCAfl7ACAITIAAATACAATACACATGGAGAGC 'rrCCI'ATCTGCCAAAGACCATCCTGAATGCCMCCACACrCACrACAAGG TTAAAAGCAITCATrACAATGrrGATCGAGGAGTTrCCCGTrGTGGCrCAG CAGGTrAAGAACGTGACTGGTATCCAGGAGGATGCGGGTnrGGTCCCCAG CCrCGCrCAGTGGATAAGGATCCAGTGTrGCrGCAAGATCACGGGCTCA c3ATCCCGTGTTCTATGGCrATGGTGTAGGCrGGTAGCrGCATGCAGCCCT. AATITGACCCCrAGCCTGGGAACTGCCATAtGCCACATGTGAGGCCCTTA AAACCrAAAAGAAAAAaAAAGAAAAGAAATATCrrACACCCAA1TATAG ATAGAGAGAAGCrAAGGTGGCAGG~CCAGGATCAAAGCCCTACCTGCCr ATCITGACACCTGAtACAAAT-rCrGTCTCrAGGGtTCCAACACTGCAT AGAACAGAGGGTCAAACATGCTACCCCCAGGGACFCCrcCTCTCAAAT GACATAAAT=GT~CCCATCTCGGGGGCAAAACTCAACAATCAATGG CATCTCTAGTACCAAGCAAGGCrcMCTCATGAAGCAAAACrCGAAGcC AGATCCATCATGACCCAAGGAAGTAAGACAGGTGTrACrGGTGAACrG TATCCICAA~rCAATATGCTCAA1TCCAACrCCCAGTCCCCGTAAATA CAACCCCCMrGGGAAGAGAGTCCTTGCAGATGTAGCCACGTrAAAAAGA GITrATAcAGAAAGGCrAGTGAGGATGCAGTGAAJACGGGATCI1CATAC ATrGCTGGTGGAAATGTAAAATGCTGCAGGCACTCTAGAAAATAATrrTGC CAGTITI=GAAAAGCTAAACAAAATAGTrAGTGCATrCrGGGTrATr TATCCCCCAGAA1AAATTTCCAkAAAACGTGTACATAATC ATrCATAACAGCCTTGTACGAAAAGMr Seq ID No. 16 GGATCCI1AACCCACTAATCGAGGATCAAACACGCATCCTCATGGACAAT ATGTTGGGITCTTAGCCTGCTGAGACACAACAGGAACTCCCCTGGCACCA CITrAGAGGCCAGAGAAACAGCACAGATAAAATTCCCTGCCCrCATGAAG CTrATAGTCTAGCGGGAGATATCATAGGCAAGATAAACACATACAA-AT ACATCATC~rrAGGTAATAATATATACrAAGGAGAAAA1TACAGGGGAGAA AGAGGACAGGAATrGCTAGGGTAGGATTATAAGTrTCAGATAGITCATCAG GAACACrGTGCTGAGAAGATAACATTAGGTAAAGACCGAAGTAGTAAG GAAATGGACCGTGTGCCTAAGTGGGTAAGACCAflCrAGGCAGCAGGAAC AGCGATGAAAGCACTGAGGTGGGTGTCACTGCACAGAGTTG TCACTGC ACAGAG1TGTGTGGGGAGGGGTAGGTCITGCAGGCrCrrATGGTCACAGG AAGAATrGTI=ACCCCACCGAGATGAAGG1TGGTGGATIMGAGCAGA AGAATAATrCrGCCrGGTIIATATATAACAGGATr1cCCTrGGGTGCrCTG ATGAGAATAATCTGTCAGGGGTGGGATAGGGAGAGATATGGCAATAGGAG _____________I CCrrGGCTAGGAGCCCACGACAATAATT-CCAAGTGAGAGG3TGGTGCTGCA 49 TTGAAAGCAGGACTAACAAGACCTGCTGACAGTGTGGATGTAGAAAAAGA TAGAGGAGACGAAGGTGCATCTAGGGTITCrGCCTGAGGAATTAGAAAG ATAAAGCrAAAGCTTATAGAAGATGCAGCGCTCTGGGGAGAAAGACCAGC AGCTCAGTITrGATCCATCTGGAATTAATITGGCATAAAGTATGAGGTA TGTGGGTTAACATTATITGUT iIITIII I ICATGTAGCrATCCAACG TCCCAGCATCATITATTAAAAGACTITCCTITCCCCTATrGGATrGTr TrGGCACCTTCACrGAAGATCAACTGAGCATAAAATGGGTCTATITCrA AGCTCITGATrCCATTCCATGACCTATTTGTTCATCTITACCCCAGTAGA CACTGCCTTGATGATTAAAGCCCCTGTTACCATGTCTGTITrGGACATGG TAAATCTGAGATGCCrATTAGCCAACCAAGCAAGCACGGCCCTTAGAGAG CrAGATATGAGAGCCTGGAATTCAGACGAGAAAGGTCAGTCCTAGAGACA TACATGTAGTGCCATCACCATGCGGATGGTGTTAAAAGCCATCAGACTGC AACAGACrGTGAGAGGGTACCAAGCTAGAGAGCATGGATAGAGAAACCCA AGCACTGAGCTGGGAGGTGCTCCTACATTAAGAGATTAGTGAGATGAAGG ACrGAGAAGATTGATCAGAGAAGAAGGAaAATCAGGAAAATGGTGCrGTC cTGAAAATCCAAGGGAAGAGATGTCCAAAGAGGAGAaAACTGATCAGTT GTCAGCTAGCGTCAATTGGGATGAAAATGGACCATTGGACAGAGGGATGT AGTGGGTCATGGGTGAATAGATAAGAGCAGCTTCFATAGAATGGCAGGGG CAAAATTCrCATCTGATCGGCATGGGTrcTAAAGAAAACGGGAAGAAAAA ATTGAGTGCATGACCAGTCCCTrCAAGTAGAGAGGTgGAAAAGGGAAGGA GGAAAATGAGGCCACGACAACATGAGAGAAATGACAGCAI11TAAAAAT TITITATITATTrtATTTTATITGCTITIAGGGCrGCCCCrGC AAcatatggaggttcccaggttaggggtctaatcagagctatagctgcca gcctacaccacagccatagcaatgccagatctacatgacctacaccacag ctcacagcaacgccggatccttaacccactgagtgaggccagagatcaaa cccatatccttatggatactagtcaggttcattaccactgagccaaaatg ggaaATCCrGAGTAATGACAGCATITITrAATGTGCC AGAAAACT TGCCACCCCGAAATGTCrCTCAGGCATGTGGATTATIrGAGCTGAAAAC GATrAAGGCCCAAAAAACACAAGAAGAAATGTGGACCTTCCCCCAACAGC CTAAAAAA1TTAGATTGAGGGCCTGTTCCCAGAATAGAGCTATTGCCAGA CITGTCTACAGAGGCrAAGGGCTAGGTGTGGTGGGGAAACCCTCAGAGAT CAGAGGGACGTATGTACCAAGCATTGACAMCCATCrCCATGCGAAT GGCCTrCTrCCCCTCTGTAGCCCCAAACCACCACCCCCAAAATCrrCrrC TGTCTAGCTGAAGATGGTGTrGAAGGTGATAGTCAGCCACITGGC GAGTTCCTCAGTTGTCTGGGTCITCCTCCGGATCCACATATTCGACr GTGTTGATTCCCTGTTACGTCrCATGGCACCAITCATTCT TAGACCAGCCCAAAGAACCAGAAGAGTGAAGGAAAATTCCACCCT GACAAATGCrAAATGAGAATCACCgCAGTAGAGGAAAATGATCTGGTgCT GCGGGAGATAGAAGAGAAAATcGCTGGAGAGATGTCACTGAGTAGGTGAG ATGGGAAAGGGGGGGCACAGGTGGAGGTGTTGCCCTCAGCrAGGAAGACA GACAGTicacagaagagaagcgggtgtccgtGGACATCTTGCCrCATGGA TGAGGAAACCGAGGCrAAGAAAGACrGCAAAAGAAAGGTAAGGATTGCAG AGAGGTCGATCCATGACTAAAATCACAGTAACCAACCCCAAACCACCATG TITCCCTAGTCrGGCACGTGGCAGGTACTGTGTAGGTMCAATATrA TTGGmGTAACAGTACCTATAGGCCTCCATCcCCTCCrCTAATACrAA CAAAAGTGTGAGACTGGTCAGTGAAAAATGGTCTcrCTCTCrATGCAAT CITTCTCAAGAAGATACATAAUITIITATITTATCATaGGCITGAAGAGC AAATGAGAAACAgCCrCCAACCTATGACACCGTAACAAAGTGMATGAT CAGTGAAGGGCAAGAAACAAAACATACACaGTAAAGACCCTCCATAATAT TGtGGGCTGGCCCAaCACAGGCCAGGTTGTAAAAGCIITATTCTIGA TAGAGGAATGGATAGTAATGTTCAACCTGGACAGAGAT*CATGTFCACT GAATCCrrCCAAAAATrCATGGGTAGTITGAAtTATAAGGAAAATAAGAC TrAGGATAAATACTTrgTCCA*GATCCCAGAGTrAATgCCAAAATCAGTT TrCAGACTCCAGGCAGCCTGATCAAGAGCCTAAACTITAAAGACACAGTC CCTTAATAACTACrATTCACAGTGCACITICAgGGCGCAAAGACTCATT GAATCCTACAATAGAATGAGTTAGATATCAAATCTCTCAGTAATAGATG 50 AGGAGACFAAATAGCGGGCATGACCTGGTCACTTAAAGACAGAAfTGAGA 1TCAAGGCrAGTGTrT=rCrACCTGTHG1TCrACAAGATGTAGCAA TGCGTCrAATTACAGACCTCrCAGGGAAGGAATTCACAACCCTCAGCAAAA ACCAAAGACAAATCrAAGACAACTAAGAGTGTTGGTLTrAAThrGGAAAAA TAACTCACTAACCAAACGCCCCrCTrAGCACCCCAATGTUICCACCATC ACAGTGCTCAGGCCrCAACCATGCCCCAATCACCCCAGCCCCAGACTGGT TATrAcCAAGTTCATGATGACTGGCCTGAGAAGATCAAAAAAGCAATGA CATCrrACAGGGGACTACCCCGAGGACCAAGATAGCAACrGTCATAGCAA ______________CCGTCACACrGC'r1TGGTCA Seq ID No.19 ggatcaaacacgcatcctcatggacaatatgttgggtcttagcctgctg. agacacaacaggaactcccctggcaccactttagaggccagagaaacagc acagataaaattccctgccctcatgaagcttatagtctagctggggagt atcataggcaagataaacacatacaaatacatcatettaggtaataatat atactaaggagaaaattacaggggagaaagaggacaggaattgctagggt aggattataagttcagatagttcatcaggaacactgttgctgagaagata acatttaggtaaagaccgaagtagtaaggaaatggaccgtgtgcctaagt gggtaagaccattctaggcagcaggaacagcgatgaaagcactgaggtgg gtgttcactgcacagagttgttcactgcacagagttgtgtggggaggggt aggtcttgcaggctcttatggtcacaggaagaattgttttactcccaccg agatgaaggttggtggattttgagcagaagaataattctgcctggtttat atataacaggatttccctgggtgctctgatgagaataatctgcaggggt gggatagggagagatatggcaataggagrccttggctaggagcccacgaca ataattccaagtgagaggtggtgctgcattgaaagcaggactaacaagac ctgctgacagtgtggatgtagaaaaagatagaggagacgaaggtgcatet agggttttctgcctgaggaattagaaagataaagctaaagcttatagaag atgcagcgctctggggagaaagaccagcagctcagttttgatccatctgg aaatttggcataaagtatgggtatgtgggttaacattatttgttt ttttttttccatgtagctatccaactgtcccageatcatttattttaaa agactttcctttcccctattggattgttttggrcaccttcactgaagatca actgagcataaaattgggtctatttctaagctcttgattccattccatga cctatttgttcatctttacccc~agtagacactgccttgatgattaaagcc cctgttaccatgtctgttttggacatggtaaatctgagatgcctattagc caaccaagcaagcacggcccttagagagctagatatgagagc-ctggaatt cagacgagaaaggtcagtcctagagacatacatgtagtgccatcaccatg cggatggtgttaaaagccatcagactgcaacagactgtppggggtacca agctagagagcatggatagagaacccaagcactgagctgggaggtgctc ctacattaagagattagtgagatgaggactgagaagattgatcagagaa gaaggaaaatcaggaaaatggtgctgtc-ctgaaaatccaagggaagagat gttccaaagaggagaaaasbctgatcagttgtcagctagcgtc-aattgggat gaaaatggaccattggacagagggatgtagtgggtcatgggtgaatagat aagagcagcttctatagaatggcaggggcaaaattctcatctgatcggca tgggttctaaagaaaacgggaagaaaaaattgagtgcatgaccagtccct tcaagtagagaggtggaaaagggaaggaggaaaatgaggccacgacaaca tgagagaaatgacagcatttttaaaattttattttattttatttatt tatttttgctttgggctgcccctgcaacatatggaggttcccaggtt aggggtctaatcagagctatagctgccagrcctacaccacagccatagcaa tgccagatctacatgacctacaccacagctcacagcaacgccggatcctt aacccactgagtgaggccagagatcaaacccatatccttatggatactag tcaggttcattaccactgagccnaaatgggaaatcctgagtaatgacagc atttttaatgtgccaggaagcaaaacttgccaccccgaaatgtctctca ggcatgtggattattttgagctgaaaacgattaaggcccaaaaaaccaa gaagaaatgtggaccttcccccaacagcctaaaaaatttagattgagggc ctgttcccagaatagagctattgccagacttgctcagaggctaagggc ____________________taggtgtggtggggaaaccctcagagatcagagggacgtttatgtaccaa 51 gcattgacatttccatctccatgcgaatggccttctcccctctgtagcc ccaaaccaccacccccaaaatcttctctgtctttagctgaagatggtgt tgaaggtgatagtttcagccactttggcgagttcctcagttgttctgggt CtttcctccTgatccacattattcgactgtgttgattttctcctgttta tctgtctcattggcacccatttcattcttagaccagcccaaagaacctag aagagtgaaggaaaatttcttccaccctgacaaatgctaaatgagaatca ccgcagtagaggaaaatgatctggtgctgcgggagatagaagagaaaatc gctggagagatgtcactgagtaggtgagatgggaaaggggtgar-acaggt ggaggtgttgccctcagctnggaagacagacagttcacagaagagaagcg ggtgtccgtggacatcttgcctcatggatgaggaaaccgaggctaagaaa gactgcaaaagaaaggtaaggattgcagagaggtcgatcatgactaa tcacagtaaccaaccccaaaccaccatgttttctcctagtctggcacgtg gcaggtactgtgtaggttttcaatattattggtttgtaacagtacctatt aggcctccatccccctctaatactaacaaaagtgtgagactggtcagt gaaaaatggtcttctutctctatgaatctttctcaagaagataicataact tttattttatcataggcttgaagagcaaatgagaaacagcctccaacct atgacaccgtaacaaaatgtttatgatcagtgaagggcaagaaacaa atacacagtaagaccctccataatattgtgggtggcccaacacaggcca ggttgtaaaagctttttattcttgtagaggaatggatagtaatgtttc aacctggacagagatratgttcactgaatecttccaaaaattcatgggta gtttgaattataaggaaaataagacttaggataaatactttgtccaagat cccagagttaatgccaaaatcagttttcgactccaggcagcctgatcaa gagcctaaactttaaagacacagtcccttaataactactattcacagttg cactttcagggcgcaagactcattgaatcctamatagaatgagtttag atatcaaatctctc-agtaatagatgaggagactaaatagcgggcatgc tggtcacttaaagacagaattgagattcaggctagtgttctttctacct gttttgtttctacaagatgtagcaatgcgctaattacagacctctcaggg aaggaatlcacaaccctcagcaaaaaccaaagacaaatctaagacaacta agagtgttggtttaatttggaaaaataactcactaaccaaacgccctct tagcaccccaatgtcttccaccatcacagtgctcaggcctcaaccatgcc ccaatcacc Seq ID No.25 GCACATGGTAGGCAAAGGACmGCI17CTCCCAGCACATCTTrCrGCAGA GATCCATGGAAACAAGACTCAACrCCAAAGCAGCAAAGAAGCAGCAAGTr CTCAAGTGATCTCC=CTACTCCCTCCrCCCAGGCTAATGAAGCCATGT GCCCCrGGGGGATrAAGGGCAGGTGTCCATrGTGGCACCCAGCCCGAAGA CAAGCAATrGATCAGOCGAGCACCTGAATGTGGACrCrGGAAlT 1-rCrCCTCACCTGTGGCATATCAGCTTrAAGTCAAGTACAAGTGACAAAC AACATAATCCTAGAAGAGAGGAATCAAGCrGAAGTCAAAGGATCACTGC CrTGATTWACGTGAATGATGACCrGGAAAATATCCrGAACAACAGCr TCAGGGTGATCATCAGAGACAAAAGTTCCAGAc3CCAGGTAGGGAAACCCT CAAGCCrrGCAAAGAGCAAAATCATGCCATGGOGTrAACCTGCrGAG TGATTrACTATATG1TACTGTGGGAGGCAAAGCGCTCAAATAGCCrGGGT AAGTATGTCAAATAAAAAGCAAAAGTGGrTG~mcMGAAATGTTArGACCr GAG3GAAGGAATATTGATAAMrACCAATAATI=CAGYAATGAMATAGA TGTGCACI1TAGTCAGTGTCICrCCACCCCGCACCrGACAAGCAGITAGA ATfATrCrAAGAATCTAGGmGCGGGGCrACATGGGAATCAGCT'rC AGTGAAGAGTTTG'ITGGAATGAITCACTAAA=mCTATrCCAGCATAA ATCCAAGAACCTCTCAGACTAGTUTATTGACACTGC1T1TCCrCCATAAT CCATCTCATCTCCGTCCATCATGGACACIMGTAGAATGACAGGTCCI'GG CAgAGACTCaCAGATGCITCGAAACATC=rIGCCrTCAAAGAATGAAC AGCACACATACrAAGGATCrCAGTGATCCACAAATTAGTTXGCCACAA TGG'TUITATGATAAAAGT=CTrIAACAGCAAATrGTIMATAATAG TrGl-rCrGCrrATAATAA1TGCATGCrCACrrCrnTCI I Im I I ICI ITI TGCT 1r=AGTGCCGCAGGTgcagcatatgaaattc caggctaggggtcaaatcagaactacacctactggccacgccacagcca 52 caatgccagatCCttaacccaatgagcgaggccagggatcgaacccatgt cctcatggatactagtcaggctcattatccgctgagccataacaggaact ccGGG'=TAATGTCGC'Ar~rrAA ccACAAAATGAATGTATrCACATAATITIAAAAGG'17AAATAATITATGA TATACAAGACAATAGAAAGAGAAAACGTCATTGCCTCrCICCACGAC AACACGCCITCCTAA1TGAMGAAGAAATAACrACTGAGCAT.GGT1AG TGTACTTC11CAGCAATTAGCXXIGTATTCATAGCCATACATATTCAATT AAAATGAGATCATGATATCACACAATACATACCATACAGCCTATAGGGAT TmACAATCATCrrCCACATGACrACATAAAA-ACCrACCAAAAAAAAA AAAAACCCACrrCATCCTCCTATFGGCTGC=rGTGCCCATrAAAAAG CTCTATCATAATTAGGTATGATGAGGATCCATITAC=rrCAAG CAACATrrCAATGCACAGTCITATATACACATIX3AGCCACIT1CT TrCTITCI1rTTTTG,IIIIILIIILIIIIIIIIInIIGTC1,i=-GTC TTCA Ggctgcatatggaggttcccaggctagctgtctaatcaga -ac tatagctgctggcctacgccacatccacagcaatacaagatctgagCcat gtctgcaacttacaccacagctcacagcaacggtggatccttaaaccact gagcaaggccaggatcaaacccatAAlCATGGCCC1AGTrGGATrT G1TAACCACTGAGCCATGATGGCAACTCCTGAGCCTACITICTAATCAT TrCCAACCCrAGGACAC~l I IrrAAGTTCAT=Tr~CCCCCCACCCCC TOT CrOAAGtGTGTTrGCITCCACTGGGTGACITCACtCCCAGGATC TCATCrGCAGGATACrGCAGCrAAGTGTATGAGCrCTGAATI-GAATCCC AACrCrGCCACrCAAAGGGATAGGAG1TCCGATGTGGCCCAATGGGAT)C AGTGGCATCTC'TGCAGTGCCAGACGCaggtccatccctggcceagcac agtgggtaatctggCATG1GCAGCrGAGGCATAGATICAAUrG TGCCTCAgATCTGATCCTTGGCCCAAGGACrGCATATGCCrCAGGGCAAC CAAAAAAGAGAAAAGGGOGTGATAGCATAG'I=CrAGAnTGGGGGAT. AATrAAATAAAGTGATCCATGTACAATGTATGGCA1TIGTAAATGCTCA ACAAArTCAACTArATggagtccatcatggctagtggaagggaat ctgattagcatccatgaggacacaggtCCAACCCCGACCTrGCTCAGTGG GCATTGCrGTGAGCrGTGGCATGGGTrrACAGACGAAGCrCGGATCrGGCA TTGCrGTGGCTGGGTGTAAGCCAgCAActacagctctrattcagcccct agcctgggaacctccatatgccTAAAAGACAAAAAATAAAAMfAAATrA AAAATAAAGAAATG~rAACTATTATGATGgTACrGCTTGCAITACTGCA AAGAAAGTCACTCIITGATACrCrAATATCTAGTGACGTGTGCrCA GTGAACrATrrGGACACIrAAmICCACTCCrCATCrCCAACITGA CAArCCTCrCrIrGGTGAGATCCACrGCrGACMrGCrCrr AAGGCAACrAGAAAAGTGCrCAGTGACAAAATCAAAGAAAGTrACCrAA TCTTCAGAATTACAATCrrAAGTTrMTGTAAAGCTTACTA1TrCAGTG GTAGTATrAI-CCI-rGGTCCCrrACAACITATCAGCTCrGATCrATTGC TGA=mCAACTFATTGTrGGAGTr=nCCTJTICCCrGTrCAT TCrGCAAATGMrGCrGAGCA11GTCAAGTGAAGATACTOGACTGGCC TrCCAAATATAAGACAATGAAACATCGGGAGTTCrCATrATGGTGCAGCA GAaacgaatccaactaggaaatgtgaggttgcaggttcgatccctgccct tgctcagtgggttaaggatccagcattaccgtgagctgtggtgtaggttg cagacgtggctcagatc-ctgcgttgctgtggctgtggcataggctggcag ctctagctctgattcgaccgctagcctgggaacctccatGCGCCCCGAGT GCAGCCCflAAAAAGCA AA AA AA A AAGAAAGAAAGAAAAAGACAATGk&JL CATCAAACAGCrAACAATCCAGTAGGGTAGAAAGAATCTGGCAACAGATA AGAGCGA1rAAATGTTCrAGGTCCAGTGACCrGCCTCrGTGCTCTACAC AGTCGTGCCACrGCrGAGGGAGAAGGTCTCTCTTGAGTrGAGTcCFGAA AGACATrAGTrGTCACAAACrAATGCCAGTGAGTGAAGGTGTrrCCAAG CAGAGGGAGAGIMGGTAAAAAGCTGGAAGTCACAGAAAGACrTrAAAGA GTITAGGATGGTGGGAGCAACATACGCTGAGATGGGGCrGGAAGGTrAAG AGGGAAACAACrATAGTAAGTGAAGCTGGACTCACAGCAAAGTGAGGAcC TCAGCATCCfrGATGGGGTnACCATGGAAACACCAAGGCACACCrrGAIT TCCAAAACAGCAGGCACCTGATTCAGCCCAATGTGACATGGTGGGTACCC _ 53 CTCTAGCTCTACCTGTTrGTGACAACTGACAACCAACGAAGTrAAGTCr GGATITACrCTGCTGATCC~rGTImGTTCACACGTCATCTATAG. CTrCATGCCAAAATAGAGTTCAAGGTAAGACGCGGGCCrrGGTrrGATAT ACATGTAGTCJrATCIT1GMGAGACAATATGGTGGCAAGGAAGAGGTTCA AACAGGAAAATACTCTCTAA1TATGA1TAAC-rGAGAAAAGCrAAAGAGTC CCATAATGACACTGAATGAAGTTCATCATIfrGCAAAAGCCrI'CCCCCCCC CCCAGGAGACIATAAAAAAGTGCAATITIAAATGAAC'TAITrACAAA ACAGAAATAGACrCACAGACATAGGAAACGAACAGATGGTrACCAAGGGT GAAAGGGAGTAGGAGGGATAAATAAGGAGTULGGGGTTAGCAGATACACC CCAGTGTACACAAAATAAACAACAGGGACCTACTATATAGCACAGGGAAC TATATGCAGTAGC'ITACAATAACCTATAATGGAAAAGAATGTGAAAAAGA ATATATGTATGCGTGTGTGTGTAACTGAATCACTrrGCTGTAACCrGAAT CrAACATAACATrGTAAATCAACTACAG -l~l 11111 ii iAAGTGCAG GGTIIGGTGi-i1 i i CTTffT1G~l~1ITG TI=rAGGGCCACACCCAGACATATGGGGGUCCCAGGctAGGGGTcTAa' flAGAGcTACAGtTGCCGGCTTGCAcacagccacagcaacatcagatcc gagccgcacttgcgacttacaccacagctcatggcaataccagatccta acccactgagcaaggcccagggatcgtacccgcaacctcatggttcctag tcagattcattTCrGCrGCGCTACAATGGGAACrCCAAGTGCAGTfTIT GTAATGTGCTtCGTCIn-rCIMGTAATCATATTCATCCTACTTCCCAATA* AATAATAAACATAAATAATAAACATACCAT17GTAAATCAACrACAAT I I IrrAAATGCAGGG'T1-rrITITr I I I GI I GTCITIl-rG CrMCrAgggccgctcccatggcatatggaggttcccaggctaggggt cgaatcggagctgtagccaccggcctacgccagagccacagcaacgcggg atcgagccgcgtctgcaacctacaccacagctcacggcaacgccggatc gttaacccactgagcaagggcagggatcgaacctgcaacctcatggttcc tagtcagaftcgttaactactgagccacaacggaaacTCCTAAAGTGCAG I AAGGIGCCMTAAArACTCIC AATAAATAAATAAATAAACAAATAAATCATAGACATGGTrrGAA=rCAAA GGAAGGGACCATCAGGCCTAGACAGAAATACGTCATCTCrAGTATI= AAAACACACrAAAGAAGACAAACATGCCrTGCCAGAGAAGCCCAGGGCCT CCACAGCTGCTrGCAAAGGGAG1rAGGC1-rCAGTAGCTGAcCCAAGGCTC TG6rCCTCIrCAGGGAAAAGGGITLTGTrCAGTGAGACAGCAGACAGCT GTCACITGTGgtggacgttcggccaaggaaccaagctggaactcaacGTA AGTCAATCCAAACGTCCTrCCIT GCTGTCrGTGTCTACXIGTCCrGT GGCrCrGAAATGATICATGTGCTGACrTCTGAAACCAGACrGACATTCF. CCAGGGCAAAACrAAAGCCTGTCATCAAACcGGAAAACTGAGGGCACAT TTrGGGCAGAACTAAGAGTCAGGCACTGGGTGAGGAAAAACTrG'rAGA ATGATAG1TCAGAAA=rIACTGGGAAGCAAAGCCCATG'TCTGAACAGA GCTCTGCTCAAGGGTCAGGAGGGGAACCAGfTTGTACAGGAGGGAAGT TGAGACGAACCCCrGTGTAtatggtttcggcgcggggaccaagctggagc tcaaacGTAAGTGGCIlCCGACGATrCTIGCTGTITCI'AATTGTT GGTrGCerT=GTCCATI=CAGTGTCATCGAA-FAGTTGTCAGG GACCAAACAAATrGCCICCCAGArrAGGTACCAGGGAGGGGACATTGCr GCATGGGAGACCAGAciOGTGGCTAATTI=AACGT1TCCAAGCCAAAATA ACTGGGGAAGGGGGCITGCTGTCCTGTGAGGGTAGGTITIATAGAAGTG GAAGTTAAGGGGAAATCGCATGTtacttttggctcggggaccaaagt ggagcccaaaattgaGTACAITICCATCAATTATY1GTGAGAITrGT cCTGTrGTGTCAmGTGCAAGTrmGACArrGGTrGAATGAGCCAT TCCCAGGGACCCAAAAGGATGAGACCGAAAAGTAGAAAAGAGCCAACIII TAAGCrGAGCAGACAGACCGAATrGTrGAGTITGTGAGGAGAGTAGGGTr TGTAGGGAGAAAGGGGAACAGATCGCrGCITr=CTrGAATrAGCCTT TCrCATGGGACTGGCITCAGAGGGGGTI=GATGAGGGAAGTGTTCrAG AGCCTTAACTGTG~gttgtgttcggtagcgggaccaagctggaaatcaaa CGTAAGTGCACFI=CrACTCC 54 Porcine Lambda Light Chain In another embodiment, novel genomic sequences encoding the lambda light chain locus of ungulate immunoglobulin are provided. The present invention provides the first reported genomic sequence of ungulate lambda light chain regions. In one embodiment, the porcine lambda light chain nucleotides include a concatamer of J to C units. In a specific embodiment, an isolated porcine lambda nucleotide sequence is provided, such as that depicted in Seq ID No. 28.

In one embodiment, nucleotide sequence is provided that includes 5' flanking sequence to the first lambda J/C region of the porcine lambda light chain genomic sequence, for example, as represented by Seq ID No 32. Still further, nucleotide sequence is provided that includes 3' flanking sequence to the J/C cluster region of the porcine lambda light chain genomic sequence, for example, approximately 200 base pairs downstream of lambda J/C, such as that represented by Seq ID No 33. Alternatively, nucleotide sequence is provided that includes 3' flanking sequence -to the J/C cluster region of the porcine lambda light chain genomic sequence, for example, approximately 11.8 kb downstream of the J/C cluster, near the enhancer (such as that represented by Seq ID No. 34), approximately 12 Kb downstream of lambda, including the enhancer region (such as that represented by Seq ID No. 35), approximately 17.6 Kb downstream of lambda (such as that represented by Seq ID No. 36, approximately 19.1 Kb downstream of lambda (such as that represented by Seq ID No. 37), approximately 21.3 Kb downstream of lambda (such as that represented by Seq ID No. 38), and/or approximately 27 Kb downstream of lambda (such as that represented bySeq ID No. 39). In still further embodiments, isolated nucleotide sequences as depicted in Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39 are provided. Nucleic acid sequences at least 80, 85, 90, 95, 98 or 99% homologous to Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39 are also provided. In addition, nucleotide sequences that contain at least 10, 15, 17, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 500 or 1,000 contiguous nucleotides of Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39are provided. Further provided are nucleotide sequences that hybridizes, optionally under stringent conditions, to Seq ID Nos 28, 31, 32, 33, 34, 35, 36, 37, 38, or 39, as well as, nucleotides homologous thereto. 55 Seq D N.28CCIrTCCTCCrGCACCTGTCAACI'CCCAATAAACCGTCCrCcITGTCATTrC Seq D N.28AGAAATCATGCTCTCCGCTCACTTGTGTCTACCCAITTCGGGC1TrGCAT GGGGTCATCCrCGAAGGTGGAGAOAGTcccccrrGGccrGGGGAAGTCG AGGGGGGCGGGGGGAGGCCI'GAGGCATGTGCCAGCGAGGGGGGTCACCTC CACGCCC~rGAGGACIMflAGAACCAGGGGCGTGGGGCCACCGCCTGAG TGGAAGGCTGTCCACaTICCCCCGGGCCCCCAGGCrCCCrCCrCCGTGT GGACC~rGTCCACCTCTGACTGGCCCAGCCACrCATGCA1TGTrrCCCCG AAACCCCAGGACGATAGCTCAGCACGCGACAGTGTCCCCCTCrGAGGGCC TCrGTCCAmrCAGGACGACCCGCATGTACAGCGTGACCACrCrGCrCAC GCCCACTCACCACGTCCrAGAGCCCCACCCCCAGCCCCATCCTTAGGGGC ACAGCCAGcTCCGACCGCCCCGGGGACACCACCCI'CTCCCCITrcCCCAG GCCCTCCCrGTCACACGCACCACAGGGCCCTCCGTCCCGAGACCCrGCTC CCTCATCCCTCGGTCCCCTCAGGTAGCCTCCACCCGCGTGTGTCCCGAG GTCCCAGATGCAGCAAGGCCCCTGGGACAACGCCAGATCTCTGCrTCCC CGACCCCrCAGAAGCCAGCCCACGCCTGGCCCCACCACCACTGCCTAACg TCCAAGTGTCCATAGGCCCGGGACCTCCAAGTCCAGGlCrGCCTrGG GATrCCGCCATGGGTCrGCCTGGGAAATGATGCAcTGGAGGAGCTCAGC ATGGGATGCGGGACCGTCCrAGGCGCTcCCTCAGGATCCCACAGCTG CCCTGTGAGACACACACACACACACACACACACACACACACACACACACA CACACAAACACGCATGCACGCACGCCGGCACACACGCTATTGCAGAGATG GCCACGGTAGCrGTGCCTCGAGGCCGAGTGGAGTGTCrAGAACTrCGGG GGcc~rCGC~~Tccc~cccG~crAG~ TCCrCArCCCATCAGGATCTCCAAGCTGCTGACCGGAGAGGAAG GGGCC'FGGGACAGGCGGGGACACTCAGACCTCCCTGCTGCCCCTCcCrG *CCrGGGCITGGACGGCTCCCCCCrCCCACGGTGAAGGTGCAGGTGGGG AGAGGGCACCcCCCTCAGCCrCCCAGACCCAGACCAGCCCCCGTGGCAGG GGCAGCCrGTGAGCCTCCAGCCAGATGCAGGTGGCCrGGGGTGGGGGGTG GAGGGGGCGGGAGGTITATGTrrGAGGCrGTATCA~rGTGTAATATIMC GGCGTGTGGGACCCATCTGACCGTCCTCGGTGAGTCCCCCITICrCTCC TCCTFGGGGATCCGAGTGAAATCrGGGTCGATMCrCrCCGTTCrCCrC CGACrGGGGCrGAGGTCGAACCTCGGTGGGGTCCGAAGAGGAGGCCCCT. AGGCCAGGCTCCrCAGCCCCrCCAGCCCGACcgGCCCTC]TGACACAGGG TCCAGCrAAGGGCAGACATG'3AGGCTGCTAGTCCAGGGCCAGGCrCTGAG ACCCAAGGGCGCTGCCCAAGGAACCCITGCCCCAGGGACCCTGGGAGCAA AGCTCCrCACTCAGAGCCTGCAGCCarGGGGTCGAGGACAAGGAGGGAC TGAGGACrGGGCGTGGGGAGTrCAGGCGGGGACACCAGGTCCAGGGAGGT GACAAAGGCGCrGGGAGGGGGCGGACGGTGCCGGGGA~rCCTCCTGGGCC CTGTGGGCTCGGGGTCCTFGTGAGGACCCTGAGGGACTGAGGGCCCCrG GCCrAGGGACT-rGCAgTgAGGGAGGCAGGGAGTGTCCCITGAGAACGTG GCCTCCGCGGGCTGGGTCCCCCrCGTGCrCCCAGCC*GGGAGGACACCCC AGAGCAAGCGCCCCAGGTGGGCGGGGAGGGTCI'CCTCACAGGGGCAGCrG ACAGATAGAGGCCCCCGCCAGGCAGATGCTTGATCCrGGCAg1-rATACTG GG'rrC**GCACAAC'ITCCCGAACAAGGGGCCCTCCGAACAGACACAGA CGCAACCCAGTCGACCcaggCTCAGCACAgAAAATGCACTGACACCCAAA ACCCTCATCTggggGCCTGCQCCGGcAtCCCGCCCCAGGACCCAAGGCCCC TGCCCCCTGGCAGCCCTGGACACGGTCCTrGTGGGCGGTGGGGTCgGGG CTGTGGTGACGGTGGCATCGGGAGCCTGTGCCCCCrCCCrGAAAGGG GAGAGGCrCAAGAGGGGACAGAAATGTCCTCCCCrAGGAAGACCTCGGAC GGGGGCGGGGGGGTGGTCTCCGACAGACAGATGCCCGGGACCGACAGACC TGCCGAGGGAAGAGGGCACCrCGGTCGGGTrAGGCTCCAGGCAGCACGAG GGAGCGAGGCTGGGAGGGTGAGGACATGGGAGCCTGAGGAGGAGCTGGAG ACMCAGCAGGCCCCCAGCTCCGGGCrrCGGGCTCTGAGATGCrCGGACG ______________CAAGGTGAGTGACCCCACCTGTGGCTGACCTGACCTCAgGGgGACAAGGC 56 TCAGCCI'GGGACTCTGTGTCCCCATCGCCITGcACAGGGGAT CCCCTGAT GGACAGTGAGCCAACGACCTCCCGTCI'CTCCCCGACCCCCAGGTCAGCCC AAgGCCaCrCCCACGGTCAACCrCIJCCCGCCCTCCTCrGAGGAGCTCGG CACCAACAAGGCCACCCTGGTGTGTCTAATAAGTc3AC-rrTrACCCGGGCG CCGTGACGGTGACCTGGAAGGCAGGCGGCACCACCGTCACCCAGGGCGTG GAGACCACCAAGCCCTCGAAACAGAGCAACAACAAGTACGCGGCCAGCAG CTACCTGGCCCTGTCCGCCAGTGACrGGAAATCTFFCCAGCGGCITCACCr GCCAGGTCACCCACGAGGGGACCATIlGTGGAGAAGACAGTGACGCCCI'CC GAGTGCGCCrAGGTCCCrGGGCCCCCACCCTCAGGGGCCI'GGAGCCACAG GACCCCCGCGAGGGTCTCCCCGCGACCCrGGTCCAGCCCAGCCCITCCTC CTGCACCrGTCAACTCCCAATAAACCGTCCTCCITrGTCATTCAGAAATCA TGCrCTCCGCrCACI-rGTGTCrACCCATITCGGGC'ErGCATGGGGTCAT CCrCGAAGGTGGAGAGAGTCCCCC'rrGGCCTTGGGgAAATCGAGGG3GGC GGGGGGAGGCCrGAGGCATGTGCCAGCGAGGGGGGTCACCrCCACGCCCC TGAGGACCTTCrAGAACCAGGGGCGTGGGGCCACCGCCAGAGTGGAAGGC TGTCCACrrrCCCCGGGCCCCCAGGCrCCCrcCCCCGTGTGGACCTG TCCACCTCTGACTGGCCCAGCCACrCATGCATrGTICCCCGAAACCCCA GGACGATAGCICAGCACGCGACAGTGTCCCCGAGGGCCrCrGTCCA TTCAGGACGACCCGCATGTACAGCGTGACCACI'CTGCTCACGCCCAGrC ACCACGTCUI'AGAGCCCCACCCCCAGCCCCATCCITAGGGGCACAGCCAG CTCCGACCGCCCCGGGGACACCACCrCrGCCCCMCCCCAGGCCCrcCCC TGTCACACGCACCACAGGGCCCTCCGTCCCGAGACCCrGCTcCCCTCATCC* CrCGGTCCCCrCAGGTAGCCrCCACCCGCGTGTGTCCCGAGOCCAGA TGCAGCAAGGCcCCTGGGACAACGCCAGATCTCrGCrCrCcCCCGACCCrC -. - -AGAAGCCAGCCCACGCCTGGCCCACCACCACrGCCTAACGTCCAAGTGTC CATAGGCTCGGGAcCrCcAaGTCCAGGflUFGCCICrGGGAflCCGCCAT GGGTCrGCCTGGAATGATGCACTIGGAGgAgCTCAGcATGGGATGcGGAA CFFGTCTAGcGOFCCrCAGATCCAcAGcTGCCrGtGAgAcacacacacac acacacacacaccAAAcaCGcATGCACGCACGOCGGCACACACGCTAflA CAGAGATGGCCACGGTAGCrGTGCCTCGAGGCCGAGTGGAGTGTCTAGAA CrCrCGGGGGTCCCCTCTGCAGACGACACTGCTCCATCCCCCCCGTGCCC TGAAGGG~rCCrCACrCTCCCATCAGGATCTrCCAAG~rGCTGACCTGG AGAGGAAGGGGCrGGGACAGGCGGGGACACCAGACCrCCCGCTGCCC CTCCTCrGCCTGGGCTTGGACGGCTCCCCCC1TCCCACGGGTGAAGGTGC AGGTGGGGAGAGGGCACCCCCCrCACcCI'CCCAGACCCAGACCAGCCCCC GTGGCAGGGGCAGCCTGTGAGCUrCCAGCCAGATGCAGGTGGCCrGGGGT GGGGGGTGGAGGGGGCGGGAGG'I=ATG'TrGAGGCTGTATrCATCrGTG TAATATlftTCGGCGGTGGGACCCATCrGACCGTCCTCGGTGAGTCrCCCC TutcttcctccttggggatccgagtgaaATcTGGGTCGATCfl'CTC1'C CGTCCCTCCGACrGGGGCrGAGGTCGAACCTCGGTgGGGTCCGAAGA GGAGGCCCCTAGGCC*GGCrCcTCAGCCCCTCCAGCCCGACCCGCCCrCr TGACACAGGGTCCAGCI'AAGGGCAGACAT***GGCTGCTAGTCCAGGGCC AGGCrcTGAGACCCAAGGGCGCI'GCCCAAGGAACCC1GCCCCAGGGACC CrGGGAGCAAAGCTCCTCACrCAGAGCCTGCAGCCCrGGgGTCTGAGGAC AAGGAGGGACTGAGGACTGGGCGTGGGGAGTrCAGGCgGGGACACCGGGT CCAGGGAGGTGACAAAGGCGCTGGGAGGGGOCGGACGGTGCCGGAGAcC CrCCTGGGCCCTGTGGGCrCGTGGTCCITGTGAGGACCCTGAGGG*CTGA GGGGCCCCTGGGCCrAGGGACI-rGCAGTGAGGGAGGCAGGGAGTGTcccr TGAGAACGTGGCCrCCGCGGGCcrGGGTCCCCCTrCGTGCCCCAGCAGGGA GGACACCCCAGAGCAAGCGCCCCAGGTGGGCGGGGAGGGTCrCCTCACAG GGGCAGCrGACAGATAGAC*GgrccCCCGCCAGACAGATGCrITATCCTGG TCag***TACGGGTCGCcAC1CCCGAACAGGGGCCCrCCGAACAGA CACAGACGCAGACCaggCTCAGCACAgAAAATGCACTGACACCCAAAACC CTCATCrGggGGCCTGGCCGGCATCCCGCCCCAGGACCCAAGGCCCCTGC CCCCTGGCAGCCCrGGACACGGTCCTCTGTGGGCGGTGGGGTCgGGGCTG TGGTGACGGTGGCATCGGGGAGCCTGTGCCCCCTCCCTGAAAGGGCGGAG 57 AGGCTCAAGAGGGGACAGAAATGTCCTCCCCTAGGAAGACCTCGGACGGG GGCGGGGGGGTGGTCTCCGACAGACAGATGCCCGGGACCGACAGACCTGC CGAGGGAAGAGGGCACCTCGGTCGGGTTAGGCTCCAGGCAGCACGAGGGA GCGAGGCTGGGAGGGTGAGGACATGGGAGCCTGAGGAGGAGCTGGAGACT TCAGCAGGCCCCCAGCTCCGGGCTrCGGGCrCrGAGATGCTCGGACGCAA GGTGAGTGACCCCACCTGTGGCrGACCTGACCrGACCtCAGGGGGACAAG GCJrCAGCC1rGGACUIgTGTCCCCATCGCCGCACAGGGGAITUCCCCrG ATGGACACrGAGCCAACGACCTCCCGTCTCTCCCCGACCCCCAGGTCAGC CCAAGGCCACTCCCACGGTCAACCrCflCCCGCCCCCrCrGAGGAGCrC GGCACCAACAAGGCCACCCrGGTGTGTCTA -Se ID No.32 GCCACGCCCACTCCATCATGCGGGGAGGGGATGGGCAGACC~rcCAGAAA GAAGCTCCCTGGGGTGCAGGTAACAGC1TCCCAGACACAGCCAGTACr AGAGTGAGGTGAATAAGACATCCTCCTTGCTTGTGAAA LTrAGGAAGTGC CCCCAAACATCAGTCATrA AGATAAATAATATGAATGCACITTlTI TITAliiiiii 11 GGII~rGGGCTAATCTGCAGCatatggaagt tcccaggctacaagtcgaaccagagctgcagctgccagc-ctacatcar-ag ccacagcaacaccagatccgagccacatctgtgactaceactgcagttca cagcaacgccagatccttaacccattgagtgaggccagggatcanaccca catcctcatggatactagtctggttcgtaaaccactgagccaCAAGGGGA ACrCCrGAATGCAATKTTrAAAATrGAAA1TAAATCrGTCACTrc'II cAcTTAAGAGTcCccrAGA1-rGGGGAAAA1TAAATATcrGTcATcITA GTGCATCI=GCTCATATGATGTGAATAAAATCcCAAAATCCATATGAAT GAAGCATCAAAATGTACATGAAGTCAGCCrGACCCrGCACGCCrCACrT TGCCTCATGTACCCCCCACCrCAAAGGAAGATGCAGAAAGGAGTCCAGCC CCrACACCGCCACCrGCCCCCACCACTGGAGCCCCCAGGTCrCCCAC CCfl1CrGAGCrrCAGTCrrC~rGTGGCATrGCCrACCrCrACAGCTGC. CCCTACTAGGCCCCCCCCrGGGGCrGAGCrCCAGGCATGGACTGGGA AAG TAGAGGTrAAAGCATGGAAAATrCCCAAAGCCACCAG1-rCCAGGCT GCCCCCCACCCCACCGCCACGTCCAAAAAGGGGCATC'rCCCAGATCrCT GG~rGGTATTGGTAGGACCCAGGACATAGTCI=ATACCAATrCTGGGT. GTGTClTAGGAAAGAaactctccctctctgtgcttcagtttcctcatcaa =AGGAGCAGGCCAGGTrGGAGGGTCTGTGACGTCGCrAAGCAGCA GGATrCTCrCrCCI rGCGGAGGAGAACTGATCCfrCACCCCCAGGAT CAACAGAGAAGCCAAGGTCTrrCAGCCITCCrGOGGACCCCrCAGAGGGAA CTCAGGGCCACAGAGCCAGACCCrGATGCCAGAAC=rrGTCATATGCCC AGACGGAGACTTCATCCCCCTCCTCCTCAGACCCFCCAGGCCCCAACAGT GAGATGrGAAGATNITrAAGAGAAGGGCAAGTCAGcT2AAGrGGGGGT AG3AGGGGAACAGGGAGTGAGGAGATCTGGCCTGAGAGATAGGAGCCCTGG TGGCCACAGGAGGACTCTIrTGGGTCCrGTCGGATGGACACAGGGCGGCCC GGGGOCATGTrGGAGCCCGGCTGGITCITACCAGAGGCAGGGGGCACCCT CrGACACGGGAGCAGGGCATG ITCCATACATGACACACCCCrCrGCTCCA GGGCAGGTGGGTGGCGGCACAGAGGAGCCAGGGACTCrGAGCAAcGouGTC CACCAGTGGGGCAGTrGGATCCAGACCrGGGCCAGCGAGAGTCrAG CCCrCAGCCGITCrCTGTCCAGGAGGGGGGTGGGGCAGGCTGGGCGCC AGAGCrCATCCCTCAAGGG'rrcCCAGGciTCCTGCCAGACCCAGAT1TCG ACCGCAGCCACCACAAGAGGATGTGGTCrGCrGTGGCAGCrGCCAAGACC TrGCAGCAGGTGCAGGGTGGGGGGTGGGGGCACCTGOGGGOCAGCTGGGGJ TCACTGAGTrCAGGG3AAAACCCC I I I ICCCCrAAACCrGOGGGCCATCC CrAGGGGAAACCACAACTrCrGAGCCCTGGCAGTGGCTGCGOAGGGA AGAGCrrCATCCTGGACCCGGGGGGGAACCCAGCTCCAAAGGTGCAAGG GGCCCAGGTCCAAGGCrAGAGTGGGCCAAGCACCGCAATGGCCAGGGAGT ____________GGGGGAGGTGGAGCrGGACTGGATCAGGGCCTCCTrGGGACTCCCrACAC 58 CCTGTGTGACATGTrAGGGTACCCACACCCCATCACCAGTCAGGGCCTGG CCCATCTCCAGGGCCAGGGATGTGCATGTAAGTGTGTGTGAGTGTGTGTG TGTGGTGTAGTACACCCCTGGCATCCGGTTCCGAGGCCrGGGTrCCTC CAAAG1TrGCTcCTGAATTAGGTCAAACTGTGAGGTCCTGATCGCCATCA TCAACrCGTrCrCCCCACCCCCATCATTATCAAGAGCTGGGGAGGGTC TGGGATITCTCCCACCCACAAGCCAAAAGATAAGCCTGCTGGTGATGGC AGAAGACACAGGATCCTGGGTCAGAGACAAAGGCCAGTGTGTCACAGCGA GAGAGGCAGCCGGACrATCAGCTGTCACAGAGAGGCCTrAGTCCGCTGAA CrCAGGCCCCAGTGACrCCTG1TCCACrGGGCACTGGCCCCCCrCCACAG CGCCCCCAGGCCCCAGGGAGAGGCGTCACAGCITrAGAGATGGCCCrGCrG AACAGGGAACAAGAACAGGTGTGCCCCATCCAGCGCCCCAGGGGTGGGAC AGGTGGGCTGGAT'ITGGTGTGAAGCCCTFGAGCCCTGgAACCCAAcCACA GCAgGGCAGflGGTAGATGCCAMfGGGGAGAGGCCCCAGGAGTAAGGGC CATGGGCCCITGAGGGGGCCAGGAGCTGAGGACAGGGACAGAGACGGcCCC AGGCAGAGGACAGGGCCATGAGGGGTGCACrGAGATGGCCACrGCCAGCA GGGGCAGCrGCCAACCCGTCCAGGGAACrTATTCAGCAG'rCAGCrGGAGG TGCCATI'GACCCrGAGGGCAGATGAAGCCCAGGCCAGGCrAGGTGGGCTG TGAAGACCCCAGGGGACAGAGCCTGTCCCTGGGCAGCACTGC=CTCA TrcrGCAGGGCrrGACGGGATCCCAAGGCcrGcrGCCCCrGATGGT.AGTG GCAGTACCGCCCAGAGCAGGACCCCAGCATGGAAACCCCAACGGGACGCA GCCTGCGGAGCCCACAAAACCAGTAAGGAGCCGAAGCAGTCATGGCACGG GGAGTGTGGACICCCYIGATGGGGCCCAGGCATGAAGGACAGAATGGG ACAGCGGCCATGAGCAGAAAATCAGCcGGAGGGGATGGGCCTAGGCAGAC G~rGGCI=ATITGAAGTGTrGGCA]TrGTCGGTGTGTATTGTrGGTA TrGAT=A1TrFTAGTATGTCAGTGACATACrGACATATrATGTAACGAC ATATATrATGTGITrIAAGAACCCAAGACGCrGTCTGTAA TGTGTCCAGAGAAGAGAGCAAGAGCTTGGCrCAGTCrCCCCCAAGGAGGT CAGT'rCCTCAACAGGGGTCCrAAATGmCCTGGAGCCA3GCCTGAATCA AGGGGgTCATATC1TACACGTGGGGCAGACCCATGGACCfl=CGGAGCA ATAAGATGGCAGGGAGGATACCAAGCrGGTCrrACAGATCCAGGGCr1-G ACCTGTGACGCGGGCGCTCC1'CCAGGCAAAGGGAGAAGOCAGCAGGAAGC TICAGAACrGGGGAGAACAGGGTGCAGACCTCCAGGciTCrrGTACAACG CACC=nATCCrGGGGTCCAGGAGGGGTCACTGAGGGAmrAAGTGGGG GACCATCAGAACCAGGTrrGTGTIMGGAAAAATGGCTCCAAAGCAGAGA CCAGTGTGAGGCCAGATTAGATGATGAAGAAGAGGCAGTGGAAAGTCQAT GGGTGGCCAGGTAGCAAGAGGGCCrATGGAGTTGGCAAGTGAATITAAAG TGGTGGCACCAGAGGGCAGATGGGGAGGAGCAGGCACTGTCATGGACrGT CTATAGAAATCTAAAATGTATACCCTr=AGCAATATGCAGTGAGTCAT AAAAGAACACATATATA1TAAATrGTGTAATTCAC'rrCrAAGGArrCA TCCCAAGGGGGGAAAATAATCAAAGATGTAACCAAAGGTrTACAAACAAG ArCATCATrAATUI-rCGTrGTrATCAACGATATrA-FATrATF ACT~ATrArATTTAlTttgttttgafttctagggccactc ccacggcatagagaggttcccaggctaggggtcaaatcggagctacagct gccggcctacgccagagccarcagcaacgcaggatctgagccacagcaatg caggatctacaccacagctcatggtaacgctggatccttaacccaatgag tgaggccagggatcgaacctgtaacttcatggttcctagtcggattcat aaccactgagccacgacaggaactccAACAflATrAATGATGGGAQAAAA CrGGAAGTAACCrAAATATCCAGCAGAAAGGGTGTGGCCAAATACAGCAT GGAGTAGCCATCATAAGGAATC'rrACACAAGCCTCCAAAAT-GTG-I~rC GAAA77GGG1TAAAGTACGTrGCAITIAAAAAGCCrGCCAGAAAATA CAGAAAAATGTCrGTGATATGTCrCrGGCTGATAGGA]TIGCITAGTI. TAATI1GGcT1ATAATIrATAG1TATGAAAATGTTCACAAGAAGA TATAMrCATI1AGC'TCTAAAATAATrATAACACAGAAGTAATrrGTG CTlTAAAAAAATATCAACACAGAAGTATATAAAGTAAAAATGaggagt tcccatcgtggctcagtgattaacaaacccaactagtatccatgaggata ________________ I tggatttgatccctggccttgctcagtgggttgaggatccagtgttgctg 59 tgagctgtggtgtaggttgcagacacagcactctggcgttgctgtgactc tggcgtaggccggcagctacagctccamtggacccttagcctgggaacc tcr-atatgectgagatacggcccTAAAAAGTCAAAAGCCAAkAAAAATAGT AAAAATrGAGTGTrrAc1'ACCACCCCGCCCACATCIATGCrAAAA CCCG~rCrCCAGAGACAAACATCGTCAGGTGGGTCTATATAMrCCAGCC CrCCTCCGTGTGTGTATGTCCGTAAAACACACACACACACACACACACG CACACACACACACACGTATCTAATTAGCAITGGTATITAGTr[CAAAAG GGAGGTCATGCrCrACCITIAGGCGGCAAATAGAITA]TIAAACAAATC TG'frGACArTrCTATATCAACCCATAAGATCrCCCATG1TrMGGAAAG GCIMGTAAGACATCAACATCrGGGTAAACCAGCATGG1T11AGGGGG3T TGTGTGGATIlT1TCATAITITIAGGCACACCrGCAgcatatggagg ttcccaggctaggggttgaatcagagctgtagctgccggcctacaccaca gccacagcaacgccagatccttaacccactgagaaaggccagggattgaa cctgcatcctcatggATGCTGGTCAGAflTrCGCTGAGCCACAACA GGAACrCCCTGAACCAGAATGC1-I-AACCATrCCACMrGCATGGACAT 1TAGATIGTICCAflAAAAATACAAATACAaggagttcccgtcgtgg ctcagtggtaacgaattggactaggaaccatgaggtttcgggttcgatc ctggccttgctcggtgggttaaggatcc-agcattgatgtgagatatggtg taggtcgcagacgtggctcggatcccacgttgctgtggctctggcgtagg ccggcaacaacagctccgattcgacccctagccTGggaacctccatgtgc cacaggagcagccctaGAAAAGGCAAAAAGACAAAAAAATAA)AAA ITrAA AATAAAAATAAAAAAATAAAATrACAAGAGACGCACAAGGAA 1 ATCCCCAAGTGTGTGCAAATGCCATATATGTATAAAATGTACTAGTGTCT CCTCGCGGGAAAG1TGcTAAAAGTGGGTTGGCTGGACAGAGAGGACAGcJ CmGACATCTCATAGGTAGTAGCAATGOGCrTCAAAATGCGTCC AGTIfrACACTCACCATAGCAAATGACAGTGCCTCCCCCACCCTrG CCAATAATGTGACAGGTGGATCrTI1TCrAITrGTGTAT~rGACAAGCA AAAAATGAGAACAggagttcctgtcgtggtgcagtggagacaaatctgac taggaaccatgaaatttcgggttcaaccctggcctcactcagtaggtaa aggatccagggttgcagtgagctgtggggtaggtcgcagacacagtgcaa atttggccctgttgtggctgtggtgtaggccggcagctatagctccatt ggacccctagectgggaacctccttatgccgtgggtgaggccctAAAAAA AAGAGTGCA AAA A AA AA A AATAGAACAATGATCATCGmATTC 1TATITG0ATCATGGTGAAACTATrC=rATAT=rrATrGAcTG' A'IrAT~rCCTATGAArrACCGGTCATAG1TIGCCrGGGTG1TI TACrCCGG=rrAGTMGGrGGTGTATI'rCrAAGAGCATAGAA ACTCrTrCATCrAITTGGAATAGTAATTCCrCATTAAGTA17TGTGCrGCA AAAAATCCCTGATCTGTI=ATGCTIrcTrGTGGGGTCrICACG AGAAAGCCTrAGTITIACACCTCAGMrTGGGTr IirCITGATTG TGTCrGTAATCTGCGGCCAACATAGGAAACACAITrACTITAGTGTrr TTC ICrAT=CTCAAGTACGTCCATrGTrITGGTGTCTGATIr TTGCCTGGG TT~nGTGTGGCAGGAATATAAACTTATGTATT=r CAAATGGAGAGCCAATGGTGTATATTrGTrGAArrCAAATGCAACJI=A TCAAACACCAAATCATCGA1TATCACAACrCITTCrGGTlTA1TGATC TAATGATCAATrCCTGTCCACGCGTI=A~ATTAGCITGGGA TTGGTGCCrGGTAGAGAACAAAGCCrCCATFA=rCAICAAATrAG TCCCGTCTA1TATCI'GCCATTGITGTAGTATrAGACTIrAAAATCAAI-I ACTGATIMCAAAAG1TATrCCI=GGTGATGTGGAATA=rIATACTTC ATAAGGTACATGGATCATIGTGGGGAATTGATGTCI=GCrA1TGTGG CCAmGTCAAG1rGTGTAATA=flACCCATGCCAACn-GCATATrGT ATGTGAGm'1ATCCCAGGGTI=AATAGGATGTIATGAAGI-rGTCA GTGTrCCACAATTCATCGCTCAGTGcrACGrTGCATAAcJGAA ACCTACTCACITIGCCTATTGCrCTrGTATCAATCATI=AGI-AACT CI-rGTGTrAATIGAGAGTITICAGCrGACTGTCTGGGGTI=CITA ATAGACTAGCCC11GTCTGTAAAGAATAAMrTATCGAATI=MrAA CACTCACACTCTCCCCACCCCCACCCCCGCrCATCICCITCATTGGGTCj 60 AAATCTGTAGAATACAATAAAAGTAAGAGTGGGAACCTrAGCCTITAAGT CGAT11nGCc=AAATGTGAATGTrGCTATGmCGGGACATrCTCI I ATCAAGTUGCGGATG iI TTAGATAATrAACrAATAAAAGACTGGAT GTITGCTTrCTrCAAATCAGAATrGTG~rGAATITATTGCTATrCrGT TrAATI=GlCAAAAA1TrACATGCACACCrAAAGATAACCATGAC CAAATAGTCCrCCGCGAGAGAAAATGT1TGGCCCCAATGCCACAGGTrA * CCTCCCGACrCAGATAAACTACAATGGGAGATAAAATCAGAT1-GGCAAA GCCTGTGGATTCTTGCCATAACTCrCAGAGCATGACTrGGGTGITTrC C'TrCTAAGTAmTTAATGGTATTIGTGTACAATAGGAAATCTAGG ACACAGAGAGTGATrCAATGAGGOGAACGCATCrGGGATGACrCrAGGC * crcrGGmGGGGAGAGcrcrA-rGAAGTAAAGACAATGAGAGGAAGCAA GTTrGCAGGGAACTGTGAGGAATIAGATGGGGAATG1TGGGI-1TGAGGT TrCrATAGGGCACGCAAGCAGAGATGCAC-rCAGGAGGAAGAAGGAGCATA AATCrAGAGGCAAAAAGAGAGGTCAGO3ACTGGAAATAGAGATGCGAGACA CCAGGGTGGCAGTCAGAGAGCACAGTGTGGGTCAGAAGACAGTGGAAGAA CACAAGGGACAGAGAGGGATCTCCAACTrCACrGGGATGAGGGCCTGT GGCCTGACCrGAGAGA1TrrCCAGGAGT-rGAGTGGTGGGAAGGAGAGGGCT * CCTGCACATGTCUFGACATGAAACGGTGCCCAGCATATGGGTGCTrGGAA GACATTGTrGGACAGATGGATGGATGATGGATGATGGATGAATGGATGGA TGGAAGATGATGGATAAATGGATGATGGATGGATGGACAGAAGGACAAAG AGATGGACAGAAAGACAGTGATCrGAGAGAGCAGAGAAGGCrrCATGAAA GGACAGGAACrGAACTGTCrCAGTGGGTGGAGACAATGGTGTAGGGGGTT TCCACATGGAGGCACCAGGGGTCAGGAATAATCTAGTGTOCACAGGCCCA GGAAcGGAAGcTGTcrGCAGGAAATrGTGGGGAAGAAccrCAGAGTCMrA AATGAGGTCAGGAGTGGTCAGGAGGGTCrGATCAGGYTAAGGACrCATGTC CATCATCACATGGTCACCTAAGGGCATGTAGCCrCAGCATCrICCATCAG GACAGTCrCAGAATGGGGGCGGGGTCACACACTGGGTGACTCAAGGCGTG GGTrCATGCCrGCCrCGOACGTGGGCCTGGGCATGOGACACCrCCAGAcC ATGGGCCCGCCCAGGGCTGCACTGocctctggtgggctagctacccgtcc aagcaacacaggacacagccctacctgctgcaaccctgtgcccgaaacgc ccatctggttcctgctccagcccggccccagggaacaggactcaggtgct agcccaatggggttttgtcgagcctcagtcagcgtggTATITrCrCCGGC AGCGAGACrCAGTrCACCGCIAGGttagtggttctatgaautCw * agcagtcctgcactctgctatgccgggaaagtcacttttgtcgctggggg ctgtttcccgtgcccttggagaatcaaggattgcccaactttctctgtg ggggaggtggctggtcttggggtgac-cagcaggaagggccccaaaagcag gagcagctgcctceagAATACAACTGTCGGCTACAGCrCAAACAGGAGc3C CTGGACTGOGGG TrAACCACCAGGGCGGCACGAAGGAGCGAGGCTGGGAG GGTGAGGACATGGGAGCCTGAGGAGGAGCTGGAGACrrCAGCAGGCCCCC AGCTCCGGGCflrCGGGCrCrGAGATGCTCGGACGCAAGGTGAGTGACCCC ACCTGTGGCI'GACCrGACCrCAGGGGGACAAGGCrCAGCCTGAGACT~rG TGTCCCCATCGC~GCACAGgggatccctgatgacactgagccaacg acctcccgtctctccccgacccccaggtcagcccaaggccgcccccacgg tcaacctCftCccgccctcctctgaggagctcggcaccaacaaggcrcacc ctggtgtgtctaagtacttctacccgAAGGGCGAATCCAGCACAC TGGCGGCCGTACrAGTGGATCCGAGCrCGGTACCAAGCrGATGCATAG ____________C7TGAGTATCTA Seq ID No.33 agatcttaaacaccgagcaaggccgggatcgpacccgcatrctcatg aatcctagttgggttcgttaaccgctgaaccacaatgggaactcctGTCT rrCACA1ThrrTCACAACCCrCCAGGATrCrGGGGTGGGTGGGOAAT CCIrAGGTACCCACI'GGGAAAGTAATCCAAGGGAGAGCrCACGGA~rcT AGGGATCGGCGGAGGAGGGAAGGTATCrCCCAGGAAACrGGCCAGGACAC __________I ATTGGTCCTrCCGCCCTCCCCTrCCCCCACrCCrCC-rCCAGACAGGACTGj 61 TGCCCACCCCCTGCCACC'FCTGGCCAGAACI'GTCCATGGCAGGTGACC 1'TCACATGAGCCCrrCCJCCCTGCCTGCCCTAGTGGGACCCTCCATACCT CCCCCTGGACCCCGTGTC=m=nCCAGTGTGGCCCTGAGCATAACT GATGCCATCATGGGCTGCrGACCCACCCGGGACTGTGTEGTGCAGTGAGT CACTTCTCrGTCATCAGG=1GTAA1GATAGATAGTGTTCATCATC A1TAGGACCGGGTGGCCTCrATGCTCTG'1TAGTCITCCAAACACrGATGAA AACCTI7CG1TGGCATAGTCCCAGCrrCCTGTTGCCCATCCATAAATCTTG ACITAGGGATGCACATCCTGTCrCCAAGCAACCACCCCTCCCCTAGGCrA ACrATAAAACrGTCCCAATGGCCCTrGTGTGGTGCAGAG1-rCATGCrTCC AGATCATrTICTGCTAGATCCATATCTCACCUrGTAAGTCATCCTATAA TAAACrGATCCATrGAnrATrrGCTTCrGTrrrCCATCTCAAAACAGC TTCrCAGTCAGTrCGAATITATrCCCCCATCCACCCATACI=CC TCAGCCTGGGGAACCCTrGCCCCCAGTCCCATGCCITCCrCCrCrG CCCAGCrCAGCACCrGCCCACCCTCACCCTrCCTGTCACrCCCTAGGACr GGACCATCCACrGGGGCCAGGACACTCCAGCAGCCrrGGC'rrCATG6G3Cr CTGAAATCCATGGCCCATCTCTATTCCTCACTGGATGGCAGGTI'CAGAGA TGTGAAAGGTCTAGGAGGAAGCCAGGAAGGAAACTGTrGCATGAAAcGcCC GGCCTGATGGTrCAGTACTTAAATAATATGAGCrCTGAGCFCCCCAGGAA CCAAAGCATGGAGGGAGTATGTGCCTCAGAATCTCTCTGAGA1rCAGCAA AGCmnrGCAGAGGGAAAATAGTGGCrCAACCTrGAGGGCCAGCATCrr GCACCACAGTTAAAAGTGGGTAT17GTIACCTGAGGCCrCAGCA1TAT GGGAACCGGGCTCTGACACAAACACAcIGTGCAGCCCGcCAcICCrCAGAAC * ACAGCAACGACCACAAGCrGGGACAGCTGCCCrGAACGGGGAGTCCACC ATGcTrGTCTCGGGTACCACCAGGTCACcATcccITGGGGGAGGTAG'rr CCATAGCAGTAGTCCCCTGAT1TCGCCrCGGGCGTGTAGCCAGGCAAG CTCCTGCCrCTGGACCCAGGGTGGACcCTFGCrCCCCACTACCCrGCACA *TGCCAGACAGTCAAGACCACTCCCACCrCrGTCrGAGGCCCCCITGGGTG TCCCAGGGCCCCCGAGCrGTCCTrA~rCATGGTTCITCCACCrGGGTAC AAAAGAGGCGAGGGACAC1TrCAGGTGCGGCrCAGAAAGGTACCr TCCrAGGQ1TITGTCCACrGGGAGTCACCI'CC17GCATCI'CAATGTCAGT GGGGAAAACTGGGTCCCATGGGGGGATrAGTGCCACTGTGAGGCCCCrGA AGTCTGGGGC~r~rAGACACrATGATGATGAGGGATGTGGTGAAAAACCC CACCCCAGCCCrrCrrGCCGGGACCCrGGGCrGTGGCTCCCCCA~rGCAC ITGGGGTCAGAGGGGTGGATGGTGGCrATGGTCAGGCATG1TECCATGA GC! GGGGGCACCCrGGOTGACIMCrCCrGTGAATCCTGAATrAGCAGCT ATAACAAATrGCCCAAACTCTMAGGCT'rAAAACAACACACATIrATCCr CrGGGTCCCAGGGTCAGAAGTCCAAAATGAGTCCrATAGGCTAAAT'rGA GGTGTCrCrGGGITGAGCTCCTCCrGGAAGCCrrCCAGCCTCrAGAGT CCCAAGTCCTTGGCTCrGGGCCC~rCCCTCAAGCMCAAAGCCACAGAAG CrrAATCrCCTCCCITCCCCrCTGAcCCrGCrCCCATCCrCATACC CTGTCCCCrCACTrGACCCrCCrGCCTCCCrCTCC'ITATAAAGACC CTGCATGGGGCCACGGAGATAATCCAGGGTAATCGCCCCTCICCAGCCC 1-YAACTCCATCCCATCTGCAAAATCCCrGTCACCCCATAATGGACCrACr GATGGTCTGGGGIAGGACGTGGACAAMrGGGGCCITATTCATCTGAT CACAACrCCAGTrCCCAGACCCCCAGACCCCCGGGCATTAGGGAAAUITC TCCCAGTICCTCrCCCTCrGTGTCCTGCCCAGTCrCCAGGATGGGCCACr CCcGAGGGCCM~CAGCTCAGGCTCCCCCrCUI I ICCCTGGCCCG TGGCCCCATCTcCTCCrCCGCrCACAGGGAGAGAACITGATITCAG=T TGGCTCrGGGGCITTCMrCrGGCCATrGGCTGAAGGGCGGGm~C TCCAGGTTAcCCGTCAGTCATCAAACCGCCCIrGGAGGAAGACCCrAA TATGATCCTTACCCrACAGATGGAGACTCGAGciCCCAGAGATCCTGAGTG ACCTGCTCACATrCACAGCAGGGACTGAACCCCAGTCACCrACCCAACTC CAGGGCCAGCG-I I l IlLT1--l--rcr~gccttttcgagggcc gctcccgcaacatatggagatttccaggctaggggtctaattggagcagt cgacactggcctaagccaaagcr-acagcaacaagggcaagccgcttctgc ____________________ agcctataccacagctcacggcaatgccggatccttaacccactgagcaa 62 agccagggattgaacctgc-aacetcatgtttcctagtcaaatttgttaac cactgacccatgacgggaactcccAGGGCTCAGCTCTTGACTCCAGGITrC GCAGCTGCCCrCAAAGCAATGCAACCCTGGCrGGCCCCGCCI'CATGCATC CGGCCTCCTCCCCAAGAGCCrGAGCCCACCTGGGCCTAGGTCCTCCrC CCrGGGACrCATGGCCTAAGGGTACAGAG1TA~rGTGGGCTGATGAAGGGA CCAATGGGGACAGGGGCCrCAAATCAAAGTG'3CrGTCTCTCTCATGTCCC TrCCTrCCCTCAGGGTCCAAAATCAGGGTCAGGGCCCCAGGGCAGGGGCT GAGAGGGCCTC'IMCrGAAGGCCCrGTCTCAGTGCAGGnrATGGGGGTCr GGGGGAGGGTCAATGCAGGGCrCACCCL1CAGTGCCCCAAAGCCTAGAGA GTGAGTGC~rGCCAGTGGQTCCCAGGCCCAATCC1GATGCCTGGGA ATG~rCAAATGCAGGAACrGTCACAACACCrrCAGTCAGGGGCTGCTCTG GGAGGAAAAACACrCAGAATrGGGGGTrCAGGGAAGGCCCAGTGCCAAGC ATAGCAGOAGCTCAGGTGGCrGCAGATGGTGTGAACCCCAGGAGCAGGAT GOCCGGCACTCCCCCCAGACCCCCAGAGCCCCAGGUrGCTGCCCT CACTGCCGACACCCCrGGGTCCACrrGCCCTrCCCACCTAAAACMn TAGGGCrCCCACT II CTCCCAAATGTGAGACATCACCACGGCrCCCAGOG AGTGTCCAGAAGGGCATCGGC'GAGAGGTCCrGACATCTGGGAGCCCA GGCCCCACAATGGACAGACGCCCrGCCAGGATGCrGC1XCAGGGTGUA GCTAGGCGGGGTGGAGATGGGGTACTIGCCrCrCAGAGGCCCCGGCCCC ACCATGAAAC~rCAGTGACACCCCAT1TC~rGAG1TCACATACCrGTAT CCrACTCCAGTCACCTrCCCCACGAACCCCTGGGAGCCCAGGATGATCr GOGGOGAGCCACGACCAGCCCACGAGTGATCCAGCrCTGCCAATCAGC AGTCA1TCCCAAGTGTrCCAGCCCrGCCAGGTCCCACrACAGCAGTAAT GGAGGCCCCAGACACCAGTCCAGCAGTTAGAGGGCrGACAGCACCAGC rrCAAGCCTCAGCATCTCAAGGTGAATGGCCAGTGCCCCTCOCCGTGGC CATCACAGGATCGCAGATATGACCCrAGGGGAAGAAATATCCrGGGAGTA AGGAAGTGCCCATATCAGATGGCCC~rGTGACCAACCTGTCCCr GAGGAITGTAC1TCCAGGCGTTAAAACAGTAGAACGCCrGCCrGTGAAOC CCCGCCAAGGGACTGCTTGGGGAGGCCCCCTAAACCAGAACACAGGCACr CCAGCAGGACCTrGAACTCTGACCACCCrCAGCAAGTGGCACCCCCCGC AGCTrCCAAGGCAC Seq 11) No.34 AACAAGATGCrACCCCACCAACAAAATI'CACCGGAGAAGACAAGGACAGG GGGTrCCrGGGGTCCrGACAGGGTCAccAAAGAGGGTrCTGGGGCAGCAG cAAcrccAGccGccI'CAGAACAGAGCCrGGAAGcrGTAcccrCAGAGCAG AGGCGGAGAGAGAAAGGGCCrCrrGGTGGGTCAGCAGGAGCAGAGGCTCA GAGGTGGGGGITGCAGCCCcCCCCTlCAACAGGCCAACACAGTGAAGCAGC TGACCCCrCCACC1TGGAGACCCCAGACI'CCT'GTCrCCCACGCCACCrrG GT1TAAGGTAAT1TIATMATATCAGAGTATGGT'rGACT-ACAATG TrGTGrrGGTrrCAGGTGTACAGCAGAGTGATTCACICrACATAGACTC ATATCTAnrCTCrCAGATCICCCATATAGGTATACAGAATAT TGAGTAGATCCCrGCI'GATTACCCATIT1ATAATI'GTATATGTTAATCC CAAACrCCrAATTrATCCCTCCCCAGACTATGATrCI=ATATCrCrATC TGTrrCUrATCGTCrCTCrAAGTCACCCrAGGAGAGCAGAGGGGTCA CGT~rGTCCGTCCGCCCAGCCACC'CrCCCACCCAGGAATCCCITG CATrrGGTGCCAAGGGCCCGGCCCCGCCCTAAAGAGAAAGGAGAACGGGA TGTGGACAGGACACCGGGCAGAGAGGGACAAGCAGAGGATGCCAGGGTAG GGAGGTCTCCAGGGTGGATGGTGGTCrGTCCGCAGGCAGGATGAGGCAGG AAGGGTGTGGATGTACTCGGTGAGGCrGGCGCATGGCCrGGAGTGTCCTG AGCCCrGGGAGGCCrCAGCCCGGATCAGATCTGTGA ITCCAAAGGGCCA CTGCATCCAGAGACCGTrGAGTGGCCCATTGTCXTGAACCATrATAGAA CACAGGACAAGCGGTACCrGACTAAGcTGCACAGAUrccATGAGGCTG ATGCCAGGGTrGTCACCCCATCrCACAGGCAGGGAAACrGATGCATATAC TGCAGAGCCAGGCAGAGGCCCrCCCAGTGCCCCCrCCCAGCCTGTGGCCC 63 CCCTCCAGTGGCTGGACACTGAGGCCACACTGGGGCACCCTGTGGAGATC tc Seq ID No.35 AGATCTGGCCAGGCCAGAGAAGCCCATGTGGTGACCTCCCTCCATCACTC CACGCCCrGACCTGCCAGGGAGCAGAAAGTAGGCCCAGGGTGGACCCGGT GGCCACCTGCCACCCCATGGCTGGGAGAAGGGAGGGCCTGGGCAAAGGGC CTGGGAAGCCTGTGGTGGGACCCCAGACCCCAGGGTGGACAGGGAGGGTC CCACACCCACAGCCATrGCTTCCCTCTGTGGGTCAGTGTCCTCATCTC ATCrGTGGGGAGGGGGCrGATAATGAATCrCCCCCATTGGGGTGGGCTTG GGGATTAAAGGGCCAGTGTCTGTGATATGCCrGGACCATAGTGACCCTCA CCCrCCCCAGCCATTGCrGTCACCTrCCGGGCTCrGCCCAGGCCTGCCr GACATGCrGTGTGACCCrGGGCAAGATGATCCCCCTTrCTGGGCCCCAGC CrCCTCTCGCTCCGGAAGTGCTTCCTGGGGAAACCTGTGGGCTGGATC CTATAGGAAACCTGTCCAATTCCTGGATGCACAGAGGGGCAGGGAGGCCC TGGGCCTGGAGGGGCAGGGAGGCTCGAGGTGGGAGCAGGGTAGGGGCCAG _TCCAGGGCAAGGAGGTGGGTGGGTAGGGTG Seq ID No. 36: GATCTGTGTTCCATCTCAGAGCTATCTTAGCAGAGAGGTGCAGGGGCCTC CAGGGCCACCAAAGTCCAGGCTCAGCCAGAGGCAATGGGGTATCGATGAG CTACAGGACACAGGCGTCAGCCCAGTGTCAGGGAGAATCACCrrGTrTGT TTCrGAGTCCTCTTAAAATAGAGTTAATrGGTCTTGGCCrTACGGTIT ACAATAACAACTGCACCCTGTAAACAACGTGAAGAGTACAGAACAACAAA TGGGGGAAAACATA1TrCACCTGAAAGAGCCACCGCTCATATrGATGG ATrCCTTCAGTTAATCCTGTTTAATGTAAACTGTAAAACAAACA TAAATAAAGAAAATGCATCrGTAAAGmAAAAGTCATATCrATGGTGAT GGTrGCAAAACACTGTGAATGTTCAC=FTGAAATCGTGAACTCrACGTGA TATGCATGTCCCGTrAATTAACCTCACAGGCTCAGAATGTGGTrCATrAT .TTCTrrAAT1TCCITAATrTATGTCCTCTGTGTGTGCCCrTAAACCA ACTACTITCAGCTTGCCTGTITITGACCTrCACATAGATGACATrITGT GAGTGTTrCITTCTCAACACrGGGTCGATACCCACCCACGCTGTCFGC TGTCACTGCGGACGTGGAGGGCCACCACCCAGCTATGGCCCCAGCCAGGC CAACACTGGATGAATCrGCCCCCAGAGCAGGGCCACCAACACTGGAGGTG CAGAGAGGGTITCITCAGGGCCATCATTATCCAAGGCATTGTITCrACrG TAAGCTITCAAAATGCrTCCCCrGATTATAAAAGAAATAATAAGATGGG GGGAAAGTACAAGAAGGGAAGTCCAGCCCAGCCTGAAGATCGTGCrGG TrGTATCrGGAGCCrGTTCCTGACAGGCCTCrATCCCAGAGTrA Seq ID No. 37: GGATCCrAGGGAAGGGAGGGCGGGGGCCTGGACAAAGGGGGCCTAAAGGA CATTCTCACCTATCCCACrGGACCctgtgtgctctgagggagggagca gagagggggttgaggecttttcccagCTCCTCTGAGTCCCCCTCCGAG CACCTGGACGGAAGCCCCrCCTCAGGGAGTCCTCAGACCCCTCCCCTCCA GCCAGGTGGCCTGTGTGGAGTCCCCAGTAAGAATAGAATGCTCAGGGCT TCGAGCTGAGCCCTGGCrACTrGGGGGGGTGCGGGGATTGGGGGTGCTG GGCGGGGAGCTGGOGTGTCACAGATGCCAGTAGGCrGTGGGCTCGGGTC TGGGGGGTCTGCACATGTGCAGCTGTGGGAAGGCCCrATrGGTGGTACCC TCAGACACATATGGCCCCTCAA1TTCTGAGACCAGAGACCCCAGTCTGGC CITCCCAGAACAGCrGCCCCrGGTGGGGGAGATGTAGGGGGGCCIrCAGC CCAGGACCCCCAACGGCAGGGCCTGAGGCCCCCATCCCCITGTCCTGGGC CCAGAGCCTCAGCTATCAGGCCTATCAGAGATCCTGGCrGCCCAGCTCAG GTrCCCCAGGAGCCAGAGGGAGGCCAGGGGTrACTAGGAAATCCGGAAAG 64 GGTCTnGAGGGTGGGCCCCACCCCCAGCFTrCACAGGAGAAACjAGAG GCCCACAGGGGGCAAAGGACTrGCCAGACTCACAATGAGCCCAGCAGCTG GACTCAAGGCCCAGTGITCGGCCCCACAACAGCACTCACGTGCCCrfGAT CGTGAGGGGCCCC=rCCAGCCAGGCATTCAGACCJTGTGACCTGCATCTA AGATTCAGCATCAGCCATrGAGCTGAAGAGCCCrCAGGGTCTGCAGTC AAGGCCACAGGGCCAGACCrCCAACGGCCAGACATCCCAGCCAGArCCr TTCTGGTCAATGGGCCCCAGTCTGGCTGGCrCCTGCAGGCCCAGTGCCG CC1rCTCCCCTGGGCCTGTGGAGTCCAGCC11CAGMrCCCACCCACA TCCTCAGCCACAATCCAGGCrCAGAGGCAATGTCCGTGGGCAGCCCCTGT GTGACCCCr~rGTGGGTGATCCTCAGTCCrACCCITAGCAGACAGCGCAT GAGGGGCCCrC~nGAACCTGAGGGATACTCCATGTCGGAGGGAGAAGCt GGCC'TrCCCCACCCCCACTrCCAGGCCTGGGGAGCAGAGAAAGACCCCA GACCTGGGTCCCrrCTAACAGGCCAGGCCCCAGCCCAGCTCrTCCACCAGC CCCAGGGGCCTCGGGTCCACGCCrGGGGACTGGAGGGTGGCGTCAGG CGCTGACCCAGAGGCAGGACAGCCAAGTrCAGGATCCCAGCCAGGTGGTC CCCGTGCACCATGCAGGGGTGTCACCCACACAGGGGTGTrGCCACCCTCA CCrGACrGTCCTCATGGGCCACATGGAGGTATCCrGGG~rCATTACrc3GT CAACATACCOGTGTCCCTGCAGTGCCCCCrCrGGcgcacgcgtgcacgcg cacacgcacacactcatacaGAGcTcrCCAGCCAACAGTGCCCrTrAGTAG GCACTGCTGTCAC'rrCrCrAAAAGGTCGCAATCATACrrGTAAAGACCCA AGATrGTrCAGAAATCCCAGATGGAGAAGTCTGGAAAGATCaTICTcC mCACGGGCrGGGAATGTGACCTGGCCAAGGTCACACAGCAAJGTG3T GGAACCCTGGCCCCTGArrcCAGcrcATrccAGT-rcccAAGOcccrGccA GAGCCCAGAGGCTGCGGCCCTCTGGGGCAGAGGAGCrGGGGTCCFrCCCCCC -ACACAGAGCACACAGCCCCGCAAGAAAAGAGACACrrGcooAoAGG AATCrCCAGACCAGAGATCCCAGTATGGGTCTCcCTATGCrGACGGGcAT GGGATGTCAAGAGGGGAGGGGGCI)GGGCTITAGGGAAACACACAAAAATC GCrGAGAACACrGACAGGTGCGACACACCCACCC~rAATGCrAACCTGTG ___________I GCCCATTACTCAgatrt Seq ED) No.3 8 GAT=CrCCrAAGACCAAGGAAAACTGGTCATACCAGGTCCA=nGTCC CCrGTGGCCATrGTCCrCCTCCCCAGAAGAACAAGCAcIJCCACrC CACAAGTAGCrCCrGATCAG~rrGGAAGCCCGGTGCJ2GCTCrGGGCCCrG GGGACACGGCAGGGGCATCAGAGACCAAATCTGGAACAA),GUCCAGTG GGTGAGGCAGGCCGGACAAGCAACACGTATACCATAATATGAGJAAA TATAATGTGAGTI"ImATGAAAGGAGGGrGCAGGTGC~GnrG CrrAGGTGGATGGTCACCCCTGAATGGAGGAGGOGGflCCCAGGGCATGT GCCrGGGGAGAAGGGCrCCTGGCAGGAGGGACAGCAAGTGCAAGGGCCCT GTGATCAAATGTGCCTrGGCAAGTrGCAGGAACAGCTAGAAGGCCAGCAAG GTTGGAACCAAGGAAGGGGTCAGGGGAGGGGCAGGGcCCCTCAGGGCCTrG CCCAGCAGCCGAGCATCGGAGATGTCCAaGmcAAATGTAccrG GGCAACCTCATGCCCATATACCATCCAACT~rGCACrAACATCJCT AGGACTGGGACCCAGCCAGTCAAGCGGGGGACCCAGAGAGCTCCGGTGT GAACACCGAGGTGCrGGTGGGTCrGCGTGTGTGGACATAGGGCAGTCCCG GTCC]ITCCTTCACrAACACGGCCCGGGAAGCCCrGTGCCrCcCGGTGCG CGGGTCGGCGCrrCCGGAGGGTACAGGCCCACCrGGAGCCCGGcJCACAGT GCATGCAAGTCGOGr7CACGGCAACCGAGCGaCTCGCAGGCAGTGG GArCACAGCCAGGGGTACAGGGCAGACCGGTCGCCTCTGCGCT CCrGGCCTGTGGCCCCrGGACGTGATCCCCAACAG1TAGCATGCCCCGCC GGTGCTGAGAACCTGGACGAGGTCCGCAGGCGTCACrGGGCGGTCACTGA GCCCGCCCCAGGCCCCGCCCrCCrGGTGACCGTGGACCG* GATGACCCrGGACCCIAGACTTCCCAGGGTGTCTCGCGGAGGUrCCrCAG CCAGGATCrCGCGTCrCCTCCTCCATAGAGGGGACGGCGCCCCCr'fGT ____________GGCCAAGGAGGGGACGGTGGGTCCCGGAGCrGGGGCGGAGAACACAGXJQA 65 GCCCCTCCCAGACCCCGCTCTGGGCAGAACCTGGGAAGGGATGTGGCCAT CGGGGGATCCCTCCAGGCCATCTCCTCAGATGGGGGCTGGTCGACTAGCT TCrGAGTCCTCCAAGGAACCGGGTCCTTCrAGTCATGACTCTGCCCAGAT GAAGAAGGAGAGCACTCTCTCCATCAGGAGGATCTGAGCnrCIOTAAT TAGAATCAGCTCCrrGGCTrCACCCCTrA AAAAAAGGTACAGAAAC=r GCAC~T1TGATCCAGTATCAGGGGAAMATCAATCAATGTGGGAGAAAUr GGCATCTrACCACACTGAATCIT]CAATCCATGAATATCCCCCrCr TCCATGCATAGGTTAATAA1TCTCAATGGAGTrAATGTAAGTI=CC TCATAGACAATrGC=rIGGACATCTC1TAGACTCATCTCrAGTAAACr GATATrCITAATGCAATATAAAATGTATCCrGCTAATGTrnCrA TTCA1TrGCTGTrATATAGAGATACAATGAGTTCCACA1TGAAACTGG ATCTGGTAAATGGCACCmnl' TFrATAGATI'CrATrAArI=rATAC AnEGTGGGAGCACATAIAATCATGTCACCTGTGAAGAATGAC AAmTGGTGCTACCCTCCCAATTTATATGTCrCAT1TCTCCCrCr GCTGGTACrCTGGCAGCAGCAGGGAAGATAATGGGCCrCCnrATCITGTC ACAAAAGGATGTIAAAGAI1TCGTrATAAAACATAACG=mCrGGT TIfTTAAAGAn'CCrCACCAGCrAAGAAAA I IITrCIATACTCTGT ATGATAAATGGGrmGACAATCATrGTGCATI=ACCrAGTG=m CrCrGCATCTITATATGrrrrCCrAATCCGAAATrGTrrOGA Tn=CrAACATGAACCAATCTrACATCCGAATGGATGGACCAGAC TAGTCCACATGTIATTCrGCCCAATGGCTAGAT!JGTGTTCaataU tgttcagaatgtttgcatctatattcttGAGTGAGACAGAGCGCCClG TTAGGmCACAACCGAGG'rrGTGTrAGCITCATAAAATGAGAximAT TUJCTAAAAGAA7Tr1CGITrCrCrGGATGAAm~GTGTAAGGTrAGA AflGCITACAGTGAagatctCGGGgCCAGTFCTflAGGGGAAGATr TrCAACAATrAAGCrCAATGCI=AGAAGAACTGAGAGTffCrATTAIT TCrrGAG1TAAATATATGTATITAAUTAGACI1CrAGGAATAGTCrCAT TrCATCTCAAATAATrGACATATGCrA1TAAAGCAGATTCTCATGAACCA rrGTAGGTATrCCAGGTarAGAAAAATG1TcCCcI1GCATcCCrAATGT GMTAA=nCAC(:rrCM~CrrIGTCTMGAGAAATCACCAAATCAT 1TrCAATIrrCAGTCATATCCCAAAGCAACCAACrCrCrACc'rrcCTGm TATCATCCCTGCrGGAT1TGITATCrACrrCIrCAGTATrrGTrCC C=CTUCrATCCrCATrCCA~rrmCCCTGTITAA~rrCTGA GATATATGCflAGUrCUICATTGAAGCC~ II1I rAICI1ITI1 -iTF--iGOTC1TITGTCTtG1TG~rTGTGTGCrATtUITGGGCCG CrCCCGCGGCATATGGAGGTTCCCAGGCTAGGAGTCGAATCGGAGCrGTA GCCACCGGCCTACGCCAGAGCCACAGCAATGCGGGATCCGAGCcGcGTCT GCAACCrACACCACAGCTCATGGCAACGCCGGATCGTrAACCCACTGAGC AAGGGCAGGAACCGAACCCGCAACCTCATGGTrCCTAGTCGGA77CGTAA CCACrGTGCCACAACAGGAACrCCGCECTII I rATHCrATAAAAA=IC TATGTACA1TAAGGTrATAGG TrCCTCATGTACCCCATTGGCrGT ATCCrCAGGGTrCTGTGGAGTGAT1TCATrATrGTrCAAG1TCAATATGT CrrCTGATI=CCAA1TGAATACCrCTCrAAATCAGTAGGTGAATAmT CrCl IIIC I rCTITCITi i I II ITI I CIrCAGCCAGGT CCATGGCATGCAGAAATTCCCAGGCCAGGAATCAAACTCTCACCATGGCA GTGACAATGTCGGATCCTTACCCACrAGGCCACCAGGGAACTCGGGAG CATATGI=rAmCCCGACATCTGAGGATGCCrAGTATGTCITCATrA ITGAmITrAGmGCCACGACrAGTATGCCATAGAGTGTAT GCrCAATiGITrrGGTCAMfGAAATGTAMfAGTCCTGCMrATGACCC AGTATGTGGTCAGTITGTCAATGTCCI1TCGCTVFGAAGAGAACCTA CATG~TGTAACrGGGTGCATGTCJGTATATAAGTCTATAGGCrGAGC CGGGGGAGCCTCrAATCTGCCGTrATCrrCTrCGAGTrA=rAGGTAC TAT1ITCflAGCCATAAACCI1AAAflCrGATATCAATATAATGACCCCA GCCCGCTTAGGGTCGGCACTrCATGTATCITI=CCATCCATTrAATOC CrCCCCACTGTIIGGCCACACCCGTGGGATATGGGAG1TCCrGGGCCAA ___________I GGATCaGATCrGAGCCGCAGCTGCCACCrATGCCACAGCAgcagcaatga 66 tggatctttaacccactgcaccacactggggattgaacccaagcctcagc agcaacccaagctactgcagagacaacaccagatccttaacctgctgtgc catagcgggaaTTCCATCCATTACITrCAAGCCAGCTGAATAACCrAG CCCACCATGCCTGGACATGGGTGCTCrGCITCAAATGA1TIGTTCAGTC AGCATCCATC-rCrGAAATGTGTGCCAAGCAT]ITATATGCATGCAAGAGTC ATGTrGGCACTTCrATCA1TITCCAACAGTrCAGTAGCC11GTATCATGA CATITTGGcc'1rcTTAcAATA1TrGAGGcrGAGCAGACTGGCCGT GCCCCTGTCCATGCTTCCAGAGCCTGTGTGCAGACTrCTGCrCrAGACAG AGACAGCrAACCATCCTGCAGTGCCCAGAAAACCCAACTCAAAGACCCTC AAGTAAGGAAGGATrrATrGGCCACGTAATCrGGAATCCAGGCATGGGG TA'ITCAGGGCCACCrGAACCAGAGGCCCrGGCCCrGrTCrIAAGCrrCr TCCrGCC~rGCCCrCGTICGGAAGTGACCCTGAAGGACAGCAATGAAGG GCAGCTCCCCCAGG43ACAGATGACTGAGAGGTCCATITCAAGTCCAACrT GGCCTAGAflGAGAGGCAGCAAGAAATATGGACCTACAGTGAGTCACAGG A1TACCAGTGGTITrGGCrGGGTrGTCAGTGTrACAGGCTAAACATrrGG GTCCCrCCAAAA1TAACATGTTGCCACTCrAACCACCAAAATCatggtat ttgggggtgggcccttggaggtaattaggtttagaaAGAATGAAGAGGG GGCCCITGTGATGGGACrAGTGCC-IATAGAGAGAGAAGAGAGAGGG Seq ID No.39 CACCrCATCCCCAACCACCJTGGATGGTGGCAAGTGGCAGGCrGAGAGGT1 GCATATGAGCrCATCAAGAGGOTCCCCACCCCACAGAGGCrGACCCAGCT GCCACTGCCACCrAGTGGCrGATCGGCCAAGAGCAGGAGCCCCAGGGGCA GCFCCATrCCCrGGGGCGGCCAGGGAACCACCrGGTGGAGGACAA1-rCC ATrGCACCrCATCCATCAGGAAAAGG TrrGCCTrcCCTrGGCAGTAATGCA TCTTCCCATAACATGGTCCCrGGCCrCITGGAATGGCITrGCCACCGTCA TGGCCrCACCCACAAAGCCITGTGTCTCAGCAAGGAACrrATrCCACAGC AAAGGACITGCAGCCrGGAATGAACrGGTCTGACTACATACCCCATrGCC CAGAAGTAGGTGGTcrATrGCAAAGTGGAGTGGC'ITACCCAAGAcrcAGT TGTGCCCAAGTGAGAGATGACrAAATGVrTrrACT GGCTGAGG1TrrATTC1TrAATCAAAGACAATrATATGGTGTGGTCCCCC CAGAGATAGAATACATGAGTCTGGGAATCAAGG*3ATAGAAGTAAGAAGAG ATI=GTCACCATrAATCCCAATAACr'CGCCCAAAGAATATrrGc1Trr GTCCI'GGCAGCTCrGCTGC1TGGCAATAACTTCUFAGAATATAATGTCr CCACCAGG3GGACrCCACAACGGOTCCATGA1TrGAAGCCAATGGGCAGA GO3AGGGGCrGCCTTACrGGTGGGACTGGTCAGCCCTGATrACrAAGGAGA AATCAGGCAACrrCAACAAAACrAAGGCAGGGGGGACTGTCrAGAACC CAAAGCACrAAGCATC'TAGTAC'I-r=AG1-rCrCAGAGCCTCCAAGAAC AAAGATrrAGCCCCrCAGCACCACCAGGTAAAGAACAGGTAAATCCAGCT GAGGACAAGAGAAATA77GAATGGATAGAGGAAGAAAGAAATrATAGATA TCAACTATGGCCTCATGACTAGAGTCTCCAGATTAAGCGGAATAAAAATA CAGATGAiTaGATCrGAACATCAGGCCAAACAACGAACAACAGTITAAGT GCGACCrAGGCAATATrGGGACATACTATACrAAAATITI=CGCTAT TrGAGCATCUTGTAfl=ATCrGGCAAC=rATCATOCCAGCGAAAAA GOAACTGTGGTAACITAGTGTAT'TIACI=GCrCAfATrGTGTATAT ACCrACflTGTA1TATCAATCATATITACrCrGTTrtCAGTATTACIMA TATAGCAGTrGGTGGTGATGGTrAGCAACATATTCAGTGGAACrGTGACT GAATGAGGAGAAATrAACAGAGTTGGCrGTGGCTACAATAACCCTTCG GGACATGTGTCCCCTCA=r]GGGGAGATGG'rragatctCGGGTAAATG TAGGGCAT~rGAGCCAGAAACCAAGATTTGCCAG~rGGTGCAATGTCA GA1TACCAGCAGAGGGTGCCAGAGGAATGCGGCAAAACCCGAGTGCCA GAAAGCACCrCCCGT1TCCAGcTT I I I CC IIrA1TA=mA1T TACGGCCCAGGAGTCCGTAATAGCGCTGAGGATGGCCCAGG~rCTrfCrCA GCAGCCCTGACTGACTAGTCAGCAATGCGCrCAGGCCCCATCrGGCCAC _____________CGGGCAGCCrCrrCrGTGGTAGCTCCAGCCTCAGCCAGTGCAAAAGGCrA 67 CCCrACACTGGCGCCACTTCTACAATCAGCACrGGCCACACCCTCCACGC CATCCGGCACGGAGCCAGGTGATCTGCCGGCCAGATTGCAGTTCGTGCTG CCTGAGTCCAGGTGATTACACGGCTGCATCI1TrTCTGGACCAtTC attccattttttt Bovine Lambda Light Chain In a further embodiment, nucleic acid sequences are provided that encode bovine lambda light chain locus, which can include at least one joining region-constant region pair and/or at least one variable region, for example, as represented by Seq ID No. 31. In Seq ID No 31, bovine lambda C can be found at residues 993-1333, a J to C pair can be found at the complement of residues 33848-35628 where C is the complement of 33848-34328 and J is the complement of 35599-35628, V regions can be found at (or in the complement of) residues 10676-10728, 11092-11446, 15088-15381. 25239-25528, 29784-30228, and 51718-52357. Seq ID No. 31 can be found in Genbank ACCESSION No. AC1 17274. Further provided are vectors and/or targetting constructs that contain all or part of Seq ID No. 31, for example at least 100, 250, 500, 1000, 2000, 5000, 10000, 20000, 500000, 75000 or 100000 contiguouos nucleotides of Seq ID No. 31, as well as ceels and animals that contain a disrupted bovine lambda gene. Seq ID No 31 1 tgggttctat gccacccagc ttggtctctg atggtcactt gaggccccca tctcatggca 61 aagagggaac tggattgcag atgagggacc gtgggcagac atcagaggga cacagaaccc 121 tcaaggctgg ggaccagagt cagagggeca ggaagggctg gggaccttgg gtetagggat 181 ccgggtcagg gactcggcaa aggtggaggg ctccccaagg cctccatggg gcggacctgc 241 agatcctggg ccggccaggg acccagggaa agtgcaaggg gaagacgggg gaggagaagg 301 tgetgaactc agaactgggg aaagagatag gaggtcagga tgcaggggac acggactcct 361 gagtctgcag gacacactcc teagaagcag gagtecctga agaagcagag agacaggtac 421 cagggcagga aacctccaga cccaagaaga ctcagagagg aacctgagct cagatctgcg 481 gatgggggga ccgaggacag gcagacaggc tccccctcga ccagcacaga ggctccaagg 541 gacacagact tggagaccaa cggacgcctt cgggcaaagg ctcgaacaca catgtcagct 601 caaaatatac ctggactgac teacaggagg ccagggaggc cacatcatcc actcagggga 661 cagactgcca gccccaggca gaccccatca accgtcagac gggcaggcaa ggagagtgag 721 ggtcagatgt ctgtgtggga aaccaagaac cagggagtct caggacagcg ctggcagggg 781 tccaggctca ggctttccca ggaagatggg gaggtgcctg agaaaacccc acccaccttc 841 cctggcacag gccctctggc tcacagtggt gcctggactc ggggtcctgc tgggctctca 901 aaggatcctg tgtccccctg tgacacagac tcaggggctc ccatgacggg caccagacct 961 ctgattgtgg tcttcttccc ctcgcccact ttgcaggtca gcccaagtcc acaccctcgg 1021 tcaccctgtt cccgccctcc aaggaggagc tcagcaccaa caaggccacc ctggtgtgtc 1081 tcatcagcga cttctacccg ggtagcgtga ccgtggtcta gaaggcagac ggcagcacca 1141 tcacccgeaa cgtggagacc acccgggect ccaaacagag caacagcaag tacgeggcca 1201 gcagetacct gagcctgatg ggcagcgact ggaaatcgaa aggcagttac agctgegagg 1261 tcacgcacga ggggagcacc gtgacgaaga cagtgaagcc tcagagtgtt cttagggccc 1321 tgggccccca ccccggaaag ttctaccctc ccaccctggt tccccctagc ccttcctcct 68 1381 gcacacaatc agctcttaat aaaatgtcct cattgtcatt cagaaatgaa tgctctctgc 1441 tcatttttgt tgatacattt ggtgccctga gctcagttat cttcaaagga aacaaatcct 1501 cttagccttt gggaatcagg agagagggtg gaagcttggg ggtttgggga gggatgattt 1561 cactgtcstc cagaatcccc cagagaacat tctggaacag gggatggggc cactgcagga 1621 gtggaagtct gtccaccctc cccatcagcc gccatgcttc ctcctctgtg tggaccgtgt 1681 ccagctctga tggtcacggc aacacactct ggttgccacg ggcccagggc agtatctcgg 1741 ctccctccac tgggtgctca gcaatcacat ctggaagctg ctcctgctca agcggccctc 1801 tgtccactta gatgatgacc cccctgaagt catgcgtgtt ttggctgaaa ccccaccctg 1861 gtgattccca gtcgtcacag ccaagactcc ccccgactcg acctttccaa gggcactacc 1921 ctctgcccct cccccagggc tccccctcac agtcttcagg ggaccggcaa gcccccaacc 1981 ctggtcactc atctcacagt tccccaggt cgccctcctc ccacttgcat ggcaggaggg 2041 tcccagctga cttcgaggtc tctgaccagc ccagctctgc tctgcgaecc cttaaaatc 2 101 agcccaccac ggagcccagc accatctcag gtecaagtgg ccgtttggt tgatgggttc 2161 cgtgagctca agcccagaat caggttaggg aggtcgtggc gtggtcatct ctgaccttgg 2221 gtggtttctt aggagctcag aatgggagct gatacacgga taggctgtgc taggcactcc 2281 cacgggacca *cacgtgagca ccgttagaca cacacacaca cacacacaca cacacacaca 2341 cacacacgag tcactacaaa cacggccatg ttggttggac gcatctctag gaccagaggc 2401 gcttccagaa tccgccatgg cctcactctg cggagaccac agctccatcc cctccgggct 2461 gaaaaccgtc tcctcaccct cc-caccgggg tgaccrccaa agctgctcac gaggagccc 2521 cacctcctcc aggagaagtt ccctg ggacc cggtgtgaca cccagccgtc cctcctgccc 2581 ctcccccgcc tggagatggc cggcgcccca tttcc-caggg gtgaactcac aggacgggag 2641 gggtcgctcc cctcacccgc ccggagggtc aaccagcccc tttgaccagg aggggggcgg 2701 acctggggct ccgagtgcag ctgcaggcgg gcccccgggg gtggcggggc tggcggcagg 2761 gtttatgctg gaggctgtgt cactgtgcgt gtttgctcgg tggagggacc cagctggcca -2821 tccggggtga gtctcccctt tccagctttc-cggagtcagg agtgacaaat gggtagattc 2881 ttgtgttttt cttacccatc tggggctgag gtctccgtca ccctaggcct gtaaccctcc 2941 cctttagc ctgttccctc tgggcttctt cacgtttcct tgagggacag tttcactgtc 3001 acccagcaaa gcccagagua tatcCagatg gggcaggcaa tatgggacgg caagctagtc 3061 caccctctta ccttgggctc cccgcggcct ccggataatg tctgagctgc ctccctggat 3121 gctteacctt ctgagactgt gaggcaagaa accccctccc camagggag gagacccgac 3181 cccagtgcag atgaacgtgc tgtgagggga ccctgggagt aagtggggtc tggcggggac 3241 cgtgatcatt gcagactgat gccccaggca gggtgagagg tcatggccgd cgacaccagc 3301 agctgcaggg agcacaggcc gggggc-aagt catgc-agaca ggacaggacg tgtgaccctg 3361 aagagteaga gtgacacgcg gggggggggc ccggagctcc cgagattagg gcttgggtcc 3421 taacgggate c-aggagggtc cacgggccca ccccagccct ctccctgcac ccaatcaact 3481 tgcaataaaa cgtcctctat tgtcttacaa aaaccctgct ctctgctcat gtcu 3541 gcccgcatt taatcgtcaa cctctecagg attctggaac tggggtgggg nnnrnnnnn 3601 nnnmnnnnn nnnnnnnnnn nnnm n nnnnnnnnnnnn nnnnnn 3661 mnnnnnnnninn nnnnnnnnnn agcttatgtg gtgggcaggg gggtagtaag 3721 atcaaaagtg cttaaattaa taaagccggc atgatatacg agttuggata aaaaatagat 3781 ggaaaagtaa gaaaggacag gaggggggtg aggcggaaga aagggggaag aaggaaa 3841 aaataagaga gaggaacaaa gaaagggagg ggggccggtg atgggggtgg gatagaatat 3901 aataattgga gtaaagagta gcgggtggct gttaattccg ggggggaata gagaaaaaaa 3961 aaaaaaaatg tgcgggtggg cggtaagtat ggagatttta taaatattat gtgtggaata 4021 atgagcgggg gtggacgggc aaggcgagag taaaaagggg cgagagaaaa aaattaggat 4081 ggaatatatg gggtaaattt taaatagagg gtgatttg ttagattgag caagatataa 4141 atatagatgg tgggggaaaa gagacaaggg tgagcgccaa aacgccctcc cgtatcattt *4201 gccttccttc ctttaccacc tcgttcaaac tctttttcga gaaccctgaa gcggtraggc 4261 ccggggctgg gggtgggata cccggggagg ggctgcgcct cctcctttgc agagggggtc 4321 gaggagtggg agctgaggca ggagactggc aggctggaga gatggctgtt gacttcctgc 4381 ctgtttgaac teacagtcac agtgccagac ceactgaatt gggctaaata ccatatttt 4441 ctggggagag agtgtagagc gagcgactga ggcgagctca tgtcatctac agggccgcca 4501 gctgcaggga ctttgtgtgt gtcgtgctcg ttgctcagtt gtgtccgact ctttatgact 4561 tcatggactg taacctgcca ggctcctctg tccgtggaat tctccaggca agaatactgg 4621 agtgggtagc caftctcate tccgggggat cttcctgacc caagaatcaa acctgagtct _A 4681 cccgcattgc aggcagcttc tttcttgtct gagccaccag ggaagcccct taagtggagg 69 4741 atctaaatag agtgtttagg agtataagag aaaggaagga cgtctataca agatccttcg 4801 gttcctgtaa ctacgactcg agttaacaag ccctgtgtga gtgagttgcc agtaattatt 4861 gctaacctgt ttctttcact cactgagcca ggtatcctgt gagacggcat acttacctcc 4921 tcttctgcat tcctcgggat ggagctgtgc ggtggcctct aggactacca catcgaccag 4981 gtcagaccca gggacagagg attgctgaga tgcactgaga agtttgtcag cctaggtctt 5041 cacccacaca gactgtgctg tcgtctacca cgtaattctt cctgtccaaa gaactggtta 5101 aacgctcctg aagcgtattc tggtcgctt caaaaagtgc ctctttcctt tataagttcc 5161 gccaatcctg gactttgtcc caggccagtc tactttatt gtgggaaagg ttggt 5221 ctttttgtt ttaaactctg cagaaattgc ttacactttt ggtgtgcaat ggctcactct 5281 tacggttcta gctgtattca aaggggttgc ttttcttgt ttttaagct ttttgaacgt 5341 ggaccatttt taaagtcttt attaaacgtc taacatcgtt tctggtttat ttctggtgg 5401 tctggccatg aggcctacgg gtcttagctc ccctaccagg gtccaaccca catcccttgc 5461 actggacggc aaggtcttaa cctttgaacc accagagagc ttctgaaagg ggctgcttt 5521 ctccaatcct cttgctccc tgcctgctgg tagggaitca gcacccctgc aatagccctg 5581 tctgttctta ggggctcagt agcctttctg cctgggtgtg gagctggggt tgtaagagag 5641 cttcatggat ttggacacga cctacgactc agaggtaaga ctccatctta gcgctgtaat 5701 gacctcttc caacaaccac ccccaccacc ctggaccact gatcaggaga gatgttctc 5761 tctcttatca tcaacgtggt cagtcccaaa cttgcacccg gcctgtcata gatgtagcag 5821 gtaagcaata aatatttgt gaatgttiag tgaattgaaa taacataagt gaaaaagaaa 5881 acacttaaaa acatgtgttt ttataattac acagtaaaca tataatcatt gtagaaaaaa 5941 atcgaaagag tggcgggggc caagtgaaaa ccaccatccc tggtatgtcc acccgcccgg 6001 gtagccccag gtaagaggtg cggacacgga tggccctgta gacacagaga cacacgctca 6061 tatgctgggt cttgtcttgt gacctcttgg ggatgatgtt attttcacga tgccattcaa 6121 accttctacc acaccatttt tagagggtcg ttcatcgtaa atcagttcac tgctnttu 6181 tctgattttg aaagtgtcac attcttcgag aaatgagaag gaacaggcgc gcataagga 6241 gaaagtaaac acgtggcctt gcttccaggg ggcactcagc gtgttggtgt gracgctggc 6301 agtcttttct ctgtgacagt catggccmt tcccaaaggt gggctcagat aagaccgcct 6361 cccatcccct gtccctgtcc ccgtccccta cggtggaacc cacccacggc acgtctccga 6421 ggcccttgg ggctgtggac gttaggctgt gtggacatgc tgctggtggg gacccagggc 6481 tgggcagcac gttgtccctg ggtcccgggc cagtgaggag ctcccaagga gc-agggctgc 6541 tgggccaaag ggcagtgcgt cccgaggcca tggacaaggg gatacaMc ctgctgaagg 6601 gctggactgc gtctccctgg ggccccttgg agtcatgggc agtggggagg cctctgctca 6661 ccccgttgcc cacccatggc tcagtctgca gccaggagcg cctggggctg ggacgccg 6721 gccggagccc ctccctgctg tgctgacggg ctcggtgacc ctgccgcccc cteectgggg 6781 ccctgctgac cgcgggggcc accccggcca gttctgagat tccectgggg tccgccctc 6841 caggatccca ggacccagga tggcaaggat gttgaggagg cagctagggg gcagcatcag 6901 gcccagaccg gggctgggca ggggctgggc gcaggcgggt gggggggtct gcacncccc 6961 acctgcnagc tgcncnnncn tttgntnncg tcctccctgn tcctggtctg tcccgcccgg 7021 ggggcccccc ctggtcttgt ttgttcccc tccccgtccc ttccccctt tttccgtcct 7081 ectcccttct tttattcgcc ccttgtggtc gttttc cgtccctctt ttgtttttn 7141 gtcttttct ttttocccct cttctccctt gctctcttt tcattcgtcg gtmctgc 7201 tCCCttCCCt CtCCCCCCCg Cttttttcc ctgtctgctt ttgtgttct ccctctctac 7261 cccccctgca gcctatttt ttatatatc cattccccc tagtatttgg ccccgctta 7321 cttcteccta attttaMt tcctttcttt aactanaatc accgtgtggt tataagtttt 7381 aaccttttt gcaccgccca caatgcaatc ttcacgcacg ccccccccgt cagcctcctt 7441 aaataccttt gcctactgcc cccctccttg tataataacg cgtcacgtgg tcaaccatta 7501 tcacctctcc accaccttac cacatttcc ttcnnnxmnnnnnn nnnnnnmn 7561 mumnnnnmn nnnnn nmxn nnnnnnnnxnnnnninnn~n 7621 Dnnnnnnnnn nnntgaaaaa agaaaaggct gggcaggtt taatatgggg gggttggagt 7681 ggaatgaaaa tgcattggag tggttgcaac aaatggaaag gtctcaggag cgctc-ctccc 7741 ccatcaggag ctggaaagaa gtggaagcaa agcaaggaat tcgtgtgatg gccagaggtc 7801 aggggcaggg agctgcaaag actgccggct gtttgtgact gnccgtctcc gggtgcattz 7861 gmtgcaggg aggcattaca ctcatgtctt ggtttgctaa ctaattctta ctattgttta 7921 gttgcaaggt catgtctgac tcttgcaac ccagggactg cagcccgcca ggctcctctg 7981 tccatgggat ttcgcaggca agaatactgg aggtggtagc cattttcftc accatgggat 8041 cttcccgagc cagaaatgga acccgagcg cctcctggc atggggtctg ctgcctaaca 70 8101 ggcagatatt tgacgtctga gccaacaggg aggacagacg gtaattatac caaccattga 8161 aagaggaatt acacactaat ctttatcaaa atctttcaaa cagtagagga gaaaggatac 8221 tctctagttt attcc-ataaa gttggaatta cgcttatcaa taaagacatt acaag-aaag 8281 aaagtgaagc cccaaatgcc ttataaatat acaagaaaaa atcttttaag atattagcca 8341 acttantcaa caaaaaatgt atcaaaagtc caagtaacat tcaccceagg aatgcaagtg 8401 tggttcagcc taagacaatc agtcatgagt ataccacgga aacaaattaa agagaaaaga 8461 cattaaatct cacaaatggt gcagaaaaag atttggcaat atcgaacatc ttttcatgac 8521 caaaggaaaa aaaagaaaca aaacaccaga aaattctgtg tagaaagaat atatctcaac 8581 ccaatgaagg gcatttatga aaaacccaca geatacatca cactccatga gaaagactga 8641 aagctttccc cactgccatt gaactctgtc ctggaaattc tagtc-acagc gacagaacaa 8701 gagaaagaaa taacggccgt ctaaactggt aggaagaaat caaagcgtct ctattctctg 8761 ggcgcataat acaatataga caaatttcta aagtecacaa aaattcctag agctcataat 8821 gaatccagaa atgcgtcagg gctcaagatt cagatgcaaa aatcgtctgg gttttgatgc 8881 accaacaaac aattccatta acaataatac caaggaatta atttaactta gaagagaaaa 8941 gacctgttta cagpgagtta taaaacatt ggtgatgaaa ttaaataaga gtaaatcata 9001 tagaaacacc gttcgtgttt tggagaccta atgtcataaa cgtggcaaca cagagacgcc 9061 tcacggggaa ccctgagcct ccttctccaa acaggcctgc tcatcatttc acaggtaacc 9121 tgagacccta aagcttgact ctgaggcact ttgagggcat gaagagagca gtagctcctc 9181 ccatgggacc gacagtcaag gcccagggaa tgaccacctg gacagatgac ttcccggcct 9241 citcagcagt cggtgcagag tggccaccag ggggcagcag agagtcgctc aacactgcac 9301. ctggagatga ggcaacctgg gcatcaggtg cccatgcagg ggctggatac ccacacctca 9361 cacctgagga caggggccgg ctttctgtgg tgtcgccctc traggatgca c-agactccac 9421 cctcttcgct tgcattgaca gcctctgtcc ttcctggagg acaagctcca ctccccat 9481 ctctccag ggggctgggg ccaacagtgt tctctcttgt ccactccagg aaeacagagc --- 9541 caagagattt atttgtctta attagaaaaa ctatttgtat tectgcattt ccccagtaac 9601 tgaaggcaac tttaaaaaat gtattcctg gacttccctg gtgggccagt ggctagactc 9661 tgagctccca gtgc-atgggg cctgggttca atccctgctc aggaaactac atc-ccacagg 9721 ctgcaaataa gatcctgcat gccacccgat gcaggcaaag aaacaagtgt tcggtatgca *978 1 tgtatttcac gtgaggtgtt tctataattt. acagrcagta ttctgtctta eacttagtCa 9841 ttcctttgag cacatgatcg gtcgatggcc cagaccacac acaggaatac tgaggcccag 9901 cacccaccgg ctgcccagaa cctcatggcc aagggtggac acttac-agga cctcagggga 9961 cctttaagaa cgccccgtgc tcttggcagc ggagcagtgt taagcatggc tctgtcctc 1002 1 gggagctgtg tctgggctgc gtgcatcacc tgtggtgtgg gcctggtgag ggtcaccgtc 10081 caggggccct cgagggtcag aagaaccttc ccttaaaagt tctagaggtg gagctagaac 10141 cagacccaca tgtgaactgc acccaaaaac agtgaaggat gagacacttc aaagtcctgg 10201 gtgaaattaa gggccttccc ctgaaccagg atggagcaga ggaaggactt ggcttccgg 1026 1 aaaccctgac gtctccaccg tgactctggc cggggtcatg gcagggccca ggatccttg 10321 gtgcaaagga ctcagggttc ctggaaaata cagtctccac ctctgagccc tcagtgagaa 10381 gggettctct cccaggagtg gggcaaggac ccagattggg, gtggagctgt ccccccagac 10441 cctgagacca gcaggtgcag gagcagcccc gggctgaggg gagtgtgagg gacgttccc 10501 ccgctctcaa ccgctgtagc cctgggctga gcctctccga ccacggctgc aggcagcccc 1056 1 caccccaccc cccgaccctg gctcggactg atttgtatcc ccagcagcaa ggggataaga 10621 caggcctggg aggagccctg cccagcctgg gtttggcgag cagactcagg gcgcctccac 10681 catggcctgg accccctect cctcggectc ctggctcact gcacaggtga gccccagggt 10741 ccacccaccc cagccagaa ctcggggaca ggcctggccc tgactctgag ctcagtggga 10801 tctgcccgtg agggcaggag gctcctgggg ctgctgcagg gtgggcagct ggaggggctg 10861 aaatcccct ctgtgctcac tgctaggtca gccctgaggg ctgtgcctgc cagggaaagg 10921 ggggtctect ttactcagag actccatcca ccaggcacat gagccggggg tgctgagact 10981 gacggggagg gtgtccctgg gggccagaga atctttggra cttaatctgc atcaggcagg 1104 1 gggcttctgt tcctaggttc ttcacgtcca gctacctctc ctttcctctc ctgcaggcgc 11101 tgtgtcctcc tacgagctga ctcagtcacc cccggcatcg atgtccccag gacagacggc 11161 caggatcacg tgttgggggc ccagcgftgg aggtganaat gttgagtggc accagcagaa 11221 gc-caggccag gcctgtgcgc tggtctccta tggtgacgat aaccgaccca-cgggggtccc 1128 1 tgaccagttc tctggcgcca actcagggaa catggccacc ctgcccatca gcggggcccg 11341 ggccaaggat gaggccgact attactgtca gctgtgggac agcagcagta acaatcctca __________11401 cagtgacaca ggcagacggg aegggagatg caaacccect gcctggccg cgcggcceag 71 1T-461 cctcctcgga gcagctgcag gtcccgctga ggcccggtgc cctctgtgct cagggcctct 11521 gttcatcttg ctgagcagcg gcaagtgggc attggttcca agtcctgggg gcatatcagc 115 81 acccttgagc cagagggtta ggggttaggg ttagggttag gctgtcctga gtcclaggac 11641 agccgtgtcc cctgtccatg ctcagcttct ctcaggactg gtgggaagat tccagaacca 11701 ggcaggaaac cgtcagtcgc ttgtggccgc tgagtcaggc agccattctg gtcagcctac 11761 cggatcgtcc agcactgaga cccggggcct ccctggaggg caggaggtgg gactgcagcc 11821 cggccccc-ac accgtcaccc caaaccctcg gagaaccgcg ctcccagga cgcctgcccc 11881 tttgcaacct gacatccgaa cattttcatc agaacttctg caaaatattc acaccgctcc 11941 ttatgcaca ttcctcagaa gctaaaagtt atcatggctt gctaaccact ctccttaaat 12001 attcttctct aacgtccatc ttccctgctc cttagacgcg ttttcattcc acatgtctta 12061 ctgcctttgg tctgctcgtg tattttcttt tttttltttt ttttattgga atatatugc 12121 gttacaatgt tgaattgaa ttggtttctg ttgtncaaca atgtgaatta gttatacatg 12181 tcctgaggag gggcggctgc gtgggtgoag gagggccgag aggagctact ccacgttcaa 1224 1 ggtcaggagg ggcggccgtg aggagaag..efgtccaa ggtaagagaa acccaagtaa 12301 gacggtaggt gttgcgagag ggcatcaga cagacaca ctgaaaccat aatcacagaa 12361 actagccaat gtgatcacac ggaccacap qgOtaaWc tcagtgaaac taagccatgc 12421 ccatggggcc aaccaagatg ggcgggftd 9fgccctgg ggccaacc-aa gatgggcggg 1248 1. tcatggtgaa gaggtctgat ggaatgtggtactggaga agggaaaggc aaaccacttc 1254 1 agtattcttg ccttgagagc c-ccatguca gtatgaaaag gcaanatgat aggatactga 12601 aagaggaact ccccaggtca gtaiggtgccc aatatgctac tggagatcag tggagaaata 12661 actccagaaa gaatgaaggg a.t.ggVgq-co~ agcaaaaaca atacccagtt gtggatgtga 12721 ctggtgatag aagcaagggc caatsa~pgaata ttgcatagga acctggaatg 1278 1 ttaagtccaa gannnnnnnn xunn mmnnnn nnnnnnnnnn nnnnn 12841 nnnmn nnmnn nnnnimn nnnnnn magaatttt 1290 1 gagcattact ttactagcgt gtgagcpt, l~gatgtg cggtagttg agcattctt 12961 ggc-attgcet ttctttgggp tggaatgaa aactgcctg ttccaggcct gtggccactg 13021 ctgagtttc caaattgct ggcgtatg gtgcatcact ttaacagcat catctutag 13081 gatttgaaat agctcaactg gaattctatc actttagcta attccattca ttagctttgt 13141 ttgtagtgat gcttcctaag gccccctgg ctttatcttc ctggatgtct ggctctg 13201 agtgatcaca ccgctgtgat tatctgggtc atgaaggtct Itttgtatag ttcttcttag 13261 gaacagatat tatgatctcc atccttgcat ctcgttatat ctagagaagc actgactccc 1332 1 ttcatggtga cgtcagatcc tcatgactaa caaatggcct ttugtaagat gagtgcctca 133 81 tggtattgag ctcccccgtc accaagacct tatgactgac ctc-ccccact gccc-caggtg 13441 cctctcgaag cgtctgagat gccgcctccc aggctgcact cctcattttg ccccaataa 13501 aacttaactt gcagctctcc agctgtgcat ctgtgtttag ttgacagtac aaatataatg 13561 gaaaattta attaaatata atctatgggg agaaatccaa acatcttatg aggggagg 13621 agggagagaa aggaaagaag aagaagcagg aggaggagga gagtagagaa acagggggag 13681 ggcggcaggg agacagaggg gaggacaccg aggggaaagg gaggaaggcg agtgcagtga 1374 1 gagagaggcc agagttcatc agagtctgga ctcgcagccc aatcccacgg gtgtgtcccg 13801 aagcagggga gagcctgagc caggcggaga cagagctgtg tctccagtcc tcgtggccgt 13861 gacctggagc tgtgtggta gcc-cccctga ccccagcctg gccctgctgg tggtcggagg 13921 cagtgatcct ggacacagtg tctgagcgtc tgtctgaaat ccctgtggag gcgccactra 13981 ggacggacct cgcctggccc cacctggate tgcaggcea ggcccgagtg gggcttcctg 14041 cctggaactg agcagctgga ggggcgtctg caccccagca gtggagcggc cccaggggcg 14 101 ctcagagctg ccggggggac acagagcttg tctgagaocc agggctcgtc tccgaggggt 14161 cccctaaggt gtcttctggc cagggtcaga gccgggatga gcacaggtct gagteagact 14221 ttcagagctg gtggctgcat ccctggggac agagggctgg gtcctaacct gggggtcaga 14281 gggcaggacg ggagcccagc tgacccctgg ggactggcct cctctgtggt ctcccctggg 14341 cagtcacagc ttccccggac gtggactctg aggaggacag ctggggcctg gctgtc-agga 14401 gggggttcga gaggccacac tcagaggagg agaccctggc ctgcttgggt tgtgactgag 14461 ttttggggt cctctaggag actctggccc tgcaggccct gcaaggtcat ctctagtgga 14521 gcaggactcc acaatiga tgaactgaat cctctaggag aggtgtggtt gtgagggggc 14581 agcattctag aaccaacagc gtgtgcaggt agCtggcacc gggtctagtg gcggcgggca 14641 gggcactcag ggccgactag gggtctgggg gattcaatgg tgcccacagc actgggtctt 14701 ccatcagaat cccagacttc acaaggcagt ttcggggatt aggtcaggac gtgagggcca 1 14761 cagagagg gtgatggcct agaca cc ttcacagaga gagctccag cgcatgata 72 14821 agatggatgg gtctgtattg tcagtttCcc cacatcaaca ccgtggtccc gccagcccat 14881 aatgctctgt ggatgcccct gtgcagagcc tacctggagg cccgggaggc ggggccgcct 14941 gggggctcag ctccggggta accgggccag gcctgtccct gctgtgtcca cagtcctccc 15001 ggggttggag gagagtgtga gcaggacagg agggtttgtg tctcacttcc ctggctgtct 15061 gtgtcactgg gaacattgta actgccactg gcccacgaca gacagtaata gtcggcttca 15121 tcctcggcac ggaccccact gatggtcaag atggctgtt tgccggagct ggagccagag 15181 aactggtcag ggatccctga gcgccgctta ctgtcttat aaatgaccag cttaggggcc 15241 tggcccggct tctgctggta ccactgagta tattgttcat ccagcagctc ccccgagcag 15301 gtgatcttgg ccgtctgtcc caaggccact gacactgaag tcaactgtgt cagttcatag 15361 gagaccacgg agcctggaag agaggaggga gaggggatga gaaggaagga ctccttcccc 15421 aagtgagaag ggcgcctccc ctgaggttgt gtctgggctg agctctgggt ttgaggcagg 15481 ctcagtcctg agtgctgggg gaccagggcc ggggtgcagt gctggggggc cgcacctgtg 15541 cagagagtga ggaggggc-ag caggagaggg gtrccaggcca tggtggacgt gcccgagct 15601 ctgcctctga gcccagca gtgctgggct ctctgagacc ctttattccc tctcagagct* 15661 ttgcaggggc cagtgagggt ttgggtttat gcaaattcac cccccggggg cccctcactc 15721 agaggcgggg tcaccacacc atcagccctg tctgtcccca gcttcctcct cggcttctca 15781 cgtctgcaca tcagacttgt cctcagggac tgaggtcact gtcaccttcc ctgtgtctga 15841 ccacatgacc actgtcccaa gcccccctgc ctgtggtc-ct gggctcccca gtggggcggt 15901 cagcttggc-a gcgtcctggc cgtggactgc ggcatggtgt cctggggttc- actgtgtatg 15961 tgaccctcag aggtggtcac tagttctgag gggatggcct gtccagtcct gacttcctgc 16021 caagcgctgc tccctggaca cctgtggacg cac-agggctg gttcccctga agccccgctt 1608 1 gggcagccca gcctctgac-c tgctgctect ggccgcgctc tgctgccccc tgctggctac 16 141 cccatgtgct gcctctagca gagctgtgat ttctcagcat aactgattac tgtctccagt 16201 actttcatgt ccctgtgacg ggctgagtta gcatttctca cactagagaa ccacagtoct 16261 cctgtgtaaa gtgatcacac tcctctctgt gggacttutg taaaagattc tgcagccagg 16321 agtcatgggt ggtcttagct gagaastgct ggatcagaga gacctgataa ccgatgtgaa 1638 1 gaggggaacc tggaagatct tcagttcagt tcatttcagt cattcagttg tgtccgactg 16441 tttgggatcc catggactgc cacacgccag trctccctgt ccatcaccaa cttctgaagc 16501 ttgttcaaac tcatgtccat caagttggag atgcctttca accatctcat cctctgteat * 16561 ccccttctcc tcccgccttc aatcttccct agrattaggg tcttttccgt gagtcagttc 16621 ttcgcatcag gtggccaagt tttggagttt cagfttcagc atcagtcctt tcaatgaata 16681 gtaaggactg afttccttta ggatggactg gtttgatatc cttgcagttc aagggactct 16741 caagagtctt ctccaacact gcagttaaaa gccatcaatt cttcggtgct cagcMctt 1680 1 tttggtacaa ctctcacatt catacatgac taccgaaaat acattagtcg tgtagaacca 16861 gtttggggct tcccacgtgg ctctagtggt aaagaatatg cctgccaact cagaagatgt 1692 1 aagagatgcg gttcaatctc tgggtcggga agatcccctg gagaagggca tgacaaccrca 16981 ctccagtatt Utgcctgga gaatcccatg gacagagaag cctggtggac tgcagtccat 17041 ggagtctcac agagtcagac acgactgaag caacttagct acttggaaaa gagcatgcac 17101 gaagctgtct aaaaaacagg tcaagaagtc ttgtgttttg aaggtttact gagaaagttg 17161 atgcactgct ccaacactte ctctcagttg aaaagatcag aagcgttaga tcaaatggtg 17221 gtcaatacct tggatgcgct ccaacaggtt atatctgcag atggaaatga aggcagttta 17281 tggggtaact ggaggacaag atgagatcat acacttggaa cactgtctgg catcaaaggc 17341 gtgtacagta aacattagct gttattagca aaataaattc agcttgaatc acccaaatca 1740 1 gatggcattc ?taaagccac tgagtggtaa aatcaggggt gtgcagccaa aacgtccatt 17461 ttgactcatt atgatttcca tgtcacaaga ctagaaagtc actttctc-ct cagc-agaaga 17521 gaaggtagaa cattttaacc tttttgga gtgtcaaggg aattttgttt acactgtaaa 17581 gteagtgaaa atattgaagc ttltcatttg tggaaaatat taaatatgta aaattgaaat 17641 tttaaaattt attcctgggt agttttgttt ttecagtagt catgcatgga tgtgagagtt 17701 ggactataaa gaaagctgag cgctgaagaa ttaatgcttt tgaactgtgg cactggagaa 17761 gactcttgag agtcccttgg tctgcaagga gatcaaacca gtccatccta aaggaaatca 17821 gtcctgaata ttcactggaa ggactgatgc tgaagctgaa actccaatac ttggccacc 17881 tgatgtgaag aactgactca tatgaaaaga ctcagatgct gggaaagaft gaaggtggga 17941 ggagaagggg acgacagagg atgagatggc tgaatggcat caccgactcg atggaratga 18001 Stctgaataa gctctgggag ttgtngatgg acagggaggc cctggagtgc tgcagtccat 18061 gggattgcaa agagttggac atgactgagt gactgaactg aactgagmt ggtaacagat 18121 atgagaatta tataatttaa atctaaactc ttggtatttc ttuctttggc ggttccaaaa 18181 gagctgtcce ttctgttaac tatataaatc cttttgaga attactaaat tgataatgtt 18241 cacaagttat ccaatttctc attactctta gttgtcagta taagaaatcc catttgatt 18301 atcatgttat agtatctgca actctaatag ttcagttctg acaaattttt aMtattta 18361 aaaatattgg catacagtaa aatttcaaac aatatacaat tctccctttc agtttaa 18421 ac-aaaacaaa acaaaagtaa tattagttaa aaaaatccgg gaagaatcca agcattaaa 18481 attgcatcac atttctatgc tagacaagct gatataaagt tataattaat aaaggattgg 18541 actattaaac tctttacata tgaggtaaca tggctctcta gcaaaacatt taaaaatatg 18601 ttgtgggtaa attattgttg tccttaaaga aataaaaaga cataagcgta agcaattggn 18661 nnnnnnnnnn nnnnnnnnnn nnnnn nnnnnnnnun nmnn 18721 nnnnnnnnnn nnnnm mmnnnnnnnn nnnnnnnnna aaatggataa ggggggagga 18781 catgggtagg ggagcgcgat ggaggaagta aggtggtcga gggagttggg gggggaataa 18841 gtgggtaaaa gggaagcggg cggaaggagg gggaagcagg agagaggggt gggcgtcaga 18901 tcggggggag gggtatgagg gagagggaat ggtagacggg gggtgggaag cataaaggaa 18961 aagatagggg ggggaaaagt tagaagaaga atgaggggat aggcggaaag ggaagagaaa 19021 tgggagaaga acagaaaaat agggggaggg ggggcgtaaa gagggggggg gagggcaggt 19081 gtggagatga cagatacggg gaatgccccg gtataaaaga gtatatggcg tggggcga 19141 aggctgtcat cctgtgggag gggggacgcg gaigaaccctt cgggctatag ggaggattcg 19201 gggggatcgt tcgggaaggc agtcagcaca gc-acccacca agggtgcagg gatggatctg 19261 gggteccaaa gaagaggccc aatcccgcgt cttggcagca aggagccctg gagactggga 19321 agtgtccagg acactkaccc aggggttcga ggaacccaga agtgtgtctg tgaagatgtg 19381 ttttgtgggg ggacaggtcc agagctttga gc-agaaalagc ggccatggcc tgtggagggc 19441 caaccacgct gatctttttt aaaaggtttt tgttttgatg tggaccattt ttaaagtett 19501 cattgaattt gctacaatat tgtttctggt ttatgctctg gtttcttcgg ctgcaaggtt. 19561 tgtgtgatcg tatctcctca accaggactg aacccacagc ccctgcactg gaaggcgaag 1962-1 tcttaaccca gatcgccagg aacgtccct *c ccctcactga tctaatccaa gacctcalt 1968 1 aaggaaaanc cgagattcaa agctccccca ggaggactcg gtggggagga gagagccaag 19741 cactcagcac tcagtccagc acggcgccct ccctgtccag ggcgagggct cggccgaagg 19801 accaccggag accctgtcgg attcaccagt aggattgtga ggaatttcaa cttacttttt 1986 1 aaatctgtct ctcaaggctg ttacaagcgg actttaccag taacttaaaa gttgaaaggg 19921 acttcccagg cggeacttgc ggtgaagaac ccgccggctg gttttaggag acataagaga 19981 tgtgggttag atccctggtt caggaggatt cccctggaga aggaaatggc aacccactc 20041 agtattcttg cctggaaagc cteacggaca gaggaggctg gcgggctac-a gtccacgggg 20101 tcgcacacga ctgaatcgac ttagcttcaa gttgagacag gaagaggcag tgactggtgg 20161 ca-aaacaccg cacccatgct c-ccaggggac ctgeagcgct ctggttcatg agctgtgcta 20221 acaaaaatca acccaacgag aggcccagac agagggaagc tgagttcatc aaacacgggc 20281 atgatgtgga ggagataatc caggaaggga cctgccaagc ccatgacaga ccggtgtcct 20341 gtctgagggc cgtcctggca gagcogtgca gggccctccg agaccgcccg agctccagac 20401 ccggctgggg gctacagggt ggggctgagc tgcaaggact ctgctgtgag cccc-acgtca 20461 gggaggatca ccttgtttgt mtctgagtt tctcttaaa tagcctttat gggtcctggt 20521 ctttggttt aaaataac-aa ctgttctccg taaacaacgt gaaaasaaac aaacaggagg 20581 aaaacaacgc agcccgggca Mttacccgg aagagccgcc tctaacactt tgacgggttg 20641 ccttctamt taaccctgtt ttcattgtaa actgtaaaaa ccacatcata aataaattaa 20701 aggtctctgt gaagtttaaa aagtaagcat ggcggtggcg atggctgtgc cacaccgtga 20761 acgctcgttt caaaacggta aattctaggg accccotggt ggtccagtgg gtgagatttt 20821 gcttccattg caggagrccgt gggtttgatc cctggttggg gaactaagat cccacatgct 20881 gtatggagtg gccaaaaaga attttttgta aatggtgagt tttaggtgac gtgaatttc 20941 cattgatgca cttcacaggc tcagatgcag ccaggcoctc aggaagcccg agtceaccgg 21001 tcctttactt ttccttagag tttttggct tctgtttctg cccttaaacc caccatgttt 2 1061 caacctcatc tgattttgga ctttataata aagttaggct gtgtttcagg aaactttgct 21121 cagtattctg taataatcta aatggaaaga atftgsaaaa agagcagaca cttgtacatg 21181 cataactgaa tcactttggt gtacacctga aactcgagtg cagccgctca gtcgtgtccg 21241 accctgcgac cccacggact gcagcacgcg ggcttccctg c-ccatcacca actcccggag 21301 ttcactcaaa cacatgtccg tcgactcggt gatgccgtcc aaccgtctca tcctctgtcg 21361 tccccttctc ctcccgcctt caatcttttc cagcatcagg gtcnntcaa atgagtcagt 2142 1 tcttcacacc aggtggccag agtattggag tttcagcttc agcatcagcc cttccaacga 21481 ccccccatac ctgaagctaa cacagtcta atccactgt ctgcaacatg aaagaaaaac 74 21541 acattttta agtttaggct gtgtgtgtct tccttctctc aacactgcgt ctgaccccac 21601 ccacactgcc cagcactgca ttccccgtgg acaggaggcc ccctgcccca cagctgcgtg 21661 ccggccggtc actgccgagc agacctgccc gcccagagtg gggcccctgg cactggggac 21721 aaggcagggg cctctccagg gccggtcact gtccactgtt cctactggtt ttgttttc-aa 21781 aagtggaggc agcgtaatat ttccctgatt ataaaaagaa gtacacaggt tctccacaaa 21841 taaaacaggg gaaaagtata aagaatggaa gttcccagca cagcctggag atcacgccgg 21901 gtgcacctgg ggtgtccttc caggctggac Ctcacatttc acgcagacat cagaaggctg 21961 cgagatctac ccagaaggct gggtagatgg gggataggtc agtgacaaac agtagacaga 22021 gagatataca gacagatgat ggatagacag acgctaagac accgagcgag gggacagacg 22081 gatggaagac accatccttt gtcactgacc acacaccac atgggtgtgg tgagccggct 22141 gtcatacttg tgaacctgct gctctcacaa caccagctgg gtccctccag ccccagcgtc 22201 ccacacagca gactcccggc tccatcccca ggcaggaatc ccaccaccaa ctggggtgga 22261 ccctccccgc aggaaggtcg tgctgtctaa ggccttgaga gcaagttac-a gacctacttc 22321 tgggaagaca gcgcacaacc gcctaccccg cagagcccag gaggacccct gagtcctagg 22381 gaagggacca cgcggcctgg acggggagcg gccccaggac gctgccc-cca ac-ctgtccca 22441 cctcactcct gctctgctct gaggcggggc gcagagaggg gccctgaggc ctcttcccag 22501 ttcttgggag cacccactgg gcctgaacca ggccagaagc cccctcctca aggtgtcccc 22561 agaccactcc cctccacctc cggttgctct gtctcctggc agcagggagc cccagtgaga 22621 agagacagct ccaggctgtg atcttggccc ctggctgctc tggcagtgtg gggggtgggg 22681 gtcgctggga ggccatgagt gctgggggtc ggggctgtga aagcacctcg aggtcagtgg 22741 gctgttggtc gggctctgcg aggtccgcac gggtagagct gtgccaggac acaggaggcc 22801 tggtcagtgg tcccaagagt cagggccaaa ggaaggggtt cgggcccctc tggttcctca 2286 1 gcttctgagg ccggggaccc cagtctggcc ttggtagggg ggcgattgga gggtacaacg 22921 atccaaaaga aaacac-acat ctacgaggga agagtcctga ggaggagaga gctacacaga * 22981 gggtctgcac actgcggaca ctgcttggag tctgagagct cgagtgcggg gcacagtgag 23041 cgaagggagg acggaacctc caaggacacc ggacgccgat ggccagagac acacgcacgt 23101 cccatgaggg ccggctgctc agacgcaggg gagctcctca ttaaggcctc tcgctgaata * 23161 gtgaggagaa ctggccccgt gtgtggggaa acttagcca gaagaaacgc tgcctggcc 23221 ccaaggatca nnrnnnnnmn nnxnnnmm ninnn nnnnnnnxn 23281 nnnnnnnnnnnnnnnnnnnnn nnnnnnnnnn tgcCCtttgC 23341 ctccagggag ggaggaagcg tggatcttgg gtttgccttg ggtttaaagg atccacccac 23401 tcccttt gccactccct gtgctggcaa tttcttaaga ctggaggtcg caangagttg 23461 gacacactga gcgagtgaac tgcactgagc ctaagaaaag tcttgaatt cctccaaaca 23521 aaacacactt gtcttgggta cuttccttgg ttttgttaca aatgtctggt cccictgtte 2358 1 tcctggccag ctcctgggtg tcattttgac ctgacgaagt caaagggagc ctggaccctc 23641 aaaatctgta ggacccagca cecctccatt acacctctgt tccecgcga acgggc-acgt 23701 gtttcgccgt ctggcgtaat gtgtaagcga cggttgta ctcgggagtc ttactctgtt 23761 tctttttctt ctggggtgac accaccatec gcacgactet gtctgaatgt gaacattgg 23821 gtgatttgat gtggcccaga ctcccccaac gaatgtacct trcaggttggt mtcttcttt 23881 tatattttgc ttttgtgaat agacacagga tcccatcagt tgtatgtagt gagaaagtaa 23941 aaacccactc agccttagct ggatggagat ctagtagtaa gatagcacgt tagc-cggaaa 24001 tggaaatttc agccagaatc tgaaaagcgt gtcctggaag gagaagaggg actcaggccc 24061 gagcacactg ctccacgctg gagcctcagg ctetgacagc tgtacctgcc ggggtcttca. 24121 tgggacaggc catgcaggcc acgatcccgt tgagaagttt cttgccmtc catcacattg 24181 gcaattgcac gctttgctct tgcttctaca tggagtttta cttttatccc agacagtttg 24241 gtttcttctc tgattttcgc caattgtaca gatcgttaca gtatttctta accacataga 24301 attcggcagg gggggtgggg ggacagggta gggtggggtg agagtgaggg gagggggctg 24361 caccgagcag catctggggt cgtagctccc tgacggggat agacctcgtg cccctgcagt 24421 gacagcacag agtcctcctc tctgaactgc cagggacgct cctgcaattg acttaatgaa 24481 aggcatctaa ttaggaattt tggggtgaca ttttcattt aagtgtgtga gcagtgatta 24541 tagttcatat cattttatag tttcgtgatt ttactagctt aaagggtttt tggggtttct 24601 mtgtuta aaagctaaaa tctgttm aattccatgg aatacaaaaa aaaaaagtct 24661 gtagaatatt ttaaagagtg aaggctttgt tcggaatgtg agcgctttgc tccactgaac 24721 cgaacggtaa taacatttgt agaagagacg cagagtgaaa ggtacctctt tttattgagt 24781 gacatgacag cacccatcgc gtgagttatt ggctggagtt tagagacagg ccatgttggg 24841 ctaaactcct taftgctgtt ctcagccttt gagtaataat cagaagcttt ctctgaagag 75 24901 agtggggtca gctgtcagac tcctaggtgt ctacctgcag cagggctggg attaaatgca 24961 gcagccagta gatacgggat ggggcaagag gtcaccttgt ccctttgttg ctgctgggag 25021 agaggcttgt cctggtgcca gtggggccaa agctgtgact ttgtgaccac aggatgtctc 25081 tgaccctgcc ttgggttccc tgagggtgga gggacagcag ggtctccccg gttccttggc 25141 cggagaagga ccccccaccc cttgetetct gacatccccc caggacttgc cccggagtag 25201 gttcttcagg atgggcatcc gggccccacc ctgactcctg gagctggccg gctagagctt 25261 gctgcagaat gaggccttgg ccattgcggc cctgaaggag ctgcccgtca agctcttccc 25321 gaggctgttt acggcggcct ttgccaggag gcacacccat gccgtgaagg cgatggtgca 25381 ggcctggccc ttcccctacc tcccgatggg ggccctgatg aaggactacc agcctcatct 25441 ggagaccttc caggctgtac ttgatggcct ggacctcctg cttgctgagg aggtccgccg 25501 taggtaaggt cgacctggca gactggtggg gcctggggtg tgagcaagat gcagccaggc 25561 caggaagatg aggggtcacc tgggaacagg cgttgggtgt acaggactgg ttgaggctca 25621 gaggggacaa aaggcacgtg ggcctccccc ccagtgtccc ttaaagtggg aaccaagggg 25681 gccccggaag ccggaggagc tgtggtgtgt ggagtgcaga gccctcgcgg ggtcctgatg 25741 cccgtcggac tctgcacagc tcagcgtgtg ccccgcggcc cggtaggcgg tggaagctgc 25801 aggtgctgga cttgcgccgg aacgcccacc agggacttct ggaccttgtg gtccggcatc 25861 aaggccagcg tgtgctract gctggagccc gagtcagccc agcccatgca gaagaggagc. 25921 agggtagagg gttccagggg tgggggctga agcctgtgcc gggccctttg gaggtgctgg 259891 tcgacctgtg cctcaaggag gacacgctgg acgagaccct ctgctacctg ctgaagaagg 26041 ccaagcagag gaggagcctg otgcacctgc gctgccagaa gctgaggatc ttcgccatgc 26101 ccatgcagag catcaggagg atcctgaggc tggtgcagct ggactccatc caggacctgg 26 161 aggtgaactg cacctggaag otggctgggc cggatgggca acctgcgcgg ctgctgctgt 26221 cgtgcatgcg cctgttgccg cgcaccgccc ccgaccggga ggagcactgc gttggccagc 26281 tdaccgccca gttcctgagc ctgccccacc tgcaggagct ctacctggac tccatctcct 26341 tcctcaaggg cccgctgcac caggtgctca ggtgaggcgt ggcgccagct ccaaagacca 26401 gagcaggcct ctcttgtttc gtgcccgctg gggacattgc cagggtgccc ggccactcgg 26461 aagtcctcac gatgccaccg ctctgaccct gggcatcttg tcaggtrcact tccctggtta 26521 gggtcagagg cgtggcctag gttanatgct gtcmagggg actccttct gggagtccgc 26581 atagtggggg cttggtgtga tgcccttggg aattctttcc gagagagtga tgtcttagct 26641 gagataatga cagataacta agcgagaagg acggtccatc aggtgtgagg ttgaagtc 26701 aaagctctgt ctctccctcc cacctgccc ttctgtcctg agctgttta ggctccaggt 26761 gagctgtggg aagtgggtga ttctggagat gacaagaagg gatcaggagg ggannattgt 26821 ggctectaag cagtccagag aagagaaaaa gtmaataag cattattgtt aaagtggctc 26881 cagtctctt aagtccaaat tataattata attttcctct aagacttctg aatacatagg 2694 1 aaatcctoag taacaggtta ttgctctgcc ttgaacacag tgataaaagc tgggaggatg 27001 cagcctaatc tgtctgtgtg aatgagttgt attgattccc tttttggcag ctgcaaactc 27061 caagcattag gaataaatat gttcactgag aaccccgaag aaagaaagaa agaaaaaaaa 27121 aaagaattgt aggtgttgat ggacgtg tggcccctga atatctgggg gatgttcacc 27181 cagggatcac gtgtaactgc tgggarcccc agccccatgt ccactgcatc cagcctgctg 27241 ttgaattccg cggatcnnnn nnnnnnnn nnnnmnnnmn nnnnn 2730 1 nnnnnnm nn nnnnnnnnnn nnnnnnnnnn nnnnnnnnn nnnnnncaat 27361 tcgagctcgg taccccaaag gtc-cgtctag tcaaggctat ggtttca gtggtcatgt 27421 atggatgtga gagttggact gtgaagaaag ctgagtgcca aagaattatt cttttgtact 27481 gggtgttgga gaagactctt gagagtccct tgaactgcaa ggagatccaa ccagtccgtt 2754 1 ctaaaggaga tcagtcctga atgttcatug gaaggactga tgctgaagct gaaactccaa 27601 tactttggcc acctgacgtg aagagttgac tvattggaaa agaccatgat gctgagagga 27661 attgggggc-a ggaggagaag gggacgacag aggatgagat ggctggatgg catcac c 27721 tcgatgngac atgagtttgg ttaaac-teca ggagttggtg atggacttgg aggcctggtg 27781 tgctgggatt catggggtcg cagagtcgga catgactgag cgactgaact gaactgaact 27841 gagctgaaga gctcacctgt accagagcte ctcaggtccl cctgcaggcc tggctgtaat 27901 ggcccccagg tcoccgtcct gcctccttca tercatcctt tcacgacagg ctgggagtgg 27961 ggtgaggtga gttgtcttgt atctagaatt tctgcatgcg accctcagag tgcaatttag 28021 ctccagagaa ctgagctcca agagtteatt ttttcctttt cttctttatg atactacect 28081 cttctgagca gagacctcat gtcagggaga aggggactet gccttcctca gccttttgtt 2814 1 ectccaagac ccacacgggg agggtcgcct gcttcactga gccggaaggt tcaaftgctc 128201 atgtcctcca gaaacacccc ccrccccaga gacccccaga aataagtgga acagcacctt 76 28261 gtttcccaga caagtgggac acacgttatg aaccacctca gtgattaaaa tagtaacctc 28321 tgtgtatgtg tatttactgg agaaggaaac ggcaacctac tccactattc ctgcctagaa 28381 aattccatgg gagagaagcc aggcaggcta cagtccacgg ggtcacagag actgaacata 28441 cacaagcaca tggaagtgta ttttgcagta ttttaaatt tgttcagttc aacatggagt 28501 acaagaattc aaatcgtgaa gtcaattgac caagaaacca gaagaaatca ctgtgttgtg 28561 atctctgtgg aggtaacatg ggtacctgtg ctctgaccct cacagcctct ggctctctct 28621 ctacatgtac atacacatat atttccatgt atgtatgtat tcggaagatt tcacatacgt 28681 ctcaccagtc cacagcccc gcgttccctg atgcccagaa catctgtgat agctgtgagt 2874 1 attgtcacca gataagatct tccaggttcc tgcactcaca ttggttatca ggtctctctg 28801 atccagcatt tctcagctaa gattccttgt gactectggc tgcagaatct tctgcaaaag 28861 tcccacagag aggagtgtga tcactgtaca caggagggcc gtggttctct agtgtgagaa 28921 aagctaactc agcccgtcac agggacgtga atgtacctga gacagtaatc agttatgctg 28981 agaaatcaca gctctgctag aggcagcaca tggggtagcc agcagggggc agcagagcac 29041 ggccaggagc cgcaggtcag aggctgggct gcccaagcgg ggcttcaggg gaacdagccc 29101 tgcgggtcca caggtgtcca gggagcagcg cttggcagga agtcaggacc ggacaggcca 29161 tcccctcagg actagtgacc acctctgagg gtcacatcca cagtgaaccc cagagcacca 29221 tgcctcagtc cacggccagg acgctgccag gctgaccgcc ccactgggga gtccagggga 29281 gaccacaggc cggggggcft gggacagtga tcatgtggtc agacacagag aaggtgacag 29341 tgacctcagt ccctgaggac aagtctgatg tgcagacgtg agaagccgag gaggaagctg 29401 gggacagaca gggctgatgg tgtggtgacc ccgcctctca gtgaggggec cccgggggtg 29461 aatttgcata aacccaagcc ctcactgccc ccacaaagct ctgagaggga ataaaggggc 29521 tcggagagcc cagcactgct gcgggctc-ag aggcagagct cggggcgcgt ccaccatggc 29581 ctgggcccct ctcgtactgc ccctcctcac tctctgcgca ggtgcggccc cccagcctcg 29641 gtccccaagt gaccaggcct caggctggcc tgtcagctra gcacaggggc tgctgcaggg 29701 aatcggggcc gctgggagga gacgctcttc ccacactccc cttcctctcc tctcttctag 29761 gtcacctggc ttcttctcag ctgactcagc cgcctgcggt gtccgtgtcc ttgggac-aga 29821 cggccagcat cac-ctgccag ggagacgact tagaaagcta ttatgctcac tggtaccagc 29881 agaagccaag ccaggccccc tgtgctggtc atttatgagt ctagtgagag accctcaggg 29941 atccctgacc ggtctctgg ctccagctca gggaacacgg ccaccctgac catcagcggg 30001 gcccagactg aggacgaggc cgactattac tgtcagtcat atgacagcag cggtgatcct 30061 cacagtgac-a cagacagacg gggaagtgag acacaaacct tccgtcctg ctcacgctct 30121 cctccagcc-c cgggaggact gtgggcacag cagggacagg cctggccgg ttcccccgga 30181 gctgagcccc caggcggcc-c cgcctcccgg ccctccaggc aggctctgca caggggcgtt 30241 agcagtggac gatggctgg caggccctgc tgtgtcggg tctggctgt ggagtgacct 30301 ggagaacgga ggcctggatg aggactaaca gagggacaga gactcagtgc taatggcccc 30361 tgggtgtcca tgtgatgctg gctggaccct cagcagccaa aatctcctgg attgacccca 30421 gaacttccca gatccagatc cacgtggctt tagaaaggct taggaggtga acaagtgggg 30481 tgagggctac catggtgacc tggaccagaa ctcctgagac ccatggcacc ccactccagt 30541 actcttccct ggaaaatccc atggacggag gagcctggaa ggcttcagcc catggggtcg 30601 ctaagagtca gacacgactg agcgacgtca ctttcccttt tcactttcat gcattggaga 30661 aggaaatggc aaccc-agtcc agtgttcctg cctggaaaat ccc-agggaca ggggagcctg 30721 gtgggctgcc atccatgggg ccacacagag tcagacacga ctgaagcaac ttagcagcag 30781 cagcagcagc ccaataaaac tcagcttaag taatggcatc taaatggacc ctattgccaa 30841 ataaggtcea ctcgcgtgca ctctgtttag gacttcagtt cctgattgtg gggtc 30901 acaagacgtg tgtgtatatt ggtgttgccg gaaaacagtg tcaatgtgag catcecagac 30961 tcatcaccct cctactccca ctattccatt gtctctgcag gtottaagca taaaggttaa 31021 gggtcttatt agatggaaga ggagtgaata ctcgtctgtg cttaacacat accaagtacc 31081 atcaaggtcc ttcctattta ttaacgtgtg ttttaatcag aaatatgcta tgtagaagca 31141 tccggacgat agcccatgtt acagacgggg aagctgaggc atgaagttct cagcaccttg 31201 tttcacgtca gacctgaaac ggggcagagc cggcagcaaa caaggttcct cttcccaagc 31261 gcccgctctt cacccgcttc ctatggcttc tcactgtgct tcctaaacta agctctcccc 31321 aaccctgtgg agacaggatt agagactua ggagaaaaga ccaggaacat cccacacccg 31381 acccgagtga gccactaaga caaggcttg taaggacaga accagcaggt gtcctcagcg 31441 agccagggag agacctcgca ccaaaaacaa tattgtagca tcctgaccct ggacttctga 31501 cctccagaaa tgtgaaaaag aaacgtgtgg ggtttaatca actcaccggt gttatttggt 31561 tatgactgcc tgagttasga aggagttggg aacaftgag tgtaggtgft tatggaacat 77 31621 aagtcttgtt tctctgaaat aaattcccaa gggtataatt cctaggttgt agggtaactg 31681 ccacaaatct aggcagctta ttaaaaaaca aagatatcac tttgccagca aaggttcata 31741 tagtcaaatt atggttttta tagtagtcat gtatggatgt aaaagttgga tcataaagaa 31801 ggctgagcac cagagaattg atcccntcaa atcgtggtgc tggagaagac tcttgagagt 31861 cccttggaca gcaaggagat ccaaccagtc aatcctaaag gaaatgaact gtgaatattc 31921 actggaagga ctgatgctga agctgaagat ccaatacmt ggccacctga tgcgaagagt 31981 tgactcattg gaaaagac-cc tgatgctgga aagcttgagg gcaggaggag aagagggcgg 32041 cagaggatga gacggttgga tggcatcact gactcaatgg acatgagttt gagccaactc 32 101 tgggagacag tgaaggatag ggaaggctgg cgtggtacag tgcatgcggt cacaaagagt 32161 ctgacacatc ttagtgactc aac-aacgaca gcaacacagg catcac-acgc ttagtgtgat 32221 aagcggcaga actgttttcc aggggtccgnnnnnmnnnmnnnnnnn 32281 mnnnnnnnnnnnmn nnnnnrnnmnnnnn mmnnnnnnin nnnnnnnnnn 32341 nnnnnnanmg tacgattcga gctcggaccc tgacattgtg agtcacgtca tgagcagctg 32401 ttttccggtc ttcagggatt gtggacgatt tctgtttggg tttgctcatg ataatttagt 32461 tacagcttag gttctttctt tccaggccac gagcgacatg ttttcaggtg agatgacgtg 32521 gtgggggatg ggcggccaag cccccactgg ggggggaggg attctgttgt gggcaggagt 32581 tggcagcatc cctgaactga tgacctgcga tccaggtgac aagaaccggg ggatattatt -32641 cctctgcctt ctcatgtcat gtcctcggtt cttcatgatg aaaacatatg acaatacagg 3270 1 ggagttagat ttgggcgggc acaactctgg gtgggggacc cggtggcatt gtgcc-cagea 32761 gggccatcaa gatgagggcg acctgggtgg tccccttctc ccctggggtc ttagttttcc 32821 cctcatggaa atgggatcag gcagcagcca tggaacaccg cgaccgtggc ttctctcac 3288 1 tc-ctcgtctg tgatmtggg tcgggatacc aggcatgaag acctggggcg gggggacatc 32941 actcctctgc agcagggagg ccgcagagtc ctccgtccat gaggacttcg tccctgggct 33001 gaccctgcgg actgctggag gctgaagctg gaggcacagg cgggctgcga ggccagggtir 3-306 1-ctgaggacga cagagecagt-ggggctgcag ctctgagcag atggcccctc gccccgggcc 33121 ctgagcttgt gtgtccagct gcaggttcgc tcaggtgagc cactacgtta tgggggaggc 33181 gccctgggca gggatcgggg gtgctgacte ctecgagatt ccgaccttct gggagcactc 33241 tggccacact ctaagcctgg caagagctgg gttcatcagt ctaactctcc tcctgaagtc 33301 caatggactc tctccatgcg gcagtcactg gatggcctct ttatcccpg tggtgtcctt 33361 ttccgctgac ctggctctcc tgaccacctc ccagcccc accatacagg aagatggcac 33421 ctggtccctg cagagctaag tccacccctg gcctggcttc agatgcctac agtcctcctg 33481 cgggaggccc cgctccc-cac taggccccaa gcctgccgtg tgagtctrag tcteacctgg 33541 aaccctrete atttcteccc agtcetcagc tcccaacccc agaggtatcc cctgcccctt 33601.tcaaggccct tgtcccttcc tggggggatg gggtgtatgg gagggcaagc ctgatccccc 33661 gagcctgtgc cgctgacaat gtccgtctct ggatcatcgc tcccctggct ctcagagctc 33721 cctggtccct ggggatgggt tgcggtgatg acaagtggat ggactctcag gtcacacctg 3378 1 tcccttccct aaggaactga cccttaaccc cgacactcgg ccagacccag aaagcacttc 33841 agac-atgtcg gctgataaat gagaaggtct ttattcagga gaaacaggaa cagggaggga 33901 ggagaggccc ctggtgtgag gcgacctggg taggggctca ggggtccatg gagaggtggg 3396 1 ggagggggtg tgggccagag ggcccccgag ggtgggggtc cagggcccta agaacacgct 3402 1 gaggtcttca ctgtcttcgt cacggtgctc ccctcgtgcg tgacctcgca gctgtaactg 34081 cctttcgatt tccagtcgct gcccgtcagg ctcagtagct gctggccgcg tatttgctgt 34141 tgctctgttt ggaggcccgg gtggtctcca cgttgcgggt gatggtgctg ccgtctgcct 3420 1 tccaggccac ggtcacgcta cccgggtaga agtcgctgat gagacac-acc agggtggcct 34261 tgttggcgct gagctcctcg gtggggggcg ggaacagggt gaccgagggt gcggacttgg 34321 gctgacccgt gtggacagag gagagggtgt aagacgccgg ggaggttctg accttgtccc 3438 1 cacggtagcc ctgtttgcct tctctgtgcc ctccgaccct tgc-cctc-agc ccctgggcgg 34441 cagacagccc ctcagaagcc attgcaatcc actctccaag tgaccagcca aacgtggcct 34501 cagagtcccc ggctgcgacc agggctgctc tcctccgtcc tcctggcccc gggagtctgt 3456 1 gtctgctctt ggcactgacc cctggccc tcagcccctg ccagacccct ccgtgacctt 34621 ccgctcatgc agcccaggtg cctcctccgt gaacccgggt cccccgccc acctgccagg 34681 acggtectga tgggagatgt ggggacaagc gtgctagggt catgtgcgga gccgggccg 34741 ggcctccctc tcctcgccca geccagcctc agctctcctg gccaaagccc ggggctrctc 34801 tgaggcctg cctgtctacc gtccgccctg cctgagtgca gggcccctcg cctcacctgc 34861 cttcagggga cggtgccccc acacagc-acc trcaaagacc ccgattctgt gggagtraga 34921 gccctgttca tatctcctaa gtccaatgct cgcttcgagg ccagcggagg ccgaccctcg 78 34981 gacaggtgtg acccctgggt cccaggggat caggtctccc agactgacga gtttctgccc 35041 catgggaccc gctcctttct gaccgctgtc ctgagatcct ctggtcagct tgccccgtct 35101 cagctgtgtc cacccggccc ctcagcccag agcgggcgag acccctctct ctctgccctc 35161 cagggccttc cctcaggctg ccctctgtgt tcctggggcc tggtcatagc ccccgccgag 35221 cccccaagct cctgtctggc ctcccggctg gggcatggag ctcacagcac agagcccggg 35281 gcttggagat gcccctagtc agcaccagcc tctggcccgc accccagcgt ctgccctgca 35341 agaggggaac aagtccctgc attcctggac caaacaccag ccccggcgcc ccgactggcc 35401 ccattggacg gtcggccact ggatgctcct gctggttacc ccaagaccaa cccgcctccc 35461 ctcccggccc cacggagaaa ggtggggatc ggcccttaag gccgggggga cagagaggaa 35521 gctgccccca gagcaagaga-agtgactttc ccgagagagc agagggtgag agaggctggg 35581 gtagggtgag agccacttac ccaggacggt gacccaggtc ccgccgccta agacaaaata 35641 cagagactaa gtctcggacc aaaacccgcc gggacagcgc ctggggcctg tcccccgggg 35701 gggctgggcc gagcgggaac ctgctgggcg tgacgggcgc agggctgcag ccggtggggc 35761 tgtgtcctcc gctgaggggt gttgtggagc cagccttc-ca gaggcc-aggg gaccttgtgt 35821 cctggaggtg ccctgtgccc agccccctgg ccgaggcagc agccacacac gcccttggg *35881 tcacccagtg ccccctcact cggaggctgt cctggccacc actgacgcct tagcgctgag 35941 ggagacgtgg agcgccgcgt ctgtgcgggg cggcagagga gtaccggcct ggcttggacc 36001 tgcccagccg ctcctggcct cactgtaagg cctctgggtg ttcctteccc acagtectca 36061 cagtccagcc aggcagcttc cttcctgggg ctgtggacac cgggctattc ctcaggcccc 36121 aagtggggaa ccctgccctt tttctccacc cacggagatg cagttcagtt tgttctcttc 36181 aatgaacatt ctctgctgtc agatcactgt ctttctgtac atctgtttgt ccatccatcg 36241 atccaacatc c-atcc-atcca tccatcaccc agccatccat ctgtcatcca acatccatec 36301 ttccatccat tgtccatcca tctgtccatc ttgcatctgt ctgtccaaca gtggccatca 36361 agcacccgtc tgccaagccc tgtgtcacac gctgggactt ggtgggggga gccctcgccc * 36421 tcccacc-ctc ccatctctctgaaacttet ggggtcaagt ctaacaaggt cccatcccgt 36481 ctagtctgag gtccccccgc agcctcctct tccactctct ctgcttctga cccacactgt 36541 gca ctcggac gaccacccag ggcccttgca tcctgtttc cttcctgacc tctttttttt 36601 ggctctggat ttatacacat tctgcctcct ggaggcgtct cagcttgagt gtcccacaga 36661 cgcctcagac tcagcatctt ccatcgaaac tgctccr-agg tcugcaga cctggtcccc 3672 1 cacattgttc tcaattcggt agatttctcc acaagccaga ggcctggact cateccataa 3678 1 tgcctgcccc tc-attgagtc agectctgtg tcctaccata accaaacatc cccttaaaaa 3 6841 tctcagaaga acaaaaaaag cacccagatg gcaCtgtCag agtttatgat gacaagaatc 36901 ctcagttcag ttcagtcact cagtcgtgtc cgactctttg cgaccccatg aatcgcagca 36961 cgccaggcct ccctgtccat caccaactcc cggagttcac tcagactcac gtccattgag 37021 tcagtgatgc catccagcca tctcatcctc tctcgtcccc ttUctcct gcccccaatc 37081 cctcccagc-a tcagagtttt ttccaatgag tcaactcttc gcgtgaggtg accaaagtac 37141 tggagttca gcftcagcat cattccttcc aaagaaatcc cagggctgat ctccttcaga 3.7201 atggactggt tggatctcct tacagtccaa gggactctca agagtcttct ccaacaccac 37261 agttcaaaag cctcaattct ttggcgctca gccttcttca cagtccaact ctcacatcca 37321 tacatgacca caggaaaaac cataaccttg actagatgga cctttgttgg caaagtaatg 37381 tctctgcttt ttaatatgct atctaggttg ctcataactt tccttecaag aagtaagtgt 37441 cttttaattt catggctgca atcaacatct gcagtgattt tggagcccca aaaaataaag 37501 tctgccactg tttccactgt ttcccatct atttcccatg aagtgatggg accagatgcc 37561 atgatctttg tttctgaat gttgagcttt aagccaactt tteactctcc actttcactt 37621 tcatcaagag gctttttagt tcctcttcac tttctgccat aagggtggtg tcatctgeat 37681 atctgaggtt attgatattt ctcctggcaa tcttgattcc agtttgtgtt tcttccagtc 37741 cagtgtttct catgatgtac tctgcatata agttaaataa gCagggtgat aatatacagc *37801 cttgacgtac tcctttucct atttggaacc agtctgttgt tccatgtcca gttctaactg 37861 ttgcttcctg acctgcatac agatttctca agaggcaggt caggtggtct ggtattccca 37921 tctctttcag aattttccac agttgattgt gatccacaca gtcaaaggct ttggcatagt 37981 caataaagca gaaatagatg tttttctgaa actctcttgc ttttccatg atccagcaga 38041 tgttggcaat ttgatctctg gttcctctgc cttttctaaa accagcttga acatcaggaa 38101 gttcacggtt catgtattgc tgaagcctgg cttggagaat tttgagcatt cctttgctag 38161 cgtgtgagat gagtgcaatt gtgcggcagt ttgagcattc tttggcattg cctttctttg 3 8221 ggattggaat gaaaactgac ctgftccagg cctgtggcca ctgttgagtt ttcccaatt __________ 3828 1 gctggcatat tgagtgcagc actttcacag catcatcttt caggaTtga aatcgctcca 79 38341 ctggaattcc atcacctcca ctagctttgt ttgtagtgat gctctctaag gcccacttga 38401 cttcacattc caggatgtct ggctctagat gagtgatcac accatcgtga ttatctgggt 38461 cgtgaagatc tttttgtac agttcttctg tgtattcttg ccacctcttc ttaatatct 3852 1 ctgcttctgt taggcccata ccgtttctgt cctcgcctat cgagccctcg cctccctacg 38581 tagagactct aagcaggaag gtgacccgtg ctgcactggg tccagc-atgc ttttattca 38641 gcagtggaac ttctgggtca tgattgtgtt taagggatgc gcatacgatt mtgaagcaa 38701 aatttaacag gacagcagtg taaagtcagt acttatttct gattaaagaa agcaaatatc 38761 cagcctgtta ctaagttaat taactaaaga aacatcutca acttaataaa cagtatctcc 38821 tgaaacttc agcatgcttc acatttaaag gcaaaaccat tttagaggcc agggttccca 38881 cgcttacgtt tattatttaa tatatgctac agattcaagc ccatgacaca aaatgggggg' 3894 1 aagagtgtga gtgttaggaa aaatgagata aaattggttt ttgcaggtga tgggctagtt 39001 tactttaaaa aaaaaaacaa aacaagctca agatgaactg aaggactatt agaactggta 39061 caagagttaa cctgtgatcg aatacaagca ggctgggcaa aactcagcag gttttcttct 39121 atacaggcag taatgattga gaatacgaaa cggcggaagc gcttacaacc tcgataacag 39181 ttctattaaa agccctagga atgaacttaa cacggnnnnn nnnnnnmnnn mnnnnnnnM 39241 nnnnnnnnnn nnnnnnnnnn nnnnnnnnrm nnnmnnnnnnnnznn 39301 nnnnnnnnnn nnnnngctcc ccccaccctc ccctccccc cccccaccac cagtgcccca 3936 1 ggtctcgtgc ccagagagct gaagatgcca gcaggcccgc tgcctgcctc gctcgcgtgg 39421 cccgggctcg ctgccggtct gcctgcccag cacacagatg c-agccccagc tctcgctgc 39481 acccgcctcc cccaggcagg actctcccac aacaccaagg gcgtctctgg gttcaggatg 39541 gccctcgttg aggtgtaaag tgcttcccgg ggctgagacg aatgggccgg agatccaaac 39601 gaggccaagg ccgccacggc gcctggcgca gggcacccat ggtgcagagc ggcccagctc 3966 1 cctccctccc tccctccctc cctgcttctt tatgcteccg gctatgtcta ttttctct 39721 gcaatttaga aatgataccg aaggacaaac accgttcccc ctgtgtgtct gctctaaacc 3 978 1 ctttatctac ttatctatti- gcgtgtccaa -gttttgctgc taagtgaatg aaggaacact 39841 acccacaagc agcaacgtcc ccacgaccct cgcctgttca actgggaatg taaatgtgct 39901 ttcaaaggac ctaagtttct atgttcaaaa ccgttgtgtg mtcttttgg gagtgaacct 39961 aggccactcg ttgttctgcc tttcaaagca Utcttaacaa ctctccagaa cccagggctt 40021 ggcttacgtt tccagaaatt ccaaagacag aracttggaa acctgatgaa gaaggcctgt 40081 gagcacagca ggggccgggg tacctgaggt aggtgggggg ctcggtgctg atggacacgg 40141 ccttgtactt ctcatcgttg ccgtccagga tctcctccac ctcggaggct ttcagcaggg 40201 tcacgctggt ggccagggtc gtgtatccat gatctgcaac cagagacggg gctgcggtca 40261 gcccgcgggc gggcagcagg caggagcagc caggagacgc agcacaccga ggtcctcaca 40321 tgcaggaggt gggggaagcg gctgtggacc trcacgactgc ccgatgtggg c-ctcttccaa 4038 1 agggccggcc tggaccctgg ctttctccag aggccctgct gggccgtccg cacaggctc 40441 agccacaggg cctcttggga caggagggct ccagagtgag ccggccggcg ggaagaggtc 40501 tgacaccgct gcagtccaca acacgaagcg aggtggagat gggatgaggg atgagaaaca 40561 cttttctttt aaaacaagag cccagagagt tggaaagagc tgctgcacac gcaacatgaa 40621 ctcctggccc cggtgccagc ggcgctggga gcccgagttc tcggcaatcc gaccacagct 40681 tgcctaggga gccgggtgga gacggagggt taggggaagg cggctcccca gggagcgcga 40741 ggcccgg cgccaaggct cgccaggggc aagcgcagct aggggcgcag ggttagtgac 40801 cggcactgca cccggcgcag gagggccagg gaggggctga aaggtcacag cagtgtgtgg 4086 1 acaagaggct ccggctcctg cgttaaaaga acgcggtgga cagaccacga cagcgccacg 40921 gacacactca taccggacgg actgcggagt gcacgcgcgc gcacacacac acacacac-ca 40981 cacac-acaca cacacggccc gggacacact cataccggac ggactgcgga gtgcacgcgc 41041 acacacacac ccaccacaca cacacccacc acacacacac cc-accacaca cacacacaca 41101 cacacacacc cccacacaca cccacacaca cccacacaca cccacacaca cac-acccaca 41161 cacacacaca cacacacaca cacacacacg gcccggtggc cccaggcgca cacagcacgg 41221 agcaaacatg cacagagcac agagcgagcg ctagcggacc ggctgccaga ccaggcgcca 4 1281 cgcgatggat tgggggcggg gacggggagg ggcgggagca aacggnnnnnnnnnm 41341 nnnnn nnnnnm nnnnnnnnnn nnnnnnnnnn nmnn nnnnnnnn m 4 1401 nnnnnnnrum munnnnnnn nnnnngtott aaagaagccg ggagcgagaa tatgacggca 4 1461 agaggatgta ggtgggggcg gggcaagagt aaagagagcg gacggtagag gggatgcgat 41521 tgtgatgcgg aagcgagacg aggagtgatg ccgtattaga ttgatagcaa gaggaacagt. 41581 aggagggggg ggggagagga gggggaggtg gggggtggtg ggtgggaagg gaactuaa 41641 aaaaagagg g agagtta g gaata aacgcgg taaaaaagaac aatttgaat 80 41701 taccagggtg gggcggccag gggggtgatt cattcttgga gggggcaaca tatggggggt 41761 ggctgtcgcg gattaggaga aaataaatat caggggtgat taagtgtttg gcgttgggga 41821 ataatgaagt aagaatcaaa tatgaatcgc gttggcatcg ttagccatcg ggggaaacat. 41881 ttcccatgca aggaaCaagg atgtgagaat gcgtccgtct gaaccaccgt cccggggtcc 41941 cagtaggact cgccgagctg atagttgccg gagcaacagt taagggagca gaagctgcta 42001 caaaaccacc acctgccaaa gtagggtctc caattacgga gtgcgcctcc tgggtgtcgg 42061 tccaaacctt tggaaaggac ctggaiataa gtgctaccca ccagatatta atataaaccc 42121 acctggccag gagaggcagg cgctgctggc acaggaagtg tccccagact cagtcatcaa 42181 ggtaaataat attttgggac ctccctggaa atccagtggt taggactctg cggttcaatc 42241 cctggtcggg gaactaagat cccacaagtc acaagacatg gc-caaattta aaaaagaaaa 4230 1 aaagagagag aaatatttag tgcaataggt ttuagaattg aaattaagct cctgc-ccacc 42361 cccacccccc aatctggatg aataaagcat tgaaatagta agtgaagtca ggctctgaca 42421 tgcactgatg tgactcacct taagcaaccc ccaccctagg actggtcggg gttccaggag 42481 tttcaggggt gccaggaaga tggagtccag cctgccct ctcccccr-ac cacgtcctcc 4254 1 actggagccg cctaccccac ctcccacccc tccgcaccct gctacccecc acccctgcc 42601 ccaggtctcc cctgtcctgt gtctgagctc cac-actttct gggcagtgtc tccctctaca 42661 gctggtttct gctgcccgct accgggcccg tcccctctgt tcagttcagt tcagtcgctc 4272 1 agtcatgtct gactctttgt gaccccatgg actgcagcac accaggcctc cctggccatc 42781 accaccccc agaacttact caaactcatg tccatcgagc cagtgatgcc atccaaccat 42841 ctcatcctct gtcgaccct tctcctggcc tcaatctttc ccagc-atcag ggtcttttcc 4290 1 aatgagtcag ttctttgcat coggtageca aagtattgga gttcagctt cagcatcatt 4296 1 tcttccaatg aatattcagg actcatttcc tttgggatga actggttgga tctccttgca * 43021 gtccaaggga ctctcaagag tcttctccaa caccacagtt caaaagcatc aattcttcag 43081 tgctcagctc tctttatagt ccaactctc-a catccatacg tgaccactgg aaaaacocata 43141 gcctcgacta gatggaactt tgtgggcaaa gtaatgtctc tgcttttgaa tatgctgtct 43201 aggttggtca taacttttct tccaaggagc aagcgtcttt taatttcatg gctgcagtca 43261 ccatctgcag tgatttttgg agcccaagaa anansigtct gtcactgttt ccactgtttc 4332 1 ccgtctatt taacggaggg aaatttccca gagcccccag gttccaggct gggccccacc 43381 ccactcccat gtcccagaga gcctggtcct ccaggctcc cggctggcgc tggtaagtc * 43441. caggatatag tctttacatc aagttgctgt gtgtcttagg aaagaaactc tccctmttg 43501 tgcctctgtt ccctcatccg cagaagtgac tgccaggtcg gggagtctgt gacgtctca 4356 1 gaagccggag gatttttcc ccatttgctg aaagagagct cggggtgggg gaagcttctg 43621 cacccctagg ateaccagag gagccagggt cttcagggtt cccggggacc cctcagtggg 43681 ggctcaggaa ccacagagcc agaccctgat tccaaaaacc tggtcacacc tccagatgac 43741 cctttgtccc ttggctccgc ctcaaatgct ccaagcccca acagtgaagc gcttaagaga 43801 aggatccacc aggcttgagt ttggggagga gggaagtggg gagctggggg agggcctggg 43861 cctgggagac aggaatccac catggcttca ggcagggtct ctggggcctg cggggtggag 43921 agcgggcagg agcagacaga ggtgactgga cacgacacac ccctccactc caagggaggt 43981 gggcaggggc ggggcacaga ggaacaagag accctgagaa ggggtccacc gagcagactg 44041 ctggaccag acatctctga gccagctgga atccagctct aagccatgct cagccc-aggc 44101 agggtatagg gcaggactga gtggagtggc cagagctgca gctgcatggg ctgggaaggc 44161 cctgcccgtc ccctgagggt ccccagggt ctagccagac tccaatttcc gaccgcagca 44221 cacacaggag gaagtggtcg gggtggagtt ggcccagagg tctgggcagg tgcagggtgg 44281 gggaaggggg gcagctggag tcacccgctg aattcaggga c-agtcccttt ttctccctga 44341 aacctggggc tgtcccgggg gccaccgcag cctccaggca gcggggggac ccagccccca 44401 atatgtgaga agagcaggtc ccaggctgga gagagcgaag caccatggtg gggagaagtt 44461 agactggatc ggggccccta ggggctcccc cggacctgca cggcagccgt cagggcaccc 44521 gcaccccatt gctgttcagt gctggccagt gtccaaggcc agggatgtgt gtgtgtgtgt 44581 gtgcgtgcgt gcgtgcgtgt gtgtgtgcgt gtgtgcgcgt gcgtgcgtgt gtgtgtgtgt 44641 gcgtgcgtgt gcgtgcgtag acgtgtgcgt gcgtgcgtgc gtgcgtgcgt gtgtgtgcgc 44701 acgcgcgcag cccagcctca gcactggacc aggcagcctg ggattcctcc aaaactgcct 44761 tgtgagtttg gtcaaaccgt gaggctctga tcaccgccat ccattcgccc cctrctgccc 44821 ccctcatcac cgtggttgtt gtcattatcg agagctgtgg agggtctggg aggcatccc 44881 acctgccagc taaaccgtga ggctgccgca atcgcactga tgcgggcaga cccgagacgc 44941 tgtgccggag acgaaggcca gcttgtcacc ccgccagagc ggcagtcggg rcacaagc-at 45001 catccaagca gtggftctct gagcccgacg gggtgatgca aaggagccag gagacacctg 81 45061 cgcgtccaag ctgggggacc ccaggtctgt tatgccggac agtaaacacg ttcagctccg 45121 gagggagagg gttcccctac cttccagggt ttctcattoc acaaacatcc aaagacaatc. 45181 cataccgaag gcgatccgtg cctttgctc-c tgagacgtgc ggaagcacag agatccacag 45241 acactgtctc ccaggatcct atgtatgta aggaaccgaa gtcccaggct gtgtgtctgg 45301 taccacatcc cacggaacag gctggactga tttcaccaa atgtagcaga aacgttaagg 45361 agtatcagct tcaaaatatg agggccagac atgtctgaga agtcccttcc agaaaagtc 45421 ctttggggtc cttccccaga gttgctgaaa cagagaaccg gaagggctgc agagctgaac 45481 ttaaacaact ggatcgcaaa ggtccgtctc atcagagcga tggttttcc agtggtcatg 45541 tatggatgag agagttggac cataaagaaa gctgagcgcc gaagaatcga tgcttttgaa 45601 ctctggtgtt ggagaagact cttgagagtc ccttggactg caaggagatc caaccagtca 45661 atcctaaagg aaatcaatcc tgaatattca tgggaaggac tgatgctgaa gctgaaactc 45721 caatacttg gccacttgat gcaaagaact gactcactgg aaaaaccctg atgctgggaa 45781 aggttgaagg caggaggaga aggggtcgac agaggatgag atggttgggt ggcaltcaccc 45841 acccatggac tcaatggaca tgggttgag taaactctgg gagttggtga tggacagaga 45901 atcctggcat gctgcggtcc atggggtcat agagagtcag acacaactga gcgactgaca 4596 1 gaactgaagc aactggcaag ccggagggta ggtgccggct gcgatgagcg ggaacgtgca 46021 acctgccacg tggagctctt cctacaccc-a gagtcctgac ggcactggga ccctagccct 46081 ccacggcctc tccagggcca cgagacaccc tcacagagc-a gagaagcgga acagagctgg 46141 tgtgcagaac caggccccgg gggtggggcg gggctggtgg gcaggcttta gtgagaagcc 46201 cttgagccct ggaaccagag cagagcagaa cagttggc-ag aggcccccct gggagaggcc 4626 1 ccc-cgcccag agtaccggcc ctgggccctg ggggagaggg cggtgctggg ggcagggaca 46321 gaaggcccag gcagaggatg ggccccgtgg gacggggcgc accaaaacag cccctgccag 46381 caaggggaag ctggggcact ttcgaccccc tccaaggagg agcccacacc agcgcatctg 46441 cccaaggtgc ccttggccct gggggcacat gaggcccagg ccaggccagg gggcccatga 46501 ggcccccagg ggtcagtgca gtgtcccag gcagccctgg cctctcatrc tgctgggcct 46561 ggcctcttat cccgtgggcg rccacggect gctgcccccg acagcggcgc ctcagagrcac 46621 agccccccgc atggaagccc cgtcaggaaa gagcccttgg agcctgcagg acaggtaagg 46681 gccgagggag tcatggtgca gggaagtggg gcttcccttc gatgggaccc aggggtgaat 46741 gaccgcaggg gcggggaacg agaagggaaa ccagctggag agaaggagcc tgggcagacg 46801 tggctgcacg cacagcgctg accctgggcc cagtgtgcct ttgtgttggg mttatut 46861 aattttgtat tgagatgcta tttatctcgt ggagcutttg ccgccctgag attttgtacc 46921 cgtggctggt gtccctcttg cctcaccccg gcctctgtag cagggcagac acggcgcaac 46981 ggggcagggc gtgcccagga ggcactgtca ttttgggggc agcggcccca caaggcaggt 47041 ctgccttcct cccctcttac aggc-agcgac agaggtccag agaggtgagg caagctgccc 47 101 aatgtc-acac agcacacggg cgcagtccca ggactgtaga aatcccggga ctagacaggc 47161 accagagtgt cctgtgtttt tnaAAnAAcg gcccaagaga agaggcaagt ctgcaaggcg 47221 tcccgggaag gcagcagggg cttggctcgg tetcccccaa ggaggccagc tcctcagcga 47281 ggttcctaag tgtctaacgg agccaagcct gaaccaaggg ggtcacgtgc agctatggga 47341 c-actgacctg ggatggggga gctccaggca aagggagtag ggaggccaag gaggagagag 47401 gggtgcacag gcctgcaggg agcttccaga gctggggaaa acggggttca gaccacgggg 4746 1 tcatgtccac cc-ctccttta tcctgggatc cggggcaggt attgagggat ttatgtgcgg 47521 ggctgtcagg gtccagttcg tgctgtggaa aaattgtttc agatcagaga ccagcgtgag 475 81 gtcaggttag aggatggaga agaagctgtg aaaaggtgat ggagagcggg gggacggtcc 47641 tcggtgatca ggcaccgaga tcgcccatgg aatccgcagg cgaattaca gtgacgtcgt 47701 cagagggctg tcggggagga acaggcactg tcatgaactg gctacaaaaa tctaaaatgt 47761 gcaccctttt cggcaatatg cagcaagtca taaaagaaaa cgcatfctt taaaattgcg 47821 taattccgct tttaggaatt catctggggg cgggggaaca atcaaaaaga tgtgaccaaa 47881 ggtttacaag ccaggaagtc aactcgttaa tgatgggaga aaaccggaaa taacctgaat 47941 atccaacaga aagggtgtga tgaagcgcag catggcacat cc-accgcaag gaatcctaac 48001 acaaacttcc aaaacaatat ttctgacgtt gggttttaa agcatgcgtg cacttcaaa 4806 1 agcttgtcag aaaacataga aatatgccaa taatgtgtct ctagccaaat tnttaattt 48121 ttgctttata atttttaaa gttataattg tatgaaatat aatataalaa ttataaacta 48181 taaaaaagtt atgaaaatgt tcacaagaag atatacatgt aattttatct tctacaatac 48241 tttttaatac cagaataacg tgcttttaaa aaagattgag cacagaagcg tataaagtaa 48301 aaattgagag tttctgetca ccaaccacac gtcttacctt gaacccatt ctccagcgag 48361 agacagtgtc atgtgggtct gtacacttct ggcctttctc ctaggcatgt atgtccctga 82 48421 aaactcacac acacggctaa tggtgctggg atttagttt tcaaaacgga ctcatactct 48481 gcttatgagc ctgcaactat ttattcagtc tgttgagatt ttctatatca gcccacatgg 48541 atcccgcatg ttctctgaat ggctctgtat gaattcaaag tttggaagaa gcagcgtgtc 48601 tttaatcatt cgcctattaa tggacgtttg gggtgtttcc actacaaaan nnnnn 4866 1 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nn nnn mnnnnnnmn 48721 nnnnnnnnnn mnnninn nnnnnnnng atacaattcg agctcggtac cctggcttga 4878 1 actatatgaa cagagaacga tgagancagt ttctcaaact tggaacagtt aacatnngg 48841 gctaaatgat tcttttgt gtggagttgg cctatgaata gaggatatta gcagcatcat 48901 ttaaccttta ctcac 'tacat acctgtagca actacatcct ctccatttgt gtcaatcaaa 4896 1 actgtctccg gacatggaca agtgtgcccc tgggatgggt ggaatgacct tttgttaaga 49021 accactgggt cagagattca tagatttttg tcttgttgac tttttaaa tacatcttgg 49081 ttattt attggtttct gctcttatct ttatgattc cttcctttta cttggggctt 49141 ccctgataga ttttcccttc tggctcagct ggtaaagaat ctgcctgcaa tgcaggagac 49201 ctgggttcag tccctgggtt gggaggatce ectggagagg agaagggcta cccaccccag 49261 tattctggcc tggaggattc catggagtgt atagtccatg gggtcgcaga gtcggacatg 49321 actgagtgac tttcacacac acatatgtcc ctggtagctc agctagtaaa gaatrccacc 49381 cgcaatgcag gagaccccgg tccaattcct gggtccggaa gattcccttt tgtttactcc 49441 ataagatctt atctggggac aaaactaaca gctatgccag accttctgga catcagggaa 49501 cgtgaggggt gtggactgga cagatgtgtg tgttctccca aacac-aaac-a tacatctgta 49561 tacatgtaca tggagagagg gggagggagg ctgtgagtct ccaggggacc gtgcaaccat .49621 gtgacattca tggaggcgtt tgcgggtgat cactacacag tttcttcttc tggtttcttg 49681 gtcaattgac tteacaattc caattectat acttcatttt agactgaggg aattttacac 49741 tattgtaaga catatgtia~ catgagttat gttcagcgcc atgagggctc attttgtgtg 49801 tccactttgc ctggaaacaa agttggactg atttacttct aggggtgcct gggggtgttt 49861 ctggaggaca ggagcatttg aacccaaggg ctcggtgaag catgagcctc tctgcaggtg 49921 gacccaggag gaacgcaagg ccgaggaagg cagactetcc tcctccctaa cccgaggtct 49981 ctgctcagaa aagggacaat ataatgacta gaagaaaaga aagaacatca gctgtgggag 50041 gtttgttctc tggagcagat tcacacgttg aggctcatgt gcaggaattc taggtgaaac * 50101 agagcagtca cccatgtgtg ttggaaaatt ttaaattaca tttgcagtta cgactttgtt 50161 taagccagac agggtagcac agc-aaagtca ccatgtggte acctgtgttt tgtaaaggag 5022'1 agagaacttg ctggcacatt caggaaaggc cgtgtctcag cttggaggc ac-actgagag 50281 gcc-acaagca gatggtgagg accagggtct cgggcagagg gatcaattca ctgctcttca* 50341 cttttgccac atctgtgtgc tgtccatcct ggccagagta gttc-agtctt cagatgctgg 50401 agttcccatt ggtagaaatc caatctgggt cattaaa cctctcttgg ttctacttaa 50461 tggttfaaa atctctttgg ctcaagaaaa aaaataaaca taattttaaa gggtggtttg 50521 gggccttgac tataaagtac attatctggg ccatttcaga gcatggttga attaatacat 50581 ttcgtgctta ctatagctec tattttcttg attctttaca ggtaatttt gttaggaatc 50641 gggtactgtg aatattttct tgttgaatac gggatctttg tattttttec taatttttt 5070 1 mtttttt ca ttttggttt taccttcagg aaagtcacta ggacteagga aagtcctttg 50761 tccgcctgtt atttcagtct cttacctggg gccagggcag cgtttcctct gggctaagtt 50821 tccccacaac cggggccagt tctcctcact ettcaccctg aggccftaat gaggagctcc 5088 1 cctgcgtctg ageagccggc cctcctgtga cgtgcgtgtg tctctggcca tcggcgtccg 50941 gtgtcctgg aggttccgtc ctcccttcgc tcactgtgcc ccgcactcga gctctcaggc 5 1001 tccaagcagt gtccgcagtg tgcagaccct ctgtgtagct ctctcctcct caggactctt 51061 ccctctagat gtgtgttttc ttttggctcc ttggacctec gctctgaacg caggcctggt 51121 gctgagtgtg atctctggag ggaagcctgg gaggctggac gggtccgccc tgcggtgtgg 51181 tgacaggtgt gggctcgggg cggggcctgc acgtrgtcct gacccgagcc gggactgggc 5 1241 tccgggcctc aggcatcact gactgaatct ccctcacaga ggggtcaggg cctgggcggg 51301 ggaaccgtct ctgcaatgac agcccctecc agggagggca cagcggggag ctgccgaggc 51361 tccagcccta gtgggaggc ggggagccca ggggagcggc ctgacggccc cacaccggcc 51421 cagggctggt tcgttctgtt tctcgagctc aacagaagct ccgaggagct gggcagttct 5 1481 ctgaattcgt cccggagtt tggctgctga gtgtcctgtc agcaccgtat ggacatccag 51541 agtccattag cagtggtctc tgtccctctg tctgtccttc atcaggctct ttgtccaggt 51601 caccacacgg ccaacaccag gacagtctgg tcccgccagc ccatcgtccc tgcggacgcc 51661 cctgtgcagc ctgccgaagg gccgggaggc cgggggaarc gggcr-aggc-c tgtccctgct 51721 gtgtccacag tcctcccggg gctggaggag agcgtgagca ggacrggagg gtttgtgtct 83 51781 cacttccccg tctgtctgtg tcactgtgag gattatcact gctgtcagct gactgacagt 51841 aatagtcggc ctcgtcctcg gtctgggccc cgctgatggt cagcgtggct gttttgectg 51901 agctggagcc agagaaccgg tcagagatc-c ctgagggccg ctcactatct ttataaatga 51961 ccctcacagg gccctggccc ggcttctgct ggtaccactg agtatattgt tcatccagca 52021 ggtcccccga gcaggtgatc ttggccgtct gtcccaaggc cactgacact gaagtcggct 52081 gggtcagttc ataggagacc acggagccgg aagagaggag ggagagggga tgagaaagaa 52141 ggaccccttc cccgggcatc ccaccctgag gcggtgcctg gagtgcactc tgggttcggg 52201 gcaggcccca gcccagggtc ctgtgtggcc ggagcctgcg ggcagggccg gggggccgca 52261 cctgtgcaga gagtgaggag gggcagcagg agaggggtec aggccatggt ggatgcgcc 52321 cgagctctgc ctctgagccc gcagcagcac tgggctctct gagacccttt attccctctc 52381 agagctttgc aggggccagt gagggttgg gtttatgcaa attcaccccc gggggcccct 52441 cactgagagg cggggtcacc acaccatcag ccctgtctgt ccrcagcttc ctcctcggct 52501 tctcacgtct gcacatcaga cttgtcctca gggactgagg tcactgtcac cttccccgtc 52561 tctgaccaca tgaccactgt cccaagcccc ccggcctgtg gtctcccctg gactccccag 52621 tggggcggtc agcctggcag CatcCtggCc gtggactgag gcatggtgct ctggggttc-a 52681 ctgtggatgt gaccctcaga ggtggtcact agtcctgagg ggatggcctg tccagtc-ctg 52741 acttcctgc-c aagcgctgct ccttggacag ctgtggaccc gcagggctgc ttcccctgaa -- 52801 gctccccttg ggcagcccag cctctgacrt gctgctcctg gccacgctct gctgccccct 52861 gctggtggpg gacgatcagg gcagcggctc ccctcccgca ggtcacccca aggcccctgt 52921 cagcagagag ggtgtggacc tgggagtcca gccctgcctg gcccagcact agaggccgcc 52981 tgcaccggga agttgctgtgctgtgaccct gtctcagggc ggagatgac-c gcgccgtccc 53041 tttggtttgt tagtggagtg gagggtccgg gatgactcta gccgtaaact gccaggctcc 53101 Stagcaacct gtgcgatgcc cccggggacc cagggctcct tgtgctggtg taccaaggtt 5316 1 ggcactagtc ccaccccagg agggcacttc gctgatggtg ttcctggcag ttgagtgcat -5322 1-ttgagaactt acatcatttt catcatcaca tcttcatcac cagtatcatc accaccatca 53281 ccattccatc atctcttctc tcttttuctt ttatgteatc tcacaatctc acacccctca 53341 agagtttgca ttggtagcat atttacttta gcacagtgtg cctctttt gsaaactggg *53401 ggctcctgc tgatacccct gggaacccat ccagaaattg tactgatggc tgaacccctg 53461 cgtttggatt cttgccgagg agaccctagg gcctcaaagt tctctgaatc acteccatag 53521 ttuacaacac tc-attgggc-c tttttact ttaatttgga aaaatatcct tgaagttagt 53581 acctacctcc acatittaca gcaggtaaag ctgcttcgca tttgagagca agtccccaga 53641 tcaataaaga gaatgggatg aacccaggat ggggcccagg ggtcctggat tcagactcca 53701 gccgtttagg acagaacttg actaggtacg aagtgagcgg ggtggggggg caatctgggg 5376 1 ggaactgtgg cacccccagg gctcggggcc atccccacca catcctggct ttcatcagta 53821 *gccccctcag cctgcgtgtg gaggaggcca gggaagctat ggtccaggtc atgctggaga 53881 atatgtgggg ctggggtgct gctgggtect aggggtctgg ccaggtcctg ctgcctctgc 53941 tgggcagtga taattggtrc tcatcctcct gagaagtcac gagtgacagg tgtctcatgg 54001 ccaagctatt ggaggaggca gtgagcactc ccaccrctgc agacatctct ggaggcatca 54061 gtggtectgt aggtggtcct ggggcttggg ccgggggacc tgagattcag ccattgactc. 54121 tcagaggggc cagctgtggg tgcagcggca gggctgggcg gtggaggata cetcaccaga 54181 gccaaaataa gagateaccc aacggataga aattgactca caccctttgg tctggcacat 54241 tctgtcttga aatttcttgt ggacaggac-a cagtccctgg ataaagggat ttctatrttg 54301 cgtgtgcaat agagctgtcg acacgcttgg ctgggacatg taatcctttg aacatggtat 54361 taaattctgt tc-actaacat ctgaaaggat ttttgcatca ataaacctaa ggtatattgc 54421 cctgtcattt ccttgtcttg tagtgtctct gagtaggctg gaaggggtaa ccagcttcac 54481 aastcgagtt aggaaattrc cttattcttc cactgtctaa tagactttca taagauagt 54541 gttaattcct ctttaaatcg ctgctataat catcactgtg gccac~cgCtgaattttt 54601 tgttaggatg atttaac aagcatttt atgatttt ctttattt cggctgtkct * 54661 gggtctcgtt gctgtgtgcc ggcgttctct cgctgtggcc agtgggggcg ctgctctcgc 54721 gttgcgaagc tcgggcttct gactgcagtg gcttctctcg ttgcagagcg cgggctecag 54781 ggcgctcagg ctcgcgtggc tgcggcacgt gggctcagta gtcctggggc acaggtgcag 54841 cagcctctca ggacgttttg ttcccagatg gtgggtcggt cgaaccggtg tcccctgcgt 54901 tgcaaggtgg attcttcacc gctggaccac cagcgacgtt ccctggaggt tttattat 54961 ggatttaagc tctcattaga tgtctcctca catttcctat Utttttga gtcagtttga 55021 tactttgttt gtgtctgtaa gtttgtecat tttatccaag tcatctaatg tgttgataga 55081 caattattgg ttagtcatct aattgttggt ttacaattt gagagcattg tcctgcaatt 84 * 55141 ccttctatct gcaagattgg taataatatc tcccaagagg agtcacaaac tgaaatgaga 55201 ttanatacag gctttttttt taaaagaatg aacttatgtt gttgcctttc tcatagatct 55261 tacttcttag catgactgta cttactgact ggggcgtttt catgtctgtg tggagagcta 55321 ccattagtac ttcttatcgc ccaaagacat cgggctcctg ggcacagtga aaacactcct * 55381 ttctgtggct attttgcaaa atatggccta gcctagcgtc ataagggatc acagctgaca 55441 actgctggaa cagagggaca tgcgaagcaa cgtgagggct ggaacctgga gggtc-ctctc 55501 tggggacagt ttaaccagct ataatggaca ttccagcatc tgggacatgg agctgtgaac 55561 tggaccaatg actgtcatt *t ttggaagaga aatcccngga gagaagggtc caggggaatc 55621 tgaggccgca tgcagtgcct caggacaggg gacaccttct ccagcagagc aggggggccc 55681 gcccaggccg cctgcagtga ttccaccagg aggagatgca tccctgcaga cctctgacag 55741 cacggccctc tcctgagaca cagggtcaca cccggggccc tggaaccctt tgagacccta' 55801 aacctttcct ttcctgacca ccctgacagc agtctagctc agaacagaca tcttcatttt 55861 cagcaggaaa atccttttcc tcgtttgagg gagcgactgg caccggagga gctgagtctt 55921 ttaaacacag gctgcctgaa cctcagggat gacctgcagc tgctcagagg aggctggagt 5598 1 gtgatagctc actetaatgt tactaaaagg aacatattgg acaccccctc tctg~iaaat 5 604 1 ttccctcctg cctctcatct cttagtccac tttatcgccg tttnactgct tttctattta * 56101 ctactcttaa cgccaaccta tcttatttcc cctcccagtt taacacggtt ttcectccac -56161 ccgctctctt taatctcaga agattctgcc tattcctcta ttatcacacg cccctactt 56221 ttattttttt tcttacccgc cttttattcc ctcccitcct cactctctat ttaattacat 56281 cttaactaca ccgcctgcgc tatcttcgaa tgtatccaaa tatmttccc ttatataaca 56341 ctccaggccg agcggctaac ttattataat ttctttatag cgcctaccta atttccctft 56401 atttctaatt atctatatat acccatgcaa tttcgnnmm nnnnnn nnn 56461 nnnninnnnnnninnnnnnn nnnnnnnnninnnnnn 56521 nm nn nnnnntgggt gtacgttata gagtaaacgc gc-atgaagaa gtgggtcaat --5658 1-ctntggctgt gagaggcagaaaataatatt atcatatata atttatgtta taacacactg* 56641 aggtggtggg ctcgtagaat agtgcggacg gggagaaagg tgggaaggag aagacacaag 5 6701 agagagatgt tcgcctcgcg ggatggatgg gcggagggat agaagaataa aaagaggaga 56761, ggtatagagg ggggcggggg gcataacgtg tggtggggta aatagtaggc ggtaattatg 56821 aaaaaaagaa agacgggggg ggcggtaaca tagaatacgc aaaaaagtca tatactgaac 56881 ggggattagg gagaagaggt ggggggcgtg gggtgcgggg gaagggtg tgtgtataat 56941 tggtatggag tgttatttga atatatatta atgtaatagg gagtgtaatt agtgaaattg 57001 tgggagtatt atattggggt gtgggggaca tggcaaagtg atgatcggga taaaaaaagt 5706 1 aaagcaagag gggaggggaa aataaggggg gggagaaggt cgaagaaasat aagaggaaga 57121 agaaagaacg ggggtggcgg gcgggggggg cgccgctctt gtatctggct tttttgttgt 57181 gtcggtggtt gttcgcgtct tgttgggtcc ggggcgggtg tgcggaaaaa aaaaaaggcg 57241 ggaggcccgg ggcccggtca cgcggcaccc ccgcgggtec ctggcttctc cttcggcagc 57301 tccgggggtc ggtgagcctg cgccctccgg *gccgccggcc cgagctgtgt gcgccctgga 57361 gaatcggagc cgctgtggca gcacgcggag ggcgcgcgca agggccacgg gacggacctt 57421 caaaggccgc ggcggagcgc ggcaagccga accgagggcg gtctggcgat cggccgagcc 57481 ctgctccccc ctcccgcgtg gccccagggt cgcgggtgga ctggggcggg tacaaagcac 57541 tcacccccgt cccgccccca gaaagcctcc caggactctc acaggacc cgccaggagg 57601 catceggttc ccccctcggc tcagttcagt tgctcagtcg tgtccaactc tttgcgacc 57661 catggactgc agcaccccaa gcttccctgt ccatcaccaa ctcccggagt ttactcaaac 57721 tcatctattg agtcagtgat gccatccaac cgtctcatrc tctgttgtcc ccttctcctc 57781 ccactttcaa tctttcccag catcagggtc tmtcttatg agccagttct tcacatcagg 57841 tggtcagagt attggagttt cagcttcagc atcagtcctt ccaatgaaca ctcaggactg 57901 atttccttta ggatggactg gctggatgca gcgccagaca ccgaccgcgt ttaccccgtg 57961 tgtcctttcc aatggctgtc ccctgcgggc ctaggggcat tggtgcgggt ttgaatcctg 58021 tggccttgaa ttttacgcct tagttccagg tccagggcag ggccatccgg attcaggatg 58081 cttcccagcc cttcaggaat ggcaggtttt catggtcctt tctgagtgag utctgagtgg 58141 tcatattggt gcccttggca gggagggctc ctgactttcc tatettcaca tcactgtccc 58201 caacccecaa gagaggcctc ttggcccagg gactgcaggg aggatgaagt caggageaga 58261 agcatggggt agggggctca ggtgggcaga ggaggcccct ctgtgaggag gaacggcaag 58321 cgaggaggga acaggggcac cggcagtgcc tggcaagctg ggtgatgtca cgactacgtc 58381 ccgaccacac agtcctctca gccagcccga gaagcagggc cctcccctga cccceatctg 58441 ggcctgggct tcagttttct cctccctgca atggggtgac tgttgcctc caggagaggg 85 58501 gagcatgtaa a 'ggtggccac tctcttctgg cagacatgcc aggcctgggc cagcctccac 58561 ccctttgctc ctgcagcccc tgctgacctg ctcctgtttg ccacaccggc ccctcctggg. 5 8621 ctgatcaggg cccccctcct gcaggaagcc ctctgggaca agcccagctt gctgtaactg' 58681 tggctttcca ctgtgacctg caacgtggga ggctgttact taaaactccc atgactggtg 58741 gattgccggt ccccagaaca aggccacgca tccctggagg ccctcgagac catttaaggt 58801 agttaaacat ttttctt tgcattca tggtatcag aaagaaaaaa aatgtatcat *58861 cagttcatca aatccatgat ttcttgacca atattgctaa gatgaggctg aaataggcat 58921 ttccattMt aaaaaactga atcactctga agaaacagat ggcaggcttc cctggtggtc 58981 cggtggttaa cagtccatgc ttccagtgct gggggcatgg gttcgatccc tgaaaantttt 59041 aaaaaggaag aaaaagatgg ctcccccgtc cctgggattc tccaggcaag aacactggag 59101 tgggttgcca tttecttctc cagtgcatga aagggaaaag ggaaagtgaa gtcgctcagt 59161 cgtgtgcgac tcttagcaac cccatggact gcagcctacc agactcctcc gtccatggga 59221 ttttccaggc aagagtactg gagtggggtg ccattgcctt ctccaggcaa acggcctgct 59281 actgctactg ctgctaaatc gcttcagtcg tgtccaactc tgtgcgaccc catagacggc 59341 agcccac-cag gctcccccgt ccctgggatt ctccaggcaa gaacactgga gtggggtgcc 59401 attgccttca gcctgctgct gctgctgcta agtcgcttca gtcgtgtccg actctgtgtg 59461 accgcataga cggcagccca ccaggctccc ccgtccctgg gattctccag gcaagaacac -9521 tggagtgggt tgccatttcc ttctccaatg catgaaagtg aaaagttaaa gtgaaattgc 59581 tcagtcgtgt ccgactctta gtgacccaat ggactgcagc ctaccagggt cctccatcca 59641 tgggattttc caggcaagag tactggagtg gggtgccatt cggcctaggg agtgagaaat 59701 cacggctgtc ttccctcttc tcgccctcta ggggtctctg tggagcctcc ctggagaggc 59761 cgcggcggct ccggggactg gagggggagg gggggttgag tcagc-cggtg gccctcccc 5982 1 cgctgcccgt ctcctccctt tttaggcaca agctgggcgc cctttttagg cgcagcctca 59881 ccctgcgggc cactgcccgt gtttcggctc cccggagata aaacagattg cctgcacccc 59941 gggtcatcac aaggattgta tgaccgtttc ccagtgtgct caccaccctc cctctgattc 60001 tcagagacgc gccctcgcct caggaggctg ctcatcccag gccaagggc ggcgtgggg 60061 ccccagcgcc ccgcacagaC aCtgccttCt gaccaectCC tcccaacagc ttacctgcca 60121 agaaggcctc ctgaccctc atcctgcccg gtggttgga gaaagcctca tctggcccct 60181 ccttctcggg gcctcagttt cceectctgt gaactggcgg attctgccaa gctgacgtcc 60241 tggccagccg cctcccgtg gccagtgtcc cccgggacac agctgaatgt ccctgctcgg 60301 gatgcacctt cccaagttgg clgtcagga ggcgggggcg agcagggaaa cccgactcct 60361 ctcagacggc ccatcgcatt ggggacgctg aggcccggag cagcggcacc ctcctggcca 60421 gggtcattct cccgccccgc cccgtccctc cgggcctccg agaccgcagc ccggcccgcc 60481 ccgggaagga ccggatccgc gggccgggcc accccccttc cctggccgcg ggcgcggggc 60541 gagtgcagaa caaaagcggg gggcggggcc ggggcggggg cggggcggag gatataaggg 60601 gcggcggccg gcggcacccc agcaggccet gcacccccgg gggggatggc tcgggccgcc 60661 ggcctccgcg gggcggcctc gcgcgccttt ttgttmtgg tgagggtgat gggggcggtc 60721 gcggggtact attttcat ttataaftgg gtattagcta gcgagtggaa ccacaccctt 60781 attccactat agccaatttt tgcgggggca tcttacatta cagactcgcc cgcctcttat 60841 ttcggtacag catatcagat cgtctcttta ctcagacact agtgattatt gtctatagta 60901 cacaaaaaga acggttgtgt cggcgtaatg gttgcatttt ccctcctrgt ttctcctgac 60961 cacctcaatt acaccaacac tctactattt aaatcacgta ttgtacgcca ccctccgccc 61021 gcgaactaaa agaatgtgca gatattctga agatauatc gttcattgtt acgccrccgcg 61081 cgcttcgcgt atattactct tagaacttct tattcgeccg agcagttatt cacccccgc 61141 aactagatgt cgccttaata tttgttctaa ccgttttgga ttctaacgat aggcgggaaa 61201 ggtagacatt cgaccgctac gacaactaaa atcgacgagc ac-aggctaft tatatcgcga 61261 ccacacgcgc gcggtataca naccgtaaaa ttatctaaca tcgagagtaa gggcacag 61321 cgaaatacaa gcggcgtggt gggagggtg tctgtagtga attcgcacct cgcgccgccg 613 81 cctctgtgcg tcgnnnmmnn xnnnnnnn nnn nnn numnnnnnn 61441 nnnnnnnnnn lnnnnlnmmmnnnnn nnn nnnnnn nnngatataa 61501 tattaataaa cagcggatag atgtgtgtaa gggaggaggt gcataagaga ttaaagagag 61561 gcgggcggag agaaatagag tagaggagga tgagagaaaa aagaaagcaa gcgtaggtac 61621 aacggcgggt gggtagtatg ataaagtgag tgtatatatt tgagtaaagg aagggmtat 61681 ggagtataaa gaagtaagga gaggagaggg cggcggagag agagagtgca aagaaaataa 61741 gtgggcaaag gcggggtggg tgagaagcag tagaagagaa gatagagaag ggggaaaaag 61801 aggaaaatga ggattagaac aagtaggaca ggatagatg! gaaaaatgag atcaggtcaa 86 61861 ggtggagaaa aagtagaaac tggggcgtga ttgtaaaaaa gggaggccgc gatggggcag 61921 caccataagc gaagagatga attaatgaaa gcaaggcagg gagaatcaaa tgagttgggt' 61981 ggaggaagga ggctgtgact tccttcgctg ccggaaagag aactagaata gcctcgggct 62041 gtggggggag gtaaagataa agtgacttct gggccctggg ggaggcccag gagtttctac 62101 cgagctgagc tgggtgcctc tcccaaatgc ccaaccccct gagagtcgac gggagagcac 62161 agcctggcca aacctgggca gggcacacgt gtccttcacc ccacagtggt cacgagccca 62221 gcgtggtcce tgcgtctggc gggaaacaca gaccctcaca cccc acacaa gggtccggcc 62281 gctttcaaat aacagcagcc gtgccctctg ggccggtgac ccggacacag agagatgaag 62341 tccgcatctc tcagagtgcg ctgtcctccg cccggtcagg cccgggtccc Ctgcttctct 62401 gaggtcacca ggagggattg catgtgggtc tcagggacac aggttcagtg atgtgacaga 62461 gggtagtggg tcccagc-agg gccggtcttt ggacccgttt ttctgaaaag ccagttggcg 62521 acctggggtc acagcaaagc tgatcctgtt tggccaggag tctcccagtg acggcctccc 62581 ccagaacatc gggcccagtg ggggctccag ggggtagact tgcctcccag ctcacgcccg 6264 1 tgtcttgaca agtccatgat ttggtaaaat taatttgtgt tggatggagt tgatttagtg 62701 gtgtgtgagt ttctgtggcg cagcaaagtc aatcagttac gcatar-acat gtatccagct 62761 cttcctacga ttctgttccc atataggtca ttatggggtg tcaggtagag cttcctgtgc 62821 tacgcagtac ggccttattc agttcagctc agtcgtgtcc gactccttgt gaccccatgg 62881 actgcagcac gccaggctcc cctgtcc-ate accaactcct ggagcttatt caaactcatg 62941 tccatcgagc cggtgatgcc atccaaccat ctcatcctct gtcgttccct ctcctcctgc 63001 cttcagtctt tcccagcacc ccctagagaa gggaatggca aaccacttcg gtattcttgc 63061 cctgagaacc ccatgaacag tacggaaagt ccttattagt tttctatttt atatatagca 63121 gtgcacacgt gtcagcccca atctcgcaat ttatcacccc cctrccgccgc cgattggtag 63181 tcatgtttgt ttctacatc tgcgactcta tttctgtttt gtaaacaagt tcatttacac 63241 cactttttt gattctgcac atacgtggca agcccacagc aaacatgctc aatggtgaaa *--63301 gactgaaagc atttcctcta agatcauaacaagacgagg atgtccactc actccgtmt 63361 tactcaacac ageccgaac gtcctagcca tggcaatcag agaagagaaa gaaattaagg 63421 aatccaaatt ggaaaagaag aagtaaaact eactctttgc aaatgacatg acacttatac 63481 ccagaaaatc ctagagatgc taccagataa ctattagagc tcatcagtga atttgttgca 63541 ggatacaaaa ttaatacaca gaaatctcct gcattcctat agactgacaa caaagtct 63601 gagaggaaa ttaaggaaac catcccacgg catgaaaaag agtaaaatac ctaggaataa 63661 agctacctaa agaggcaaaa gacctgtact cagaaaacta tnaatactg acaaaggaaa 63721 tcagacgaca cagagagaga gagataccac gctcttggat gagaagaatc gatagtgtga 63781 caatgactat actacccaga gaaacataca gattcagtac aacccctatc aaattcccaa 63841 tggcattttt cacagaatca gaattagaac aaaaagttt acaagtttca gggaaacaag 63901 aaagatccta aagagccaga gcaatcttga gaaagaaaaa tggagctgga agagteaggc 63961 tccctgagtt ctgactgtgt atacaaagct ggcatgattt ttaacagcag gggtgtaaat 64021 gaacttgttc acaaaacaga tggtggggtg ggcttccctg gtggctcagc tggtaaagaa 64081 tcctcctgca acgcaggaga cctgggttcg atccctaggc tgggaagatc ccctggagaa 64141 gggaaaggct acccactcca gtattctggc ctggaaaatt ccaaggacra tatagtccat 64201 gggmtgcaa agagtcggac acgactgagc gacaccaat cctggaaacg tcccattgtg 64261 gacggtgaac tggggttgtc caagctcagg gtaaccgttt gctgagtgac tgacactcct 64321 tctcatgggt taaaatgtgg ggcccaaggc caggaccaga ccccgcagtc agccaggcag 64381 accctgtgca gccccagcga gtgtgtggcc gccgtggagt tcctggcccc catgggcctc 64441 gactggagcc cctggagtga gcccattccc tcccagcccg tgagaggctg ggtgcagccc 64501 taaccatttc ccacccagtg acagatccgc ctgtgtggaa acctgctctt gtccccaggg 64561 aacctggcag gactcaggga gaatgtctca gggcggccac agatcagggg ctgggggggc 64621 agggctgggt ccagcagagg ccctgtgccc actccccgga aagagcagct gatggtcagc 64681 atgacccacc agggcaccga cgcgtgcttg cacacaggcc gccccctcat ggtgacactc 64741 ttttcctgtg gccacatctc gccccctcag gt ccctctg ctccccagct cctggcctgg 64801 gaacctcttc cccgccccgg ggacgtcagg gctggtgtcc actgagcatc ccatgcccgg 64861 gactgtgctg atcaccagca cctgcacccc ctctcgggtc tcaccaggat gggcaactcc 64921 tgcccatcca gcacccagcc tcctgggtac acatcggggg aggagggaga agcctgggc 64981 agacececag tgggctccct aaggaggaca gaaaggctgc cgtgggccag ccgagagcag 65041 ctctctgaga gacgtgggac cccagaccac ctgtgagcca cccgcagtgt ctctgctcac 65 101 acgggccacc agcccagcac tagtgtggac gagggtgagt gggtgaggcc caggtgcac _________ 65161 agggcaagtg ggtgaggccc gagtggacag ggtgagtggg tgaggcccag gtagaccagg *87 65221 gcccatgtgg gtgaggcccg ggtggaccag agtgagcggg tgaggcccag gtggacaggg 65281 cgagcgggtg aggcccaggt ggacagggcg agcgggtgag gcccgggtgg acagggcgag 65341 cgggtgaggc ccgggtggac agggcgagcg ggtgaggccc gggtggacag ggcgagtggg 65401 tgaggcccgg gtggaccagg gcgagtgggt gaggcccggg tggacagggc gagtgggtga 65461 ggcccgggtg gaccagggcg agtgggtgag gcccaggtgg acagggtgag tgggtgaggc 65521 ccaggtagac cagggcccag agcaaagccc cggctcagca gtgatttcct gagcgcccac 65581 tgcttgcagg gacctcagcg atggtaaggc agccctgttg ggggctcccg actggggaca 65641 gcatgcagag agcgagtggt cccctggaga aacagccagg gcatggccgg gcgccctgcc 65701 aggctgcccc aggggccaca gctgagccc gaggcggcca ggggc-cggga c-agccctgat 65761 tctgggttgg gggctggggg ccag *agtgcc ctctgtgcag ctgggccggt gacagtggcg 65821 cctcgctccc tgggggcccg ggagggacgg tcaggtggaa aatggacgtt tgcgggtc-tc 65881 tggggttgac agttgtcgcc attggcactg ggctgttggg gcccagcagc ctcaggccag 65941 cacccccggg gctccccacg ggccccgcac cctc-acccca cgcagctggc ctggcgaaac 66001 caagaggccc tgacgcccga aatagccagg aaaccccgac cgaccgccca gcctggcag 66061 caggtgcctc cctetccccg gggtgggggg aggggttgct cc-agttctgg aagcttccac 66121 cagcccagct ggagaaaggc ccacatccca gcacccaggc cgcccaggcc cctgtgtcca 66181 ggcctggccg cctgagacca cgtccgtcag aagcggcatc tcttatccca cgatcctgtg 66241 tctgggatcc tggaggtcat ggcccctctc ggggccccag gagcccatct aagtgccagg 6630 1 ctcagagctg aggctgccgc gggacacaga ggagctgggg ctggcctagg gcaccgcggt 66361 cacacttccc ctgccgccrc tcacttggga ctctttgcgg ggagggactg agccaagtat 66421 ggggatgggg agaaaaatgg ggacccteac gatcactgc-c ctgggagcc tggtgcgtet 66481 ggagtaacaa tgcggtgact cgaageacag ctgttcccca cgaggcctca cagggtcU 66541 ctccagggga cgggacctca -gatggccagt cactcatcca ttccccacga ggcctcacag 66601 ggtccttctc caggggacgg gacctcagat ggccagtcac tcatccattc cccatgaggt 66661 ctcacagggt ccttctccag gggacgggac ctcagatggc cagtcactca tccattccc 66721 acgaggcctc acagggtect tetccagggg acgggacccc agatgggcca gteactc-atc 66781 catccgtctg tgcaccatr cgtccaacca tcacccttcc ctccatccat ctgaaagct 66841 ccctgaggcc tccccgggga cccagcctgc atgcggccct cagctgctca tcccaggcca 66901 gtcaggcccg geacagtcaa ggccaaagtc agacctggaa ggtgcctgct tcaccacggg 66961 aggagggggg ctgtggacac agggcgccc atgccctgcc cagcctgccc cccgtgctcg 67021 gccgagatgc tgagggcaac gggggggcag gaggtgggac agac-aggcca gcgtgggggg 6708 1 ccagc tgccg cctggctgcg ggtgagcaga ctgcccct caccrcaggt acaggtctc 67141 ctgatgtccc ctgccctccc tgcctcrctg tccggctcca atcagagagg tccggcatt 67201. ccagggctcc gtggtcctca tgggaataaa aggtggggaa caagtacccg gcacgctct 6726 1 ctgagccceac ccccaaacac acacaaaaaa atecctecac cggtgggact teaccagcte 67321 gttctcaggg gagctgccag ggggtcccc agccccagga agccaggggc r-aggcctgca 67381 agtccacagc cataacacca tgtcagctga cacagagaga cagtgtctgg tggacaggtg 67441 cccccacctg cgagcctgga gagtgtggcc ctcgcctgcc ccagccgcgg tcagtcggct 6750 1 cagcaaccgc tgtccactcc cagcgccctg gcctcccctg tgggcccagg tcaagtcctg 67561 ggggtgaagc taagtcaggg agcctcatcc atgcccagcc cggageccac agcgccatca 67621 agaaatgctt cttccctcca tcaggaaaca ttagtgggaa agacaagagc tggggggttc 6768 1 tggggtcctg ggggatcaga tgaaggggtc tgggagcagc agcagcctca ggcaccccaa 67741 aacaaggccc aggagctgga ctcccagggc tgaggggcag agggaaggaa ggcctcctgg 67801 ggggttggca tgagcaaagg cacccaggtg ggggctgagc acccctcggc tggcacaa 67861 aggcccccac tgcagtacct tccccctcgg agacc-ctggg ctcccgtctc ccgcctggcc 67921 tgccatcctg ctcaccaccc agaaatccct gagtgcggtg ccatgtgact gggccctgc 67981 ctggggagga aggagattca gacagacagg atgccagggc agagaggggc gagcagagga 68041 tgctgggagg gggcccgggg aggcctgggg ggcagggggg caggagttct ccagggtgga 68101 cggcgctgtg ctatgctcgg tgagcacaga ggccccgggt gtcccaggcc tgggaaccca 68161 gcagaggggc agggacgggg ctcaaaggac ccaaaggccg agcctgacc agacctgtgg 68221 gtccagaagg cagctgcgcc ctgaggccac tgagtggccc cgtgtcccga accaccgctg 68281 aaacatggga cacacgttcc caggcggagc cactcctgcc ttccgggagg ctcccagcgg 68341 gctcatcgct ccatcccaca gggagggaaa ccgaggccca gatgacgaac atcccggcga 68401 gcaggtcaaa gccagcccct ggggtcccct ctcccggcct gggcctccc ctctgcaggg 68461 tgggaaaccg aggccacaca ggggctccat ggggctgcc tctgccaggc cctggacacc 6852 1 ccpcgggtga cccccgcctc tatcatccca gccctgccag gccctggaca ccccgtggat 88 68581 gacccccgcc tctatcatcc cagccctggg ggacagatgg gaggcccaag cgtggacccc 68641 ctggccac-cc cctaccccac agccgggagg agccgggagc tggtggccaa gggcctagag 68701 gagccagann nnnnnnnnn nnnnnmrmnn nnnnnunnn nnnnnnnnnn nnnnnznmnn 6876 1 nnnnnnnnnD nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnca atatagaggg 68821 ggtgggataa agggtaatat gatgtttagg tagttagagt taaattagaa gggtttggat 68881 aaagattaat aaaattacaa gcgtacatat cgtgtgagtg tgggtgataa tatttgtgta 68941 tgtggggaat agaagtgagt gtgagtagta ttcaagatgt aagtgtgcga ataicaggtct 69001I gagcgattg aatggaagtg aaaaaaagcg tgtgtgtgga ggaggcggga gaggaagata 69061 gtgtggggga agaaaagaag gctagtgggt aaagaaatat cagtaggcgg ttgacgaaag 69121 aagaactagg aagaattaat ataaaaataa agggaggatt anaaataaa gagggaggag 69181 gtaacggaaa tagttagtta agaaaagaat ggagagtgga ggtaagataa ataagggagt 69241 aatgggagtg aggaggasla aataa...aaa tggtgaggga aaiagagta gaatgagaac 69301 aagaatgaaa aagggagtga agggggtgaa aaaaagtgaa gttgaaagaaa gaggaaaaaa 69361 aaggagaaga taaaaaata aaataaaaaa aggaaaaaaa agaaaaaaag.aaagaagggt 69421 taaaggacga aaagaaggga agagaaaaaa aatagtttaa gtgggggagg gtaaaa 694 81 attaataaag taaatatggt tgtggtcgaa aaaaaaaaaa aaattgttgt gttgatgaga 69541 agaaaagaaa aaagaagaaa gggaaaagca anagaaagg agagaaaaag acaaccceac 69601 cgcccgggcg catggagggt gaggatggcg cacgcccgcg gatggcacag catcacagca 69661 atcctaaaac gttttcagac cggtgcatct tcaccgcgcg cgcgccccgc ccggccctcc 69721 tcccgccctg accgcggacc cccacccgca ccggggagcc tacccccacc ccggggacgc 69781 tccgccacgc taaggtcagg actgccgtga agacgcgccg gggtgaaaac gmttatctt 69841 catgacataa gcgagtggtt ttgaaacagg tttacaaacc ctcgtgaaga cgcac-cctta 6990 1 gcgttaggtt ttgttttt accatgtgac gatgcaacta aftttct ctcttcca 69961 gtggctagtc gcctccagag cgaggggtat ctcttgtaca gagaccctcg gaacatccgg -7002-1 -aggtagtttc ccacctaggggtaaagcgag aaggctcatt acgagggccg gggctcctcg 70081 gggaagggca gggccctggc gcagaggctc tgccacctca gtgacacgca gaccacgcgc 70141 ggcctgcagg cgccgggctc tgaaagcagg caaagcccga tctgctgaca tcaggggutc 70201 cgcagcagcg aaggtctggc ccgcacctgg cccactggva gggggtaagc tctgcctccc 70261 gacgacagca ccaagttcag gaagggccac gcagacactg gtgagacacg gcccccccgg 70321 agctgcrcga gaagctctga ctttgcacta aagatctctg gcgcggtcca aaaatgtaag 70381 gcctctcttc cttttatctt aagactttga tatttttcg atgtaataaa taccaagaag 70441 ggcttttaat ttcagacaga tgtaggataa tttcccccgt agcccttgct gctttgttta 7050 1 gtaacgaaac tcaaaccaga aataccaaag gaattntcca aagagtttca aaagcgctta 70561 tcagcaatca ctagactgct gcatar-atca tcactgcccc aaacaatagc ctgcctgtgc 70621 cagttactca aagtactact tacttgacga aaacaaatct agtcctaacg tttttacaaa 70681 gaactccac tcttccgcca acttttcaga aacaaccact cgatcacgtg gcaggggacc 70741 gtggctggac tgggtgctgg ctccttctgt gaccaggcaa cactgccccc ttetcggcct 70801 ccctacgcct cttgacaaat gttcatcagc tgtaaagttc accccacgag ggacccacut 7086 1 ctgctatttc ccacgtarct accccattat aggagttttc tttgtgacag tttctgcatt 7092 1 tttcatggat ttagaggttt acataatcag ggctgctgaa cagcatgaga gacgtggcca 70981 caaggtccct cctgcacctt gccgcagggg cagggcgagt tatctggctt gagcgtggtt 71041 accatcaggg ggtaaacaca gtttccagga cgttttgc aagacactga cccggatgcc 7 1101 cccactacca ccgtgcaggt cctgeaggcc tcccgccte ccaggcctt cccgaggtcc 71161 cttcggaact taggggactc ggtctgcccc cctgggtMt c-cctgcacca gcttttgccc 71221 cctctggacc caggttcc aaaggaaaa, cgaaggtgtg ggtatggaag ctcccgggc 71281 tcctctcagc tgtgcctctg catggtgatg acggctgccc atcggggggg gcaggactgg 71341 ggcagctgcg gacaccctcc raaggctgct acccccgagt ggtgtggggc gctgtgggca 71401 cgctctgctc agcgcacctc ctggaaacca gcgcctgccg tctgcccggg gcaaccggcc 71461 cgggagccaa gcaccactgc cgtcagagga gctgctggct gtgagtggac gccagtctag 71521 ctctgaaccc tgcccaggcc tcctgaggtc tgaacattgt aaaatcaggc cccggacggc 71581 aactgcctct ccctcctgcc gtctggtctc cataaactgc atctraggac aaatcttctc 71641 actcaccagg gctgaaacag aagactgcag ctatctttct caaatctaag gtgtgctaca 71701 gggcaagtcg cagaaactgt ctggcctaag catctcatca gatgcctgag acaagagctg 71761 tggacgccaa gctggagcca gagctcctcg cgttctgccc acctggcacc gcgttccacc 71821 cagtaaacgc aggcttgatt ttcaaaagta ccaccgactc agagccaatg ctaaaccgac 71881 cactttcct gcccattaga U tcttgtag ctaa tcaatctgcc agtcccaea 89 71941 tgccgcctct gtgcccacag gctggcgaag acctttctga gctacggcat gtggcaggca 72001 gcggcacctc tcttcagtac ggccagctgt caaggggagc gtttctgtga tgatgtgaaa. 72061 atacattgca tccggccc-cg tgtttcatga acacgggtga ggaaaggaaa cacacaaagt 72121 tctgatgcga ctgacagcac gggtctcata actcaatac-a agtcagacaa accacaggga 72181 gtcacaggga atcccaatag cctcatctag tgtgaccatc atgaggctta atttattcag 72241 tgtattcaat cataaagagg gggaaaaatt gtaaaaaaaa aaaaaaagaa agagtgaaat 72301 gtgtaatact gaaaactgtt gctaggagaa gcaagcattg gcgtttgtaa ctgctttgac 72361 tccccaagac ccacactcgc ctcgctacaa aagggaggca ctgctgctca gtacttgcac 72421 acccgaactg cggatttgta atttaaaaat gtgtgtgtgg acacagcaca agccagagac 72481 tgccaaaggt tgagggacac tggaagaact taatatactt ggtgratgct gccagtgaca 7254 1 gtcagtcacc agctgattca atagagtgcc gaaaggtcac cttttggta aggatgaagg 72601 ggttctgggc tcgtttactt gcactaactc agagttagtc cgagatatcc gaagtgccag 72661 gtgcctccca tttgctgatg gatctagctc agggacggct gggccctagc catccaaaaa 7272 1 tcaagcattg ttctcccaac ctgtcttctc gctgataatg gaaggtcaga acgcccaccc 72781 gcceacctca aagtcaaaga acaccaagcg ggtgagtcc cactaagctc ggtgtttcca 72841 atcagcggtt tcaggattc agctggggca atgagggagg gagcgtgcga gggatccaac 72901 acctcgcccc gtgcgcagca agggataacc caicaccccg tttctgtacg tccggctgga 72961 gttgtggaac tcagcgcgga cccggggcca ccgcgacccc cgggaccctg gccgcgcggc 73021 gcatccccgc tgccgggaca cgggtaagcg tccccaaact gccggacgcg gggcggggcc 73081 ttctccgcca cgccccgata ggccacgccc aaggacaagg atggtcgtgc ccagacggc 73141 ggggcgggnn nnnnnnim nninnnnnnnnnnnmnnmnnnn 7320 1 nnmnnnnn Df llllllDfffffffff fnnlln nnnnncg gagggggggg 7326 1 ggcggggcgg gggctgccgc cgcgcgtata ggacggtggt cgcccggcct ggggtccggc 73321 cgggaatgac cccgcctctc c-ccgcatecc gcagccgccc cgccgcgccc tctgccgcgc 73381 acccgcctgc gcaccctgtcg ccctcggccg cggccccggc ccccgccccg tcgggccagc 73441 ccggcctgat ggcgcagatg gcgaccaccg ccgccggagt ggccgtgggc tcggctgtgg .73501 gccacgtcgt gggcagcgct ctgaccggag ccttcagtgg ggggagctca gagcccgcc 73561 agcctgcggc ccagcaggtg agcaagggct caggggaaac tgaggcccga cacagagccg 73621 cagcaagaag gatcctactg gtcactcggc tgttggcctg gggtcatcac aggcgggcte 7368 1 tcccaaccca tcccctgagg ccaaggtccc tagaaccccg tgggcagaca ccaaccagc 73741 cttaaatat ggggaaacca aggtgcttag gggtcagaga tagccctagg tcgcccaacc 73801 ctagtagaag ggagggctgt tggagttcct gagtgcccgc tctcccacc cccgggaggc 73861 cccttcctga gcccaagggt gactggtagt cagtgacmt gggcctgccg acctgtaccc 73921.cactgggcac cccaccagtc ctgagccaca tttgggctta gtgacggggt cagggateat 73981 gaggatcaat gtggctgagc caggaaggtg ttagaacctg tcggcctgga gttcatkmc 74041 geactgccct gggctttct agacccatgt cccgc-ctcct gccccacctg cccctgttcc 74 101 cgcaccecac cagcagcggc aggggcttcg agagggctgt gggcteac-cc tamtcaggg 74161 atggagccgc taagacctgg ggcacactgc ccgctaggga cccctgaggc accagggccg 74221 ggggctctgc ggaggggcag ccgccacccc cagctttgga gtcctctccc gggtgcccag 74281 cccgagctga tccggctgcc tcccacgctg tgecccaggg cccggagcgc gccgccccgc 74341 agcccctgca gatggggccc tgtgcctatg agatcaggca gttcctggac tgctccacca 74401 cecagagcga cctgaccctg tgtgagggct tcagcgaggc cctgaagcag tgcaagtaca 74461 accacggtga gcggctgctg cccgactggc gccagggtgg gaagggcggt ccacggctcc 74521 cactccttcg gggtgctccc gctattccca ggtgctrctg cacttcccat gtgcteccga 74581 ttctccctgg tgctccctct cctcctggct gctcctttgc ctcccaggtg ctcccacttc 74641 tccctggtgc tcctgctcct cccggcggct cctgtacctt cggcctgacc tcctcrctct 74701 acaggtctga gctccctgcc ctaagagacc agagcagatt gggtggccag crctgcaccc * 74761 acctgcaccc ccctcccacc gacagccgga ccatgacgtc agattgtacc caccgagctg * 74821 ggacccagag tgaggagggg gtecctcacc ccacagatga cctgagatga aaacgtgcaa 74881 ttaaaagcct ttattttagc cgaacctgct gtgtctcetc ttgttggact gtctgcgggg 74941 ggcggggggg agggagatgg aagtcccact gcggggtggg gtgccacccc ttcagctgct 7500 1 gccccctgtg gggagggtga ccttgtcatc ctgcgtaatc cgacgggcag cgcagaccgg 75061 atggtgaggc actaactgct gacctcaagc ctcaagggcg tccgactccg gccagctgga 75121 gaccctggag gagcgtgccg cctccttctc gtctctgggg gcccctcggt ggccteacgc 75181 tctgtcggtc accttgcccc tcttgctgat gcaattcc cgtaattgca gattcagcag 75241 gaggaatgct tcgggccttt-gcacctgacgcatgagcag aggtcacggc cagcccct 90 75301 ggatctcagt ccagctcggc cgcttggccg tgacgttcca ggtcacaggg cctgccggca 75361 cagaggagca ggcccttcag tgccgtcgag cactcggagc tgctgcctcc gctgagttca 75421 ctcagtgtct acgcacagag cgccactgt gtaccaggcc ctattCCacg ttccccagtc 75481 accgagcccc cagggctggt ggggac-ctgc cctcgggtac actgtgtccc gtcacgtggc 75541 Mtacgtgtg tctctgaggg aggctggcat tgcggtccac ctctcagcac aaacatctgt 75 601 cccctgggaa gggggtccca ttuctgggtg cgagcagcc cctggggtcc gtgtctcctc 75661 cttacctggc tcaggcccc ggctcctggg tcctggacag cagggagcc-c acccctcggg 7572 1 gctgtggagg gggaccttgc ttctggaggc cacgccgagg gcccaggcgc cgc-ctccggc 75781 cgtcgccctg agggagcagg cccgacgcca gcgcggctcc tctgtgaggc ccgggaaacc 75841 ctgcctgagg gtgcgggtgg gcaggtgccc ctgcccccag gctctcctgt gtgagtgaca 75901 ctcaccagcc agctctggat gccacccatc cgggttctcc aggaggcact catagcgggt 75961 ggggtcccct cctccccc tctgtggagg gagggagtct gatcactggg aggctggtgg 76021 tccgtacccg cccccccgac tctggacgtg tttactaccc ccgcctgggc tcaggacagg 7608 1 gcattggatg ggaaggacag ggctgggtcc tggccaggct gggggctctg cagggcatgg 76141 gtgcccctgt ctcttcttat attccaacgt cactgcaggg gggcgcaaat cttggaccce 76201 acttactgat gatctgcate aggacatagg tcccccctcc tgc-agcgggg ggctggccac 76261 ggagggcgct ggggaaggcc cetcctccag cccctcggcg aggctcacca ggtgcccatc .7632 1 ctcagccagc agggcgacgc tcgctgggag ggcggagagg gaggcagggc agggctggta 76381 cgacccccgc tggggcgggg gggccctcag rccggtcctcc agcacccttg ctgccccccc 76441 tcaccgtcag ggggcacctg gccgctctgc ctc-aggtggg cggtgagggt cccaaggeca 7650 1 caccaggtgt tcaccagctc ccagcagctg gctgtgggag aggggcagag gtgggcgc-at 7656 1 ggcacccgcc ttcccccag accaggatgc tctgccttc-c tcccgcccat ctccceagae 76621 atctgaagga ctcttgcctc caccatgcag ccccgcctcc accagaagct caggttccc 76681 gecccccctc cccgaagctg caggacocct gaccagcgaa gagatgggac agttggaaca ~76741 cacgctcccc cagcagcggc acagcagctg tgtggcccag aagagcccgc ctccct 76801 caagcaactc cccatggatg tcatcccatg garaccccct tccccacacc gcctrctcgt .7686 1 tctcccctc caaggcagag ggaacgcacc cccacctgtc tgctaggaca ggggacccea 76921 cttacctccg aacatcacct tgaitanacat ggccgtggtg gggacagatc cctccgacce *76981 ccaacttccg acctggggaa ggagctgggg tggagctcga ctgcagggtg gggccctgtg 77041 ggaggtgtac gggtggagag ggtgatgggt gggtgggctc aagcggagct ccttgctcag 77 101 tccaggcggt ccctgcagct agtccaggat ccteagcctt ctccccctca ctggatcagg 77161 gaagactgag gttccctocc ctgcccccc acccagcttc caagctggtc tctgtggcag 77221 tgggagctgc caagaggtct gagcggccag tatccgggta acggggttg tggagggtcc 77281 gggcattccc ggtgcagggc tctagtgggg gctggagcct cgggcccaga gctgtccag 77341 gaccagtgcc ctcccaccgc cgccgcccgc aaggagagac agagctccca ggcggggagt 7740 1 cggaggttrc tggaggggga gcatcctcaa ctctgcaggc ccccttccca ggcgcactcc 7746 1 cggcctccc gtcttctgtc ccctgctctt gttgaagtat gattggcata cagtteacag 77521 ccactcttcg gagtgttctc cacactaagg atacagaaca tgtecctcgt ccceccaaac 77581 tcccagccag gctgtcacga agagggaggc ggccgacggg gcagggcctt gcactcctgc 77641 gtgtggggtc cacaggggtc gtccccgtgt cggtggcccc ttcctctcac gccaggaggg 77701 tccccttgcc tggaggtgcc gtggatccgc tcgctgcctg ctctttgggt tgtttcccgc 77761 atggggtgat gatgaagagg ccagtacaga cactcgccag caggtctctg ggtgaacagg 77821 cattuatttc tctttcctga gggcagatcc tgggagtggg gtgccggacc gtccggggag 77881 agtatgcttc tgtttctaag aagctgccgt gttctccagt gtgctgcacc atgtcacggc 77941 ccctctgtgc gtctggactc aggagacctc cttctcagcg gccctccccc ccaggtggtc 78001 aggccatctg tgcccttctg ggggcagagc tcagcgccgg aggcgggagg aggcccagat 78061 cccagcgcag cccaccagcg ttgctctgct tccctcggca ttcatagctg gagaaagggc 78121 aaggagcacc ggctgaagcc ccacctggag gacgcacttc gatggcagca ggtgctcaga 78181 ggtggccccg ggcagcattc cccagacgca caggccagtg ctttcttccc aggacaccac 78241 tgtgtctggg gacccgagtc ctgcagc-acg gtcgggagcg gctgtgccca gattccggcc 78301 tgcacccttg gctccagcca ccacccctgt ttgtcaaggg gtttttgtct utcgagccgc 78361 cgaggaggga gtcttttgtc tgcagtgtca cagaagtgcc ataaagaggg gcccacagtg 78421 ggagctttat aacattggtg cggagggctg taacaggtca gggaggcact tgagggagc 78481 ttctagggcg atggagatgt tctaaaatt ggtctgggt caggctacag agatgtgtgg 78541 gtgtgtgtgt gtgtgtgtgt aaaaccctcg agccacacgt gtgaggtctg tgcatgtgac 78601 cgtacacagg agacctcggt ggaaagcagc cacctgctct gactgcacct gtggatttcc 91 78661 agctcctgcc ctcaggcggc cctgcggggc ccactggctg acggggagac ggcaccgccc 7872 1 tcccccgctg tcagggtggg ggggctgacg attgcatgt cgtgtcaggg tccagcggcc 78781 tcccttgcgt ggaggtcccg aagcacctgg agcgccgccc gcagaacagc ggactcctgc 78841 ctgcctccct gcctctggcc atggcctgcc cgcctctggc cctctttctg ctcggggccc 78901 tcctggcagg tgagccctcc caaggcctgg ctcacctagg ggtgtgtaag acagcacggg 78961 gctctagaag taaatcgcgg ggaagtaaat cgtagtgggc aggggggatg gtttccgaag 79021 gggccctgag ggggacagga gacctggcct cagtttcccc actggtgagt gaccagatag 79081 ccagggtacc tttggactct gactctgggg ggctctcaga gactggtctc ctactcagtt 79141 tttcagaggg gaagctggtg tggccttgtc actgccctgc agggcctc-ag ggacaagcta 79201 tccctgagga ggtctccagc agtcagtggc cggaggctga gccgatggat atagtaacag 79261 cccaggcggc ctcttggggg tggtcagcct gtagccaggt tttggacgag ccgaagtgac 79321 ctaagtgatg ggggtctgca gagcaaggga tgagggtggg cagcaggagg acccagagc 79381 caccagccca ccctctgaat tctggaccct tagctgeatg tggctccttg ggaagacggg 79441 gcttaagggt tgcccgctct gtggcccaca cagtgctgat tccacagcac tggctgtgag 79501 cttttgggag cagattctcc cggggagtct gacccaggct ttgtggggca ggggctggag 79561 ggaaggggcc caggccagac ctgagtgtgt gtctctcagc ctcccagcca gccctgacca 79621 agccagaagc actgctggtc ttcccaggac aagtggccca actgtcctgc acgatcagcc 79681 cccattacgc catcgtcggg gacctcggcg tgtcctggta tcagcagcga gcaggcagcg 79741 ccccccgcct gctcctctac taccgctcag aggagcacca acaccgggcc cccggcattc 79801 cggaccgctt ctctgcagct gcggatgcag cccacaacac ctgcatcctg accatcagcc 79861 ccgtgcagcc cgaagatgac; gccgattatt actgcttugt gggtgactta ttctaggggt 79921 gtgggatgag tgtcttccgt ctgcctgcca cttctactcc tgaccttggg accctctctc 7998 1 tgagcctcag tttcctcct ctgtgaaatg ggttaataa actcaccatg tcaacasta 80041 ctgctctgag ggttatgaga tcctgtggc tcggggtgtg ggggtaggga tggtcctggg 80101 gattactgca gaagaggaag-cacctgagac ccttggcgtg gggcccagcc tccccaccag 80161 cccceagggg cccagactgg tggctcttgc cttcctgtga cgggaggagc tggagtgaga 80221 gansaaaggaa ccagcctttg ctggtcccgg ctctgcatgg ctggttgggt trcaacacte 80281~ aacgagggga ctggaccggg tcttcgggag cccctgccta ctcctgggtg gggcaagggg 80341 gcaggtgtga gtgtgtgtgt ggggtgcaga cactcagagg cacctgaagg caggtgggca 80401 gagggczaggg gaggcatggg cagcagccct cctggggtag agaggcaggc ttgccaccag 80461 aagcagaact tagccctggg aggggggtgg gggggttgaa gaacacagct ctcttetcte 80521 ccggttcctc taagaggcgc cacatgaaca gggggactac ccatcagatg nmnnn 80581 nnnnmnnnixnn nnmnnnnmnn nnnnnnnn nnmm 80641 nnm n immnnn nnnnnnnnn agagggtggg tgggtggaat ttaatatagt 80701 ggtgcgcgtg gagcgtgggc ggcgcattta aggcggtcat ctaaaatagt ggataggggg 80761 tggtgtgaca ataacgggtg gtggatgtgg tttacggggg gtgcaatagt tctgagttg 80821 ttagtgtctt cttgatgggg ttgcggcgtg tggacctacg ccttgagtat gtgggggggg 80881 aaaagcagtg agggtagtag ggatgggaaa tattggtgga ggttctttgt tggtgtattt 80941 tttggtatta tgttgggtgg tggagtggtg ggttgggtgt aatttcgctt gcgttatgtg 8 1001 tttttttct ttucgtgtc gtgggttggg ttggttggtg ctttgtggtg gtggtgggtt 81061 gtggtataaa aaaaaatgtg tggutgtgct cagcttagcc ctataacggt cggctttgtt 81121 tcttgtttgt tctgtgggcg tgagcggatg gctcgggcct c-cgtgctccg cggcgcggcc 81181 tcgcgcgccc tcctgctccc gctgctgctg ctgctgctgc tcccgccgcc gccgctgctg 81241 ctggcccggg cccgcggcc gccggtgagt gcccgccgte ctccagccec cccgccccgc 81301 cccgccctcc acgccgaggg gcgccggctc gcagagctgg atccaagggg gtgcccggga 81361 gtggcccggc gcggcccgtt accccgaaac gctgtctggg tgccccgggg gtgtggtgga 8 1421 tagtgagctt cccgtccctg gaagtatgca agtgaagccg gcgccggat cgctcgggct 81481 ggctggtgag cgggcgggac tcggtcgggc gctagacgca cgccgccagc cccccagctc 81541 ccagacctgc ccactccgcg cccgcccggc cgcgatcccg ggtgtgtgtg tgtgttgcag 8 1601 gggagggaca gcgggagtgg ctacagggct cccgactcac cgcagggaca aagacccgcg 81661 ggtccccagc tggcgtcagc cgccaggtgt gtggcctcgg tgagcacacc tccaggcggg 81721 agggttgagg gaagcgctgt ggggagggca tgcggggtct gagcctggaa gagacggatg 81781 ctaccgcctg ggacctgtga gtggcgggat tgggaggcta tggaatcagg aggcagccta 81841 agcgtgagag ctccggtgtg gcctggcggg ggtggtaggg gggggacgcc cctgtgtgtg 81901 ccagcctgcg tgtgccctaa aggctgcgcc ctcccccact gctggggctt cgggggacca 18 1961 gtcacagcct aggctactgc aggcgcar-ag ctccccggga grcccggccca cgcgggtgtg 92 82021 ccgctgagcc tccagcctgt cggggcaggg gtggggggca gggatggggt cgttagcggg 82081 gttgggggca gacgcccagg cagactctct.gggcacagct ccggtgacaa gggaggtctg 82141 gcaagcctgg gccccttctg tccagccacg ccagctctgc cctggccagt cttgccccct 82201 ggcagtgctg gggatggaag ggggagcggg tacctcagte tgggggccct gcctcctccc 82261 cagccccgcc cggcccccta ggcctagggg cagagtctag gggtcaccct ggggagctgc 82321 tgaatccgcg ggtttaggaa ccggagggac ctgggcttt gaaccacgtg gccctaggtg 82381 agccctccgg cgcctcggta gccctcaccc ccagccttgt ccaggtgggc gggtgggagg 82441 cgacagtgcc cactgctggg ctgaacagcg tctgcaggga ggccaggaga gctgggcaca 82501 cggacacgtt ccatcacctg gagctgccac tgtgccactt gtgcggggtc aggcggggtc 82561 tgagccgggc tgtcatctgt cacgccacag atatgcaggg ggcactcggg gtcgcctcgg 82621 acatgcttat ccctggacgg ctgttggcag ggccgggaag gctctgtaaa tatttatcca 82681 tcccagctca cagctttcag ggttgatgaa agccccgccg cccgcccact gtgggggacc 82741 ccgccttccc ttctggagcc agcggggtga ggggtgggg gagatggacc tgcctgccca 82801 ggagcaggcg gtgtgactct ggcaggtcac ttgacctctc tgagcctcag ggagggcccg 82861 ggatggtgtg cggatgctct ctgccttcct ccc-agectga ccagtgtcct cccctcgggg 82921 tcgcctcctg cccaccgcag'agggggtggc tatggggacc tgggccgatg gcaggcaggc *82981 cggagagggc atgcccggct cagccgtgcc cagcacttcc cagtccaggg gcccccgcca 83041 ctcccagccg ctggctgcct cccatttucc cgattgcagg ttggcc-ccga ggctgaccgg *83 101 agcctctggc tcagctggga gactgaattc cccaagcaat tcctcaagga tgtgtgaggc 83161 tgtggtgtgg tgcctatccg ggagaggtgg ggtgagcgga ctgggcacct rcgcccaggg 83221 caggc-ccagg gagacgctgg ctgacgagca ggcaggcctg caaggaggac gagcagccat 83281 ctcaggaatg tgggttttgg agacaagcca cagctggggg ggtggggggg ccatgggtgg 8334 1 ggaggcctga tcccc-aggtc taggtccagc tctgggctcc ctcgccgtgt gaccctgggc 83401 caag acctgg acctctctgg gcccgtctc tcctggg aggtggggcg atgcctgctc 83461 cccaatcccc cagggctgtg gatgaggcag acgaggtgtg tgctcatccc cacctc-actg 83521 ccttccagca gccccgggcg gggggggtgg tggggactgg cgcacccagg tgaggatcag 83581 gccttggagc tagggagggc cccccagccc caggccagaa aggacacggg gagacagaat 83641 gcaggagggc ggcagagcag gggccagcgg tggggaaact gaggccaaga gcctgtggac 83701 gatgtgctcc aggaaaggac ctcgctgcct ggggcctgga tcctagagcc tccaggagcg 83761 gtgaccatga cgtgggcagg gaaccggagg cccggcttg caggtggacc cggcgcgagt 83821 cactcttcct ctctggccct gagagcttcc ttccgctgc cgctcctgtg ttctaatgtc 83881 aagtctggag gcctgggggg caggtggggg ctgactgeca ggtgggggag ggcaggaatt 8394 1 tggcagagca gcgtcccaga gtgggagaag ccagcccatg gaggggactc tctccatgcc 84001 tgctgcccca aagggcgtta tagagagagg tcggttaccc cttcgccatg gccccgttcc 84061 cattgaacag atgggaaagt ggaggctgag agaaggctgt gacttgccca gggtctccgt 84121 ggeatggaac tgggcctgct gagtctcagg ccggggatct cgctgctgca ctgagcacgc 84181 caggatgcag gggctgggc ctggacctag cgcctcgtgg gggcaagaga ggaaggcacg 84241 ctggctgc ctgtcacect ccaccccacc gtggcttgtt gctcaggcct tcctgggggc 84301 agaggagagg ggagattca ctcgctggca ggctaggccc tgggctctct ggggctccgg 84361 gggaacaatg cagccctggt ctttctgagg agggtccttg gacctccac-c agggttgagg 84421 aaaggatttc tgttcctcct ggaggtcacg gagccgaeat ggggaggagc aggggcaggc 84481 ccggggccca catcctcogt gtgagacctg gacgtgtgtc cteccacctg acgctggggg 84541 tggggggtgg gggccggggg ggptccagtg aaccctgccc ccaaattgtc tggaagacag 84601 cgggtacttg gtcatttccc cttcctcctc ttcgttgcc ctggtgggga cagtccctcc 84661 cctggggaag ggggacccca gcctgaagaa cagagcagag ctggggtcag gggtgtgctg 84721 ggagcgcaga gagcctcctg ctctgcctgc tggtcattcc tggtggctct ggagtcggca 84781 gctggtgggg agcggctggg gtgctcgtct gagctctggg gtgc-ccaggg rcctggpgaa 84841 ttgccagagg ctgaggccga gggtggggcc ctggcggccc ggctcctgcc ccaaatatgg 84901 ctcgggaagg ccacagcggc actgagcaga caggrcgggc cagacgggcg ctgaggctcc 84961 cggcctctcc cccagctccg ctgtgaccct cacctgcggc ccggggtgcc agggcccccg 85021 cttggttctg ccgtgtcttt gcaggctgat cccacgggct ctccctgcct ctctgagctt 8508 1 ccgcctttc caggcagggg aaccgcgacc tccaggctgg gacgcgggga ggggtatgc 85141 gccaggtcag aatcacccct ccaccgggag agcgtggtcc aggggccctg gcagggtggg 85201 gaccgagcat ctgggaactg ccagccaccc ccacccatgc agaggggaca tacagaccac 85261 acggaggctg tgcctccgct gcagcaactg gagaac-accc agccgcggcc aaacataaat 85321 aactaaataa taaaagtttt aaagatcgtt acttaaaaaa acaagtgtgc cccagtgatc 93 85381 ggaccccagt tcccggtgcc ctgagtggtg ccggccctgt gctgagcatg gcctggttgg 85441 ttcacccca gatccacact aaagggtggg atcaccccta ctagtcaggt gagcagatgc 85501 agggggggag ggcggcagcc cctccatgct ggtgigtggc cgtggtgggt gtcctgggca 85561 ggagccagct cacggagctg gagaggacag acctgggggg ttgggggcgc ccaggaagaa 8562 1 acgcaggggg agaggtgtct gccgggggtg ggggtccctt cgaggctgtg cgtgaagagg 85681 gcaggcgggc ctgcagcccc acctacccgt ccccggccca aacggcggga gtaagtgacc 85741 ctgggcacct ggggccctcc aggagggggc gggaggcctt gggatcagca tctggacgcc 85801 agtcagcccg cgccagagcg ccatgctecc cgacggcctc cgctggagtg aggctgcgct 85861 gacacccaca ccgctgaccc gggcctctet cccgctcagg atgccccccg ccgccacccc 85921 gtgagcagag ggccacagcc ctggcccgac gcccctcccg acagtgacgc ccc-cgccctg 85981 gccarccagg aggccctccc gcttgctggc cgccccagac ctccccgctg cggcgtgcct 86041 gacctgcccg atgggccgag tgcccgcaac cgacagaagc ggttcgtgct gtcgggcggg 86 101 cgctgggaga agacggacct cacctacagg tagggccagt ggccacgagc tggcctttga 86161 tctccacctg ctgtctgaga cacgctggag ctggggggag ggcagatccc tatggccaac 86221 aggctggagt gtcccccaac tcccgtgccc actgctcaac accccaaacc cacacttaga 86281 tgcactecca tgccctccct tgggagcacg gtctccacac ceacctggcc accccacaca 86341 cccgtggggc acggccgtta gtcacccacg caarctctgc gggcaccgtg ctgcgggcca 8640 ggccctggga ctctcagtga gggaggcaga cacggcccct cctccggggg agcgaggtgc. 86461 tccccacgcc cggttcagct ctagcaccgc actcgggacc ctc-acaggga gggacccact 86521 ggggcaggcc aggtgacggc tcgggtgacc tcggcccctg gcgctgagac tacacttcct 86581 gcagtgggcg gcgaagatgg gtgtggtgtc ccacgtcgtt gcagcgggga ctcctggggc 86641 ctcggaagtg tcctgggcgg ggagcctggg gagcaggaag ggcaggtctt ggggtccaag 86701 gcctccccac ggtcaggtct gggagggggc ctcggggctc ttgggteett tccgcccagt 8676 1 gcagaccctc gcggccacct aagggcacac agaccacaca aagctgtgcc catgcagtgt 86821 -gggggtggt gcgcacccc agagcacact gggcccacat cacgcacgcc tgccccctca 86881 ctgtgcatcc ggggaaactc ctggccccga cagccagcgg ggctgacgct accccgtgag 86941 ccagacccag gcccccctca ccgcccctgt cctccccagg atcctccggt tcccatggca 87001 gctgctgcgg gaacaggtgc ggcagacggt ggcggaggcc ctccaggtgt ggagcgatgt 8706 1 cacaccgctc accttcaccg aggtgcacga gggccgcgcc gacatcgtga tcgacttcac 87121 caggtgagcg ggggcctgag ggcaccccca ccctgggaag gaaacccatc tgccggcagc 87181 cactgactct gcccctaccc accccccgac aggtactggc acggggacaa tctgcccttt 8724 1 gatggacctg ggggcatcct ggcccacgcc ttcttcccca agacccaccg agaaggggat 87301 gtccacttcg actatgatga gacctggacc atcggggaca acc-agggtag gggctggggc 87361.cccacmtcc ggaggggccc tgtcgaggcc ccggagecgg gcccgggctc tgcgtccgct 87421 ggggagctcg cgcattgccg ggctgtctec ctctcgg cacggatctc ctgcaggtgg 87481 cggcacacga gtttggcc-ac gtgctcgggc tgcagcacac gacagctgcg aaggccctga 87541 tgtccccctt ctacaccttc cgctacccac tgagcctcag cccagacgac cgc-aggggca 87601 tccagcagct gtacggccgg cctcagctag ctcecacgtc caggcctccg gacctgggcc 87661 ctggcaccgg ggcggacacc aacgagatcg cgccgctgga ggtgaggccc tgctccccct 87721 gcccacggct gccttgag ctccaacatg ggctectcct aarccttcgc tctoarccca 87781 gccggacgcc ccaccggatg cctgccaggt ctcctttgac gcagccgcca ccatccgtgg 87841 cgagctcttc ttcttcaagg caggctttgt gtggcggctg cgcgggggcc ggctgcagcc 87901 tggctaccct gcgctggcct ctcgccactg gcaggggctg cccagccctg tggatgcagc 87961 cttcgaggac gcccagggcc acatctggtt cttccaaggt gagtgggagc cgggtcacac 88021 tcaggagact gcagggagcc aggaacgtca tggccaaggg tagggacaga cagacgtgat 88081 gagcagatgg acagacggag ggggtcccgg agtttgggg cccaggaaga gcgtgactca 88141 ctcctctggg cacagctggg aggcttcctg gaggaggcgg ttctcgaagc gggagtagga 88201 taaaaggtat tgcaccccat gaagcacgtg tgatecttgc ccctagagac aaggctctgg 8826 1 ggctcagagg tggtgaagtg acccacatga gggcacagct tggagaatgt cgggagggat 88321 gtgagctcag tgtgccagag atgggagcct ggagcatgcc aaggggcagg gcctgctgcc 88381 tgagagctgg cactggggtg ggcagccaag tgcagggatg gagcgggcgc ccaggtggcc 88441 tctttgctgc teagaacgac ctttcccatg tatacctccc agcgccgctg gcattgccca 88501 gtgtccttct tgggggcagg agtaccaagc aggeattatt actggccttt tgtgt 88561 ggacaacgaa actgaggctg ggaaggtccg aggtggtgtt ggtggcggaa ggtggccgct 88621 gggcagccct gttgcagcac acarccccca cccaccgtt ctccaacagg agctcagtc 88681 tgggtgtatg acgggagaa gccggtcctg ggccccgcgc ccctctccga gctgggcctg 94 88741 caggggtccc cgatccatgc cgccctggtg tggggctccg agaagaacaa gatctacttc 88801 ttccgaagtg gggactactg gcgcttccag cccagcgccc gccgcgtgga cagccctgtg 88861 ccgcgccggg tcaccgactg gcgaggggtg ccctcggaga tcgacgcggc cttccaggat 88921 gctgaaggtg tgcagggggc aggccctctg cccagc-cccc tcccattccg cccctcctcc 88981 tgccaaggac tgtgctaact ccctgtgctc catcrugtg gctgtgggca ccaggcacgg 89041 catggagact gaggcccgtg cccaggtccc ttggatgtgg ctagtgaaat cagtccgagg 89101 ctccagcctc tgtcaggctg ggtggcagct cagaccagac cctgagggca ggcagaaggg 89161 ctcgcccaag ggtagaaaga ccctggggct tccttggtgg ctcagacagt aaagcgtctg 89221 cctgcaatgc gggagacctg gattcgatcc ctgggtragg gagatcccct ggAgaaggaa 89281 atggcaatgc cctccggtac tgttgcctgg aaaattccat ggacagagca gcctggaagc 89341 tccatggggt cgcgaagagt cagacacaat ggagcgactt cactgtctta agggccacct 89401 gaggtcctca ggttcaagg aacccagcag tggccaaggc ctgtgcccat ccctctgtc 89461 acttaccagg ccctgaccct cctgtctcct caggcttcgc ctacttcctg cgtggccgcc 89521 tctactggaa gtttgacccc gtgaaggtga aagccctgga gggcttcccc cggctcgtgg 89581 gccccgactt cttcagctgt actgaggctg ccaacacttt ccgctgatca ccgcctggct 89641 gtcctcaggc cctgacacct ccacacagga gaccgtggcc gtgcctgtgg ctgtaggtac *89701 caggcagggc acggagtcgc ggctgctatg ggggcaaggc agggcgctgc caccaggact -89761 gcagggaggg ccacgcgggt cgtggccact gccagcgact gtctgagact gggcaggggg *89821 gctctggcat ggaggctgag ggtggtcttg ggctggctcc acgcagcctg tgcaggtcac 89881 atggaaccca gctgcccatg gtctccatcc acacccctca gggtcgggcc tcagcagggc 89941 tgggggagct ggagccctca ccgtrctcgc tgtggggtcc catagggggc tggcacgtgg 90001 gtgtcagggt cctgcgcctc ctgcctccca caggggttgg ctctgcgtag gtgctgcctt 90061 ccagtttggt ggttctggpg acctattccc caagatcctg gccaaaaggc caggtcagct 90121 ggtgggggtg cttcctgcca gagaccctgc accctggggg ccccagcata cctcagtcct *9018-1-atcacgggtc-agatcctcca aagccatgta aatgtgtaca gtgtgtataa agctgtmtg 90241 tttattt tttaaccgac tgtcattaaacacggtcgtt ttctacctgc ctgctggggt 90301 gtctctgtga gtgcaaggcc agtatagggt ggaactggac cagggagttg ggaggcttgg * 90361 ctggggaccc gctcagtccc ctggtctca gggctgggtg ttggutcagg gctccccctg *90421 ctccatctca tcctgcttga atgcctacag tggcttcaca gtctgctccc catctcccca 90481 gcggcctctc agaccgtcgt ccaccaagtg ctgctcacgt tttcgatcc agccactgtc 90541 aggacacaga accgaactca aggttactgt ggctgactcc tcactctctg gggtctactt 90601 gcctgccacc ctcagagagc caaggatccg cctgtgatgc aggagtgagt gaagtcgctc 90661 agccgagtcc gactctttgc aaccccatag gactgtagcc taccaggctc ctctgtctat 90721 gggatttttc aggcaagagt gctggagtgg gttgccattt ccttctccag gggatcttcc 9078 1 caaccctggt ctcccgcata gcaggcagac tctttactgt ctgagccacc aggcaatgc-a 90841 ggagacctag gttcagtctc tgggtgggga agatcccctg gagaagggaa tgacaacctg * 90901 cttcagtatt cttgattggg gaatcccatg gacaaaggag cctggaggcc tacagcccat 90961 agggtgcaaa gagacacgac tgagcaagtc acacacac-ag agccctacgt ggatgctcat 91021 egcggcacct catagctgcc atgtatcagg tgttggcatg ggcagccatc agcagggggc 91081 cattuctgac ccactgcctt gttccaccgg atacacgggt gccttcctgt gtgtcgggcc 91141 cactcggctg tcagcgecca agggc-agggc tgtcgggagg cacagggcac agagttaagg 9 1201 aggggatggg gacgttagct cctccccagc tctcagcgga tgcagcaggc aaaacaaacg 91261 ctaggaatcc tgccaaaccc ggtagtctct gcccatgctc gccccatccc cagagccaca 91321 agaacgggag ctggggggtg gcccggagct gggatactgg tccctgggcc cgcccatgtg 91381 ctcggccgca cagcgtcctc cgggcgggga aactgaggca cgggcgcctc cggcttcctc 91441 cccgccttcc gggcctcgcc tcgttcctcc tcaccagggc agtattccag ccccggctgt 91501 gagacggaga agggcgccgt tcgagtcagg gccgcggctg ttatttctgc cggtgagcgg 91561 ccttccctgg tacctccact tgagaggcgg ccgggaaggc cgagaaacgg gccgaggctc 91621 ctttaagggg cccgtggggg cgcgcccggc ccttttgtec gggtggcggc ggcggcgacg 91681 cgcgcgtcag cgtcaacgcc cgcgcctgcg cactgagggc ggcctgcttg tcgtctgcgg 91741 cggcggcggc ggcggcggcg gaggaggcga accccatctg gcttggcaag agactgagn 91801 nnzmnnnnnn nnnnmnn nnnnnnnnnnnnnnnnnnnnn 91861 rnnnnn nnnnrmnnn~ nnnn munnnmct gcaggtgc-cg gcggtgacgc 91921 ggacgtacac cgcggcctgc gtcctcacca ccgccgc-cgt ggtaaccgcc cccgggggtt 91981 gccaaggtta cgattggacc ctccccgccc cgaccctgct cccctagggt gggtgggtcg 92041 ggggcagt tctaagatct cctggttccg cagcagctg aactcctcag tcccttcca .95 92101 ctctacttca acccgcacct cgtgttccgg aagttccagg tgaggccgcc ccgccccttg 92161 cacttgctgg cccaacccct cccgcccagc gctggcctga ccgcccccca ccccgcccac 92221 ccc-acgcagg tttggaggct catcaccaac ttcctcttct tcgggcccct gggautcagc 92281 ttcttcttca acatgctctt cgtgtatcct gcgccgtggt ggaagcggga ggagggcggg 92341 gcgggggac-c gggcgggagg cagcgggccc cgggaagctg agaccctcca aggggc-acgc 92401 ttcctatacc aaagccgcag gttccgctac tgccgcatgc tggaggaggg ctccttccgc 9246 1 ggccgcacgg ccgacttcgt cttcatgtt ctcttcgggg gcgtcctgat gactgtatc 9252 1 ttcccgggct cggggaccta tgggtc-cggg ccxctgctgg ccctgaggc-c ctgcttgagc 92581 gcatgccaca gagggagagt tgcgaccccg agctgagggt gtttttgagc gtacatcacg 92641 tgctcagctg caggtgcccc tgtcgaactc cagggctaca cccaaaatac cacagggcag 92701 ggtgcccagg ggctgagtcc tgaatgcagg tagccaggag gatetagggc tgggcccggg 9276 1 ggctggggtg aagtggagag gcagggccga tcagggggc-c cctggaggcc accgtttggt 92821 cttagagtgg gaagcgaaac caacctgctt gagggtttca ggggtttagg aagtc-agagg 92881 ggccctgggc agggcacaag accttgactc tggcccagct actggggctc ctgggtagcc 92941 tcttcttcct gggccaggcc ctcacggcc-a tgctggtgta cgtgtggagc cgccgcagcc 93001 ctggggtgag ggtcaacttc tttggcctcc tcaccttcca ggcgccgttc ctgccctggg 93061 cgctcatggg cttttcaatg ctgctgggca actccatcct ggtggacctg ctgggtgagc 93121 ctgctgtcca gggagcctgc cccaagctgg gtgtgctggg ccagagccct ggtcctctcc 93 181 ccgcccccac ccctcttccc cactcctggc grccccatec ttccagcccc tccaacaagt 9324 1 cagcctatag gttttactta ttcgagcctg acccattgc tgacgcttgt gtggggcccg 93301 acccggtagg gatgggtggc tcagggtgcc tgctcacagc tccacttctt ctgacgtc-ct 93361 caggcctgac ctcctcccag gttctgccta ctctgggcca agcctggccr. cacgctgggc 93421 tggctggccg tgcagggcat cagaccccca tgctttgggg gcttcagggc tgtggagggt 93481 ggcctcggca ttggcgcctc tccracaggg attgcggtgg gccacgtcta ctacttcctg -93541 gaggacgtct tccccaacca gr-ctggaggc aagaggctgc tgctgacccc cagcttccg 93601 tgagtgctga cagc-cttrcc cacccccttc cccagatggc tetctacccc atgagggggg 93661 gggaccctgc cagctgccgc tcagcgtggg ctccteccca caggaaactg ctactggatg 93721 ccccagagga ggaccccaat tacctgcccc tccccgagga gcagccagga cccctgcagc 93781 ogtgaggacg accteaccca gagccgggtc ccccaccccc accoctggcc tgcaacgrcag 93841 ctccctgtcc tggaggccgg gcctgggccc agggcccccg ccctgaataa acaagtgacc 93901 tgc-agcctgt tcgccacagc actggctctc ctgccgcggc cagcctctcc acgcggggca 93961 ggtgctgctg gccgagagcc agggccacca agcctgacgt gctctccgac ccagaacatt 94021 ggcacagctg gaggcccaga gagggtccag aacctgccca ctcgccagca gaactctgag 94081 cacagagggc agccctgctg gggttcteat ccctgccctg cctgtgccgt aattcagctt 9414 1 ccactgatgg ggctcacatc tcaggggcgg ggctgggact gggatgctgg gttgtgctga 94201 gctttggccg tgggggccct cctgtcccga actagcaacc cccaagggga cetctgctte 94261 atttcccagc caggccactg aaggacgggc caggtgcaga agagggccag gcoctttctg 9432 1 tgactccgaa gcctcaagtg tcagtgtttg cagagtccag tggctgaggc agaggcctct 94381 gggaagctct gcccctgccg tttgcagctg aggccggcag gagcctcacc tggtccccag 94441 ctcacgggca ttggaggacc agtccgcacg gtggtttact cctgggtcgg caccagccgc 94501 cgccggctgt ccctttcaca gaggataaaa gtactcgctc tggagttgga cttaatgtt 94561 gtcatgaaac ctctggccca gcagcgggct ccgcagtggg tggcaggtga aggcccctcc 94621 ccgggcctct ccaggcaggt gccgcctggc cagcagggaa ggcaggcagt gtcatcccc 94681 actggctctg gggctcaggc tacctcctgc tgtggccgga acatctcccc cagtggtgga 94741 gcccagtgtc cgtgaggcca gctgggcctg aaaccttcct ctctgaagc-c ccgctgtcc 94801 cttgccctgt atggagggca gaggctggag cgcaagttcc taggatgtgc ttgcgagacc 94861 cccgagccca ggggcgaggc ccatctcagc ccacccccga actggaaacc cttggagctc 94921 tgcccctcgt ggtgtgaggc ccctgctatg cgaccctcag ccctgccagc aacggaaggt 94981 gcagggcccg ggcccacggg cttaacgcaa ctgggcctgg gtcacctgcg gggcctggte 95041 ccaggaggaa gacccaggtg ccaccctcct gggtgcracg tccaggtcac gtggggaccc 95 101 gtccatgtra cagaagatgc agggtcaccc ggtgagctgg cgccgggccc tgecagagc-a 95161 ccagccgcgg gtggaggtgg gccccagctc tcctgtcagg cacgtggtgc tgggaggtgc 95221 ggccggagca gtgcccacca gctgcagcag gacaggtggg cacaggccca ccagcagtgc 95281 ccgcacggga tgggcccctg caagggccag agaagccacg ctcctggctg ggggctggge 95341 tgggactgac aggtggccct gccctctgcg ccccactact tcccagccac ccgggactcc _________ 95401 aaggacttgc tgagctgggc aggtgggacg ccgaggggag tcaaactgct cgtgggggca 96 95461 ggaggggcgg tccacagggc tgagccctga gctgaaccct ggccctgctc gtggttgtgg 95521 gggtgggggg gtccagtggc gccctagccc tgctgaggcc cagctgggac gtgcgcgccg 95581 gagggcgagg ggCCagccca tgccatgctg tcccccgttc tc-agctccat gctaccactt 95641 tgaagaaaca gaacctgttg ccttttt tagaaagtgt tgcttgccct gcctggggct 95701 tctatacaaa aaacaaacac agctcaacgt ggcctctcct gaccagagac gggcggtggg 95761 gactggggct cagcagacgg aatgtgtccc cggcggcggg agaccaggag gcccctggc 9582 1 cgctcctcag gacggctggg ctgtccac ctggtcccct ccgagccaga agatggagga 95881 gaggtgggct gatctccaga tgctccctgg gagccaagcg ccacggggtg gtcaccaggc 95941 cggggccgtg ttggccagac gcctcatccg cctgtgggag ggggagggca gcaacccccg 96001 gatctctcag gcaaccgagt gaggaggcag gagcccccag cccctccctc ggccgctctg 96061 ctgcgtgggg ccctgaagtc gtcc~tctgtc tcgcccccct ccccagggag agtgagcctg 96121 ttctgggctg tggtcagacc tgcccgaggg ccagcctcgc ccggggccct gtcctgcctg 9618 1 gaaggggctg gggcagcacc ttgtgttccg gtcctggtcc cggatcttct tctccatctc 96241 tgcatccgtc agggtctcca gcagcgggca ccactggtca gcgtcgcctg tgttccggat 96301 ggcaatctcc accgtgggca gggggttctc actgtggagg acgagagagg tagacggctc 96361 acagagcagc tgcaggagag gcccctagaa agcagtgtcc accccgclgc gggcagacag 96421 gacatggagc ctggtttctg cacc-cggctc ccgacacagg gcggccgggc acgctgccaa 96481 catggcatct ccgggtctgc atgtggggag gggtccacag gacagtgctg caggtccagc 96541 cattcccagt ggacttgctg ggaggaggag ggccgtccgc cccgctcagt gtccaggaga 96601 aaggagagca aaggagtcca tccacccagg agtggagtcc cagggcccct gccctgacca 96661 gcctgcaggg ggcccctcgg cccacatcac aggggcccag aatccataag ccctgactgc 96721 tccaccccgg ggcccctcaa agacgcgcct agactccgtc cgagggccac ctgcacaccc 96781 tctggcgaag tggactcagg gctgggggtc agcctcggtg aggccgcaaa ggctggggac 96841 tcctggccga gctgctgcct ctgccaggag ccaggcccag cctgccggcg agrctcagcc -96901lacgcccteac-ccaccctgcc-cgcggcgcca cgctggcctc cgggtoctct cctctggcct 96961 cctgctgggc cactggtgct cagccccagc agtcggcctg ccaggagccc tgcagagtca 97021 gcccccagag ggaggagggg gcccggggga acagcacagg aacaaacaga cccctggcct 97081 tagtttuagc tectcatctg gaaaatgggg acagtgtcct tgctgcgagg ggtttcagag 97141 gaccactgcc atgcaacacc cagcacacae ccactgcgtg gggctcggg cccgagccgg 9720 1 tgcccccgag tcccaggctg gtggctgggc cgccccagcc accctgccga cagctgcttc 9726 1 ccagccgggc ggtgctgcgg cagtccagaa gccagcactg cagacccaaa tgtcactcct 97321 cacgttgcgg gctcccagct gccttccttg ggggcagcag acacgaat caccaagccc 97381 acgccgacgg gagcaaaceac gtcttcctct taaacaagtg cgggtcccgg aggccctgtg 97441 tttacctccc tgtggctccg ggaagattgc atcccagggg gttgttctaa accaagggct 97501 gctcgggcca ggcctggaag gaggggcctg gagccaggag cccaccctta cgggcattcg 97561 gcttcctggg tctcaaggcc ggctgggacc ctgrcattccc accacccgcc aggtgcaagc 97621 agggggccg tgtcggagga ggcagagggc ctggagggtc. gtcttcgacg tgacctcact 97681 tttacaacct cacaggtgcg gcaggccagc tgggaggcat ggctgtgccc tcctggtaga 97741 Igigaacaag actgcaggga gtgatccccc tgaacttccc caaccaggag gagacaisac 97801 tcggtgtcgc cctcctgctt aagatcact gactctggac aaggggccca gcccacccga 97861 tggggaaagg gcagtccttc caacaagcgg tgctgggacg ggacccggca ggccatggtt 97921 tctcagctat gacaccagca gcacaagcac cccgagaaaa acagctaagc tgggcactgt 9798 1 cacacaagtg aactccaaac ccaagaaaac cacaaaaagc ctgcggatct tcagatatgt 98041 gggaagggac ctgtatctgg aatgtataac gaactcctga aaagtgaaag tgttagtcac 98101 tcagtctgtt cagctctttg caaccccatg gacggtagcc tgccaggcte ctctgcccat 98161 gggattctct aggcaagaat actggagtgg gttgccatgc cttcctccag gggatcttcc 9822 1 caacccaggg attgaacctg tgtctctctt gcactggcag gcgggttct taccagtagc 98281 gccacctgag tagaaacact ccaggtgccc tgagtgtcag agcaggaggg actcggccra 9834 1 ggcctgtgag gggaccctct ccgagtcccc tgctgcacag cagtgagagg tgcgttctga 98401 gtcagcctcc agggatgagg gacttggtgt cgacatcact cccaggacct caggatctgc 98461 tctgggaagc gaggctcc aggctggccc caggcccgct ggcctcagct cgtgagccgt 98521 gcgtggacag gtgccatgag caggcctccc acgggactcg gggcgcggcc tggaccccgg 98581 ggctgccagt ggtcgcgggg ggccccgtgt ggcggctgtt ccctctcttg ctccgagtcc 98641 taggaacatg gtgggcgctg cctcctgggg tttctggaga agcagctgag atgcaaacag 98701 ccccacgcgc tccctcagct gttccctgtc acgggtggcc ccttggtgac ggcctccatg 98761 caggacg gacagctcga ceagccgcg aaaaccacac ggacg gcagctcgag 97 98821 cagccgcgta aagcctgaca tccaatttgg aagcctcccg cagtggaaga ggggcccggg 98881 gacggggctg cccggggcga gctccaccgg gtcgggggtc acgaggagcc cacccgcgtc 98941 cccgccacca gcacctggga ccagataccc tccccgctct gagggcggcc tgaacgccgc 99001 cccctcccac gggggcgccc accgcctgct cgtggactga acaagaggCg gcagtggcct 9906 1 ccagaccccc tcgggggagg gcagacctgt ccgagactga gcacaagtcc agggaatgag 99121 caagggtctc agtaatgtcc ccaccgggac gggacgggag gaggcgacag aggccgctga 99181 ggtgcggggc agccctcagt agctggcatc aaggccccag gcagtcccgg ggcatccccg 99241 cagggggcgg gggcgaccac cggcccgagc ccaggcagtc ccggggcatc cctgcagcgg 9930 1 gcgggggcga ccaccggccc gagccctacc tgaaggcgta ggtcttctga tgccagctca 99361 gctgtccccg gatgctgtag gcgatggtgg tgacgaactc cccgccagc cccagctcgg 99421 agcacagctt cagagcgaac ttctcgggcg agttctcctt ctccgacatg tcccactcga 99481 actggtccac caaggagatg ttccccacgt ggatgttcag ctggcccggg agcacagaca 99541 tgagccagag cggccccctc tggggccagg ccgcaccctc accacccctt ctcccggaa 9960 1 catccccgcc tcgttcttgg ccgcgcccct gtgctgctac ttggggtaag gaaaacaacc 9966 1 cccatctctc tgaaaagggt taactagcga ggaagatgcg ctggtaactg gaaaactccc 99721 tacaaagaaa gcttggatct gatggcttca ctggtgaatt ccaccaaaca tttcaagcac 9978 1 taacaccaat ccttatcaaa tcctgccaaa aaactgaaaa ggaaggaaca catcataact 99841 ccctgccttg ataccaaagc cagacasaga tactacgaga aaggaaaggt gcagaccggc 99901 acttactgtg gacattgatg tgaaacctca gcagacacga gcaaaactac attcaccagc 99961 acgtcagaag aatcacacac cgttataaat gatgggatga tgacacaacc acattataaa 100021 cggtggggct tactctggtg atgtaaggac ggctcagtaa gaaaaccggt caatgccatg 10008 1 aaccacttga 'acagagtgaa ggacaaaaaac cacacagtca tcttgataat tggaggaaaa 10014 1 tcattagaca aacttcaacg tgctttcacg ataaaagcac tc-agtaaact aagatcagat 100201 ggaaaccaca tcaacaagat taattcagtc aaaaaattca ctgcaagtat cacccacaat 100261 ggcagaagac tggtaacttt t~ctctaaga tcaggaacga gccaaagata cccagtcttg 100321 ccacttttgt tcaatatagc gttggaattt ctactcagtg cagtgcagtc gctcagtcgt 100381 gtccgactct tttcgacccc atggatcaca grcacgccagg cctccctgtc catcaccaac 100441 tcccggagtt cacccaaact catgtgcact gagtcagtga tgccatccag ccatetcatc 100501 ctctgtcgtc cccttctcct cctgcct=c atoccttcca gcagttaggc aagaaaaata 100561 aawcaaggt atccacctgg aatggaagaa gtaaaactat ctctggtccg agatguaca 100621 atcttatatg cagagtttaa gatgctaaca anatactatt agaactaatg aatgaattca 100681 gcaakgtacc aggatacaaa gtcaacgtgc aaaaatcagc cgcatttta catgctaaca 100741 ctgcacaatc tgaagaagaa aggatgaaca aattacaata icataaaaaa gaatamatc 100801 cttagaaatt aacttgatca aagagatgta csatgaacaa tatamaaat actgaaagaa 100861 attgaagata taaataaatg guaacate ctatgtccat ggattggaag acttaaaatt 100921 attaagctgt caaggctatg gtttcag tggteatgta tggatgtgag agttggacta 100981 taaagaaagc tgagcaccga agaagtgatg cttntgaact gtggtgttgg agaagactct 10 1041 tgagaggtcc ttggactgca aggagatcca accagtccat cctaaaggag atrcagtcctg 101101 ggtgttcatt ggaaggactg atgttaaagc tgaaactcca atacttggc cacctgatgc 101161 gaagagctga ctcatttgaa aagaccctga tgctgggtaa gattgagggc gggaggggaa 101221 ggggacaaca gaggatgaga tggttggatg gcatcaccga ctcaatggac atgggttugg 101281 gtggactctg gaagttggtg atggacaggg aggcctggcg tgctgcggtt catggggttg 101341 tgaggagtcg gacacgactg agcgactgaa ctgaactgaa catgaatacc caaagcaatc 101401 tacaaagcca aatgtaatcc ctatcaauat cccaatagca ttctgcaga aacaggaaaa 101461 aaaatcttaa aattcatatg gaatctaagg aaaagcaaag gatgtctggt caaaacaatg 10 1521 acgaaaagaa caacaaagct ggaagactea cacttectga tttagaact tactgcaaag 101581 atacaataat gaaaacactg tgggactaac gtaaaagcag acacgtgggc caacgggaca 101641 gcccagaaat aaactctcaa ataagcagtc aaatgatttt caacagagat gccaagacca 101701 ctcagtgaag gaaagtgttt gcaaccaacg gttttgggaa anaagaaccc acatgcgaaa 101761 gaalgaagtg ggacccttac ccagccccat ctacagasat caactcasla cagacagaac 10 1821 atatggctca agccataaaa cgctcagaaa aacagagcaa agctttatga tgttggattt 101881 ggcggtgatt tctcagatat gacgtcaaag gcataggtga taagcgaaaa aataaactgg 10 1941 acttcaccaa aatacaacac ftctatgcat ccaaggacac taccgacagc ataacaaggc 102001 agcccagggp aaggaggaaa catccgcaaa tcacagcatc tgggaacaga ccgctgcctg 102061 tgagatacag ggaaccgata aaaacaagaa aacagc-aaaa CCCggactca aaaatgggaa 102121 ggactceagc agacacagga gacagicaag ccgccagcag gtcactaatc agcaagcaag 98 * 102181 gcccgcaaag gcccgtatcc aaggctgtgg ttttccagt ggtcatgtag gaaagagagc 102241 tggatcgtaa gaaagctgag cgctgaagaa ttgattgaac tgtggtgttg gagaagactc 102301 ttgagagtcc cttggactgc aagatcaaac cagtccattc tgaaggagat cagtcccgaa 102361 tagtcactga aggactgatg ctgtagctcc aatactttgg ccacctgatt cgaagaactg 102421 actcattggc aaagaccctg atgctgggaa agattgaagg caggaggaga aggggacgac 102481 agaggatgag atggttggat ggcatcactg actccatgga catgagcttg ggcaagctcc * 102541 gggagagagt gaaggacagg gaagrcctggc gtgctgcagc ccgtgggtcc caaatctttg 102601 gaccaagcga ctgaacaata acaaatcaac agggaaatgc aaatcaaaac cacagtgaga 102661 tactgtccac caccaggcag gcgttcttca gcggggttcg gggcaggtgg tgccctcttc 102721 tctcgtaacg cccccaggac cgcgggggct gctgagacag catggggtgt gcttggccta 102781 gcctgcccat gacaagagtg gcAgtgtgct cgcctcactg cgcccttccc tgctctgccc 102841 accagctggg ccacccctgg gaccacccag cttccgctcc gtggacggca aggccgcagc 102901 agcgcccgga cacgcccaga acgtggtgcc ctccteagaa gtcggcctgt gcccttcctg 102961 ggacaagccg cccaagagac agtcttccag agccctgccc cacaacacgg accccagaca 103021 ggctcctgtg gaggcctcca cgcacctccg cacctcgcaa gccccgagga caaggcaggc 103081 ccgctgcggg tgaggagccg cctaccttga taatgacgcg ctggtctgac tggtcttcc 103141 ggatgctgtc cgtggggtag gactcgatct gctgtctgat ggcagaggca atggctggca 103201 cgaatgtcag tgggttcaga tccaggtcgt cacagagaat ctctgagaac atctccgggg 103261 tcatcagctt ctctgaaacg atgacggagc-gggggaacc-c ccagtggacc acagggccta 103321 cggtcagcgt gctcagcccc ggcctccccc agccttgcct cctctgccac cgcccccccg 103381 ggtgacgaca ggacccctg gcagcacgca gacagagctg agtgcacgcc agccagggcg 103441 gcggacggac cattcatgtt ccaggtaaag gcatcccgca gcttctgccc gtcaatctcc 103501 atgtccgtc ggatggggac cagcacctcg ggctgggacg cgttctcgtg gatcacggct 103561 gggtcgtggt cgtcgaagct ggaaggggag cggccgcgtg ctcagcaaag cgggctgggc * i03621lcccftjtccc agggcctccc tctctgcacc actggtcgctgagacctgcc cagagaggac 10368 1 ctgtccacta cgggccgggc cggcagaaac agggctggcg ggggtccacg cggggcggga 103741 ggggagctgc cgactcggca gcgggacaag ctcagaggtt ccctgcagga agagggttt 103801 aagccccaga gcaggcagp ttctcccagc agctgtgggg aagaaagggt atgtccagaa 103861 gaagaaaccc tggaacaaag gccgaggggc aggagggttg aggagctgct tggagagcag 103921 tgaagggggg ctgggcggct ggggggtgct ggggagcctc ggtggccaag cacccagggc 103981 tccccacctg cagcctggac cccgagggag ccccagagga cggagagcaa ggcagctccg 104041 cactcacacc tgccctttag gatggggaag agggaagaga cgggggctgc ggggggcaag 104101 gaaaccaggc acgccccgct tagacccggg ggcgagaacc acttccaag aacgcagggg 104161 cgccaatgat gaacaatggg tagcagcccg caggcgggag gcccggtggc cgaggcccct 104221 caccagagcg ggaaggtccg cttcttgtcg cggcccatgc ggttcctgtt gatggtggtg 104281 gagcagggca cggcgtccag gtggtgcgag ctgttgggca gggtgggcac ccactggctg 104341 ttrctcttgg ccttctgttc cctgggagac acagacgccc gtccgctcag ccttgggcc 104401 aaaagccgcc ccccagccgc caggttgtgg ccagtggacg cccgccatgc ccctctgggc 104461 ccaggcccc atggggacct ctgtgcgccc agctccgcgg tggttattcc ccaggctcca 104521 agcggcacct gctcggggtc accagttta ggggaggagg agagggcagg ggc-cccagcc 104581 cagtctgtga gctgtc-accc ccaggcteca agcggcarcct gctcggggtc acc-agttta 104641 ggggaggagg agagggcagg ggccccagcc cagtctgtga gctgtcaccc ccaggctcca 10470 1 agcggcacct gctcggggtc accagttta ggggaggagg agagggcagg ggccccagcc 104761 cagtctgtga gctgtcaccc ccaggctcca agcggcacct gctcggggte accagtmta 104821 ggggaggagg agagggcagg ggccccagcc cagtctgtga gctgtcacc-c gtgctatgtg 104881 ctgggctggg cactcaggaa agagggtcag ggtteacggg ggggtggcgc gcagatttcc 104941 aggagageec cgagggcagc agagaggagg ctrcaggtcaa tggttgggca gggggccagg 10500 1 gctggagaca cagagagggt cccgattcgg gggggtgccc tcagcaggtg gctgggagtc 105061 cctgggggtt tgcacacttt cgatcaggct gttafttcg acgcttggtc cagcctgag 105121 caggtaatgc ctctggcctc cgggccttca gggatggaaa gatactctag aaagcgggac 105181 tcaaagtaac tcaaggaact cgcgtcccac agtggggagc ccttctctcc aatttacatg 105241 gggcgtttac tacgaggaaa ataccgaagg ccgtmtgag ctgaggctcc cgggc-cgggc 105301 tgtccgtttg tgagactgct cgtcacccct gggecacatc cctggtggcc aagggggcaa 105361 tcagtgcggt gactgcacga cacacctctg cagccctgcc ccacagctgt caccatcggt 10542 1 gacgtccacc ccctggagaa cctgaccact gcccggtttc ccgctaaaac agcgcccttc 105481 caggatgggg ggeagaggga gaggccttg cctttcact cctcttctgc agcgggggcc 99 105541 cctcgcaccc cagtgcccgg gcccaggagc gc-cccttggg gtggggcagg gagggatcca 105601 cacaccaagg ggagccagga cccccccaaa tctgctgccc tgccctgata cccgagacct 105661 ggggaaacgg gggactgggg ctgatgcggg caggaccaag aactgaggcg gtgagaeggg 105721 gtccccacca caggccatct ggctggcagt ttctactccg ggcctgcagg ccaagaggga 105781 aaaggtgccc cactcagatc aggcgcctcc cgtccccagg gagggcctac aaggtcagat 105841 cctttgtaac ttccacgggc aaaactggct tgctgggcct gtgcgggccg catgggcgtg 105901 gaccaccac-a cctttcccca ctgagtctcc agccggagct gtcacccagg tccccccagg 105961 ccagccccac cccgccacct tgcagtagcc tctcgtatcc aggccgaggc tgcccggtcg 106021 acccctcctg cctgatggcc tcaagtggac aatgcgagtc acgttgcagc acgtgagtgg 106081 gacgggcagc gccacgcggg gtccgggcat ccgagtccca ccactcagcc tcctccgc 106141 tgcagagagg tctgtccaag agccctgggg gccatccagc ccctgtccga cctggc-cggt 10620 1 gtggaagagg gggtgtgcca cccctcctgg ggggctggct gggcgctggg caggcccctc 106261 ctaagagtgg agcccactgg tggttttcct gcagcccac ctccacacag cagttctcac 10632 1 tgcccagtaa caggaggcta ctggcctagc tctctccctc gtgtgatgga ctcaaccagg 106381 agcgttcacg gccccacac-a gggttctcgg ctgctgcatg aggatctcaa agccccatcc 106441 acgtgcatgt aatctcctcc ggtaacttct ctagggaagc ccggctatcc tgccatcctc 106501 accgcaccac cagggcgaga aaagccatct cc~agcgctea catccacaat gggccaggcc 106561 gtgagcacac caccttcttc gggaggttgt gggggcgggn ninnnnnnnn 106621 nnnnnnn mnnnnnnnn nnnnnnnnnnnnnn nnnnnmnnxn 106681 nnnnn nnnnnnnnng cgcgccccc ccccccgcgg cgccggcacc ccgggcggcg 106741 gcccccggcg ctgggagcag gtgcggggcc gcggc-cgctc gtgagcctcc agcccggagg 106801 acgggccccg ggggccggcc cggtgcccag gccctgggag ccccggaggc cagagtgcca 106861 gagggccgga ggacccggga aggcccgaga gaggtgggaa gcacggggtt ccagccctag 106921 gcc-atttcog ccccaaagcc atcggtgaaa ccattgctgg ccccagataa aagcgtc-gcc 106981 aactttttca ccccggcgga gactttagcg ggtagctgcc ccctaggggg aatggaaaaa 107041 ccaggattta rcaggtgggt ggaggtcaca actgcccaga trctgagaaa gaggggteag 107101 tggggcggga agattagtgg ggagaggagc tttcagaacc caagggaatg aaacgaggct 107161 tgaggttggt tatccagcag ccgccccctg ccccgtgagt gagcgaaggc tgggcccctt 10722 1 attgtcacat cttccagctc ttcgctagaa aaccagt tttaaatact gtggcagctg 107281 agtcaaacaa taaggaaaag cccgactctt tgagagccag gcacaaggcg tctgtgacag 107341 ggtctccagg ctgcccattt gcagtctctg aaacggaggg ttttcgaga aggaggtctt 10740 1 ggggtgcctg ccagaattgg'agggggc gcgggaagtg aggacccaga agagagjgct 107461 tggcccgctg caaggaggtc actggacact ggagctgaag cgccagccga aactggac 10752 1 tcgaaatctg tctccgtgcc agccacaagg cctatgattt tccttggcga cgttcagcat 107581 cttaggagga gctggcgggg gaggcgggta gttcgtgggc ggttgcagca gggcaggaag 107641 gtgaggaacc tgaggctggt cagagagctg gttggagtga tgcccatcgg tggacccgct 107701 ggagaaggcc tgagtagaga aggtctaagc ttaacgggga aggggtgggc cagggtgga 107761 atggggtggg aagtttgagg agggggagca gtggagatgg gggttgtgpg gaatgggagt 107821 gagcttagac gtcttgagga tactgcagtt ctgtgctttt tttcacacct ggctgaaaat 10788 1 tcactgaaaa caaaacaacc cttgctctgt gacagcctag aggggtggga gggaggctta 107941 agagggaggg gacgtgcgtg tgcctatggg cgattcatgt gggtgXacgg cagaaagcaa 108001 cacagtatgt aattarcctc caattaaaga tcaagtacaa cttaaaaacc ccaaacacaa 10806 1 cattgtaagt cagctagact ccagtaaaca mtcagtaag aagattcaac tgggaatgag 108 121 ttccgccgtg actatcctga tgaaftecc gtgtcttctt gaggccattc ctctttgaac 108181 ttccgtgttt ggggaagcgt gcctttgtat ggagtectga ggagtaaatg agacgggctt 10824 1 gtagaaggcc tagtagtgcc ttgcacgcgg cagatgctca ataacctcga gttgtcacca 108301 ttatggtacc tcaagagtct ccttggagct tgcacggttt ctgaatgggg tcctgcgggg 108361 ctcccttggg gctcccacat ggggttgggg ggctgagtgg ggtgtccccg ctccttgctt 108421 gtcccctgtg gaaraccccc ttccacccga gcagctctgc tMgtctet tgtgtttgtt 108481 tatatctcct agattgttgt tcagtcgctc agtcgtgtcc aactctccga cccratggac 108541 tgcagcacac caggccttct grctcacca tctcccggag cttgctcaaa ctcctgtcca 108601 ttgagttgct gatgccgtcc aaccatctcg tcctctgtcg tccccttctc ctttgacct 108661 cagtcttcc cagcatcagg gtcmttcca atgagtcagc tcttgactc aggtggccaa 10872 1 gtattggagc ttcagcttca ttatcagtrc ttccaatgaa tattcagggt tgattt 10878 1 taggattgag tgacttgatc tccftgcagt ccaagggact ctcaagagtc ttcaacacca 108841 cagttcaaaa gcatcagttc ttcggcactc agccttcttt atgatccaac gcccacatcg 100 108901 gtacatgact actggaaaaa ctttggctca gagataattg acttgattga atacaaagtt 108961 cttggcaaa aaataaaagt gtggcaagca gtactgacac aaaagcaagt ggcttttcct 109021 ccgttgagtc atttatttat tcagtgggtg tgtgcgtgta gagacggagc ggctgtgctg 109081 ggagctgggg cttccacttc agaggagccc cggacctgcc ctcggggagt tcacaggcag 109141 tgctgcgggg ggtcctgcca ggacgcctgc cctgcgagtg cccagtgctg tgatggatgc 109201 gtgtcccgca tctgcggcca ctggggccac gtgcccgaga ttgtccgggt ctgagggtgc 109261 agagaagagg aggcatttgg actgagtctg gaaaaatgag catgtggcca cgtgagaagc 109321 cagtggtgag gggaccagtc aggcggagga aagagcggct catacgagtt gtggagctgg 109381 aagcatgagg gtgtgtggaa geagaggccg gggacagggc cgcagggccg gccatggagg 109441 gcgtgggctg ctgcaggctc ctgagaaggg ggacgctgcc atcatgaccg ggtttaggtg 109501 ttgaccctg gtgtccacgt agaggacaga tgtgtggggg gggagctgga gatgggratc' 109561 catcgggagt cagcctggag agaggcagag accccgtcag tgggccctca ggacgtggat 109621 ggggcggatg ttgggaagat ctgactcctg ggttccggct ggggctrcgg gctggagggg 109681 tgccgcccac cgagcacagg aggcaaacag atgccctctc ccagcaagac Cccagcccca 109741 gcaccctccg gggccggact ccgcccctct tccagaatgg ctcccttgct gtcctcgccc 109801 atctttccgg tgccctgagc ctctagagtc tggacaccag cgtccgcctt gcgcttgtt 109861 ctgggaagtc tctggcttgt ctctgactca cceaggaccg tcttcgaggg caaggutgtg -I 0992-1tccttggttc catctgcttt ggggtccggc tcctcgctgc ttgacctgct gatgtgacag * 109981 tgtctcttgt ttcttttca gaatccgaga gcagctgtgt gtgtcccaga cagacccagc 110041 cgctgggatg acgggcccct ctgtggagat ccccccggcc gccaagctgg gtgaggcttt 110101 cgtgtttgcc ggcgggctgg acatgcaggc agacctgttc gcggaggagg acctgggggc 110 161 cccctttctt caggggaggg ctctggagca gatggccgtc atctacaagg agatccctct 110221 cggggagcaa ggcagggagc aggacgatta ccggggggac ttcgatctgt gctccagcc 110281 tgttccgcct cagagcgtec ccccgggaga cagggcccag gacgtgagc. tgttcggcc -110341 gactcctc cagaaacecag acccgactgc gtaccggate acgggcagcg gggaagccgc 110401 cgatccgcct gecagggagg cggtgggcag gggtgacttg gggctgeagg ggccgcccag 110461 gaccgcgcag cccgccaagc cctacgcgtg tcgggagtgc ggcaaggcct tcagccagag 110521 ctcgcacctg ctccggcacc tggtgaUca c-accggggag aagccgtatg agtgcggcga 1105 81 gtgcggcaag gccttcagcc agagctcgca cctgctccgg caccaggcca tccacaccgg 110641* ggagaagccg tacgagtgcg gcgagtgcgg caaggccttc cggcagagct cggccctggc 110701 gcagcacgcg aagacgcaca gcgggaggcg gccgtacgtc tgccgcgagt gcggcaagga 110761 ctteagccgc agctceagcc tgcgcaagca cgagcgcatr cacaccgggg agaagcccta 110821 cgcgtgccag gagtgcggca aggccttcaa ccagagctcg ggcctgagcc agcaccgcaa 1108 81 gatcc-actcg ctgcagaggc cgcacgcctg cgpgctgtgc gggaaggcct tctgccaccg 110941 ctcgcacctg ct8cggeacC agcgcgtcca cacgggcaag aagccgtacg cctgcgcgga 1 11001 ctgcggcaag gccttcagcc agagctccaa cctcatcgag caccgcaaga cgcacacggg 111061 cgagaggccc taccggtgcc acaagtgcgg caaggccttc agccagagct cggcgctcat 11I1121 cgagcaccag cgcacccaca cgggcgagag gccttacgag tgcggccagt gcggcaaggc 11I1181 cttccgccac agctcggcgc tcatccagca ccagcgcacg cacacgggcc gcaagcccta 111241 cgtgtgcaac gagtgcggca aggccttccg ccaccgctcg gcgctcatcg ageactacaa 111301 gacgcacacg cgcgagcggc cctacgagtg caaccgctgc ggcaaggcct tccggggcag 111361 ctcgcaccte ctccgccacc agaaggtcca cgcggcggac aagctctagg gtccgcccgg 111421 ggcgagggca cgccggccct ggcgcccccg gcccagcggg tggacctggg gggccagccg 111481 gaeggcggaa tcccggccgg ctcttctctg ccgtgacccc ggggggttgg ttttgcrctc 111541 cattcgcttt ttctaaagtg cagacgaata cacgtcagag ggacgaagtg gggttaagcc 111601 cccgggagac gtccggcgag ctctaacgtc agacacttga agaagtgaag cggactcgca 111661 gcccgtacag cccggggaag atgagtccaa agtcgagggt caccttggcc actgcagggt 111721 cgctcggcgg tggggcggag cgggtgcagg agggctcctc ctgggcttgg ggtggcaggc 111781 gaggaccccg cgcctctcag ccctcggcct gggttggctg agggcgggcc tggctgtagg 111841 ccctccagcg gaggtggagg cgctgcccgg ctcagccagg cacaggaccc tgccacgagg 111901 agtagccctc cgccagaccc ggcgtccagg ctggggcgcc tgcggggcct ccgttctgtg 111961 gctgggcagc ctgcgccctg tccagggatg aaggggttcc ggtctgaagg gctgggttea 11202 1 gggtccagct ctggccrctc ctgccttggt gtcctggagg aagcccaag gctccgtttc 112081 cctctccagg aggtggggac gttgggaatg ccacattecc ctggggggtg tgtgtgtgtg 112141 ttcaaggctc ccattcagac tgggactggg cactcacgpg ctttggcaac tggcaactga 112201 ggacggagac ccagggtgac accccacctc ctgctgcggc ccccccggca ggggagacac 112261 aggcccgtct ggttcccaag atggcagggc ccctccccct ccagcttgtg ccctgggtgt 112321 ggtgcctggg gctacagcga cccttccgg ttccccgggc cagttcagct gggcatcctc 1123 81 agggcggggc tctgagggtg ccatgtttcc agagctcctc ctcctcccac cagtagcagg 112441 cgggcggcca gctcccaggc agccccctgg catcgcctag gtgcacacct gcccgctgtg 112501 acccagcaag gcttgaaggt ggccatccca gttaagtec ctgrccctgg cccaggaatg 1125 61 ggctcgggca gggccgcatc tggctgcccc agaagcgtct gtccctggcc tctgggagtt 112621 ggcggtggtc tctggtactg tccctcgcag ggccccttag cactgctcgg ggaggaggtg 112681 ggctgaactg attttgaagt tttacatgtc tgcggccgca gtcctacgag cccgtcaggg 112741 tcatgctggt tatttcagca gatggggctt ggctcggc-ag ctaggatggt cctgaataaa 112801 aatgggaagg ccagagctgt tcctccatra gcaggcttgg cagctgggga c-gtgaaagg 112861 acaggtctgc tggtctgggg agaccagctc tgtgcagccc ctgctgtccg tgggggtact 112921 aaaccagccc ctgtgtgcgc ccatctgagt ggcagcccgc ctggaggatc gcccatcact 11298 1 tgtgagaatt gagagaatgc tgacaccccc gcttggtgca gggggacagg gccccctaag 113041 atctacctcc ttgccccacc cccgggaccc cctcagcctt ggccaggact gtrcttactg 113 101 ggcagggcag tcatccactt ccaacctttg ccgtctcctc cgcgcgctgt gctccc-agcc 113161 aaattgtttt afttttcc aagcatcact ttgcacacgt caccactctc cttaaaacca 11322.1 cccttccgga gtctcctgct cgtaaatcgc cggttcagc caacctgggt cgccccccaa 113281 gcccagcaag cctgctgagc cccgcgcctc ccagctactt cacgctcgcc tcaagcttct 113341 aaacgcggac cttctccccc ccacccccat ccctttcttt tctgatttat gtaacacggc 113401 aggtaagact cctctcctga agggttgaca gactcacaca aaaccgtggt cagaccaggc 113461 aagtgcttt tttcagaagt gtgagcggaa cctagtcttc agctcatgct ctttccttgt 113521 ttcttatgt gttctaagtc ctttgacttg ggctcccaga cagcgacgtt gtaagaggcc 1135 81 gtcctggtag catttgaatt gtcetcgagt ttcgttgtcg gattttgttt tattgtctta 113641 gttttccctt cttttgcag acgttgttgp ctgtcgtaaa gctccagttc ntggttctgt -113701 ttactaatea aattgttlg tcaaagtaca tgtattctgc tctttct atcttttg 113761 ftgcttaata ttaacacttt acatttetaa gattaattat ttaggtaatt aataatmtt 113821 aacaffcta gtaaacgtgg gtacttgggt ctgtgttttetttgtag ttacagcttt 11388 1 ttctgctcta tactgttgac gtctgggttt ttttttgctc ttaggaaMt ccctttgacc 113941 ccattattat tattttaatt agtatttt aataattaaa aattagtgtt tttaaattaa 114001 ccctaatcct aaccccagtg atgactgctt cagtcattgc tgttacttat tatgtgctgg 11406 1 tgtcaggatt tttaagtgtc catagacatt ctctgagcct gaatatatta tragt 114121 acagcatttg tgtactctca agaaacgtgt tttcactctg toagttcggt ttgttacctc 114181 agtctttatg ttattttgct ccagtccgca cttgctctaa cttgtcttcc cttcgaggtg 114241 tgaggacgcc tggcagccgg tgagcatgcc ggggtccggg gtcgtgggcc caggcgccca 114301 gcaaagc-cct gtgggtgtgt gcacggctgg gctgctccgg gaggaagcct gtggccccac 114361 ggtagttagg agcgctggtt tacctggtca caccacggtc tggttttgtg tgctttcc 11442 1 tgacgtgttt ctgttttgcc ttggtttcta ttctgtttt tgagtgc-cgt ttacgctttg 114481 ttagtcatgc cgttatctcg atagacaggg tgtacgtgat caagtgatta ccgtattgg 11454 1 agcagatgtc tatttacag agatgaactg agaacctgtg cctttgcatg ccctctttgc 114601 ctctttaat gcttctagct tcaacttctc tttccaaac attataatgg aaaccccttg 114661 cttttttt tttaatttgc atttgcatga gagtttattt agctcggeat tttattt 11472 1 aaatttgtgt atatattttt gctatatate tgtaacttat aaacagcaaa ttbttggatt 114781 ttgctttctg attctttctg taattcttct tacatflagaa gttctectat gagtaac-att 114841 gctgtttaga gtgaggcatg atttatttcc agcttagtat gtattgggtc ggttaacccc 114901 caaaggtcat gctcatcccc gcccctctc tgtgagttat tgtccgagtg tggagcgccc 114961 tgtctaggcc gacgagagac ccaccatcgg gcacacctgc ccctcctggt ctggtcagtg 115021 ccgggctctg tcctgagtcc actcctgatg tcacaggctg gtgcttcagc gacctcggct 115081 gtgacacgga gggtgtgatg gcactgccea gcceeatggg gcttgggga ctaaaggatg 115141 cacacctgcc tggcagactg agggcacagg tgtttcteac actgtcagcg tgaaata 115201 ttcctttgat tttctaccct aactcccaaa ggccgttaa cataagctag aatgctacgt 115261 ggtgcttgat tacattttag aaaagtta gcaaatacca cgagatgcag caaagaacta 115321 gacctracag atcaggccgc ctgcataagg gagcccacac agtcgtggga gacggggac 115381 ctctcccacg tcctgtctgt ccc-aggatgg teccctcacc cgccccctct ctcccctcgc 115441 cctcctgtgg tgggggccgg ccaccatcac agctgcagag cctcaagaag ggggtcgccc 115501 tggccactcc cgtggcagga gggacacgag ggcaggagct taccgcgggt gcagtggtct -115561 cggatcagct cagctggccg ctgcggggte ggggggacag ttcagtggga ggcaggagcc 102 115621 cccactacag ctgccaggac ttctcagagg tgacaagggg gttcagtcac ctcagcccag 115681 gtggaaacca aatggcctct tgcgcggctc ctggggccac gcggaggttc gctgggatca 115741 caggtatctg gatgtgtgcg ccatggacat gcaccacctt cggggggtaa ggggtgggga 115801 aaggcagccc ctttcttttg ggggaccccc tcttcagtgt ctgataacca ggaaaccaaa 115861 tcagaaggtg gtctgggggt gctgagcagg gtgtctccta caccacaggc cacac-actca 11592 1 cacagcctcc aggactccag tggggctgag cgctggagac tcacccacgt ttgctacccc 115981 cccacccaag gccatcccag aacagctgcc tgcgtcctca cggctggccc ctcccctctg 11 6041 gtctaaccca gtgtgggtgg gccggcctgg ggtctccacc tgcctcctgc tgttccctgg 116 101 gctgctggct gtctgcagat gcggggccct ggcccggaga agccccatca gAgcccagag 116161 gacgggagtg gagcggggag gtgagvcccg gagtctcgag gggccagagg caaa atactg 116221 ggctgtgtc-c ctggaaggca gtttcccatg aaaccttcaa tataggccgc cccagacgat 116281 cagcctcatc tgctacgtgg attcctcccc gtagcgaatg gtgattgggt tctacatgga 116341 cccgggactt ctgtttgaat tataatcttt ccccactgc ccctccaggg atctggaaaa 116401 tggaggcctg ggctagacgg aagcttccte caagattctt tattgaaggg attcgaagaig 116461 aaacaggtgg tcagtaatct gtgggggatg gaggggtgag cgctacgtgt aacggttta 116521 ctgttgctac gggaccagtt ttgatgtctt tccccttcaa gaagcagacc caaacaccga *116581 gatgctgagg ttagcagcac agagcgggft catccacaag gcaaccggc agggaga=c -116641 gagacgctct-ggaatctgcc tcrccatggg cacgggctgg gtgctcacgg atgaagacca *116701 agcagcaggt ggcgtggggc gtggggagcc tgcggaaagc gatggacaag gtgcgggacc 116761 gcggtccgcg cggtggaccc aagctccgcc tctgcgctgc agcgcgagct gggggcggag 116821 cttccaggga cccgcgaccg cgcccagtgg gagggtccgc ggtccacca gtcctaacag 116881 ctcagctcca gctngacgcc gctgagtccg gctttctaga gagcaacccc ggcgggtatt 11694 1 ttatggttct ggcttcctga ttggaggaca cgcgagtctt agaacaccct tgattagtgc 117001 gggcaggcgg aatggatttg actgatcacg atctgcagtt tcaccatctc aggggccgcc 11706 1 ctc-accca cctatcctgc caaagggggg gcctcggtgc tgagatcggg gccaoacgtg 11712 1 cactagacgg tcggtcagcg ctgctgctga gcggacccgg ggccatcctc acaccgccac 117181 tggcccctgt getcaataua aggaaggaaa gcgggaaaag cgctutctgg ccgcggtggc 117241 ctcgcgcgtt cctccatcgc catctgctgg cagagcccgg catggcaccc gctgcaeaga 117301 aacctcggtg tccgtttggg tgccccatcc ttgaccccga gagagcaccc tccgtccaaa 117361 atgaaaaac-a gctgctccca agagtcatta taatcac-agc caattgtgtt aattcgtect 117421 cggatccact cacagttcca cggaacattc tgctaacctc tgacaactrc tacataaagc 117481 aatactgaga agaaaagaac gtggttgata aatacaaagg catacaacai taaggagcaa 11754 1 agaaaaaaga cagtc-ctcgc agttctgttt tgttcatctc tcatgagtag gatggcagat 117601 aaaacacaga atgcccagtg aataatmta gtctaagtat gtccccaata ctgcctaate 117661 ttcaatctn accttatttt tanslatatat atttttgct ggtcacteat cagtteatgc 117721 accaaagcct ttgtttcttg actcctaact ttftgacccc tctggggtga gggaccc 11778 1 taacctcgag agcccatcac acagtccct tgggactaga ccntctttg ccc-atrcacag 117841 ctgaccggaa gggccagccc atggccagcg ctcgcgcccc ctggcggaca gactctgcgc 117901 ggcagccccg ggagcccagg tgcgaccccg cggtctctgg cgccctctag tgtggaaaga 117961 tctcctcctg gtgttcccag tcattgggct gtattttatt agagaagatg ctcgcgtgac 118021 gatgatgatg gtcctttacc gggaggcacg ttggggcgc gtcggctcag gggccgagct 118081 attagcctgc atcgcgccca caggcatcgc gtccccctga gccgggtcag ctgtgggctg 118141 tectgacacg ggtttccccc agtctctggc ccgctgtcc tccraggtca gtgtcr-agcg 118201 ttgcccttct ggttgtggac ttgtgcagcg gtetcakcag atggaggggc gaccctaaag 118261 gatgtattga ggcatctcag cactgtcctc cgcccaggtt tgctggtcag cagtgaagtg 118321 accgggaaaa ggggctgtct tggggtcctt tcagaggcct gggttagacc aaagttttct 118381 agaagattca ccattgcagg gagtcaaaga caaaactagg gtggtcagca atctgtgggg 118441 gattcggcgg tgagggaatt ctgaatgcta catgtaatgg ttctatt gttagggaac 118501 attttcccc cctacaaaca gc-aggcctaa atactgagat gtcaggtttg catcaaagg 118561 cgggttcatr cacaaggcaa ccagagaacg ctctggaatc tgcctccctg cgggcacagg 118621 ctgggtgctc acggatgaag accaageagc aggtggcgtg gggagtgggg agcctgggga 118681 aagcgatgga caaggtgcga ggacctccgg cgcgagctgg aggcggagct tccaggga 118741 cgcggccacg cccagtggga gggtcagcgg tccatccagt cctaacagct c-agctccaac 118801 tagacgctgc tgagtctggc tttctagaga acactccggg cgggtatttt attgttttgg 118861 cttcgtgact ggaggacgtt caagtcttaa aacacccttg attagtgcgg ggaggcggaa 118921 tggatttgac tgatcacgac ccgcagtttc accatctcag gggccgccct caccccctc 103 118981 taccctacca aaggtggggg catcggtgct gagatctggg gtgacacata aaatcaggtg 119041 aagtcttagg acagggggcc gattccaggt cctagggtgc agaaaaaacc tacctggccc 119101 cgggctagac agcgtggagg gcgtggcccg ggtggtgca cagaagtggc ccccaactgg 119161 tcagaaggtg tgggagccca gggctggtct actgcagaag gggtcgcctg gtggacagag 11922 1 tggggcctga gtgcctgctg aactggtccg tcagggctgc tgagcagaca cgggccatca 119281 tcactggctc ctgtgctcga tagaagggag ggaaaccagg aaagcaaagg cgctttatgg 119341 ccgcttttgt gtttcgcgtt cctctagcac cgtctgccgg cagaacgcgg cattacatcc 1194 01 gctggccaaa cctcggggtc cggcttggat gtccccatcc ttgtctcgga gatctcacct 119461 ctcagcagtt cccctgggga caatgtcgag aagatgcgac cttgacccgg agctcggtgg 119521 agagggtgcc ctgggttctt tccgcagttg cttggagtgg aggtgcctca tgttgggctg 1195 81 ggaacgggag gaaggaaaca ggtcatgatt gagatgctct agacagactg tccctgctct 119641 tgccaaattt cagaagattg tctttaataa atattccatt ttttgtatgc ccttaggtct 119701 atttccagac actttaaata tattgaaaga ctttaaatat ttatataaaa atattattta 119761 tagactgtat aaaaggaaca gttagaactg gacttggaac aacagactgg ttccaaatag 119821 gaaaaggagt acgtcaaggc tgtatattgt caccctgctt atttactta tatgcagagt 119881 acatcatgag aaacgctggg ctggaagaaa cacaagctgg aatcaagatt gccgggagaa 119941 atatcaataa cctcagatat gcagatgaca ccaecctat ggcagaaagt gaagaggaac 120001 tcaaaagcct cttgatgaag gtgasagagg agagcgaaaa agttggctta aagctca 120061 tttagaaaac gaagatcatg gcatctggtc ccatcacttc atggaaatag atggggaaac 120121 agttgagaca gtgtcagact ttattttgg gggctccaat gaaattaaaa gacgcttact 120181 tcttggaagg aaagttatga ccaacctaga cagcatatta aaaagcagag acactactt 12024 1 gccagcaaag gtccgtctag tcaaggctat ggtttttcca gtggtc-atgt atggatgtga 120301 gagttggact gtgaagaagg ctgagcaccg aagaagtgat gcttttgaac tgtggtgttg 120361 gagaagactc ttgagaggcc cttggactgc aaggagatcc aAccagtcca tcgtaaagga 12042-1 gatcaccccc tgggtggtca tggaggac tgatgttgaa gctgaaactc cagtacutg 120481 gctadcctaat gcgaagagct gactcattgg slaagacct gatgctggga aagattgaag 120541 gtgggaggag aaggggacaa cagaggatga gatggttgga ttgcatcact gactcgatgg 120601 acgtgagtct gagtgaagtc tgggagttgg tgatggccag ggaggccctg gcgtgctggc 120661 ggttcatggg gtcgcaaaga gtcggccatg actgagtgac tgaactgaac tgatecagaa 12072 1 atmaaaatt aatatataaa ccaaatccat gcagacaatt ataagcatat attataaatg 120781 cataattata agcaagtata tgttatattt ataatagttt ataatgtatt tataagcaag 120841 tatatattat tataagcata attgtaagta gaagtaact tgggctttcc tggtggctca 120901 gacagtaaag aatctgcctg cagtacagga gaccgggttc gatccctggt ttgggaaat 120961 tccctggaga agggaatggc aaccaactcc aacatgttg cctggagaat tccatggac-a 121021 gaggagcccg gaaggttgca gtccatgggg ttgcaaagag ctggatacaa cagagtgact 121081 aacacatgta tataaataaa tttacctata tattgtatat atatttataa acatattcag 121141 atattataiaa taattagaaa catattatac atgtatttaa atactgttat aaacataaat 121201 ttaaaaaata atttcagcc ctttggcttg ggggtgtgtt tgtggacgtc tttgtgctac 121261 tgttcctgaa gtggagctct cccctcccaa accagctttt gaaatgactg ggaaagcaat 121321 ggaatacata agcatcagga agatagcaac agagctgtca ttcttcacag agggtgtgct 121381 tgagtgtgta gcaagtcccg cagaatgtag acagattaat atagtctatt aaaaatagtg 121441 tagcaaatt acgaggtgcg atttcaagta taaagactta ctgggtctct cagttcagtt 121501 cagtcgcttg gttgtgtccg actctttttg accccatgga ccgcagcacg ccaggcctcc 121561 ctgtccatca ccaactcctg gagttcactc aaactcatgt ccatcgagtc ggtgatgcca 12162 1 tccaaccatc tcatcctctg gcgtCCCCtt CtCCtCccac cttcaatctt tcccagcatc 121681 agggtctttc ccagtgagtc agttctttgc atcaggtggc cagagtagtg gagttcagc 121741 ttcagcatcg gtccttccaa tgaatattct ggactgattt cctttaggat tgactggttg 12 1801 gatctccttg cagttcaagg gactctcaag agtctc aacagcacag tctatgaita 121861 gaatagcaaa tgaatagaga ataacattta cgaggatata tttaccatt gcataaata 121921 tatcagcttg tagagaacag acttgttccc aggggagagg gtgggtaggg atggagtggg 121981 agtttgngat cancagaagc gagctgttat atagaagatg gataaaaagg atacaca 122041 atgtectact gtgtggcacc gggaectata ttcagtagct tgtgagaaac c-ataatcgac 122101 aagactgagg aaaagtatat atatatgtat gtacttgagt tgctftgctg tac-agaagaa 122161 attaacacaa cattgtaaat cgatatttca atagaatcca cccccccaaa tatataagtt 122221 tcctggagat ggagacggca acccactcca ttcttgcac ccaatattct tgcctggagg 122281 atcccatgga tagaggatcg caaagactcg gacataaccc agcgactaac actttccctt 104 122341 tcaaatgtgt aggtttacta gcgtgaatct acagagatgc ccaagacatt cgtttatgag 122401 gaaaactcca cacgcagctt cactgagaat tattaaacct attaaaggga gagagcgcc-a 122461 ggatattcat ggaftgaaag attcgatgtg gtcaagttgc cagttttccc caaactgatt 122521 ggtaattcc ccaggagctg gctcaaggcg caaaattccc tttaccttttaaugagac 122581 gaagcca agg agccgattct ggttgagaga cgctcaggtc ctctgcggg agagcagccc 122641 tcttcctccc ggtcgcctgg gcagtttcga ggccacgacc agaaggactt ggctccctgt 122701 gtcgcgcact cagaagtctc cctctccgtc ccaaggactc agaagctggg cgtcctgccc 122761 gcagcagagg aggcagcctg gaggggcccc gcgggcacag cggtccgggt ttcagccgag 122821 ttgcccgccc cgcccctcta cctgggcgct gccgcccggc tccggggccg gccgtgccct 12288 1 ccgtggccgc aaggcgtcgc tgtccccccg ctggaagtgc tgacccggag gaaggggcc 12294 1 agacggaggg actcggagc-c tccgagtgac accctgggac tccgagcgct ggagcctggc 123001 gtcaccccag gcaggggcag tgggggcccg gggcggggtc aggggcctcc cccggttctc 123061 atttgacacc gcgggggtgc gctgggcaca gtgtcc-aggg gccacgtucc gaggaggggc 123121 gcgatgvagg -cccgggcgcg gcctgtcccg ggcgcgagtc cagctgcttt gcagaggtgg 123181 cggcaggtcg cagtgaccct cacagagacg ccccactctg cggctccagg tgggcctgtg 123241 cccccagaa gtgctgacct gtgcaccggg aaggcacagg gcccccagc catgtctgcg 123301 atggaagagc cggaaccgcg ccatgcccgt ctcgCtgc cggc-aggcac Ccgccgtgtg 123361 tccacacgct gagccatctg gctcccctlg cugacatac acccaggacc tgagtgtgca 123421 ggaagttaga aggggc-aggt gtggtgac-ac gatgccatcc agcatcacct gagaacctgg 123481 acaaacctca ggggcccagc ctgctctgtg aggccccgag ggccggcccc tccccggacc 123541 cctgccttga atccggccac actgcccgcc ttcctgctcc tgcggcttgt cagacacgc, 123601 tgagcccagg gcctgtgcac tcgctgtccc ttctgccagg actgctcctc cccaggctct 123661 tgctggggct ccccttcttc attcgggggt ggcctctctt gttcagtggc tcagctgtgc 123721 ccagtctttg caaccccatg gactgcagca cgccaggctt ccctgtcctt cactagctc 12378 1 tggagtttgc traaactcat gtccattgag tcagtgatgc tatccaacc-a tctcatcctt 123841 tgctgcccac ttcttctcct gctctcatc tttcccagca tcagggtctt ttccaatgag 123901 ttagctctct gc-atcaggag gccaaagtat tggagcttca gcatcagtec ttccagtgaa 12396 1 tatgcgaggt tgattcct tagaattgac tggttggatc tccttectgt *ccagagaact 124021 ctcaaggt ttetccagca ccacagtcgg agagcatcag ttcucagtg atcaggmtc 12408 1 tttatagccc agctctcaca tcggtacatg actattggaa aacccatagc tttgattaga 12414 1 tggaccttca ttggcaaagt gatgggcctt cattggccct gctttttaat acaccatcta 12420 1 ggtttgtcgt agctttcctt ccaaagagca aacatcttt aatttcctgg ctgcagtaac 124261 catrcatagt gattttggag cccaagaaaa taaaatctgc cactgtttcc acttttccc 124321 cttctatttg ctatgaagtg aggggactgg atgccatgat cttagtttaa accagcagtt 12438 1 gtcacccga ccgcttcctt tcctaaagag ctc *atcacac ctccr-actgg aatgcaatgt 124441 gttgcctgte cgcctgcttc acctcctggg actgctgc aggcttggt ctctgaggcc 12450 1 cctgccgtat ccccagggcc cagagcagtg ctgggcttcg agtccgatca gggactatgt 12456 1 gtgtggactg gatggtgctt gcttcttctg gggaacgaga gacctgggcc tggggaacga 124621 ggggacctgg tgtgaccgga tctcctccct cgggagagga gccaagcgag tggacacagg 124681 tcagtgtgtc ttgctcctgt gtggcaggtg tcccgtctgt gtctgteatc ttggcatttc 124741 ggtgtttctg tgaacccagc ccctccctc ctgatacccc ateccatrcag cacagaggag 124801 actgggcttg gggactctct ggtcctgaga ttcctctccg catgtgactc ccccctcctg 124861 gggggagcag gcaccgtgtg tgaggagggt ggaagcttt caagaccccc agcttttctg 124921 tcccaggggg ctctggcagg gccttgggag ctggaatgag ctggaatctg ggccagtggg 124981 ggtttccctg gtggtaaaga acccgcctgc ccatgcacga ggcataagag acgcgggttc 125041 gatc-actggg tcgggaagat cccctacagg agggcatggc aacccactcc agtattcttt 125 101 cctgaagaat cccttggaca gaggagcctg gtgggctar-a gtctctgggg tggcaaggag 125161 tcggacacga ctgaagcgac ttaccatgca cgcacgcggg gtcaggggtc agggccgcge 125221 tgcttacctg ctgtgtgacc ttagccaggt cacaccccc aggctgtgaa agagaacagt 125281 cttccagc tcgggcatcc aggtctttac agacgtgcct gtgagctttg tgactctggc 125341 tctgtggccg ctagagggcg ctgtccgccg ggccctatgt gcgtgcacgc atgtgagcat 125401 gttcgcatac gtgtgtgcat ctgtcggggg cgcacggtgc ggggacacgg gcacgcggtc 125461 aggaacgcag cc-cggacacc tecacgtggc ccgcgagtac cgtcaggtgg gggctgtggc 125521 tccgctgtgt gggtgacccg ccctccccc gcgaacgtgg tgcatagtga ccgcctggct 125581 gggccctga gctcagccat cctgccccc gggtragctc ccgacaggcc cagctctagg 125641 ccccaggcgt ggaccgaggc ccccajgccc cggcctgtga gatgggacct ccgtctgggg 105 125701 ggctcattct gctcccggag gcctggcagg cccctcctct ttggcattgc ataccctcgc 125761 attggggtgg gtaagcacag taccccatgc ctgtggcccc gtgggagcgg cctgctcagg 125821 gaggccggag cctcagctac agggetgtca caccgggctg cagaggaaga agacgggagc 125881 gaggcctaca ggaacctagc caggccctgg cccactgagc cgacaggagc ctggccagag 125941 gcetgcacag gacggggtgg cggggggggt ggggtggggt gctgggcccc gtggccttga 126001 ctgcagaccc cgagggctcc tcagettaga acggccaagc ctgagtcttg ggggtgcagg 126061 tcaggggg Primers In another embodiment, primers are provided to generate 3' and 5' sequences of a targeting vector. The oligonucleotide primers can be capable of hybridizing to porcine immunoglobulin genomic sequence, such as Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. In a particular embodiment, the primers hybridize under stringent conditions to Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. Another embodiment provides oligonucleotide probes capable of hybridizing to porcine heavy chain, kappa light chain or lambda light chain nucleic acid sequences, such as Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. The polynucleotide primers or probes can have at least 14 bases, 20 bases, 30 bases, or 50 bases which hybridize to a polynucleotide of the present invention. The probe or primer can be at least 14 nucleotides in length, and in a particular embodiment, are at least 15, 20, 25, 28, or 30 nucleotides in length. In one embodiment, primers are provided to amplify a fragment of porcine Ig heavy chain that. includes the functional joining region (the J6 region). In one non-limiting embodiment, the amplified fragment of heavy chain can be represented by Seq ID No 4 and the primers used to amplify this fragment can be complementary to a portion of the J-region, such as, but not limited to Seq ID No 2, to produce the 5' recombination arm and complementary to a portion of Ig heavy-chain mu constant region, such as, but not limited to Seq ID No 3, to produce the 3' recombination arm. In another embodiment, regions of the porcine Ig heavy chain (such as, but not limited to Seq ID No 4) can be subcloned and assembled into a targeting vector. In other embodiments, primers are provided to amplify a fragment of porcine Ig kappa light-chain that includes the constant region. In another embodiment, primers are provided to amplify a fragment of porcine Ig kappa light-chain that includes the J region. In one non limiting embodiment, the primers used to amplify this fragment can be complementary to a portion of the J-region, such as, but not limited to Seq ID No 21 or 10, to produce the 5' 106 recombination arm and complementary to genomic sequence 3' of the constant region, such as, but not limited to Seq ID No 14, 24 or 18, to produce the 3' recombination arm. In another embodiment, regions of the porcine Ig heavy chain (such as, but not limited to Seq. ID No 20) can be subcloned and assembled into a targeting vector. I. Genetic Targeting of the Immunoglobulin Genes The present invention provides cells that have been genetically modified to inactivate immunoglobulin genes, for example, immunoglobulin genes described above. Animal cells that can be genetically modified can be obtained from a variety of different organs and tissues such as, but not limited to, skin, mesenchyme, lung, pancreas, heart, intestine, stomach, bladder, blood vessels, kidney, urethra, reproductive organs, and a disaggregated preparation of a whole or part of an embryo, fetus, or adult animal. In one embodiment of the invention, cells can be selected from the group consisting of, but not limited to, epithelial cells, fibroblast cells, neural cells, keratinocytes, hematopoietic cells, melanocytes, chondrocytes, lymphocytes (B and T), macrophages, monocytes, mononuclear cells, cardiac muscle cells, other muscle cells, granulosa cells, cumulus cells, epidermal cells, endothelial cells, Islets of Langerhans cells, blood cells, blood precursor cells, bone cells, bone precursor cells, neuronal stem cells, primordial stem cells, hepatocytes, keratinocytes, umbilical vein endothelial cells, aortic endothelial cells, microvascular endothelial cells, fibroblasts, liver stellate cells, aortic smooth muscle cells, cardiac myocytes, neurons, Kupffer cells, smooth muscle cells, Schwann cells, and epithelial cells, erythrocytes, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils, adipocytes, chondrocytes, pancreatic islet cells, thyroid cells, parathyroid cells, parotid cells, tumor cells, glial cells, astrocytes, red blood cells, white blood cells, macrophages, epithelial cells, somatic cells, pituitary cells, adrenal cells, hair cells, bladder cells, kidney cells, retinal cells, rod cells, cone cells, heart cells, pacemaker cells, spleen cells, antigen presenting cells, memory cells, T cells, B cells, plasma cells, muscle cells, ovarian cells, uterine cells, prostate cells, vaginal epithelial cells, sperm cells, testicular cells, germ cells, egg cells, leydig cells, peritubular cells, sertoli cells, lutein cells, cervical cells, endometrial cells, mammary cells, follicle cells, mucous cells, ciliated cells, nonkeratinized epithelial cells, keratinized epithelial cells, lung cells, goblet cells, columnar epithelial cells, squamous epithelial cells, osteocytes, 107 osteoblasts, and osteoclasts. In one alternative embodiment, embryonic stem cells can be used. An embryonic stem cell line can be employed or embryonic stem cells can be obtained freshly from a host, such as a porcine animal. The cells can be grown on an appropriate fibroblast-feeder layer or grown in the presence of leukemia inhibiting factor (LIF). In a particular embodiment, the cells can be. fibroblasts; in one specific embodiment, the cells can be fetal fibroblasts. Fibroblast cells are a suitable somatic cell type because they can be obtained from developing fetuses and adult animals in large quantities. These cells can be easily propagated in vitro with a rapid doubling time and can be clonally propagated for use in gene targeting procedures. Targeting constructs Homologous Recombination In one embodiment, immunoglobulin genes can be genetically targeted in cells through homologous.recombination. Homologous recombination permits site-specific modifications in endogenous genes and thus novel alterations can be engineered into the genome. In homologous recombination, the incoming DNA interacts with and integrates into a site in the genome that contains a substantially homologous DNA sequence. In non-homologous ("random" or "illicit") integration, the incoming DNA is not found at a homologous- sequence in the genome but integrates elsewhere, at one of a large number of potential locations. In general, studies with higher eukaryotic cells have revealed that the frequency of homologous recombination is far less than the frequency of random integration. The ratio of these frequencies has direct implications for "gene targeting" which depends on integration via homologous recombination (i.e. recombination between the exogenous "targeting DNA" and the corresponding "target DNA" in the genome). A number of papers describe the use of homologous recombination in mammalian cells. illustrative of these papers are Kucherlapati et al., Proc. Natl. Acad. Sci. USA 81:3153-3157, 1984; Kucherlapati et al., Mol. Cell. Bio. 5:714-720, 1985; Smithies et al, Nature 317:230-234, 1985; Wake et al., Mol. Cell. Bio. 8:2080-2089, 1985; Ayares et al., Genetics 111:375-388, 1985; Ayares et al., Mol. Cell. Bio. 7:1656-1662, 1986; Song et al., Proc. Natl. Acad. Sci. USA 84:6820-6824, 1987; Thomas et al. Cell 44:419-428, 1986; Thomas and Capecchi, Cell 51: 503 512, 1987; Nandi et al., Proc. Natl. Acad. Sci. USA 85:3845-3849, 1988; and Mansour et al:, 108 Nature 336:348-352, 1988. Evans and Kaufman, Nature 294:146-154, 1981; Doetschman et al., Nature 330:576-578, 1987; Thoma and Capecchi, Cell 51:503-512,4987; Thompson et al., Cell 56:316-321, 1989. The present invention can use homologous recombination to inactivate an immunoglobulin gene in cells, such as the cells described above. The DNA can comprise at least a portion of the gene(s) at the particular locus with introduction of an alteration into at least one, optionally both copies, of the native gene(s), so as to prevent expression of functional immunoglobulin. The alteration can be an insertion, deletion, replacement or combination thereof. When the alteration is introduce into only one copy of the gene being inactivated, the cells having a single unmutated copy of the target gene are amplified and can be subjected to a second targeting step, where the alteration can be the same or different from the first alteration, usually different, and where a deletion, or replacement is involved, can be overlapping at least a portion of the alteration originally introduced. In this second targeting step, a targeting vector with the same arms of homology, but containing a different mammalian selectable markers can be used. The resulting transformants are screened for the absence of a functional target antigen and the DNA of the cell can be further screened to ensure the absence of a wild-type target gene. Alternatively, homozygosity as to a phenotype can be achieved by breeding hosts heterozygous for the mutation. Targeting Vectors In another embodiment, nucleic acid targeting vector constructs are also provided. The targeting vectors can be designed to accomplish homologous recombination in cells. These targeting vectors can be transformed into mammalian cells to target the ungulate heavy chain, kappa light chain or lambda light chain genes via homologous recombination. In one. embodiment, the targeting vectors can contain a 3' recombination arm and a 5' recombination arm (i.e. flanking sequence) that is homologous to the genomic sequence of ungulate heavy chain, kappa light chain or lambda light chain genomic sequence, for example, sequence represented by Seq ID Nos. 1, 4, 29, 30, 12, 25, 15, 16, 19, 28 or 31, as described above. The homologous DNA sequence can include at least 15 bp, 20 bp, 25 bp, 50 bp, 100 bp, 500 bp, lkbp, 2 kbp, 4 kbp, 5 kbp, 10 kbp, 15 kbp, 20 kbp, or 50 kbp of sequence, particularly contiguous sequence, homologous to the genomic sequence. The 3' and 5' recombination arms 109 can be designed such that they flank the 3' and 5' ends of at least one functional variable, joining, diversity, and/or constant region of the genomic sequence. The targeting of a functional region can render it inactive, which results in the inability of the cell to produce functional immunoglobulin molecules. In another embodiment, the homologous DNA sequence can include one or more intron and/or exon sequences. In addition to the nucleic acid sequences, the expression vector can contain selectable marker sequences, such as, for example, enhanced Green Fluorescent Protein (eGFP) gene sequences, initiation and/or enhancer sequences, poly A tail sequences, and/or nucleic acid sequences that provide for the expression of the construct in prokaryotic and/or eukaryotic host cells. The selectable marker can be located between the 5' and 3' recombination arm sequence. Modification of a targeted locus of a cell can be produced by introducing DNA.into the cells, where the DNA has homology to the target locus and includes a marker gene, allowing for selection of cells comprising the integrated construct. The homologous DNA in the target vector will recombine with the chromosomal DNA at the target locus. The marker gene can be flanked on both sides by homologous DNA sequences, a 3' recombination arm and a 5' recombination arm. Methods for the construction of targeting vectors have been described in the art, see, for example, Dai et al., Nature Biotechnology 20: 251-255, 2002; WO 00/51424. Various constructs can be prepared for homologous recombination at a target locus. The construct can include at least 50 bp, 100 bp, 500 bp, lkbp, 2 kbp, 4 kbp, 5 kbp, 10 kbp, 15 kbp, 20 kbp, or 50 kbp of sequence homologous with the target locus. The sequence can include any contiguous sequence of an immunoglobulin gene. Various considerations can be involved in determining the extent of homology of target DNA sequences, such as, for example, the size of the target locus, availability of sequences, relative efficiency of double cross-over events at the target locus and the similarity of the target sequence with other sequences. The targeting DNA can include a sequence in which DNA substantially isogenic flanks the desired sequence modifications with a corresponding target sequence in the genome to be modified. The substantially isogenic sequence can be at least about 95%, 97-98%, 99.0-99.5%, 99.6-99.9%, or 100% identical to the corresponding target sequence (except for the desired sequence modifications). In a particular embodiment, the targeting DNA and the target DNA can share stretches of DNA at least about 75, 150 or 500 base pairs that are 100% identical. 110 Accordingly, targeting DNA can be derived from cells closely related to the cell line being targeted; or the targeting DNA can be derived from cells of the same cell line or animal as the cells being targeted. Porcine Heavy Chain Targeting In particular embodiments of the present invention, targeting vectors are provided to target the porcine heavy chain locus. In one particular embodiment, the targeting vector can contain 5' and 3' recombination arms that contain homologous sequence to the 3' and 5' flanking sequence of the J6 region of the porcine immunoglobulin heavy chain locus. Since the J6 region is the only functional joining region of the porcine immunoglobulin heavy chain locus, this will prevent the exression of a functional porcine heavy chain immunoglobulin. In a specific embodiment, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the J6 region, optionally including J1-4 and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the J6 region, including the mu constant region (a "J6 targeting construct"), see for example, Figure -1. Further, this J6 targeting construct can also contain a selectable marker gene that is located between the 5' and 3' recombination arms, see for example, Seq ID No 5 and Figure 1. In other particular embodiments, the 5' targeting arm can contain sequence 5' of J1, such as depicted in Seq ID No. 1 and/ or Seq ID No 4. In another embodiments, the 5' targeting arm can contain sequence 5' of J1, J2 and/ or J3, for example, as depicted in approximately residues 1-300, 1-500, 1-750, 1-1000 and/ or 1-1500 Seq ID No 4. In a further embodiment, the 5' targeting arm can contain sequence 5' of the constant region, for example, as depicted in approximately residues 1-300, 1-500, 1 750, 1-1000, 1-1500 and/ or 1-2000 or any fragment thereof of Seq ID No 4 and/ or any contiguous sequence of Seq ID No. 4 or fragment thereof. In another embodiment, the 3' targeting arm can contain sequence 3' of the constant region and/ or including the constant region, for example, such as resides 7000-8000 and/ or 8000-9000 or fragment thereof of Seq ID No 4. In other embodiments, targeting vector can contain any contiguous sequence or fragment thereof of Seq ID No 4. sequence In other embodiments, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the diversity region, and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the diversity region of the porcine heavy chain locus. In a further embodiment, the targeting 111 vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the mu constant region and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the mu constant region of the porcine heavy chain locus. In further embodiments, the targeting vector can include, but is not limited to any of the following sequences: the Diversity region of heavy chain is represented, for example, by residues 1089-1099 of Seq ID No 29 (D(pseudo)), the Joining region of heavy chain is represented, for example, by residues 1887-3352 of Seq ID No 29 (for example: J(psuedo): 1887-1931 of Seq ID No 29; J(psuedo): 2364-2411 of Seq ID No 29, J(psuedo): 2756-2804 of Seq ID No 29, J (functional J): 3296-3352 of Seq ID No 29), the recombination signals are represented, for example, by residues 3001-3261 of Seq ID No 29 (Nonamer), 3292-3298 of Seq ID No 29 (Heptamer), the Constant Region is represented by the following residues: 3353-9070 of Seq ID No 29 (J to C mu intron), 5522-8700 of Seq ID No 29 (Switch region), 9071-9388 of Seq ID No 29 (Mu Exon 1), 9389-9469 of Seq ID No 29 (Mu Intron A), 9470-9802 of Seq ID No 29 (Mu Exon 2), 9830- 10069 of Seq ID No 29 (Mu Intron B), 10070-10387 of Seq ID No 29 (Mu Exon 3), 10388-10517 of Seq ID No 29 (Mu Intron C), 10815-11052 of Seq ID No 29 (Mu Exon 4), 11034-11039 of Seq ID No 29 (Poly(A) signal) or any fragment or combination thereof. Still further, any contiguous sequence at least about 17, 20, 30, 40, 50, 100, 150, 200 or 300 nucleotides of Seq ID No 29 or fragment and/ or combination thereof can be used as targeting sequence for the heavy chain targeting vector. It is understood that in general when designing a targeting construct one targeting arm will be 5' of the other targeting arm. In other embodiments, targeting vectors designed to disrupt the expression of porcine heavy chain genes can contain recombination arms, for example, the 3' or 5' recombination arm, that target the constant region of heavy chain. In one embodiment, the recombination arm can target the mu constant region, for example, the C mu sequences described above or as disclosed in Sun & Butler Immunogenetics (1997) 46: 452-460. In another embodiment, the recombination arm can target the delta constant region, such as the sequence disclosed in Zhao et al. (2003) J imunol 171: 1312-1318, or the alpha constant region, such as the sequence disclosed in Brown & Butler (1994) Molee Immunol 31: 633-642. Seq ID No.5 GGCCAGACTTCCTCGGAACAGCTCAAAGAGCTCTGTCAAAGCCAGATCCC ATCACACGTGGGCACCAATAGGCCATGCCAGCCrCCAAGGGCCGAACrGG GTTCTCCACGGCGCACATGAAGCCTGCAGCCTGGCTTATCCTCITCCGTG GTGAAGAGGCAGGCCCGGGACTGGACGAGGGGCTAGCAGGGTGTGGTAGG 112 CACC~rGCGCCCCCCACCCCGGCAGGAACCAGAGACCCrGGGGCTGAGAG TGAGCCTCCAAACAGGATGCCCCACCMFCAGGCCACCMTCAATCCAGC TACACTCCACCGCCAFCCCTCGGGCACAGGGCCCAGCCCCTGGATC TTGGCCrGGCrCGACITGCACCCACGACGCACACACACATCCTAACGT GCrGTCCGCTCACCCCTCCCCAGCGTGGTCCATGGGCAGCACGGCAGTGC GCGTCCGGCGGTAGTGAGTGCAGAGGTCCCTTrCCCCTCCCCCAGGAGCCC CAGGGGTGTGTGCAGATCIGGGGGCTCCI'GTCCCTI7ACACCITCATGCCC CrCCCCTCATACCCACCCTCCAGGCGGGAGGCAGCGAGACUI=GCCCAG GGACrCAGCCAACGGGCACACGGGAGGCCAGCCCTCAGCAGCTGGCcc AAAGAGGAGGTGGGAGGTAGGTCCACAGCrGCCACAGAGAGAAACCCTGA CGGACCCCACAGGGGCCACGCCAGCCGGAACCAGCrCCCTCGTGGGTGAG CAATGGCCAGGGOCCCGCCGGCCACCACGGCrGGCCr1GCGCCAGCrGAG AACTCACGTCCAGTGCAGcIGAGACTCAAGACAGCCrGTGCACACAGCCrC GGATCTGCrCCCATrCAAGCAGAAAAAGGAAACCGTGCAGGCAGCCCrC AGCATrrCAAGGATGTAGCAGCGGCCAACrTTnCGTCGGCAGTGGCCGA 1TAGAATGACCGTGGAGAAGGGCGGAAGGGTCFrCGTGGGCrCrGCGGC CAACAGGCCCrGGrCCACCrGCCCGCTGCCAGCCCGAGGGGCTrGGGCC GAGCCAGGAACCACAGTGCrCACCGGGACCACAGTGACrGACCAAACTCC CGGCCAGAGCAGCCCCAGGCCAGCCGGGCrCTCGCCCTGGAGGACTCACC ATCAGATGCACAAGGGGGCGAGTGTGGAAGAGACGTGTCGCCCGGGCCAT* TrGGGAAGGCX3AAGGGACC1TCCAGGTGGACAGGAGGTGGGACGCACTCC AGGCAAGGGACTGGGTCGCCAAGGCCrGGGGAAGGGGTACI'GGCrrGGGG G1TAGCCIrGGCCAGGGAACGGGGAGCG(GGCGGGGGGCTGAGCAGGGAGG ACCrGACC1'CGTGGGAGCGAGGCAAGTCAGGCITCAGGCAGC AGCCGCAC ATcccAGAccAGGAGGCTGAGGcAGGAGGGGcrrocAGcGOGGGOGGG~c CrGCCTGGCrCCGGGGGCTC~rGGOGOACGCGGCrTGmCCGTGTC CCGCAGCACAGGGCCAGCGCrGGGCUI'ATGCITACCITGATGTCrGGG GCCGGGGCGTCAGGGTCGTCGTCrCCI'CAGGGGAGAGTCCCCrGAGGCTA CGOCrGGO*GGGGACTATGTGCAGCTCCACCAGGGGCCrGGGGACCAGGG CCGGAcCAGGCrCGCAGCCCGGAGGACGCGGCAGCGGCTCTGGTCTCTCCAGC ATCrGGCCCrCGGAAATGGCAGAACCCCrGGCGGGTGAGCGAGYCGAGAG CGGGTCAGACAGACAGGGJGCCGGCCGGAAAGGAGAAG1TGGGGGCAGAGC CCGCCAGGGGCCAGGCCCAAGGITCrGTGTGCCAGGGCCrGGGTGGGCAC AITGGTGTGGCCATGGCACAGACGCGTGATCAAGGGCGAITrCCAGC ACACrGGCGGCCGTrACAGTgatcccggcgcgcctaccgggtagggg aggcgcttttcccaaggcagtctggagcatgcgctttagcagccccgctg ggcacttggcgctacacaagtggcctctggcctcgcacacattccacatc caccggtaggcgccaaccggctccgttctttggtggcccctcgcgccac cttctactcctccctagtcaggaagttcccccccgccccgcagctcgcg tcgtgcaggacgtgacaaatggaagtagcacgtctcactagtctcgtgca gatggac-agcaccgctgagcaatggaagcgggtaggcctttggggcagcg gccaatagcagctttggctccttcgcttctgggctcagaggctgggaag gggtgggtrcgggggcgggctr-aggggcgggctaggggcggggcgggcg ccgaggtcctccggaagccggc-attctgcscgcttcaaagcgcacg tctgccgcgctgttctcctcttcctcatctccgggcctttcgacctgcag ccatatgggatcggcr-attpacaagatggattgcacgcaggttctccg gccgcttgggtggagaggctattcggctatgactgggcacaacagacaat cggrctgctctgatgccgccgtgttrccggctgtcagcgcaggggcgcccgg ttcttttgtcaagaccgacctgtccggtgccctgaatgaactgeaggac gaggcagcgcggctatcgtggctggccacgacgggcgttccttgcgcagc tgtgctcgacgttgtrcactgaagcgggaagggactggctgctattgggcg aagtgccggggcaggatctcrctgtcattcacttgctcctgccgagaaa gtatrccatcatggctgatgcaatgcggcggctgcatacgcttgatccggc tacctgcccattcgaccaccaagcgaaacatcgcatcgagcgagcacgta ctcggatggaagccggtcttgtcaatcaggatgatrctggacgaagagcat _________________ aggggcteg cacgaactigtgccaggctrcaaggcgcgcatgcc 113 cgacggcgaggatctcgtcgtgacccatggcgatgcctgcttgccgaata tcatggtggaaaatggccgcttttctggattcatcgactgtggccggctg ggtggcggatcgctatcaggacatagcgttggctacccgtgatattgc tgaagagcttggcpggcgaatgggctgaccgcttcctcgtgcttaggta tcgccgcteccgatcgcagcgeatcgccttctatcgccttcftgacgag ttcttctgaggggatcaattcTCITAGATGCATGCTCGAGCGGCCGCCAGT GTGATGGATATCTGCAGAATrCGCCCTtCCAGGCGTTGAAGTCGTCGTGT CCTCAGGTAAGAACGGCCCrCCAGGGCCT1TAATTrGCTCrCGTCTGT GGr'TrGACTCrGATCCrCGGGAGGCGTCrGTGCCCCCCCCGGGGA TGAGGCCGGCMGCCAGGAGGGGTCAGGGACCAGGAGCCTGTGGGAAGTrT CrGACGGGGGCTGCAGGCGGGAAGGGCCCCACCGGGGGCGAGCCCCAGG CCGCrGGGCGOCAGGAGACCCGTOAGAGTGCGCCTrGAGGAGGGTGTCrG CGGAACCACGAACGCCCGCCGGGAAGGGCTTGCTGCAATGCGGTMrCAG ACGGGAGGCGTCITCTGCCTCACCGTCI=CAAGCCCITGTGGGTCrGA AAGAGCCATGTCGGAGAGAGAAGGGACAGGCCrGTCCCGACCTGGCCGAG AGCGGGCAGCCCCGGGGGAGAGCOGGGCGATCGGCCrGGGCrTGTGAGG CCAGGTCCAAGGGAGGACGTGTGGTCCTCGTGACAGGTGCACrrGCGAAA CCTTAGAAGACGGGGTATGTTGOAAGCGGCTCCTGATG'rTAAGAAAAGG GAGACTGTAAAGTGAGCAGAGTCCCAAGTGTG1-rAAGGI=rAAAGGTC AAAGTGTMTAAACCrTGTGACGCAGTTrAGCAAGCGTGCGGGGAGTGA ATGGGGTGCCAGGGTGGCCGAGAGGCAGTACGAGGGCCGTGCCGTCCrCT AATTCAGGGCrAG=fTGCAGAATAAAGTCGGCCTGTITCrAAAAGCA 'TrGGTGGTGCrGAGCTGGTGGAGGAGGCCGCGGGCAGCCCTGGCCACCrG CAGCAGGTGGCAGGAAGCAGGTCGGCCAAGAGGCrATI=AGGAAGCCAG AAAACACGGTCGATGAA I1ATAGCTrCrGGTrrCCAGGAGGTGGTGOG CATGGCTIGCGCAGCGCCACAGAACCGAAAGTGCCCA~rGAGAAAAAAC AACrCCTGCrAAITGCATF1TCrAAAAGAAGAAACAGAGGCrGACGG AAACTGGAAAGTrCCrG1TIAA~rACTCGAATrGAGTI=CGGTCI-rAG cTATCAACrGCTCACIAGAICA=rICAAAGTAAACGMrAAGAGCC GAGGCATrCCrATCCF~rrCrAAGGCGTTATrCCrGGAGGCrCATrCACC GCCAGCACCrCCGCrGCCrGCAGGCATrGCrGTCACCGTCACCGTGACGG CGCGCACGAT1TCAG'TrGGCCCGCI-rCcCCrCGTGATrAGGACAGACGC GGGCACI'CrGrCCCAGCCGTCrrGGCrCAGTATCrGCAGGCGTCCGTCrC GGGACGGAGCrCAGGGGAAGAGCGTGACrCCAGTTGAACGTGATAGTCGG TGCGTTGAGAGGAGACCCAGTCGGGTGTCGAGTCAGAAGGGGCCCGGGGC CCGAGGCCCTGGGCAGGACGGCCCGTGCCCGCATCACGGGCCCAGCGTC CTAGAGGCAGGACTCTGGTGGAGAGTGiTGAGGGTGCCTGGGGCCCCTCCG GAGCTGGGGCCGTGCGGTGCAGGTrGGGCTCTCGGCGCGGTGTGCTGT TTrGCGGGA1TGGAGGAATrC=rCAGTGATGGGAGTCGCCAGTGAcC GGGCACCAGGCrFGGTAAGAGGGAGG3CCGCCGTCGTGGCCAGAGCAGCTGG GAGGGTTCGGTAAAAGGCCGCCCGMrCCI=AATGAGGACrI=CCTG GAGGGCAT1AGTCrAGTCGGGACCGTJTCGACrCGGGAAGAGGGATGC GGAGGAGGGCATGTGCCCAGGAGCCGAAGGCGCCGCGGGAGAAGCCCAG GGCTCTCCCTGTCCCCACAGAGGCGACGCCAC'rGCCGCAGACAGACAGGGC CrITCCCCrGATGAGGCAAAGGCGCCTCGGCTCITGCGGGGTGCTGGG GGGGAGTCGCCCCGAAGCCGCTCACCCAGAGGCCTGAGGGGTGAGACTGA CCGATGCCrrGGCCGGGCCGGGGCCGGACCGAGOGGGACTrCCGTGGA GGCAGGGCGATGGTGGCTGCGGGAGGGAACCGACCCTGGGCCGAGCCCcGG CFGOCGA7ECCCGGGCGAGGGCCCrCAGCCGAGGCGAGTGGGTCCGYGCG GAACCAcCI=CrGCOCAGCGCCACAGGGCrCTCGGGACrGTCCGGGGC GACGCrGGGCrGCCCGTGGCAGGCCTGGGCTGACCrGGACITCACCAGAC AGAACAGGGCIMCAGGGCTGAGCrGAGCCAGGTrITAGCGAGGCCAAGTG GGGCrGAACCAGGrCAACrGGCCGAGCrGGGTrGAGCrGGGCrGAC~r GGGCTGAGCTGAG~rGG~rGGGCrGGGCrGGGCTGGG3CTGGGCrGGGCr GGACGGCrGAGCrGAGCrGGGrrGAGCTGAGCrGAGCrGGCCTGGGTTG ____________AGCrGGGCrGGGTGAGCrGAGCTGOGUrGAGCTGGGUrGAGCrGGGTrG 114 ATCTGAGCTGAGCTGGGCrGAGCTGAGCAGGCTGGGGTGAGCGGGCTG AGCTGG1TGAGYrGGGTTGAGCTGAGCTGAGCrGGGCTGTGCrGGCrGA GCrAGGCrGAGCTAGGCTAGGTrGAGOGGGCrGGGCrGAGCrGAGCTAG GCrGGGCrGATITGGGCTGAGCrGAGCTGAGCTAGGCrGCGTTGAGCrGG CrGGGCTGGAUTGAGCFGGCrGAGCrGGCrGAGCTGGGCrGAGCrGGCCT GGGTrGAGCITGAGCrGGACTGGYTGAGCTGGGTCGATCTGGGTTGAGCT GTCCrGGG11rGAGTGGGCrGQGTGAGCTGAGCrGOGGTGAGCTGGGCr CAGCAGAGCrGGGTGGOrGAGCGGG~rGAGCTGAGCTGGGCrGAGCr GGCUrGGGTrGAGCrGGGCTGAGCrGAGCrGGGCTGAGCrGGCCTGTGT GAGarGGGCI7GGGUrGAGCGGGCrGAGCrGGA~rGAGCrGGGTrGAGCT GAG0rGGGcrGGGcrGTGcrGAcTGAGcrGGGCTGAGcrAGGCTGGGGTG AG~rGGGerGAG~rGATCCGAGCrAGGCrGGCrGGMGGGCTGAGCTG AGCTc3AGCrAGciCTGGATrGATCrGGCrGAGCrGOGTrGAGCrGAGCTGG GrGAGCrGGTCrGAGCTGGCCrGGGTCGAGCGAGCrGGACrGGm'1GA GCrGGGTCGATCrGGGCTGAGCrGGCCTGGTGAGCTGG43CTGGGnrGA GCTGAGCrGGGTrGAGCrGGGrGAGCrGAGGGCGGGGTGAGCrGGGCT GAACrAGCCTAGCTAGGTGGGCrGAGCTGGGCrGGTrGGGCrGAGCrG AGCGAGCrAGGCGCATGAGCAGOCTGAGCrGGGCTGAGCAGGCCTGG GGTGAGCrGGGCTAGGTGGAGCrGAGCrGGGTCGAGCTGAGTrGGGCrGA GCTGGCCTGGGT1GAGGTAGGCrGAGCTGAGCrGAGCTAGGCrGGGTrGA GCrGCTGGGCTGG]-ITGCGCrGGGTCAAGCTGGGCCGAGCrGGCCrGGG TrGAGCrGGGC]CGGTrGAGCTGGGCrGAG~rGAGCCGACCrAGGCTGGG ATGAGCrGGGCrGA1TGGGCrGAGCTGAGCrGAGCTAGCrGCATrGAG CAGGrGAGGGGCCGGAGCCGGCCrGGGGTGAGCrGGGCrGAGCrG CGCrGAGCrAGGCrGGG0TrGAGCrGGCrGGGCFGGmGCGCGGGTCAA GCrGGGCCGAGCrGGCCTGGGATGAG~rGGGCCGGTI-GGGCTGAGCrGA GCrGAGrAGGCrGCAMrAGCAGGCrGAGCrGGG~rGAGCrGGCCGGGG GTGAGCrGGGCrGAGCrAAGCrGAGCrGGGCrGG1TGGGCrGAGUFGGC TGAGCI'GGGTcCTrGCrGAGCrGGGCTGAGCrGACCAGGGGTGAGCrGOGC TGAGTAGG~rGGGCrCAGCrAGGCrGGGnGATCTGGCAGGGCrGGIT GCGCrGGGTCAAGCrCCCGGGAGATGGCCrGGGATGAGCTGGGCIrGG Trr GGGrGAGCGACYrGAG~rGAGCTAGGCrGCATrGAGCAGGCTGAGCrG GG0FGAGCrGGCUFGGGGTGAGCTGGGCrGGGTGGAGCrGAGCrGGGCrG AA~rGGGCrAAGCrGGCrGAGCrGGATCGAGCrGAGCrGGCI'GAGCTGG CCrCGGGGTrAGCTGGGCTGAGCTGAGCrGAGCTAGTGCTGGGTTGAGCrGG CrGGGCITGGTIGCGCTGGGTCAAGCTGGGCCGAGCTGGCCrGGGTTGAG CTGGGCrGGGCrGAGCGAGCAGGCrGGGTGAGCTGGGCTGGGCrGAG CjGAGCrAGGrGCATrGAGCrGGCGGGATGGATrGAGCrGGCrGAGCT CGCTrGAGCTGGCrGAG~rGGGerGAGCTGCCTCGGGTrGACGGCTGG G1GAGCTGACrGGGCrGAGCTGGGCrCAGCAGAGCrGGGTrGAGCrGA GCrGGGTGAGCGOTAcGGTAGYCAGAGCrGGG'nGAGCrGA GCrGGGTTGAGCrGGGCTCGAGCAGAGCrGGGrrGAGCTGAGCrGGGTrG ACGCrGGGCTCAGCAGACGrGGGnrGAG~rGAGCTGGG1TIGAG~rGGGCFG AGCrAGCTGGGCTCAGCTAGGCrGGGITGAGCTGAGCrGGGCrGAACTGG GaGAG~rGOvGCGAACGGGCTGAGCGGGCrGAGCGGGCrGAGCAGA G(-7GGGCrGAGCAGAGCrGGGrrGGTCrGAGCrGGGTGAGCTGGGCrGA GCTGGGC-TGAGCAGAGTEGGG]TGAGCTGACGCrGGGUCAGCrGGGC~rGA GCrAGGCrGGGOTGAGCTGGGTrGAGUrGGGCTGAGCTGGGCrGGGTrGA GCGGAGCrGGGrGAACTGGGCrGAGCTGGGCrGAGCGGAACrGGGT-rGA TCrGAATrGAGCrGGGCrGAGCCGGGCGAGCCGGGCrGAGCrGGGCrAG G1TGAGCITGGGTGAGCTTGCCrCAGCrGGTCrGAGCTAGGTTGGGTGGA GCrAGGCrGGATrGAGCrGGGCrGAGCrGAGCrGATCrGGC~rCAGCrGG GrGAGGTAGGCTGAAC-GGGCGTGCrGGGCFGAGCGAGCTGAGCCAG TITGAGCTGGG'IrGAGCTGGGCTGAGCTGGGCTGTGTIrGATCJ=CCrGA ACrGGGCrGAGCTGGGCTGAGCrGGCCrAGCrGGATGAACGGGGGTAAG ____________CTGGGCCAGGCrGGACrGGGCrGAGCrGAGCrAGGCrGAGCrGAG1-rGAA 115 TrGGGTTAAGCTGGGCTGAGATGGGCTGAGCTGGGCTGAGCTGGGTTGAG CCAGGTCGGACTGGGTTACCCTGGGCCACACGGGCTGAGCTGGGCGGAG CTCGATrAACCTGGTCAGGCTGAGTCGGGTCCAGCAGACATGCGCTGGCC AGGCTGGCTTGACCTGGACACGTTCGATGAGCTGCCTTGGGATGGTTCAC CrCAGCTGAGCCAGGTGGCTCCAGCrGGGCTGAGCTGGTGACCCTGGGTG ACCrCGGTGACCAGGTTGTCCTGAGTCCGGGCCAAGCCGAGGCrGCATCA GACTCGCCAGACCCAAGGCCTGGGCCCCGGCTGGCAAGCCAGGGGCGGTG AAGGCTGGGCrGGCAGGACTGTCCCGGAAGGAGGTGCACGTGGAGCCGCC CGGACCCCGACCGGCAGGACCTGGAAAGACGCCTCTCACTCCCCITrCrC TrCTGTCCCCTCrCGGGTCCrCAGAGAGCCAGTCTGCCCCGAATCrCrAC CCCCTCGTCrCCrGCGTCAGCCCCCCGTCCGATGAGAGCCTGGTGGCCCT GGGCrGCCTGGCCCGGGACITCCrGCCCAGCrCCGTCACCTCrCCrGGAA Porcine Kappa Chain Targeting In particular embodiments of the present invention, targeting vectors are provided to target the porcine kappa chain locus. In one particular embodiment, the targeting vector can contain 5'. and 3' recombination arms that contain homologous sequence to the 3' and 5' flanking sequence of the constant region of the porcine immunoglobulin kappa chain locus. Since the present invention discovered that there is only one constant region of the porcine immunoglobulin kappa light chain locus, this will prevent the expression of a functional porcine kappa light chain immunoglobulin. In a specific embodiment, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the constant region, optionally including the joining region, and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the constant region, optionally including at least part of the enhancer region (a "Kappa constant targeting construct"), see for example, Figure 2. Further, this kappa constant targeting construct can also contain a selectable marker gene that is located between the 5' and 3' recombination arms, see for example, Seq ID No 20 and Figure 2. In other embodiments, the targeting vector can contain a 5' recombination arm that contains sequence homologous to genomic sequence 5' of the joining region, and a 3' recombination arm that contains sequence homologous to genomic sequence 3' of the joining region of the porcine kappa light chain locus. In other embodiments, the 5' arm of the targeting vector can include Seq ID No 12 and/ or Seq ID No 25 or any contiguous sequence or fragment thereof. In another embodiment, the 3' arm of the targeting vector can include Seq ID No 15, 16 and/ or 19 or any contiguous sequence or fragment thereof. 116 In further embodiments, the targeting vector can include, but is not limited to any of the following sequences: the coding region of kappa light chain is represented, for example by residues 1-549 of Seq ID No 30 and 10026-10549 of Seq ID No 30, whereas the intronic sequence is represented, for example, by residues 550-10025 of Seq ID No 30, the Joining region of kappa light chain is represented, for example, by residues 5822- 7207 of Seq ID No 30 (for example, J1:5822-5859 of Seq ID No.30, J2:6180-6218 of Seq ID No 30, J3:6486-6523 of Seq ID No 30, J4:6826-6863 of Seq ID No 30, J5:7170-7207 of Seq ID No 30), the Constant Region is represented by the following residues: 10026- 10549 of Seq ID No 30 (C exon) and. 10026-10354 of Seq ID No 30 (C coding), 10524-10529 of Seq ID No 30 (Poly(A) signal) and 11160-11264 of Seq ID No 30 (SINE element) or any fragment or combination thereof. Still further, any contiguous sequence .at least about 17, 20, 30, 40, 50, 100, 150, 200 or 300 nucleotides of Seq ID No 30 or fragment and/ or combination thereof can be used as targeting sequence for the heavy chain targeting vector. It is understood that in general when designing a targeting construct one targeting arm will be 5' of the other targeting arm. Seq ID No.20 ctcaaacgtaag cttttcgactgatttttgettttaattgt tggtggctttttgtcatttcaggtttctcgnattagttgtcag ggaccaaacaaattgccttcccagattaggtaccagggaggggacattgc tgcatgggagaccagagggtggctaatttttaacgtttccaagccaaaat aactggggaagggggcttgctgtcctgtgagggtaggtttttatagaagt ggaagttaaggggaaatcgtatggttcacttttggeteggggaccaaag tggagcccaaaattgagtacattttccatcaattatttgtgagatttttg tcctgttgtgtcatttgtgcaagtttttgaattttggttgaatgagcca ttcccagggacccaaaaggatgagaccgaaaagtagaaaagagccaactt ttaagctgagcagacagaccgaattgttgagtttgtgaggagagtagggt ttgtagggagaaaggggaacagatcgctggctttttetctgaattagcct ttctcatgggactggcttcagagggggtttttgatgagggaagtgttcta gagc taactgtgggttgtgtcggtagcgggaccaagctggaaatcaa acgtaagtgcacttttctactcctttttctttcttatacgggtgtgaaat tggggacttttcatgtttggagtatgagttgaggtcagttctgaaggag tgggactcatccaaaaatctgaggagtaagggtcagaacagagttgtctc atggaagaacaaagacctagttagttgatgaggcagctaaatgagtcagt tgacttgggatccaaatggccagacttcgtctgtaaccaacaatctaatg agatgtagcagcaaaaagagatttccattgaggggaaagtaaaattgtta atattgtggatcacetttggtgaagggacategtggagattgaacgtaa gttttttttctactaccttctgaaatttgtetaaatgccagtgttgac ttttagaggcttaagtgtcagttttgtgaaaaatgggtaaacaagagcat ttcatatttattatcagtttcaaaagttaaactcagetccaaaaatgaat ttgtagacaaaagattaatttagccaaattgaatgattcaaaggaaaa aaaaattagtgtagatgaaaaaggaattcttacagctccaaagagcaaaa gcgaattaattttetttgaactttgccaaatcttgtaaatgatttttgtt ctttacaatttaaaaaggttagagaaatgtatttcttagtctgttttctc tcttctgtctgataaattattatatgagataaaaatgaaaanaatagga tgtgetaaaaaatcaptaagaagttagaaaaatatatgtttatgtag 117 ttgccacttaattgagaatcagaagcaatgttattttaaagtctaaaat gagagataaactgtcaatacttaaattctgcagagattctatatcttgac agatatctccttttcaaaaatccaattnctatggtagactaaatttgaa atgatcttcctcataatggagggaaaagatggactgaccccaaaagctca gatttaagaaaacctgtttaaggaaagaaaatannagaactgcatt ttaaaggcccatgaatttgtagaaaalataggaaatattttaataagtgta ttcttttattttcctgttattacttgatggtgtttttataccgccaagga ggccgtggcaccgtcagtgtgatctgtagaccccatggcggccttttt gcgattgaatgaccttggcggtgggtccccagggctctggtggcagcgca ccagccgctaaaagccgctaaauactgccgctaaaggccacagcaacccc gcgaccgcccgttcaactgtgctgacacagtgatacagataatgtcgcta acagaggagaatagaaatatgacgggcacacgctaatgtggggaaaag ggagaagcctgattftttttggattctagagataaaattcccag tattatatcctttaataaaaatttctattaggagattataaagaattt aaagctantttggggtgtaattctttcagtagtctttgtcaa atggatttaagtaatagaggcttaatccaatgagagaaatagacgrcata accctttcaaggcaaaagctacaagagcaaaaattgaacacagcagccag ccatctagccactcagattttgatcagttttactgagtttgaagtaaata tcatgaaggtataattgctgawaaaaaataagatacaggttgcacat ctttaagtttcagaaatttatggcttcagtaggpttatatttcacgtat acaaagtatctaagcagataaaatgccattaatggaaacttaatagaa tatattttaaattccttcattctgtgacagaaatttctaatctgggtc autracctaccctttgaaagagttuagtaatttgctatttgccatr. gctgtttactccagctaafftcaaaagtgatacttgagaattatttt tggtmgcaaccacctggcaggactattttgggccattttaaaactctt ttcaaactaagtatttaaactgttctaaaccatttagggcctttaaaa atcmttttatgattaaacttcgttaaaagttattaaggtgtctggca agaacttccttatcaaatatgctaatagtttaatctgttaatgcaggata tautaagtptaaggcttaccaaacagagtatcttcatagca tatttcccctcttttttagaattcatatgattttgctgccaaggct attttatataatctctggaaaaaagaatagtaatgaaggttaaaagagaag aaaatatc~agaacattaagaattcggtattttactaactgcttggttaac. atgaaggttttattttattaaggtttctatctttataaaatctgttcc cttttctgctgatttctccaagcaaaagattcttgatttgtttttaact cttnctctccacccaagggcctgaatgcccacaaaggggacttccagga ggrccatctggcagctgctcaccgtcagaagtgaagrccagccagttcctc tgggcaggtggccaaaatacgttgacccctcctggtctggctgaarcct tgccccatatggtgacagccatctggccagggcccaggtctccctctgaa gc-ctttgggaggagagggagagtggctggcccgatcacagatgcggaagg ggctgactcctcaaccggggtgcagactctgcagggtgggtctgggccca acacacccaaagcacgcccaggaaggaaaggcagcttggtatcactgcc agagctaggagaggcaccgggaaaatgatctgtccaagacccgttcttgc ttctaaactccggggggteagatgaatgttgtctgcctga gcatctccctgcaagaagcggggaacaca ggaaggaagaaaag atgaactgaacaagatgcaaggcaaaaaaggGGTCTAGCCGCGoTCr AGGAAGC1T~rAGGGTACcT=AGGGATCCCGGCGCGCCCTACCGGGTA GGGGAGGCGCTI=CCCAAGGCAGTCrGGAGCATGCGC'=AGCAGCCCC GCTGGGCACITGGCGCTACACAAGTGGCCrCrGGCCTCGCACACATrCCA CATCCACCGGTAGGCGCCAACCGGCrCCGTrCITGGTGGCCCrrCGCG CCACCICrACrC~rCCCCrAGTCAGGAAGTTCCCCCCCGCCCCGCAGCT CGCGTCGTGCAGGACGTGACAAATGGAAGTAGCACGTCrCACI2AGTCrCG TGCAGATGGACAGCACCGCTGAGCAATGGAAGCGGGTAGGCCrrGGGGC AGCGGCCAATAGCAG=rrGGCrCCITCGCITCrGGGCCAGAGGCrGG. GAAGGGTGGGTCCGGGGGCGGGCTCAGGGCGGGCrCAGGGGCGGGGCG. GGCGCCCGAAGGTCCTCCGGAAGCCCGGCATTCrGCACGCrCAAAAGCG _____________CACGTCTGCCGCGCrGTrCrCCTCrrCCrCATCTCCGGC rrrcGACC'r 118 GCAGCCAATATG43GATCGCCATTGAACAAGATGGAT-rGCACGCAGGTrC TCCGGCCGCTrTGGGTGGAGAGG~rATTCGGCTATGACrGGGCACAACAGA CAATCGGCTGCTCTGATGCCGCCGTG1rCCGGCTGTCAGCGCAGGGGCGC CCGGTTCITTGTCAAGA.CCGACCrGTCCGGTGCCCrGAATGAACrGCA GGACGAGGCAGCGCGGCTATCGTGGCGGCCACGACGGGCGTCCTTGCG CAGCrGTGCrCGACGTTGTCACTGAAGCGGGAAGGGACrGGCTGCTATrG GOcGAAGTGccGGGOcAGGATcrccTGTcATcrcAcU1TGcTccrGccGA GAAAGTATCCATCATGGCrGATGCAATGCGGCGGCTGCATACGC1GATC CGGCTACCrGCCCATCGACCACCAAGCGAAACATCGCATCGAGCGAGCA CGTACTCGGATGGAAGCCGGTCITGTCAATCAGGATGATCTGGACGAAGA GCATCAGGGGCTCGCGCCAGCCGAACTGTrCGCCAGGCrCAAGGCGCGCA TGCCCGACGGCGAGGATCrCGTCGTGACCCATGGCGATGCCTGCITGCCG AATATCATGGTGGAAAATGGCCGCTITCrGGATrCATCGACTGTGGCCG GCTGGGTGTGGCGGATCGCrATCAGGACATAGCGTrGGCrACCCGTGATA TrGCTGAAGAGCrrGGCGGCGAATGGCrGACCGCrCCrCGTGCrrAC GGTATCGCCGCrCCCGATrCGCAGCGCATCGCCYECrATCGCCITCITGA CGAGTT7CTrGAGGGGATCAATrCrCrAGAGCTCGCTGATCAGC~rCGA CrGTGCCrTCrAGTGCCAGCCATCrGTrGnrTGCCCCrCCcCCCGTGCCr TCCrGACCCrGGAAGGTGCCACrCCCACrGTCCi1TCCrAATAAAATGA GGAAATrGCATCGCATTGTCrGAGTAGGTGTCATrCTATrCrGGGGGGTG* GGGTGGOCAGGACAGCAAGGGGGAGGA1TGGGAAGACAATAGCAG3CAT GCTGGGGATGCGGTGGGrCrATGGCrrrGAGGCGGAAAGAACCAGCTG GGGGCGCGCCCctcgagcggccgccagtgtgatggatatctgcagaattc gcccttggatcaaacacgc-atrcctratggacaatatgttgggttcttagc ctgctgagacaacaggaactcccctggc-accactttagaggccaga aacagcacagataaattcctgccctcatgaagcttatagtctagctgg ggagatatcataggcaagataaacacatacaaatacatcatcttaggtaa taatatatactaaggagaaaattaaggggagaaaggaggaatgc tagggtagptagttagatagtcatcaggaaactgttgctgag aagataacatttaggtaaagaccgaagtagtaaggaaatggaccgtgtgc ctnagtgggtaagar-cattctaggcagcaggaacagcgatgaaagrcactg aggtggtcactgcacagagttcactgca-a gttgtgtgggg aggggtaggtcttgcaggctcttatggtrcacaggaagaattgtttctc craccgagatgaggttggtggattttgagcagaagaataattctgcctg gttatatataacagatttccctgggtgctctgatgagaataatctgtc aggggtgggatagggagagatatggcaataggagccttggctaggagccc acgacaataattccaagtgagaggtggtgctgcattgaaagcaggactaa caagarctgctgar-agtgtggatgapaaaatgaggagacgaaggt gcatctagggttttctgcctgaggaattagaaagataaagctaaagctta tagaagatgcagcgctctgggagaaagaccagcagctcagttttatc atctggaattaattttggcataaagtatgaggtatgtgggttaacattat ttgtttttttccatgtagctatccaactgtcccagcatratttat ttaaaagactttccmtcccctattggattgtutggcaccttactga agatcaactggataaaattgggtctattctaagctcttgattccat ccatgacctatttgttcatctttaccccagtagacactgccugatgatt aaagccrcctgttaccatgtctgttttggacatggtaaatctgagatgcct attagccaaccaagcaageacggcccttagagagctagatatgagagcct ggaattcagacgagaaaggtcagtcctgagacatacatgtagtgccatc accatgcggatgggttaaaagccatcagactgcaacagactgtggapgg. gtaccagctagagagcatggatagagaaacr-caagcactgagctgggag gtgctcctcattaagagattagtgagatgaagactgagaagattgatc agagaagaaggaaatcaggaaasatgggctgtcctgaaaatccaaggga agagatgttccaaagaggagaaaactgatcagttgteagctagcgtcaat tgggatgaaatggaccattggacagggatgtagtgggtcatgggtga atagataagagcagcttctatagaatggcaggggcaaaattctcatctga _________________ I tcggcatgggtctaaagaaaacgggaagaaaaaattgaggcatgacc-a 119 gtcccttcaagtagagaggtggaaaagggaaggaggaaaatgaggccacg acaacatgagagaaatgacagcatttttaaaaattttttattttatttta tttatttatttttgctttttagggctgcccctgcaacatatggaggttcc caggttaggggtCtaatcagagtatagtgccagcctacaccacagcca tagcaatgccagatctacatgacctacaccacagctcacagcaacgccgg atccttaacccactgagtgaggccagagatcaaacccatatccttatgga tactagtcaggttcattaccactgagccaaaatgggaaatectgagtaat gacagcattttttaatgtgccaggaagcaaaacttgcaccccgaaatgt ctctcaggcatgtggattattttgagctgaaaacgattaaggcccaaaaa acacaagaagaaatgtggacttcccccaacagccnaaaaatttagatt gagggcctgttcccagaatagagctattgccagacttgttacagaggct aagggctaggtgtggtggggaaaccctcagagatcagagggacgtttatg taccaagcattgacatttccatetccatgcgaatggcettcttccctct gtagccccaaaccaccacccccaaaatettettctgtctttagctgaaga tggtgttgaaggtgatagtttcagccactttggcgagttcctcagttgtt ctgggtctttcctccTgatccacattattcgactgtgtttgattttctcc tgtttattgttcattggcacccatttcattttagccagcccaaaga acetagaagagtgaaggaaaatttettcaccctgacaaatgctaaatga gaatcaccgcagtagaggaaaatgatctggtgctgcgggagatagaagag aaaatcgctggagagatgtcactgagtaggtgagatgggaaaggggtgac acaggtggaggtgttgccctcagtaggaagacagacagttcacagaaga gaagcgggtgtecgtggacatttgcetcatggatgaggaaaCgaggct aagaaagactgcaaaagaaaggtaaggattgcagagaggtcgatccatga ctaaaatcacagtaaccaaccccaaaccacatgttttcctagtctgg cacgtggcaggtactgtgtaggttttcaatattattggtttgtaacagta cctattaggcctccateccctcctctaatactiaangtgtgagactg gtcagtgaaaaatggtettctttctctatgaatctttcaagaagatac ataactttttattttatcataggcttgaagagcaaatgagaaacagcctc caacetatgacaccgtaacaaaatgtttatgatcagtgaagggcaagaaa caaaacatacacagtaaagaccctccataatattgtgggtggcccaacac aggccaggttgtaaaagctttttattctttgatagaggaatggatagtaa tgtttcaacctggacagagatcatgttcactgaatcctccaaaaattca tgggtagtttgaattataaggaaaataagacttaggataaatactttgtc caagateccagagttaatgccaaaatcagttttcagactccaggcagcct gatcaagagcctaaactttaaagacacagtcccttaataactactattca cagttgcactttcagggcgcaaagactcattgaatcctacaatagaatga gtttagatatcasatctctcagtaatagatgaggagactaaatagcgggc atgacctggtcacttaaagacagaattgagattcaaggctagtgttttt ctacctgttttgtttctacaagatgtagcaatgcgctaattacagacctc tcagggaaggaa Porcine Lambda Chain Targeting In particular embodiments of the present invention, targeting vectors are provided to target the porcine heavy chain locus. In one embodiment, lambda can be targeted by designing a targeting construct that contains a 5' arm containing sequence located 5' to the first JC cluster and a 3' arm containing sequence 3' to the last JC cluster, thus preventing functional expression of the lambda locus (see, Figures 3-4). In one embodiment, the targeting vector can contain any contiguous sequence (such as about 17, 20, 30, 40, 50, 75, 100, 200, 300 or 5000 nucleotides of contiguous sequence) or fragment thereof Seq ID No 28. In one embodiment, the 5' targeting 120 arm can contain Seq ID No. 32, which includes 5' flanking sequence to the first lambda J/C region of the porcine lambda light chain genomic sequence or any contiguous sequence (such as about 17, 20, 30, 40, 50, 75, 100, 200, 300 or 5000 nucleotides of contiguous sequence) or fragment thereof (see also, for example Figure 5). In another embodiment, the 3' targeting arm can contain, but is not limited to one or more of the following: Seq ID No. 33, which includes 3' flanking sequence to the J/C cluster region of the porcine lambda light chain genomic sequence, from approximately 200 base pairs downstream of lambda J/C; Seq ID No. 34, which includes 3' flanking sequence to the J/C cluster region of the porcine lambda light chain genomic sequence, approximately 11.8 Kb downstream of the JIC cluster, near the enhancer, Seq ID No. 35, which includes approximately 12 Kb downstream of lambda, including the enhancer region; Seq ID No. 36, which includes approximately. 17.6. Kb downstream of lambda; Seq ID No. 37, which includes approximately 19.1 Kb downstream of lambda; Seq ID No. 38, which includes approximately 21.3 Kb downstream of lambda; and Seq ID No. 39, which includes approximately 27 Kb downstream of lambda, or any contiguous sequence (such as about 17, 20,. 30, 40, 50, 75, 100, 200, 300 or 5000 nucleotides of contiguous sequence) or fragment thereof of Seq ID Nos 32-39 (see also, for example Figure 6). It is understood that in general when designing a targeting construct one targeting arm will be 5' of the other targeting arm. In additional embodiments, the targeting constructs for the lambda locus can contain site specific recombinase sites, such as, for example, lox. In one embodiment, the targeting arms can insert thesite specific recombinase site into the targeted region. Then, the site specific recombinase can be activated and/ or applied to the cell such that the intervening nucleotide sequence between the two site specific recombinase sites is excised (see, for example, Figure 6). Selectable Marker Genes The DNA constructs can be designed to modify the endogenous, target immunoglobulin gene. The homologous sequence for targeting the construct can have one or more deletions, insertions, substitutions or combinations thereof. The alteration can be- the insertion of a selectable marker gene fused in reading frame with the upstream sequence of the target gene. Suitable selectable marker genes include, but are not limited to: genes conferring the ability to grow on certain media substrates, such as the tk gene thymidinee kinase) or the hprt gene (hypoxanthine phosphoribosyltransferase) which confer the ability to grow on HAT 121 medium (hypoxanthine, aminopterin and thymidine); the bacterial gpt gene (guanine/xanthine phosphoribosyltransferase) which allows growth on MAX medium (mycophenolic acid, adenine, and xanthine). See, for example, Song, K-Y., et al. Proc. Nat'l Acad. Sci. U.S.A. 84:6820-6824 (1987); Sambrook, J., et al., Molecular Cloning-A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1989), Chapter 16. Other examples of selectable markers include: genes conferring resistance to compounds such as antibiotics, genes conferring the ability to grow on selected substrates, genes encoding proteins that produce detectable signals such as luminescence, such as green fluorescent protein, enhanced green fluorescent protein (eGFP). A wide variety of such markers are known and available, including, for example, antibiotic resistance genes such as the neomycin resistance gene (neo) (Southern, P., and P. Berg, J. Mol. Apple. Genet. 1:327-341 (1982)); and the hygromycin resistance gene (hyg) (Nucleic Acids Research 11:6895-6911 (1983), and Te Riele, H., et al., Nature 348:649-651 .(1990)). Other selectable marker genes include: acetohydroxyacid synthase (AHAS), alkaline phosphatase (AP), beta _ galactosidase (LacZ), beta. glucoronidase (GUS), chloramphenicol acetyltransferase (CAT), green fluorescent protein (GFP), red fluorescent protein (RFP), yellow fluorescent protein (YFP), cyan fluorescent protein (CFP), horseradish peroxidase (HRP), luciferase (Luc), nopaline synthase (NOS), octopine synthase (OCS), and derivatives thereof. Multiple selectable markers are available that confer resistance to ampicillin, bleomycin, chloramphenicol, gentamycin, hygromycin, kanamycin, lincomycin, methotrexate, phosphinothricin, puromycin, and tetracycline. Methods for the incorporation of antibiotic resistance genes and negative selection factors will be familiar to those of ordinary skill in the art (see, e.g., WO 99/15650; U.S. Patent No. 6,080,576; U.S. Patent No. 6,136,566; Niwa et al., J. Biochem. 113:343-349 (1993); and Yoshida et al., Transgenic Research 4:277-287 (1995)). Combinations of selectable markers can also be used. For example, to target an immunoglobulin gene, a neo gene (with or without its own promoter, as discussed above) can be cloned into a DNA sequence which is homologous to the immunoglobulin gene. To use a combination of markers, the HSV-tk gene can be cloned such that it is outside of the targeting DNA (another selectable marker could be placed on the opposite flank, if desired). After introducing the DNA construct into the cells to be targeted, the cells can be selected on the appropriate antibiotics. In this particular example, those cells which are resistant to G418 and 122 - gancyclovir are most likely to have arisen by homologous recombination in which the neo gene has been recombined into the immunoglobulin gene but the tk gene has been lost because it was located outside the region of the double crossover. Deletions can be at least about 50 bp, more usually at least about 100 bp, and generally not more than about 20 kbp, where the deletion can normally include at least a portion of the coding region including a portion of or one or more exons, a portion of or one or more introns, and can or can not include a portion of the flanking non-coding regions, particularly the 5'-non coding region (transcriptional regulatory region). Thus, the homologous region can extend beyond the coding region into the 5'-non-coding region or alternatively into the 3'-non-coding region. Insertions can generally not exceed 10 kbp, usually not exceed 5 kbp, generally being at least 50 bp, more usually at least 200 bp. The region(s) of homology can include mutations, where mutations can further inactivate the target gene, in providing for a frame shift, or changing a key amino acid, or the mutation can correct a dysfunctional allele, etc..The mutation can be a subtle change, not exceeding about 5% of the homologous flanking sequences. Where mutation of a gene is desired, the marker gene can be inserted into an intron or an exon. The construct can be prepared in accordance with methods known in the art, various fragments can be brought together, introduced into appropriate vectors, cloned, analyzed and then manipulated further until the desired construct has been achieved. Various modifications can be made to the sequence, to allow for restriction analysis, excision, identification of probes, etc. Silent mutations can be introduced, as desired. At various stages, restriction analysis, sequencing, amplification with the polymerase chain reaction, primer repair, in vitro mutagenesis, etc. can be employed. The construct can be prepared using a bacterial vector, including a prokaryotic replication system, e.g. an origin recognizable by E. coli, at each stage the construct can be cloned and analyzed. A marker, the same as or different from the marker to be used for insertion, can be employed, which can be removed prior to introduction into the target cell. Once the vector containing the construct has been completed, it can be further manipulated, such as by deletion of the bacterial sequences, linearization, introducing a short deletion in the homologous sequence. After final manipulation, the construct can be introduced into the cell. 123 The present invention further includes recombinant constructs containing sequences of immunoglobulin genes. The constructs comprise a vector, such as a plasmid or viral vector, into which a sequence of the invention has been inserted, in a forward or reverse orientation. The construct can also include regulatory sequences, including, for example, a promoter, operably linked to the sequence. Large numbers of suitable vectors and promoters are known to those of skill in the art, and are commercially available. The following vectors are provided by way of example. Bacterial: pBs, pQE-9 (Qiagen), phagescript, PsiX174, pBluescript SK, pBsKS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene); pTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia). Eukaryotic: pWLneo, pSv2cat, pOG44, pXTI, pSG (Stratagene) pSVK3, pBPv, pMSG, pSVL (Pharniacia), viral origin vectors (M13 vectors, bacterial phage 1 vectors, adenovirus vectors, and retrovirus vectors), high, low and adjustable copy number vectors, vectors which have compatible replicons for use in combination in a single host (pACYC184 and pBR322) and eukaryotic episomal replication vectors (pCDM8). Other vectors include prokaryotic expression vectors such as. pcDNA II, pSL301, pSE280, pSE380, pSE420, pTrcHisA, B, and C, pRSET A, B, and C (Invitrogen, Corp.), pGEMEX-1, and pGEMEX-2 (Promega, Inc.), the pET vectors (Novagen, Inc.), pTrc99A, pKK223-3, the pGEX vectors, pEZZ18, pR1T2T, and pMC1871 (Phannacia, Inc.), pKK233-2 and pKK388-1 (Clontech, Inc.), and pProEx-HT (Invitrogen, Corp.) and variants and derivatives thereof. Other vectors include eukaryotic expression vectors such as pFastBac, pFastBacHT, pFastBacDUAL, pSFV, and pTet Splice (Invitrogen), pEUK-Cl, pPUR, pMAM, pMAMneo,. pBIl0l, pBI121, pDR2, pCMVEBNA, and pYACneo (Clontech), pSVK3, pSVL, pMSG, pCH110, and pKK232-8 (Pharmacia, Inc.), p3'SS, pXT1, pSG5, pPbac, pMbac, pMCIneo, and pOG44 (Stratagene, Inc.), and pYES2, pAC360, pBlueBacHis A, B, and C, pVL1392, pBlueBacILI, pCDM8, pcDNA1, pZeoSV, pcDNA3 pREP4, pCEP4, and pEBVHis (Invitrogen, Corp.) and variants or derivatives thereof. Additional vectors that can be used include: pUC18, pUC19, pBlueScript, pSPORT, cosmids, phagemids, YAC's (yeast artificial chromosomes), BAC's (bacterial artificial chromosomes), P1 (Escherichia coli phage), pQE70, pQE6O, pQE9 (quagan), pBS vectors, PhageScript vectors, BlueScript vectors, pNH8A, pNH16A, pNH18A, pNH46A (Stratagene), pcDNA3 (Invitrogen), pGEX, pTrsfus, pTrc99A, pET-5, pET-9, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia), pSPORT1, pSPORT2, pCMVSPORT2.0 and pSV-SPORT1 (Invitrogen), pTrxFus, pThioHis, pLEX, pTrcHis, pTrcHis2, pRSET, pBlueBacHis2, 124 pcDNA3.1/His, pcDNA3.1(-)/Myc-His, pSecTag, pEBVHis, pPIC9K, pPIC3.5K, pAO815, pPICZ, pPICZO, pGAPZ, pGAPZO, pBlueBac4.5, pBlueBacHis2, pMelBac, pSinRep5, pSinHis, pIND, pIND(SP1), pVgRXR, pcDNA2.1, pYES2, pZErOi.1, pZErO-2.1, pCR-Blunt, pSE280, pSE380, pSE420, pVL1392, pVL1393, pCDM8, pcDNAI.1, pcDNA1.1/Amp, pcDNA3.1, pcDNA3.i/Zeo, pSe, SV2, pRc/CMV2, pRc/RSV, pREP4, pREP7, pREP8, pREP9, pREP 10, pCEP4, pEBVHis, pCR3.1, pCR2.1, pCR3.1-Uni, and pCRBac from Invitrogen; O ExCell, 0 gtl 1, pTrc99A, pKK223-3, pGEX-1 OT, pGEX-2T, pGEX-2TK, pGEX-4T-1, pGEX 4T-2, pGEX-4T-3, pGEX-3X, pGEX-5X-1, pGEX-5X-2, pGEX-5X-3, pEZZ18, pR1T2T,. pMC1871, pSVK3, pSVL, pMSG, pCH110, pKK232-8, pSL1180, pNEO, and pUC4K from Pharmacia; pSCREEN-lb(+), pT7Blue(R), pT7Blue-2, pCITE-4abc(+), pOCUS-2, pTAg, pET 32LIC, pET-30LIC, pBAC-2cp LIC, pBACgus-2cp LIC, pT7Blue-2 LIC, pT7Blue-2, OSCREEN-1, OBlueSTAR, pET-3abcd, pET-7abc, pET9abcd, pET1labcd, pET12abc, pET 14b, pET-15b, pBT-16b, pET-17b-pET-17xb, pET-19b, pET-20b(+), pET-21abcd(+), pET 22b(t),_pET-23abcd(+), pET-24abcd(+),_pET-25b(+), pET-26b(+), pET-27b(+), pET-28abc(+), pET-29abc(+), pET-30abc(+), pET-31b(+), pET-32abc(+), pET-33b(+), pBAC-1, pBACgus-1, pBAC4x-1, pBACgus4x-1, pBAC-3cp, pBACgus-2cp, pBACsurf-1, pig, Signal pig, pYX, Selecta Vecta-Neo, Selecta Vecta-Hyg, and Selecta Vecta-Gpt from Novagen; pLexA, pB42AD, pGBT9, pAS2-1, pGAD424, pACT2, pGAD GL, pGAD GH, pGAD1O, pGilda, pEZM3, pEGFP, pEGFP-1, pEGFP-N, pEGFP-C, pEBFP, pGFPuv, pGFP, p6xHis-GFP, pSEAP2-Basic, pSEAP2-Contral, pSEAP2-Promoter, pSEAP2-Enhancer, pOgal-Basic, pOgal-Control, pOgal Promoter, pOgal-Enhancer, pCMVO, pTet-Off, pTet-On, pTK-Hyg, pRetro-Off, pRetro-On, pIRESIneo, pIRESihyg, pLXSN, pLNCX, pLAPSN, pMAMneo, pMAMnco-CAT, pMAMneo LUC, pPUR, pSV2neo, pYEX4T-1/2/3, pYEX-SI, pBacPAK-His, pBacPAK8/9, pAcUW31, BacPAK6, pTriplEx, Ogt1O, Ogt11, pWE 15, and OTriplEx from Clontech; Lambda ZAP II, pBK-CMV, pBK-RSV, pBluescript II KS +/-, pBluescript II SK +/-, pAD-GAL4, pBD-GAL4 Cam, pSurfscript, Lambda FIX II, Lambda DASH, Lambda EMBL3, Lambda EMBL4, SuperCos, pCR-Scrigt Amp, pCR-Script Cam, pCR-Script Direct, pBS +/-, pBC KS +/-, pBC SK +/-, Phagescript, pCAL-n-EK, pCAL-n, pCAL-c, pCAL-kc, pET-3abcd, pET-1 labcd, pSPUTK, pESP-1, pCMVLacI, pOPRSVI/MCS, pOPI3 CAT,pXT1, pSG5, pPbac, pMbac, pMClneo, pMClneo Poly A, pOG44, pOG45, pFRTOGAL, pNEOOGAL, pRS403, pRS404, pRS405, pRS406, pRS413, pRS414, pRS415, and pRS416 from Stratagene and variants or derivatives 125 thereof. Two-hybrid and reverse two-hybrid vectors can also be used, for example, pPC86, pDBLeu, pDBTrp, pPC97, p 2

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5 , pGAD1-3, pGADlO, pACt, pACT2, pGADGL, pGADGH, pAS2-1, pGAD424, pGBT8, pGBT9, pGAD-GAL4, pLexA, pBD-GAL4, pHISi, pHISi-1, placZi, pB42AD, pDG202, pJK202, pJG4-5, pNLexA, pYESTrp and variants or derivatives thereof. Any other plasmids and vectors may be used as long as they are replicable and viable in the host. Techniques which can be used to allow the DNA construct entry into the host cell include, for example, calcium phosphate/DNA co precipitation, microinjection of DNA into the nucleus, electroporation, bacterial protoplast fusion with intact cells, transfection, or any other technique known by one skilled in the art. The DNA.can be single or double stranded, linear or circular, relaxed or supercoiled DNA. For various techniques for transfecting mammalian cells, see, for example, Keown et al., Methods in Enzymology Vol. 185, pp. 527-537 (1990). In one specific embodiment, heterozygous or homozygous knockout cells can be - produced. by transfection of primary fetal fibroblasts with a knockout vector containing immunoglobulin gene sequence isolated from isogenic DNA. In another embodiment, the vector can incorporate a promoter trap strategy, using, for example, IRES (internal ribosome entry site) to initiate translation of the Neor gene. Site Specific Recombinases in additional embodiments, the targeting constructs can contain site specific recombinase sites, such as, for example, lox. In one embodiment, the targeting arms can insert thesite specific recombinase target sites into the targeted region such that one site specific recombinase target site is located 5' to the second site specific recombinase target site . Then, the site specific recombinase can be activated and/ or applied to the cell such that the intervening nucleotide sequence between the two site specific recombinase sites is excised. Site-specific recombinases include enzymes or recombinases that recognize and bind to a short nucleic acid site or sequence-specific recombinase target site, i.e., a recombinase recognition site, and catalyze the recombination of nucleic acid in relation to these sites. These enzymes include recombinases, transposases and integrases. Examples of sequence-specific recombinase target sites include, but are not limited to, lox sites, att sites, dif sites and frt sites. Non-limiting examples of site-specific recombinases include, but are not limited to, 126 bacteriophage P1 Cre recombinase, yeast FLP recombinase, Inti integrase, bacteriophage X, phi 80, P22, P2, 186, and P4 recombinase, Tn3 resolvase, the Hin recombinase, and the Cin recombinase, E. coli xerC and xerD recombinases, Bacillus thuringiensis recombinase, TpnI and the p-lactamase transposons, and the immunoglobulin recombinases. In one embodiment, the recombination site can be a lox site that is recognized by the Cre recombinase of bacteriophage Pl. Lox sites refer to a nucleotide sequence at which the product of the cre gene of bacteriophage P1, the Cre recombinase, can catalyze a site-specific recombination evenL A variety of lox sites are known in the art, including the naturally. occurring loxP, loxB, loxL and loxR, as well as a number of mutant, or variant, lox sites, such as. loxP511, loxP514, lox.DELTA.86, lox.DELTA.117, loxC2, loxP2, loxP3 and lox P23. Additional example of lox sites include, but are not limited to, loxB, loxL, loxR, loxP, loxP3, loxP2 3 , loxA86, loxA 117, loxP5 11, and loxC2. In another embodiment, the recombination site is a recombination site that is-recognized by a recombinases other than Cre. In one embodiment, the recombinase site can be the FRT sites. recognized by FLP recombinase of the 2 pi plasmid of Saccharomyces cerevisiae. FRT sites refer to a nucleotide sequence at which the product of the FLP gene of the yeast 2 micron plasmid, FLP recombinase, can catalyze site-specific recombination. Additional examples of the non-Cre recombinases include, but are not limited to, site-specific recombinases include: att sites recognized by the Int recombinase of bacteriophage X (e.g. attl, att2, att3, attP, attB, attL, and attR), the recombination sites recognized by the resolvase family, and the recombination site recognized by transposase of Bacillus thruingiensis. in particular embodiments of the present invention, the targeting constructs can contain: sequence homologous to a porcine immunoglobulin gene as described herein, a selectable marker gene and/ or a site specific recombinase target site. Selection of Homologously Recombined Cells The cells can then be grown in appropriately-selected medium to identify cells providing the appropriate integration. The presence of the selectable marker gene inserted into the immunoglobulin gene establishes the integration of the target construct into the host genome. Those cells which show the desired phenotype can then be further analyzed by restriction 127 analysis, electrophoresis, Southern analysis, polymerase chain reaction, etc to analyze the DNA in order to establish whether homologous or non-homologous recombination occurred. This can be determined by employing probes for the insert and then sequencing the 5' and 3' regions flanking the insert for the presence of the immunoglobulin gene extending beyond the flanking regions of the construct or identifying the presence of a deletion, when such deletion is introduced. Primers can also be used which are complementary to a sequence within the construct and complementary to a sequence outside the construct and at the target locus. In this way, one can only obtain DNA duplexes having both of the primers present in the complementary chains if homologous recombination has occurred. By demonstrating the presence of the primer sequences or the expected size sequence, the occurrence of homologous recombination is supported. The polymerase chain reaction used for screening homologous recombination events is known in the art, see, for example, Kim and Smithies, Nucleic Acids Res. 16:8887-8903, 1988; and Joyner et al., Nature 338:153-156, 1989. The specific combination of a mutant polyoma enhancer and a thymidine kinase promoter to drive the neomycin gene has been shown to be active in both embryonic stem cells and EC cells by Thomas and Capecchi, supra, 1987; Nicholas and Berg (1983) in Teratocarcinoma Stem Cell, eds. Siver, Martin and Strikland (Cold Spring Harbor Lab., Cold Spring Harbor, N.Y. (pp. 469-497); and Linney and Donerly, Cell 35:693-699, 1983. The cell lines obtained from the first round of targeting are likely to be heterozygous for the targeted allele. Homozygosity, in which both alleles are modified, can be achieved in a number of ways. One approach is to grow up a number of cells in which one copy has been modified and then to subject these cells to another round of targeting using a different selectable marker. Alternatively, homozygotes can be obtained by breeding animals heterozygous for the modified allele, according to traditional Mendelian genetics. In some situations; it can be desirable to have two different modified alleles. This can be achieved by successive rounds of gene targeting or by breeding heterozygotes, each of which carries one of the desired modified alleles. 128 Identification Of Cells That Have Undergone Homologous Recombination In one embodiment, the selection method can detect the depletion of the immunoglobulin gene directly, whether due to targeted knockout of the immunoglobulin gene by homologous recombination, or a mutation in the gene that results in a nonfunctioning or nonexpressed immunoglobulin. Selection via antibiotic resistance has been used most commonly for screening (see above). This method can detect the presence of the resistance gene on the targeting vector, but does not directly indicate whether integration was a targeted recombination event or a random integration. Certain technology, such as Poly A and promoter trap technology, increase the probability of targeted events, but again,. do not give direct evidence that the desired phenotype, a cell deficient in immunoglobulin gene expression, has been achieved. In addition, negative forms of selection can be used to select for targeted integration; in these cases, the gene for a factor lethal to the cells is inserted in such a way that only targeted events allow the cell to avoid.deat._ Cellsselected by thestmethods. can then..b.e.assayed for.gene disruption, vector integration and, finally, immunoglobulin gene depletion. In these cases, since the selection is based on detection of targeting vector integration and not at the altered phenotype, only targeted knockouts, not point mutations, gene rearrangements or truncations or other such modifications can be detected. Animal cells believed to lacking expression of functional immunoglobulin genes can be further characterized. Such characterization can be accomplished by the following techniques, including, but not limited to: PCR analysis, Southern blot analysis, Northern blot analysis, specific lectin binding assays, and/or sequencing analysis. PCR analysis as described in the art can be used to determine the integration of targeting vectors. In one embodiment, amplimers can originate in the antibiotic resistance gene and extend into a region outside the vector sequence. Southern analysis can also be used to characterize gross modifications in the locus, such as the integration of a targeting vector into the immunoglobulin locus. Whereas, Northern analysis can be used to characterize the transcript produced from each of the alleles. Further, sequencing analysis of the cDNA produced from the RNA transcript can also be used to determine the precise location of any mutations in the immunoglobulin allele. 129 In another aspect of the present invention, ungulate cells lacking at least one allele of a functional region of an ungulate heavy chain, kappa light chain and/or lambda light chain locus produced according to the process, sequences and/or constructs described herein are provided. These cells can be obtained as a result of homologous recombination. Particularly, by inactivating at least one allele of an ungulate heavy chain, kappa light chain or lambda light chain gene, cells can be produced which have reduced capability- for expression of porcine antibodies. In other embodiments, mammalian cells lacking both alleles of an ungulate heavy chain, kappa light chain and/or lambda light chain gene can be produced according to the process, sequences and/or constructs described herein. In a further embodiment, porcine animals are provided in which at least one allele of an ungulate heavy chain, kappa light chain and/or lambda light chain gene is inactivated via a genetic targeting event produced according to the process, sequences and/or constructs described herein. In another aspect of the present invention, porcine animals are provided in which both alleles of an ungulate heavy chain, kappa light chain and/or lambda light chain gene are inactivated via a genetic targeting event. The gene can be targeted via homologous recombination. In other embodiments, the gene can be disrupted, i.e. a portion of the genetic code can be altered, thereby affecting transcription and/or translation of that segment of the gene. For example, disruption of a gene can occur through substitution, deletion ("knock-out") or insertion ("knock-in") techniques. Additional genes for a desired protein or regulatory sequence that modulate transcription of an existing sequence can be inserted. In embodiments of the present invention, alleles of ungulate heavy chain, kappa light chain or lambda light chain gene are rendered inactive according to the process, sequences and/or constructs described herein, such that functional ungulate immunoglobulins can no longer be produced. In one embodiment, the targeted immunoglobulin gene can be transcribed into RNA, but not translated into protein. In another embodiment, the targeted immunoglobulin gene can be transcribed in an inactive truncated form. Such a truncated RNA may either not be translated or can be translated into a nonfunctional protein. In an alternative embodiment, the targeted immunoglobulin gene can be inactivated in such a way that no transcription of the gene occurs. In a further embodiment, the targeted inmnunoglobulin gene can be transcribed and then translated into a nonfunctional protein. 130 II. Insertion of Artificial Chromosomes Containing Human Immunoglobulin Genes Artificial Chromosomes One aspect of the present invention provides ungulates and ungulate cells that lack at least one allele of a functional region of an ungulate heavy chain, kappa light chain and/or lambda light chain locus produced according to the processes, sequences and/or constructs described herein, which are further modified to express at least part of a human antibody (i.e. immunoglobulin (Ig)) locus. This human locus can undergoe rearrangement and express a diverse population of human antibody molecules in the ungulate. These cloned, transgenic ungulates provide a replenishable, theoretically infinite supply of human antibodies (such as polyclonal antibodies), which can be used for therapeutic, diagnostic, purification, and other clinically relevant purposes. In one particular embodiment, artificial chromosome (ACs) can be used to accomplish the transfer of human immunoglobulin genes into ungulate cells and animals. ACs permit targeted integration of megabase size DNA fragments that contain single or multiple genes. The ACs, therefore, can introduce heterologous DNA into selected cells for production of the gene product encoded by the heterologous DNA. In a one embodiment, one or more ACs with integrated human immunoglobulin DNA can be used as a vector for introduction of human Ig genes into ungulates (such as pigs). First constructed in yeast in 1983, ACs are man-made linear DNA molecules constructed from essential cis-acting DNA sequence elements that are responsible for the proper replication and partitioning of natural chromosomes (Murray et al. (1983), Nature 301:189-193). A chromosome requires at least three elements to function. Specifically, the elements of an artificial chromosome include at least: (1) autonomous replication sequences (ARS) (having properties of replication origins - which are the sites for initiation of DNA replication), (2) centromeres (site of kinetochore assembly that is responsible for proper distribution of replicated chromosomes at mitosis and meiosis), and (3) telomeres (specialized structures at the ends of linear chromosomes that function to both stabilize the ends and facilitate the complete replication of the extreme termini of the DNA molecule). In one embodiment, the human Ig can be maintained as an independent unit (an episome) apart from the ungulate chromosomal DNA. For example, episomal vectors contain the 131 necessary DNA sequence elements required for DNA replication and maintenance of the vector within the cell. Episomal vectors are available commercially (see, for example, Maniatis, T. et al., Molecular Cloning, A Laboratory Manual (1982) pp. 368-369). The AC can stably replicate and segregate along side endogenous chromosomes. In an alternative embodiment, the human IgG DNA sequences can be integrated into the ungulate cell's chromosomes thereby permitting the new information to be replicated and partitioned to the cell's progeny as a part of the natural chromosomes (see, for example, Wigler et al. (1977), Cell 11:223). The AC can be translocated to, or inserted into, the endogenous chromosome of the ungulate cell. Two or more ACs can be introduced to the host cell simultaneously or sequentially. ACs, furthermore, can provide an extra-genomic locus for targeted integration of megabase size DNA fragments that contain single or multiple genes, including multiple copies of a single gene operatively linked to one promoter or each copy or several copies linked to separate promoters. ACs can permit the targeted integration of megabase size DNA fragments that contain single or multiple human immunoglobulin genes. The ACs can be generated by culturing the cells with dicentric chromosomes (i.e., chromosomes with two centromeres) under such conditions known to one skilled in the art whereby the chromosome breaks to form a minichromosome and formerly dicentric chromosome. ACs can be constructed from humans (human artificial chromosomes: "HACs"), yeast (yeast artificial chromosomes: "YACs"), bacteria (bacterial artificial chromosomes: "BACs"), bacteriophage P1-derived artificial chromosomes: "PACs") and other mammals (mammalian artificial chromosomes: "MACs"). The ACs derive their name (e.g., YAC, BAC, PAC, MAC, HAC) based on the origin of the centromere. A YAC, for example, can derive its centromere from S. cerevisiae. MACs, on the other hand, include an active mammalian centromere while HACs refer to chromosomes that include human centromeres. Furthermore, plant artificial chromosomes ("PLACs") and insect artificial chromosomes can also be constructed. The ACs can include elements derived from chromosomes that are responsible for both replication and maintenance. ACs, therefore, are capable of stably maintaining large genomic DNA fragments such as human Ig DNA.. In one emobidment, ungulates containing YACs are provided. YACs are genetically engineered circular chromosomes that contain elements from yeast chromosomes, such as S. cerevisiae, and segments of foreign DNAs that can be much larger than those accepted by 132 conventional cloning vectors (e.g., plasmids, cosmids). YACs allow the propagation of very large segments of exogenous DNA (Schlessinger, D. (1990), Trends in Genetics 6:248-253) into mammalian cells and animals (Choi et al. (1993), Nature Gen 4:117-123). YAC transgenic approaches are very powerful and are greatly enhanced by the ability to efficiently manipulate the cloned DNA. A major technical advantage of yeast is the ease with which specific genome modifications can be made via DNA-mediated transformation and homologous recombination (Ramsay, M. (1994), Mol Biotech 1:181-201). In one embodiment, one or more YACs. with integrated human Ig DNA can be used as a vector for introduction of human Ig genes into. ungulates (such as pigs). The YAC vectors contain specific structural components for replication in yeast, including: a centromere, telomeres, autonomous replication sequence (ARS), yeast selectable markers (e.g., TRP1, URA3, and SUP4), and a cloning site for insertion of large segments of greater than 50 kb of exogenous DNA. The marker genes can allow selection of the cells carrying the YAC and serve as sites for the synthesis of specific restriction endonucleases. For example, the TRP) and URA3 genes can be used as dual selectable markers to ensure that only complete artificial chromosomes are maintained. Yeast selectable markers can be carried on both sides of the centromere, and two sequences that seed telomere formation in vivo are separated. Only a fraction of one percent of a yeast cell's total DNA is necessary for replication, however, including the center of the chromosome (the centromere, which serves as the site of attachment between sister chromatids and the sites of spindle fiber attachment during mitosis), the ends of the chromosome (telomeres, which serve as necessary sequences to maintain the ends of eukaryotic chromosomes), and another short stretch of DNA called the ARS which serves as DNA segments where the double helix can unwind and begin to copy itself. In one embodiment, YACs can be used to clone up to about 1, 2, or 3 Mb of immunoglobulin DNA. In another embodiment, at least 25, 30, 40, 50, 60, 70, 75, 80, 85, 90, or 95 kilobases. Yeast integrating plasmids, replicating vectors (which are fragments of YACs),can also be used to express human Ig. The yeast integrating plasmid can contain bacterial plasmid sequences that provide a replication origin and a drug-resistance gene for growth in bacteria (e.g., E. coli), a yeast marker gene for selection of transformants in yeast, and restriction sites for inserting Ig sequences. Host cells can stably acquire this plasmid by integrating it directly into a 133 chromosome. Yeast replicating vectors can also be used to express human Ig as free plasmid circles in yeast. Yeast or ARS-containing vectors can be stabilized by the addition of a centromere sequence. YACs have both centromeric and telomeric regions, and can be used for cloning very large pieces of DNA because the recombinant is maintained essentially as a yeast chromosome. YACs are provided, for example, as disclosed in U.S. Pat. Nos. 6,692,954, 6,495,318, 6,391,642, 6,287,853, 6,221,588, 6,166,288, 6,096,878, 6,015,708, 5,981,175, 5,939,255, 5,843,671, 5,783,385, 5,776,745, 5,578,461, and 4,889,806; European Patent Nos. 1 356 062 and 0 648 265; PCT Publication. Nos. WO 03/025222, WO 02/057437, WO 02/101044, WO 02/057437, WO 98/36082, WO 98/12335, WO 98/01573, WO 96/01276, WO 95/14769, WO 95/05847, WO 94/23049, and WO 94/00569. In another embodiment, ungulates containing BACs are provided. BACs are F-based plasmids found in bacteria, such as E. Coli, that can transfer approximately 300 kb of foreign DNA into a .host cell. Once the Ig DNA has been cloned into the host cell, the newly inserted segment can be replicated along with the rest of the plasmid. As a result, billions of copies of the foreign DNA can be made in a very short time. In a particular embodiment, one or more BACs with integrated human Ig DNA are used as a vector for introduction of human Ig genes into ungulates (such as pigs). The BAC cloning system is based on the E. coli F-factor, whose replication is strictly controlled and thus ensures stable maintenance of large constructs (Willets, N., and R. Skurray (1987), Structure and function of the F-factor and mechanism of conjugation. In Escherichia coli and Salmonella Typhimurium: Cellular and Molecular Biology (F. C. Neidhardt, Ed) Vol.2 pp 1110-1133, Am. Soc. Microbiol., Washington, D.C.). BACs have been widely used for cloning of DNA from various eukaryotic species (Cai et al. (1995), Genomics 29:413-425; Kim et al. (1996), Genomics 34:213-218; Misumi et al. (1997), Genomics 40:147-150; Woo et al. (1994), Nucleic Acids Res 22:4922-4931; Zimmer, R. and Gibbins, A.M.V. (1997), Genomics 42:217 226). The low occurance of the F-plasmid can reduce the potential for recombination between DNA fragments and can avoid the lethal overexpression of cloned bacterial genes. BACs can stably maintain the human immunoglobulin genes in a single copy vector in the host cells, even after 100 or more generations of serial growth. 134 BAC (or pBAC) vectors can accommodate inserts in the range of approximately 30 to 300 kb pairs. One specific type of BAC vector, pBeloBac11, uses a complementation of the lac2Z gene to distinguish insert-containing recombinant molecules from colonies carrying the BAC vector, by color. When a DNA fragment is cloned into the lacZ gene of pBeloBac11, insertional activation results in a white colony on X-Gal/IPTG plates after transformation (Kim et al. (1996), Genomics 34:213-218) to easily identify positive clones. For example, BACs can be provided such as disclosed in U.S. Pat. Nos. 6,713,281, 6,703,198, 6,649,347, 6,638,722, 6,586,184, 6,573,090, 6,548,256, 6,534,262, 6,492,577,. 6,492,506, 6,485,912, 6,472,177, 6,455,254, 6,383,756, 6,277,621, 6,183,957, 6,156,574, 6,127,171, 5,874,259, 5,707,811, and 5,597,694; European Patent Nos. 0 805 851; PCT Publication Nos. WO 03/087330, WO 02/00916, WO 01/39797, WO 01/04302, WO 00/79001, WO 99/54487, WO 99/27118, and WO 96/21725. In another embodiment, ungulates containing bacteriophage PACs are provided. In a particular embodiment, one or more bacteriophage PACs with integrated human Ig DNA are used as a vector for introduction of human Ig genes into ungulates (such as pigs). For example, PACs can be provided such as disclosed in U.S. Pat. Nos. 6,743,906, 6,730,500, 6,689,606, 6,673,909, 6,642,207, 6,632,934, 6,573,090, 6,544,768, 6,489,458, 6,485,912, 6,469,144, 6,462,176, 6,413,776, 6,399,312, 6,340,595, 6,287,854, 6,284,882, 6,277,621, 6,271,008, 6,187,533, 6,156,574, 6,153,740, 6,143,949, 6,017,755, and 5,973,133; European Patent Nos. 0 814 156; PCT Publication Nos. WO 03/091426, WO 03/076573, WO 03/020898, WO 02/101022, WO 02/070696, WO 02/061073, WO 02/31202, WO 01/44486, WO 01/07478, WO 01/05962, and WO 99/63103,. In a further embodiment, ungulates containing MACs are provided. MACs possess high mitotic stability, consistent and regulated gene expression, high cloning capacity, and non immunogenicity. Mammalian chromosomes can be comprised of a continuous linear strand of DNA ranging in size from approximately 50 to 250 Mb. The DNA construct can further contain one or more sequences necessary for the DNA construct to multiply in yeast cells. The DNA construct can also contain a sequence encoding a selectable marker gene. The DNA construct can be capable of being maintained as a chromosome in a transformed cell with the DNA construct. MACs provide extra-genomic specific integration sites for introduction of genes encoding proteins of interest and permit megabase size DNA integration so that, for example, 135 genes encoding an entire metabolic pathway, a very large gene [e.g., such as the cystic fibrosis (CF) gene (- 600 kb)], or several genes [e.g., a series of antigens for preparation of a multivalent vaccine] can be stably introduced into a cell. Mammalian artificial chromosomes [MACs] are provided. Also provided are artificial chromosomes for other higher eukaryotic species, such as insects and fish, produced using the MACS are provided herein. Methods for generating and isolating such chromosomes. Methods using the MACs to construct artificial chromosomes from other species, such as insect and fish species are also provided. The artificial chromosomes are fully functional stable chromosomes. Two types of artificial chromosomes are provided. One type, herein referred to as SATACs [satellite artificial chromosomes] are stable heterochromatic chromosomes, and the another type are minichromosomes based on amplification of euchromatin. As used herein, a formerly dicentric chromosome is a chromosome that is produced when a dicentric chromosome fragments and acquires new telomeres so that two chromosomes, each having one of the centromeres, are produced. Each of the fragments can be replicable chromosomes. Also provided are artificial chromosomes for other higher eukaryotic species, such as insects and fish, produced using the MACS are provided herein. In one embodiment, SATACs [satellite artificial chromosomes] are provided. SATACs are stable heterochromatic chromosomes. In another embodiment, minichromosomes are provided wherein the minichromosomes are based on amplification of euchromatin. In one embodiment, artificial chromosomes can be generated by culturing the cells with the dicentric chromosomes under conditions whereby the chromosome breaks to form a minichromosome and formerly dicentric chromosome. In one embodiment, the SATACs can be generated from the minichromosome fragment, see, for example, in U.S. Pat. No. 5,288,625. In another embodiment, the SATACs can be generated from the fragment of the formerly dicentric chromosome. The SATACs can be made up of repeating units of short satellite DNA and can be fully heterochromatic. In one embodiment, absent insertion of heterologous or foreign DNA, the SATACs do not contain genetic information. In other embodiments, SATACs of various sizes are provided that are formed by repeated culturing under selective conditions and subcloning of cells that contain chromosomes produced from the formerly dicentric chromosomes. These chromosomes can be based on repeating units 7.5 to 10 Mb in size, or megareplicons. These megareplicaonscan be tandem blocks of satellite DNA flanked by heterologous non-satellite 136 DNA. Amplification can produce a tandem array of identical chromosome segments [each called an amplicon] that contain two inverted megareplicons bordered by heterologous ["foreign"] DNA. Repeated cell fusion, growth on selective rnedium and/or. BrdU [5 bromodeoxyuridine] treatment or other genome destabilizing reagent or agent, such as ionizing radiation, including X-rays, and subcloning can result in cell lines that carry stable heterochromatic or partially heterochromatic chromosomes, including a 150-200 Mb "sausage" chromosome, a 500-1000 Mb gigachromosome, a stable 250-400 Mb megachromosome and various smaller stable chromosomes derived therefrom . These chromosomes are based on these repeating units and can include human immunoglobulin DNA that is expressed. (See also US Patent No. 6,743,967 In other embodiments, MACs can be provided, for example, as disclosed in U.S. Pat. Nos. 6,743,967, 6,682,729, 6,569,643, 6,558,902, 6,548,287, 6,410,722, 6,348,353, 6,297,029, 6,265,211, 6,207,648, 6,150,170, 6,150,160, 6,133,503, 6,077,697, 6,025,155, 5,997,881, 5,985,846, 5,981,225, 5,877,159, 5,851,760, and 5,721,118; PCT Publication Nos. WO 04/066945, WO 04/044129, WO 04/035729, WO 04/033668, WO 04/027075, WO 04/016791, WO 04/009788, WO 04/007750, WO 03/083054, WO 03/068910, WO 03/068909, WO 03/064613, WO 03/052050, WO 03/027315, WO 03/023029, WO 03/012126, WO 03/006610, WO 03/000921, WO 02/103032, WO 02/097059, WO 02/096923, WO 02/095003, WO 02/092615, WO 02/081710, WO 02/059330, WO 02/059296, WO 00/18941, WO 97/16533, and WO 96/40965. In another aspect of the present invention, ungulates and ungulate cells containing HACs are provided. In a particular embodiment, one or more HACs with integrated human Ig DNA are used as a vector for introduction of human Ig genes into ungulates (such as pigs). In a particular embodiment, one or more HACs with integrated human Ig DNA are used to generate ungulates (for example, pigs) by nuclear transfer which express human Igs in response to immunization and which undergo affinity maturation. Various approaches may be used to produce ungulates that express human antibodies ("human Ig"). These approaches include, for example, the insertion of a HAC containing both heavy and light chain Ig genes into an ungulate or the insertion of human B-cells or B-cell precursors into an ungulate during its fetal stage or after it is born (e.g., an immune deficient or immune suppressed ungulate) (see, for example, WO 01/35735, filed November 17, 2000, US 137 02/08645, filed March 20, 2002). In either case, both human antibody producing cells and ungulate antibody-producing B-cells may be present in the ungulate. In an ungulate containing a HAC, a single B-cell may produce an antibody that contains a combination of ungulate and human heavy and light chain proteins. In still other embodiments, the total size of the HAC is at least to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Mb. For example, HACs can be provided such as disclosed in U.S.. Pat. Nos. 6,642,207, 6,590,089, 6,566,066, 6,524,799, 6,500,642, 6,485,910, 6,475,752, 6,458,561, 6,455,026, 6,448,041, 6,410,722, 6,358,523, 6,277,621, 6,265,211, 6,146,827, 6,143,566, 6,077,697, . 6,025,155, 6,020,142, and 5,972,649; U.S. Pat. Application No. 2003/0037347; PCT Publication Nos. WO 04/050704, WO 04/044156, WO 04/031385, WO 04/016791, WO 03/101396, WO 03/097812, WO 03/093469, WO 03/091426, WO 03/057923, WO 03/057849, WO 03/027638, WO 03/020898, WO 02/092812, and WO 98/27200. Additional examples of ACs into which human immunoglobulin sequences can be inserted for use in the invention include, for example, BACs (e.g., pBeloBAC1 I or pBAC108L; see, e.g., Shizuya et al. (1992), Proc Natl Acad Sci USA 89(18):8794-8797; Wang et al. (1997), Biotechniques 23(6):992-994), bacteriophage PACs, YACs (see, e.g., Burke (1990), Genet Anal Tech App] 7(5):94-99), and MACs (see, e.g., Vos (1997), Nat. Biotechnol. 15(12):1257-1259; Ascenzioni et al. (1997), Cancer Lett 118(2):135-142), such as HACs, see also, U.S. Pat. Nos. 6,743,967, 6,716,608, 6,692,954, 6,670,154, 6,642,207, 6,638,722, 6,573,090, 6,492,506, 6,348,353, 6,287,853, 6,277,621, 6,183,957, 6,156,953, 6,133,503, 6,090,584, 6,077,697, 6,025,155, 6,015,708, 5,981,175, 5,874,259, 5,721,118, and 5,270,201; European Patent Nos. 1 437 400, 1 234 024, 1 -356 062, 0 959 134, 1 056 878, 0 986 648, 0 648 265, and 0 338 266; PCT Publication Nos. WO 04/013299, WO 01/07478, WO 00/06715, WO 99/43842, WO 99/27118, WO 98/55637, WO 94/00569, and WO 89/09219. Additional examples incluse those AC provided in, for example, PCT Publication No. WO 02/076508, WO 03/093469, WO 02/097059; WO 02/096923; US Publication Nos US 2003/0113917 and US 2003/003435; and US Patent No 6,025,155. In other embodiments of the present invention, ACs transmitted through male gametogenesis in each generation. The AC can be ihntegrating or non-integrating. In one ambodiment, the AC can be transmitted through mitosis in substantially all dividing cells. In another embodiment, the AC can provide for position independent expression of a human 138 inmunogloulin nucleic acid sequence. In a- particular embodiment, the AC can have a transmittal efficiency of at least 10% through each male and female gametogenesis. In one particular embodiment, the AC can be circular. In another particular embodiment, the non integrating AC can be that deposited with the Belgian Coordinated Collections of Microorganisms--BCCM on Mar. 27, 2000 under accession number LMBP 5473 CB. In additional embodiments, methods for producing an AC are provided wherein a mitotically stable unit containing an exogenous nucleic acid transmitted through male gametogenesis is identified; and an entry site in the mitotically stable unit allows for the integration of human. immunoglobulin genes into the unit. In other embodiments, ACs are provided that include: a functional centromere, a selectable marker and/or a unique cloning site. Tin other embodiments, the AC can exhibit one or more of the following properties: it can segregate stably as an independent chromosome, immunoglobulin sequences can be inserted in a controlled way and can expressed from the AC, it can be efficiently transmitted through the male and female germline and/ or the transgenic animals can bear the chromosome in greater than about 30,40, 50, 60, 70, 80 or 90% of its cells. In particular embodiments, the AC can be isolated from fibroblasts (such as any mammalian or human fibroblast) in which it was mitotically stable. After transfer of the AC into hamster cells, a lox (such as loxP) site and a selectable marker site can be inserted. In other embodiments, the AC can maintain mitotic stability, for example, showing a loss of less than about 5, 2, 1, 0.5 or 0.25 percent per mitosis in the absence of selection. See also, US 2003/0064509 and WO 01/77357. Xenogenous Immunoglobulin Genes In another aspect of the present invention, transgenic ungulates are provided that expresses a xenogenous immunoglobulin loci or fragment thereof, wherein the immunoglobulin can be expressed from an immunoglobulin locus that is integrated within an endogenous ungulate chromosome. In one embodiment, ungulate cells derived from the transgenic animals are provided. In one embodiment, the xenogenous immunoglobulin locus can be inherited by offspring. In another embodiment, the xenogenous immunoglobulin locus can be inherited through the male germ line by offspring. In still further embodiments, an artificial chromosome 139 (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human immunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof. In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement. In a further embodiment, the human immunoglobulin loci can include any fragment of a human immunoglobulin heavy chain and a human immunoglobulin light chain that can undergo rearrangement In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens. In other embodiments, the transgenic ungulate that lacks any expression of functional endogenous inununQglobulins can.be further. genetically modified to express an xenogenous immunoglobulin loci. In an alternative embodiment, porcine animals are provided that contain an xenogeous immunoglobulin locus. In one embodiment, the xenogeous immunoglobulin loci can be a heavy and/ or light chain immunoglobulin or fragment thereof. In another embodiment, the xenogenous immunoglobulin loci can be a kappa chain locus or fragment thereof and/ or a lambda chain locus or fragment thereof. In still further embodiments, an artificial chromosome (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast *AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human immunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof. In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement. In a further embodiment, the human immunoglobulin loci can include any fragment of a human immunoglobulin heavy chain and a human immunoglobulin light chain that can undergo rearrangement. In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens. 140 In other embodiments, the transgenic ungulate that lacks any expression of functional endogenous immunoglobulins can be further genetically modified to express an xenogenous immunoglobulin loci. In an alternative embodiment, porcine animals are provided that contain an xenogeous immunoglobulin locus. In one embodiment, the xenogeous immunoglobulin loci can be a heavy and/ or light chain immunoglobulin or fragment thereof. In another embodiment, the xenogenous immunoglobulin loci can be a kappa chain locus or fragment thereof and/ or a lambda chain locus or fragment thereof. In still further embodiments, an artificial chromosome (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast. AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human immunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof. In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement. In a further embodiment, the human inmunoglobulin loci can. include. any fragment of a human immunoglobulin heavy chain and a human immunoglobulin light chain that can undergo rearrangement. In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous inmunoglobulin in response to exposure to one or more antigens. In another embodiment, porcine animals are provided that contain an xenogeous immunoglobulin locus. In one embodiment, the xenogeous immunoglobulin loci can be a heavy and/ or light chain immunoglobulin or fragment thereof. In another embodiment, the xenogenous immunoglobulin loci can be a kappa chain locus or fragment thereof and/ or a lambda chain locus or fragment thereof. In still further embodiments, an artificial chromosome (AC) can contain the xenogenous immunoglobulin. In one embodiment, the AC can be a yeast AC or a mammalian AC. In a further embodiment, the xenogenous locus can be a human imnimunoglobulin locus or fragment thereof. In one embodiment, the human immunoglobulin locus can be human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof. In another embodiment, the human immunoglobulin locus can include any fragment of a human immunoglobulin that can undergo rearrangement. In a further embodiment, the human immunoglobulin loci can include any fragment of a human immunoglobulin heavy 141 chain and a human immunoglobulin light chain that can undergo rearrangement. In still further embodiment, the human immunoglobulin loci can include any human immunoglobulin locus or fragment thereof that can produce an antibody upon exposure to an antigen. In a particular embodiment, the exogenous human immunoglobulin can be expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens. Human immunoglobulin genes, such as the Ig heavy chain gene (human chromosome 414), Ig kappa chain gene (human chromosome #2) and/or the Ig lambda chain gene (chromosome #22) can be inserted into Acs, as described above. In a particular embodiment, any portion of the human heavy, kappa and/or lambda Ig genes can be inserted into ACs. In one embodiment, the nucleic acid can be at least 70, 80, 90, 95, or 99% identical to the corresponding region of a naturally-occurring nucleic acid from a human. In other embodiments, more than one class of human antibody is produced by the ungulate. In various embodiments, more than one different human Ig or antibody: is produced by the ungulate. In one embodiment, an AC _continingoth a human. Ig heavy-chain gene._and-Ig light chain gene, siu ch.as an automatic human artificial chromosome ("AHAC," a circular recombinant nucleic acid molecule that is converted to a linear human chromosome in vivo by an endogenously expressed restriction endonuclease) can be introduced. In one embodiment, the human heavy chain loci and the light chain loci are on different chromosome.arms (i.e., on different- side of the centromere). In one embodiments, the heavy chain can include the mu heavy chain, and the light chain can be a lambda or kappa light chain. The Ig genes can be introduced simultaneously or sequentially in one or more than one ACs. In particular embodiments, the ungulate or ungulate cell expresses one or more nucleic acids encoding all or part of a human Ig gene which undergoes rearrangement and expresses more than one human Ig molecule, such as a human antibody protein. Thus, the nucleic acid encoding the human Ig chain or antibody is in its unrearranged form (that is, the nucleic acid has not undergone V(D)J recombination). In particular embodiments, all of the nucleic acid segments encoding a V gene segment of an antibody light chain can be separated from all of the nucleic acid segments encoding a J gene segment by one or more nucleotides. In a particular embodiment, all of the nucleic acid segments encoding a V gene segment of an antibody heavy chain can be separated from all of the nucleic acid segments encoding a D gene segment by one or more nucleotides, and/or all of the nucleic acid segments encoding a D gene segment of an 142 antibody heavy chain are separated from all of the nucleic acid segments encoding a J gene segment by one or more nucleotides. Administration of an antigen to a transgenic ungulate containing an unrearranged human Ig gene is followed by the rearrangement of the nucleic acid segments in the human Ig gene locus and the production of human antibodies reactive with the antigen. In one embodiment, the AC can express a portion or fragment of a human chromocome that contains an immunoglobulin gene. In one embodiment, the AC can express at least 300 or 1300 kb of the human light chain locus, such as described in Davies et al. 1993 Biotechnology. 11: 911-914. In another embodiment, the AC can express a portion of human chromosome 22 that contains at least the X light-chain locus, including V;L gene segments, JL gene segments, and the single Cx gene. In another embodiment, the AC can express at least one V, gene segment, at least one JX gene segment, and the Cx gene. In other embodiment, ACs can contain portions of ._the lambda locus, such as described inPopov et al. J Exp Med. 1999-May 17;189(10):1611-20. In another embodiment, the AC can express a portion of human chromosome 2 that contains at least the K light-chain locus, including VK gene segments, J. gene segments and the single CK gene. In another embodiment, the AC can express at least one V, gene segment, at least one JK gene segment and the C,, gene. In other embodiments, AC containing portions of the kappa light chain locus can be those describe, for example, in Li et al. 2000 J Immunol 164: 812 824 and Li S Proc Nati Acad Sci U S A. 1987 Jun;84(12):4229-33. In another embodiment, AC containing approximately 1.3 Mb of human kappa locus are provided, such as descibed in Zou et al FASEB J. 1996 Aug;10(10):1227-32. In further embodiments, the AC can express a portion of human chromosome 14 that contains at least the human heavy-chain locus, including VH, DH, JH and CH gene segments. In another embodiment, the AC can express at least one VH gene segment, at least one DH gene segment, at least one JH gene segment and at least one at least one CH gene segment. In other embodiments, the AC can express at least 85 kb of the human heavy chain locus, such as described in Choi et al. 1993 Nat Gen 4:117-123 and/or Zou et al. 1996 PNAS 96: 14100-14105. In other embodiments, the AC can express portions of both heavy and light chain loci, such as, at least 220, 170, 800 or 1020 kb, for example, as disclosed in Green et al. 1994 Nat Gen 7:13-22; Mendez et al 1995 Genomics 26: 294-307; Mendez et al. 1997 Nat Gen 15: 146-156; 143 Green et al. 1998 J Exp Med 188: 483-495 and/or Fishwild et al. 1996 Nat Biotech 14: 845-851. In another embodiment, the AC can express megabase amounts of human immunoglobulin, such as described in Nicholson J Immunol. 1999 Dec 15;163(12):6898-906 and Popov Gene. 1996 Oct 24;177(1-2):195-201. In addition, in one particular embodiment, MACs derived from human chromosome #14 (comprising the Ig heavy chain gene), human chromosome #2 comprising the Ig kappa chain gene) and human chromosome #22 (comprising the Ig lambda chain gene) can be introduced simultaneously or successively, such as described in US Patent Publication No. 2004/0068760 to Robl et al.. In another embodiments, the total size of the MAC is less than or equal to approximately 10, 9, 8, or 7 megabases. In a particular embodiment, human Vh, human Dh, human Jh segments and human mu segments of human immunoglobulins in germline configuration can be inserted into an AC, such as a YAC, such that the Vh, Dh,~ Jh and mu DNA segments form a repertoire of immunoglobulins containing portions which correspond to the human DNA segments, for example, as described in U.S. Patent No. 5,545,807 to the Babraham Insttitute. Such ACs, after insertion. into ungulate cells and generation of ungulates can produce heavy chain immunoglobulins. In one embodiment, these immunoglobulins can form functional heavy chain light chain immunoglobulins. In another embodiment, these immunoglobulins can be expressed in an amount allowing for recovery from suitable cells or body fluids of the ungulate. Such immunglobulins can be inserted into yeast artifical chromosome vectors, such as decribed by Burke, D T, Carle, G F and Olson, M V (1987) "Cloning of large segments of exogenous DNA into yeast by means of artifical chromosome vectors" Science, 236, 806-812, or by introduction of chromosome fragments (such as described by Richer, J and Lo, C W (1989) "Introduction of human DNA into mouse eggs by injection of dissected human chromosome fragments" Science 245, 175-177). Additional information on specific ACs containing human immunoglobulin genes can be found in, for example, recent reviews by Giraldo & Montoliu (2001) Transgenic Research 10: 83-103 and Peterson (2003) Expert Reviews in Molecular Medicine 5: 1-25. AC Transfer Methods The human immunoglobulin genes can be first inserted into ACs and then the human immunoglobulin-containing ACs can be inserted into the ungulate cells. Alternatively, the ACs 144 can be transferred to an intermediary mammalian cell, such as a CHO cell, prior to insertion into the ungulate call. In one embodiment, the intermediary mammalian cell can also contain and AC and the first AC can be inserted into the AC of the mammalian cell. In particular, a YAC containing human immunoglobulin genes or fragments thereof in a yeast cell can be transferred to a mammalian cell that harbors an MAC. The YAC can be inserted into the MAC. The MAC can then be transferred to an ungulate cell. The human Ig genes can be inserted into ACs by homologous recombination. - The resulting AC containing human Ig genes, can then be introduced into ungulate cells. One or more ungulate cells can be selected by techniques described herein or those known in the art, which contain an AC containing a human Ig.. Suitable hosts for introduction of the ACs are provided herein, which include but are not limited to any animal or plant, cell or tissue thereof, including, but not limited to: mammals, birds, reptiles, amphibians, insects, fish, arachnids, tobacco, tomato, wheat, monocots, dicots and algae. In one embodiment, the ACscan be condensed (Marschall et al Gene Ther. 1999 Sep;6(9):1 6 34-7) byany reagent known in the art, including, but. not limited to, spermine, spermidine, polyethylenimine, and/ or polylysine prior to introduction into cells.The ACs can be introduced by cell fusion or microcell fusion or subsequent to isolation by any method known to those of skill in this art, including but not limited to: direct DNA transfer, electroporation, nuclear transfer, microcell fusion, cell fusion, spheroplast fusion, lipid-mediated transfer, lipofection, liposomes, microprojectile bombardment, microinjection, calcium phosphate precipitation and/or any other suitable method. Other methods for introducing DNA into cells, include nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells. Polycations, such as polybrene and polyornithine, may also be used. For various techniques for transforming mammalian cells, see e.g., Keown et al. Methods in Enzymology (1990) Vol.185, pp. 527-537; and Mansour et al. (1988) Nature 336:348-352. The ACs can be introduced by direct DNA transformation; microinjection in cells or embryos, protoplast regeneration for plants, electroporation, microprojectile gun and other such methods known to one skilled in the art (see, e.g., Weissbach et al. (1988) Methods for Plant Molecular Biology, Academic Press, N.Y., Section VHI, pp. 421-463; Grierson et al. (1988) Plant Molecular Biology, 2d Ed., Blackie, London, Ch. 7-9; see, also U.S. Pat. Nos.. 5,491,075; 5,482,928; and 5,424,409; see, also, e.g., U.S. Pat. No. 5,470,708,). 145 In particular embodiments, one or more isolated YACs can be used that harbor human Ig genes. The isolated YACs can be condensed (Marschall et al Gene Ther. 1999.Sep;6(9):1634-7) by any reagent known in the art, including, but not limited to spermine, spermidine, polyethylenimine, and/ or polylysine. The condensed YACs can then be transferred to porcine cells by any method known in the art (for example, microinjection, electroporation, lipid mediated transfection, etc). Alternatively, the condensed YAC can be transferred to oocytes via sperm-mediated gene transfer or intracytoplasmic sperm injection (ICSI) mediated gene transfer. In one embodiment, spheroplast fusion can be used to transfer YACs that harbor human Ig genes to porcine cells. In other embodiments of the invention, the AC containing the human Ig can be inserted into an adult, fetal, or embryonic ungulate cell. Additional examples of ungulate cells. include undifferentiated cells, such as embryonic cells (e.g., embryonic stem cells),'differentiated or somatic cells, such as epithelial cells, neural cells epidermal cells, keratinocytes, hematopoietic cells, melanocytes, chondrocytes, B-lymphocytes, T-lymphocytes, erythrocytes, macrophages, monocytes, fibroblasts, muscle cells, cells from the female reproductive system, such as a mammary gland, ovarian cumulus, granulosa, or oviductal cell, germ cells, placental cell, or cells derived from any organ, such as the bladder, brain, esophagus, fallopian tube, heart, intestines, gallbladder, kidney, liver, lung, ovaries, pancreas, prostate, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, ureter, urethra, and uterus or any other cell type described herein. Site Specific Recombinase Mediated Transfer In particular embodiments of the present invention, the transfer of ACs containing human immunoglobulin genes to porcine cells, such as those described herein or known in the art, can be accomplished via site specific recombinase mediated transfer. In one particular embodiment, the ACs can be transferred into porcine fibroblast cells. In another particular embodiment, the ACs can be YACs. In other embodiments of the present invention, the circularized DNA, such as an AC, that contain the site specific recombinase target site can be transferred into a cell line that has a site specific resombinase target site within its genome. In one embodiment, the cell's site specific recombinase target site can be located within an exogenous chromosome. The exogenous 146 chromosome can be an artificial chromosome that does not integrate into the host's endogenous genome. In one embodiment, the AC can be transferred via germ line transmission to offspring. In one particular embodiment, a YAC containing a human immunoglobulin gene or fragment thereof can be circularized via a site specific recombinase and then transferred into a host cell that contains a MAC, wherein the MAC contains a site specific recombinase site. This MAC that now contains human immunoglobulin loci or fragments thereof can then be fused with a porcine cell, such as, but not limited to, a fibroblast. The porcine cell can then be used for nuclear transfer. In certain embodiments of the present invention, the ACs that contain human immunoglobulin genes or fragments thereof can be transferred to a mammalian cell, such as a CHO cell, prior to insertion into. the ungulate call. In one embodiment, the intermediary mammalian cell can also contain and- AC and the first AC can be inserted into the AC of the mammalian cell. In particular, a YAC containing human immunoglobulin genes or fragments thereof in a yeast cell can be transferred to a mammalian cell that harbors a MAC. The YAC can be inserted in the MAC. The MAC can then be transferred to an ungulate cell. In particular embodiments, the YAC harboring the human Ig genes or fragments thereof can contain site specific recombinase trarget sites. The YAC can first be circularized via application of the appropriate site specific recombinase and then inserted into a mammalian cell that contains its own site specific recombinase target site. Then, the site specific recombinase can be applied to inegrate the YAC into the MAC in the intermediary mammalian cell. The site specific recoombinase can be applied in cis or trans. In particular, the site specific recombinase can be applied in trans. In one embodiment, the site specific recombinase can be expressed via transfection of a site specific recombainse expression plasmid, such as a Cre expression plasmid. In addition, one telomere region of the YAC can also be retrofitted with a selectable marker, such as a selectable marker described herein or known in the art. The human Ig genes or fragments thereof within the MAC of the intermediary mammalian cell can then be transferred to an ungulate cell, such as a fibroblast. Alternatively, the AC, such as a YAC, harboring the human Ig genes or fragments thereof can contain site specific recombinase target sites optionally located near each telomere. The YAC can first be circularized via application of the appropriate site specific recombinase and then inserted into an ungulate cell directly that contains its own site specific recombinase target 147 site within it genome. Alternatively, the ungulate cell can harbor its own MAC, which contains a site specific recombinase target site. In this embodiment, the YAC can be inserted directly into the endogenous genome of the ungulate cell. In particular embodiments, the ungulate cell can be a fibroblast cell or any other suitable cell that can be used for nuclear transfer. See, for example, Figure 7; Call et al., Hum Mol Genet. 2000 Jul 22;9(12):1745-51. In other embodiments, methods to circularize at least 100 kb of DNA are provided wherein the DNA can then be integrated into a host genome via a site specific recombinase. In one embodiment, at least 100, 200, 300, 400, 500, 1000, 2000, 5000, 10,000 kb of DNA can be circularized. In another embodiment, at least 1000, 2000, 5000, 10,000, or 20,000 megabases of DNA can be circularized. In one embodiment, the circularization of the DNA can be accomplished by attaching site specific recombinase target sites at each end of the DNA sequence and then applying the site specific recombinase to result in circularization of the DNA. In one embodiment, the site specific recombinase target site can be lox. In another embodiment, the site specific recombinase target site can be Flt. In certain embodiments, the DNA can be an artificial chromosome, such as a YAC or any AC described herein or known in the art. In another embodiment, the AC can contain human immunoglobulin loci or fragments thereof. In another preferred embodiment, the YAC can be converted to, or integrated within, an artificial mammalian chromosome. The mammalian artificial chromosome is either transferred to or harbored within a porcine cell. The artificial chromosome can be introduced within the porcine genome through any method known in the art including but not limited to direct injection of metaphase chromosomes, lipid mediated gene transfer, or microcell fusion. Site-specific recombinases include enzymes or recombinases that recognize and bind to a short nucleic acid site or sequence-specific recombinase target site, i.e., a recombinase recognition site, and catalyze the recombination of nucleic acid in relation to these sites. These enzymes include recombinases, transposases and integrases. Examples of sequence-specific recombinase target sites include, but are not limited to, lox sites, att sites, dif sites and frt sites. Non-limiting examples of site-specific recombinases include, but are not limited to, bacteriophage P1 Cre recombinase, yeast FLP recombinase, Inti integrase, bacteriophage , phi 80, P22, P2, 186, and P4 recombinase, Tn3 resolvase, the Hin recombinase, and the Cin recombinase, E. coli xerC and xerD recombinases, Bacillus thuringiensis recombinase, TpnI and the p-lactamase transposons, and the immunoglobulin recombinases. 148 In one embodiment, the recombination site can be a lox site that is recognized by the Cre recombinase of bacteriophage P1. Lox sites refer to a nucleotide sequence at which the product of the cre gene of bacteriophage P1, the Cre recombinase, can catalyze a site-specific recombination. event A variety of lox sites are known in the art, including the naturally occurring loxP, loxB, loxL and loxR, as well as a number of mutant, or variant, lox sites, such as loxP511, loxP514, lox.DELTA.86, lox.DELTA.117, loxC2, loxP2, loxP3 and lox P23. Additional example of lox sites include, but are not limited to, loxB, loxL, loxR, loxP, loxP3, loxP23, loxA86, loxA117, loxP5 11, and loxC2. In another embodiment, the recombination site is a recombination site that is recognized by a recombinases other than Cre. In one embodiment, the recombinase site can be the FRT sites recognized by FLP recombinase of the 2 pi plasmid of Saccharomyces cerevisiae. FRT sites refer to a nucleotide sequence at which the product of the FLP gene of the yeast 2 micron plasmid, FLP recombinase, can catalyze site-specific recombination. Additional examples of the non-Cre recombinases include, butare not limited to, site-specific recombinases include: att sites recognized by the Int recombinase of bacteriophage X (e.g. attl, att2, att3, attP, attB, attL, and attR), the recombination sites recognized by the resolvase family, and the recombination site recognized by transposase of Bacillus thruingiensis. IV. Production of Genetically Modified Animals In additional aspects of the present invention, ungulates that contain the genetic modifications described herein can be produced by any method known to one skilled in the art. Such methods include, but are not limited to: nuclear transfer, intracytoplasmic sperm injection, modification of zygotes directly and sperm mediated gene transfer. In another embodiment, a method to clone such animals, for example, pigs, includes: enucleating an oocyte, fusing the oocyte with a donor nucleus from a cell in which at least one allele of at least one immunoglobulin gene has been inactivated, and implanting the nuclear transfer-derived embryo into a surrogate mother. Alternatively, a method is provided for producing viable animals that lack any expression of functional immunoglobulin by inactivating both alleles of the immunoglobulin gene in embryonic stem cells, which can then be used to produce offspring. 149 In another aspect, the present invention provides a method for producing viable animals, such as pigs, in which both alleles of the immunoglobulin gene have been rendered inactive. In one embodiment, the animals are produced by cloning using a donor nucleus from a cell in which both alleles of the immunoglobulin gene have been inactivated. In one embodiment, both alleles of the immunoglobulin gene are inactivated via a genetic targeting event. Genetically altered animals that can be created by modifying zygotes directly. For mammals, the modified zygotes can be then introduced into the uterus of a pseudopregnant female capable of carrying the animal to term. For example, if whole animals lacking an immunoglobulin gene are desired, then embryonic stem cells derived from that animal can be targeted and later introduced into blastocysts for growing the modified cells into chimeric animals. For embryonic stem cells, either an embryonic stem cell line or freshly obtained stem cells can be used. In a suitable embodiment of the invention, the totipotent cells are embryonic stem (ES) cells. The isolation of ES cells from blastocysts, the establishing of ES cell lines and their subsequent cultivation are carried out by conventional methods as described, for example, by Doetchmann et al., J. Embryol. Exp. Morph. 87:27-45 (1985); Li et al., Cell 69:915-926 (1992); Robertson, E. J. "Tetracarcinomas and Embryonic Stem Cells: A Practical Approach," ed. E. J. Robertson, IRL Press, Oxford, England (1987); Wurst and Joyner, "Gene Targeting: A Practical Approach," ed. A. L. Joyner, IRL Press, Oxford, England (1993); Hogen et al., "Manipulating the Mouse Embryo: A Laboratory Manual," eds. Hogan, Beddington, Costantini and Lacy, Cold Spring Harbor Laboratory Press, New York (1994); and Wang et al., Nature 336:741-744 (1992). In another suitable embodiment of the invention, the totipotent cells are embryonic germ (EG) cells. Embryonic Germ cells are undifferentiated cells functionally equivalent to ES cells, that is they can be cultured and transfected in vitro, then contribute to somatic and germ cell lineages of a chimera (Stewart et al., Dev. Biol. 161:626-628 (1994)). EG cells are derived by culture of primordial germ cells, the progenitors of the gametes, with a combination of growth factors: leukemia inhibitory factor, steel factor and basic fibroblast growth factor (Matsui et al., Cell 70:841-847 (1992); Resnick et al., Nature 359:550-551 (1992)). The cultivation of EG cells can be carried out using methods described in the article by Donovan et al., "Transgenic Animals, Generation and Use," Ed. L. M. Houdebine, Harwood Academic Publishers (1997), and in the original literature cited therein. 150 Tetraploid blastocysts for use in the invention may be obtained by natural zygote production and development, or by known methods by electrofusion of two-cell embryos and subsequently cultured as described, for example, by James et al., Genet. Res. Camb. 60:185-194 (1992); Nagy and Rossant, "Gene Targeting: A Practical Approach," ed. A. L. Joyner, IRL Press, Oxford, England (1993); or by Kubiak and Tarkowski, Exp. Cell Res. 157:561-566 (1985). The introduction of the ES cells or EG cells into the blastocysts can be carried out by any method known in the art. A suitable method for the purposes of the present invention is the microinjection method as described by Wang et al., EMBO J. 10:2437-2450 (1991). Alternatively, by modified embryonic stem cells transgenic animals can be produced. The genetically modified embryonic stem cells can be injected into a blastocyst and then brought to term in a female host mammal in accordance with conventional techniques. Heterozygous progeny can. then be screened for the presence of the alteration at the site of the target locus, using techniques such as PCR or Southern blotting. After mating with a wild-type host of the same species, the resulting chimeric progeny can then be cross-mated to achieve homozygous hosts. After transforming embryonic stem cells with the targeting vector to alter the immunoglobulin gene, the cells can be plated onto a feeder layer in an appropriate medium, e.g., fetal bovine serum enhanced DMEM. Cells containing the construct can be detected by employing a selective medium, and after sufficient time for colonies to grow, colonies can be picked and analyzed for the occurrence of homologous recombination. Polymerase chain reaction can be used, with primers within and without the construct sequence but at the target locus. Those colonies which show homologous recombination can then be used for embryo manipulating and blastocyst injection. Blastocysts can be obtained from superovulated females. The embryonic stem cells can then be trypsinized and the modified cells added to a droplet containing the blastocysts. At least one of the modified embryonic stem cells can be injected into the blastocoel of the blastocyst. After injection, at least one of the blastocysts can be returned to each uterine hom of pseudopregnant females. Females are then allowed to go to term and the resulting litters screened for mutant cells having the construct. The blastocysts are selected for different parentage from the transformed ES cells. By providing for a different phenotype of the blastocyst and the ES cells, chimeric progeny can be readily detected, and then genotyping can be conducted to probe for the presence of the modified immunoglobulin gene. 151 In other embodiments, sperm mediated gene transfer can be. used to produce the genetically modified ungulates described herein. The methods and compositions described herein to either eliminate expression of endogenous immunoglobulin genes or insert xenogenous immunoglobulin genes can be used to genetically modify the. sperm cells via any technique described herein or known in the art. The genetically modified sperm can then be used to impregnate a female recipient via artificial insemination, intracytoplasmic sperm injection or any other known technique. In one embodiment, the sperm and/ or sperm head can be incubated with the exogenous nucleic acid for a sufficient time period. Sufficient time periods include, for example, about 30 seconds to about 5 minutes, typically about 45 seconds to about 3 minutes, more typically about 1 minute to about 2 minutes. In particular embodiments, the expression of xenogenous, such as human, immunoglobulin genes in ungulates as described herein, can be accomplished via intracytoplasmic sperm injection. The potential use of sperm cells as vectors for gene transfer was first suggested by Brackett et al., Proc., Nati. Acad. Sci. USA 68:353-357.(1971). This was followed by reports of the production of transgenic mice and pigs after in vitro fertilization of oocytes with sperm that had been incubated by naked DNA (see, for example, Lavitrano et al., Cell 57:717-723 (1989) and Gandolfi et al. Journal of.Reproduction and Fertility Abstract Series 4, 10 (1989)), although other laboratories were not able to repeat these experiments (see, for example, Brinster et al. Cell 59:239-241 (1989) and Gavora et al., Canadia Journal of Animal Science 71:287-291 (1991)). Since then, there have been several reports of successful sperm mediated gene transfer in chicken (see, for example, Nakanishi and Iritani, Mel. Reprod. Dev. 36:258-261 (1993)); mice (see, for example, Maione, Mol. Reprod. Dev. 59:406 (1998)); and pigs (see, for example, Lavitrano et al. Transplant. Proc. 29:3508-3509 (1997); Lavitrano et al., Proc. Natl. Acad. Sci. USA 99:14230-5 (2002); Lavitrano et al., Mol. Reprod. Dev. 64-284-91 (2003)). Similar techniques are also described in U.S. Pat. No. 6,376,743; issued Apr. 23, 2002; U.S. Patent Publication Nos. 20010044937, published Nov. 22, 2001, and 20020108132, published Aug. 8, 2002. In other embodiments, intracytoplasmic sperm injection can be used to produce the genetically modified ungulates described herein. This can be accomplished by coinserting an exogenous nucleic acid and a sperm into the cytoplasm of an unfertilized oocyte to form a transgenic fertilized oocyte, and allowing the transgenic fertilized oocyte to develop into a transgenic embryo and, if desired, into a live offspring. The sperm can be a membrane-disrupted 152 sperm head or a demembranated sperm head. The coinsertion step.can include the substep of preincubating the sperm with the exogenous nucleic acid for a sufficient. time period, for example, about 30 seconds to about 5 minutes, typically about 45 seconds to about.3 minutes, more typically- about 1 minute to about 2 minutes. The coinsertion of the sperm and exogenous nucleic acid into the oocyte can be via microinjection. The exogenous nucleic acid mixed with the sperm can contain more than one transgene, to produce an embryo that is transgenic for more than one transgene as described herein. The intracytoplasmic sperm injection can be accomplished by any technique known in the art, see, for example, US Patent No. 6,376,743. In. particular embodiments, the expression of xenogenous, such as human, immunoglobulin genes in ungulates as described herein, can be accomplished via intracytoplasmic sperm injection. Any additional technique known in the art may be used to introduce the transgene into animals. Such techniques include, but are not limited to pronuclear microinjection (see, for example, Hoppe, P. C. and Wagner, T. E., 1989, U.S. Pat. No. 4,873,191); retrovirus mediated _gene tsferinto germ lines (see,.rexample, Van der Putten et al., 1985, Proc. Natl. Acad. Sci., USA 82:6148-6152); gene targeting in embryonic stem cells (see, for example, Thompson et al., 1989, Cell 56:313-321; Wheeler, M. B., 1994, WO 94/26884); electroporation of embryos (see, for example, Lo, 1983, Mol Cell. Biol. 3:1803-1814); cell gun; transfection; transduction; retroviral infection; adenoviral infection; adenoviral-associated infection; liposome-mediated gene transfer, naked DNA transfer; and sperm-mediated gene transfer (see, for example, Lavitrano et al., 1989, Cell 57:717-723); etc. For a review of such techniques, see, for example, Gordon, 1989, Transgenic Animals, Intl. Rev. Cytol. 115:171-229. In particular embodiments, the expression of xenogenous, such as human, immunoglobulin genes in ungulates as descrbed herein, can be accomplished via these techniques. Somatic Cell Nuclear Transfer to Produce Cloned, Transgenic Offspring In a further aspect of the present invention, ungulate, such as porcine or bovine, cells lacking one allele, optionally both alleles of an ungulate heavy chain, kappa light chain and/or lambda light chain gene can be used as donor cells for nuclear transfer into recipient cells to produce cloned, transgenic animals. Alternatively, ungulate heavy chain, kappa light chain and/or lambda light chain gene knockouts can be created in embryonic stem cells, which are then used to produce offspring. Offspring lacking a single allele of a functional ungulate heavy chain, 153 kappa light chain and/or lambda light chain gene produced according to the process, sequences and/or constructs described herein can be breed to further produce offspring lacking fimctionality in both alleles through mendelian type inheritance. in another embodiment, the present invention provides a method for producing viable pigs that lack any expression of functional alpha-1,3-GT by breeding a male pig heterozygous for the alpha-1,3-GT gene with a female pig heterozygous for the alpha-1,3-GT gene. In one embodiment, the pigs are heterozygous due to the genetic modification of one allele of the alpha 1,3-GT gene to prevent expression of that allele. In another embodiment, the pigs are heterozygous due to the presence of a point mutation in one allele of the alpha-1,3-GT gene. In another embodiment, the point mutation can be a T-to-G point mutation at the second base of exon 9 of the alpha-1,3-GT gene. In one specific embodiment, a method to produce a.porcine animal that lacks any expression of functional alpha-1,3-GT is provided wherein a male pig that contains a T-to-G point mutation at the second base of exon 9 of the alpha-1,3-GT gene is bred with a female pig.that contains a T-to-G point mutation at the second base of exon 9 of the alpha 1,3-GT gene, or vise versa. The present invention provides a method for cloning an animal, such as a pig, lacking a functional immunoglobulin gene via somatic cell nuclear transfer. In general, the animal can be produced by a nuclear transfer process comprising the following steps: obtaining desired differentiated cells to be used as a source of donor nuclei; obtaining oocytes from the animal; enucleating said oocytes; transferring the desired differentiated cell or cell nucleus into the enucleated oocyte, e.g., by fusion or injection, to form NT units; activating the resultant NT unit; and transferring said cultured NT unit to a host animal such that the NT unit develops into a fetus.

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- Nuclear transfer techniques or nuclear transplantation techniques are known in the art(Dai ct al. Nature Biotechnology 20:251-255; Polejaeva et al Nature 407:86-90 (2000); Campbell et al, Theriogenology, 43:181 (1995); Collas et al, Mol. Report Dev., 38:264-267 (1994); Keefer et al, Biol. Reprod., 50:935-939 (1994); Sims et al, Proc. Natl. Acad. Sci., USA, 90:6143-6147 (1993); WO 94/26884; WO 94/24274, and WO 90/03432, U.S. Pat. Nos. 4,944,384 and 5,057,420). A donor cell nucleus, which has been modified to alter the immunoglobulin gene, is transferred to a recipient oocyte. The use of this method is not restricted to a particular donor 154 cell type. The donor cell can be as described herein, see also, for example, Wilmut et al Nature 385 810 (1997); Campbell et al Nature 380 64-66 (1996); Dai et al., Nature Biotechnology 20:251-255, 2002 or Cibelli et al Science 280 1256-1258 (1998). All cells of normal karyotype, including embryonic, fetal and adult somatic cells which can be used successfully in nuclear transfer can be employed. Fetal fibroblasts are a particularly useful class of donor cells. Generally suitable methods of nuclear transfer are described in Campbell et al Theriogenology 43 181 (1995), Dai et al. Nature Biotechnology 20:251-255, Polejaeva et al Nature 407:86-90 (2000), Collas et al Mol. Reprod. Dev. 38 264-267 (1994), Keefer et al Biol. Reprod. 50 935-939 (1994), Sims et al Proc. Nat'l. Acad. Sci. USA 90 6143-6147 (1993), WO-A-9426884, WO-A 9424274, WO-A-9807841, WO-A-9003432, U.S. Pat. No. 4,994,384 and U.S. Pat. No. 5,057,420. Differentiated or at least partially differentiated donor cells can also be used. Donor cells can also be, but do not have to be, in culture and can be quiescent. Nuclear.donor cells which are quiescent are cells which can be induced to enter quiescence or exist in a quiescent _state in vivo._ Prior art methods havealso used embryonic cell types in cloning procedures (Campbell et al (Nature, 380:64-68, 1996) and Stice et al (Biol. Reprod., 20 54:100-110, 1996). Somatic nuclear donor cells may be obtained from a variety of different organs and tissues such as, but not limited to, skin, mesenchyme, lung, pancreas, heart, intestine, stomach, bladder, blood vessels, kidney, urethra, reproductive organs, and a disaggregated preparation of a whole or part of an embryo, fetus, or adult animal. In a suitable embodiment of the invention, nuclear donor cells are selected from the group consisting of epithelial cells, fibroblast cells, neural cells, keratinocytes, hematopoietic cells, melanocytes, chondrocytes, lymphocytes (B and T), macrophages, monocytes, mononuclear cells, cardiac muscle cells, other muscle cells, OxtendedO cells, cumulus cells, epidermal cells or endothelial cells. In another embodiment, the nuclear donor cell is an embryonic stem cell. In a particular embodiment, fibroblast cells can be used as donor cells. In another embodiment of the invention, the nuclear donor cells of the invention are germ cells of an animal. Any germ cell of an animal species in the embryonic, fetal, or adult stage may be used as a nuclear donor cell. In a suitable embodiment, the nuclear donor cell is an embryonic germ cell. Nuclear donor cells may be arrested in any phase of the cell cycle (GO, GI, G2, S, M) so as to ensure coordination with the acceptor cell. Any method known in the art may be used to 155 manipulate the cell cycle phase. Methods to control the cell cycle phase include, but are not limited to, GO quiescence induced by contact inhibition of cultured cells, GO quiescence induced by removal of serum or other essential nutrient, GO quiescence induced by senescence, GO quiescence induced by addition of a specific growth factor, GO or G1 quiescence induced by physical or chemical means such as heat shock, hyperbaric pressure or other treatment with a chemical, hormone, growth factor or other substance; S-phase control via treatment with .a chemical agent which interferes with any point of the replication procedure; M-phase control via selection using fluorescence activated cell sorting, mitotic shake off, treatment with microtubule disrupting agents or any chemical which disrupts progression in mitosis (see also Freshney, R. I,. "Culture of Animal Cells: A Manual of Basic Technique," Alan R. Liss, Inc, New York (1983). Methods for isolation of oocytes are well known in the art. Essentially, this can comprise isolating oocytes from the ovaries or reproductive tract of an animal. A readily available source of oocytes is slaughterhouse materials. For the combination of techniques such as genetic engineering, nuclear transfer and cloning, oocytesmust generally be matured in vitro before these cells can be used as recipient cells for nuclear transfer, and before they can be fertilized by the sperm cell to develop into an embryo. This process generally requires collecting immature (prophase 1) oocytes from mammalian ovaries, e.g., bovine ovaries obtained at a slaughterhouse, and maturing the oocytes in a maturation medium prior to fertilization or enucleation until the oocyte attains the metaphase II stage, which in the case of bovine oocytes generally occurs about 18-24 hours post-aspiration. This period of time is known as the "maturation period". In certain embodiments, the oocyte is obtained from a gilt. A "gilt" is a female pig that has. never had offspring. In other embodiments, the oocyte is obtained from a sow. A "sow" is a female pig that has previously produced offspring. A metaphase II stage oocyte can be the recipient oocyte, at this stage it is believed that the oocyte can be or is sufficiently "activated" to treat the introduced nucleus as it does a fertilizing sperm. Metaphase IU stage oocytes, which have been matured in vivo have been successfully used in nuclear transfer techniques. Essentially, mature metaphase II oocytes can be collected surgically from either non-superovulated or superovulated animal 35 to 48, or 39-41, hours past the onset of estrus or past the injection of human chorionic gonadotropin (hCG) or similar hormone. The oocyte can be placed in an appropriate medium, such as a hyalurodase solution. 156 After a fixed time maturation period, which ranges from about 10 to 40 hours, about 16 18 hours, about 40-42 hours or about 39-41 hours, the oocytes can be enucleated. Prior to enucleation the oocytes can be removed and placed in appropriate medium, such as HECM containing 1 milligram per milliliter of hyaluronidase prior to removal of cumulus cells. The stripped oocytes can then be screened for polar bodies, and the selected metaphase II oocytes, as determined by the presence of polar bodies, are then used for nuclear transfer. Enucleation follows. Enucleation can be performed by known methods, such as described in U.S. Pat. No.. 4,994,384. For example, metaphase II oocytes can be placed in either HECM, optionally containing 7.5 micrograms per milliliter cytochalasin B, for immediate enucleation, or can be placed in a suitable medium, for example an embryo culture medium such as CRIaa, plus 10% estrus cow serum, and then enucleated later, such as not more than 24 hours lateror not more than 16-18 hours later. Enucleation can be accomplished microsurgically using a micropipette to remove the polar body and the adjacent cytoplasm. The oocytes can then be screened to identify those of which have been successfully enucleated. One way to screen the oocytes is to stain the oocytes with 1 microgram per milliliter 33342 Hoechst dye in HECM, and then view the oocytes under ultraviolet irradiation for less than 10 seconds. The oocytes that have been successfully enucleated can then be placed in a suitable culture medium, for example, CRlaa plus 10% serum. A single mammalian cell of the same species as the enucleated oocyte can then be transferred into the perivitelline space of the enucleated oocyte used to produce the NT unit. The mammalian cell and the enucleated oocyte can be used to produce NT units according to methods known in the art. For example, the cells can be fused by electrofusion. Electrofusion is accomplished by providing a pulse of electricity that is sufficient to cause a transient breakdown of the plasma membrane. This breakdown of the plasma membrane is very short because the membrane reforms rapidly. Thus, if two adjacent membranes are induced to breakdown and upon reformation the lipid bilayers intermingle, small channels can open between the two cells. Due to the thermodynamic instability of such a small opening, it enlarges until the two cells become one. See, for example, U.S. Pat. No. 4,997,384 by Prather et al. A variety of electrofusion media can be used including, for example, sucrose, mannitol, sorbitol and 157 phosphate buffered solution. Fusion can also be accomplished using Sendai virus as a fusogenic agent (Graham, Wister Inot. Symp. Monogr., 9, 19, 1969). Also, the nucleus can be injected directly into the oocyte rather than using electroporation fusion. See, for example, Collas and Barnes, Mol. Reprod. Dev., 38:264-267 (1994). After fusion, the resultant fused NT units are then placed in a suitable medium until activation, for example, CRlaa medium. Typically activation can be effected shortly thereafter, for example less than 24 hours later, or about 4-9 hours later, or optimally 1-2 hours after fusion. In a particular embodiment, activation occurs at least one hour post fusion and at 40-41 hours post maturation. The NT unit can be activated by known methods. Such methods include, for example, culturing the NT unit at sub-physiological temperature, in essence by applying a cold, or actually cool temperature shock to the NT unit. This can be most conveniently done by culturing the NT unit at room temperature, which is cold relative to the physiological temperature conditions to which embryos are normally exposed. Alternatively, activation can be achieved by application of known activation agents. For exam pe, penetration of oocytes.by sperm during fertilization has been shown to activate prefusion oocytes to yield greater numbers of viable pregnancies and multiple genetically identical calves after nuclear transfer. Also, treatments such as electrical and chemical shock can be used to activate NT embryos after fusion. See, for example, U.S. Pat. No. 5,496,720, to Susko-Parrish et al. Fusion and activation can be induced by application of an AC pulse of 5 V for 5 s followed by two DC pulses of 1.5 kV/cm for 60 ps each using an ECM2001 Electrocell Manipulator (BTX Inc., San Diego, CA). Additionally, activation can be effected by simultaneously or sequentially by increasing levels of divalent cations in the oocyte, and reducing phosphorylation of cellular proteins in the oocyte. This can generally be effected by introducing divalent cations into the oocyte cytoplasm, e.g., magnesium, strontium, barium or calcium, e.g., in the form of an ionophore. Other methods of increasing divalent cation levels include the use of electric shock, treatment with ethanol and treatment with caged chelators. Phosphorylation can be reduced by known methods, for example, by the addition of kinase inhibitors, e.g., serine-threonine kinase inhibitors, such as 6-dimethyl-aminopurine, staurosporine, 2-aminopurine, and sphingosine. Alternatively, phosphorylation of cellular proteins can be inhibited by introduction of a phosphatase into the oocyte, e.g., phosphatase 2A and phosphatase 2B. 158 The activated NT units, or "fused embyos", can then be cultured in a suitable in vitro culture medium until the generation of cell colonies. Culture media suitable -for culturing and maturation of embryos are well known in the art. Examples of known media, which can be used for embryo culture and maintenance, include Ham's F-10+10% fetal calf serum (FCS), Tissue Culture Medium-199 (TCM-199)+10% fetal calf serum, Tyrodes-Albumin-Lactate-Pyruvate (TALP), Dulbecco's Phosphate Buffered Saline (PBS), Eagle's and Whitten's media, and, in one specific example, the activated NT units can be cultured in NCSU-23 medium for about 1-4 h at approximately 38.6*C in a humidified atmosphere of 5% C02. Afterward, the cultured NT unit or units can be washed and then placed in a suitable media contained in well plates which can contain a suitable confluent feeder layer. Suitable feeder layers include, by way of example, fibroblasts and epithelial cells. The NT units are cultured on the feeder layer until the NT units reach a size suitable for transferring to a recipient female, or for obtaining cells which can be used to produce cell colonies. These NT units can be cultured.until at least about 2 to 400 cells, about 4 to 128 cells, or at least about 50.cells. Activated NT units can then be transferred (embryo transfers) to the oviduct of an female pigs. In one embodiment, the female pigs can be an estrus-synchronized recipient gilt. Crossbred gilts (large white/Duroc/Landrace) (280-400 lbs) can be used. The gilts can be synchronized as recipient animals by oral administration of 18-20 mg Regu-Mate (Altrenogest, Hoechst, Warren, NJ) mixed into the feed. Regu-Mate can be fed for 14 consecutive days. One thousand units of Human Chorionic Gonadotropin (hCG, Intervet America, Millsboro, DE) can then be administered i.m. about 105 h after the last Regu-Mate treatment. Embryo transfers can then be performed about 22-26 h after the hCG injection. In one embodiment, the pregnancy can be brought to term and result in the birth of live offspring. In another embodiment, the. pregnancy can be terminated early and embryonic cells can be harvested. Breedingfor Desired Homozygous Knockout Animals In another aspect, the present invention provides a method for producing viable animals that lack any expression of a functional immunoglobulin gene is provided by breeding a male heterozygous for the immunoglobulin gene with a female heterozygous for the immunoglobulin gene. In one embodiment, the animals are heterozygous due to the genetic modification of one allele of the immunoglobulin gene to prevent expression of that allele. In another embodiment, 159 the animals are heterozygous due to the presence of a point mutation in one allele of the alpha immunoglobulin gene. In further embodiments, such heterozygous knockouts can be bred with an ungulate that expresses xenogenous immunoglobulin, such as.human. In one embodiment, a animal can be obtained by breeding a transgenic ungulate that lacks expression of at least one allele of an endogenous immunoglobulin wherein the immunoglobulin is selected from the group consisting of heavy chain, kappa light chain and lambda light chain or any combination thereof with an ungulate that expresses an xenogenous immunoglobulin. In another embodiment, a animal can be obtained by breeding a transgenic ungulate that lacks expression of one allele of heavy chain, kappa light chain and lambda light chain with an ungulate that expresses an xenogenous, such as human, immunoglobulin. In a further embodiment, an animal can be obtained by breeding a transgenic ungulate that lacks expression of one allele of heavy chain, kappa light chain and lambda light chain and expresses an xenogenous, such as human, immunoglobulin with another transgenic ungulate that lacks expression of one allele of heavy chain, kappa light chain and lambda light chain with an ungulate and..expresses an xenogenous, such as human, immunoglobulin to produce a homozygous transgenic ungulate that lacks expression of both alleles of heavy chain, kappa light chain and lambda light chain and expresses an xenogenous, such as human, immunoglobulin. Methods to produce such animals are also provided. In one embodiment, sexually mature animals produced from nuclear transfer from donor cells that carrying a double knockout in the immunoglobulin gene, can be bred and their offspring tested for the homozygous knockout. 'These homozygous knockout animals can then be bred to produce more animals. In another embodiment, oocytes from a sexually mature double knockout animal can be in vitro fertilized using wild type sperm from two genetically diverse pig lines and the embryos implanted into suitable surrogates. Offspring from these matings can be tested for the presence of the knockout, for example, they can be tested by cDNA sequencing, and/ or PCR. Then, at sexual maturity, animals from each of these litters can be mated. In certain methods according to this aspect of the invention, pregnancies can be terminated early so that fetal fibroblasts can be isolated and further characterized phenotypically and/or genotypically. Fibroblasts that lack expression of the immunoglobulin gene can then be used for nuclear transfer according to the 160 methods described herein to produce multiple pregnancies and offspring carrying the desired double knockout. Additional Genetic Modifications In other embodiments, animals or cells lacking expression of functional immunoglobulin, produced according to the process, sequences and/or constructs described herein, can contain additional genetic modifications to eliminate the expression of xenoantigens. The additional genetic modifications can be made by further genetically modifying cells obtained from the transgenic cells and animals described herein or by breeding the animals described herein with animals that have been further genetically modified. Such animals can be modified to climate the expression of at least one allele of the alpha-1,3-galactosyltransferase gene, the CMP Neu5Ac hydroxylase gene (see, for example, USSN. 10/863,116), the iGb3 synthase gene (see, for example, U.S. Patent Application 60/517,524), and/or the Forssman synthase gene (see, for gxamnple, _UkPatent Application 601568,922)... In additional embodiments, the animals discloses herein can also contain genetic modifications to expresss fucosyltransferase, sialyltransferase and/ or any member of the family of glucosyltransferases. To achieve these additional genetic modifications, in one embodiment, cells can be modified to contain multiple genentic modifications. In other.embodiments, animals can be bred together to achieve multiple genetic modifications. In one specific embodiment, animals, such as pigs, lacking expression of functional immunoglobulin, produced according to the process, sequences and/or constructs described herein, can be bred with animals, such as pigs, lacking expression of alpha-1,3 galactosyl transferase (for example, as described in WO 04/028243). In another embodiment, the expression of additional genes responsible for xenograft rejection can be eliminated or reduced. Such genes include, but are not limited to the CMP NEUAc Hydroxylase Gene, the isoGloboside 3 Synthase gene, and the Forssman synthase gene. In addition, genes or cDNA encoding complement related proteins, which are responsible for the suppression of complement mediated lysis can also be expressed in the animals and tissues of the present invention. Such genes include,, but are not limited to CD59, DAF, MCP and CD46 (see, for example, WO 99/53042; Chen et al. Xenotransplantation, Volume 6 Issue 3 Page 194 August 1999, which describes pigs that express CD59/DAF transgenes: Costa C et al, Xenotransplantation. 2002 Jan;9(l):45-57, which describes transgenic pigs that express human 161 CD59 and H-transferase; Zhao L et al.; Diamond LE et al. Transplantation. 2001 Jan 15;71(1):132-42, which describes a human CD46 transgenic pigs. Additional modifications can include expression of tissue factor pathway inhibitor (TFPI). heparin, antithrombin, hirudin, TFPI, tick anticoagulant peptide, or a snake venom factor, such as described in WO 98/42850 and US Patent No. 6,423,316, entitled "Anticoagulant fusion protein anchored to cell membrane"; or compounds, such as antibodies, which down regulate the expression of a cell adhesion molecule by the cells, such as described in WO 00/31126, entitled "Suppression of xenograft rejection by down regulation of a cell adhesion molecules" and compounds in which co-stimulation by signal 2 is prevented, such as by administration to the organ recipient of a soluble form of CTLA-4 from the xenogeneic donor organism, for eample as described in WO 99/57266, entitled "Immunosuppression by blocking T cell co-stimulation signal 2 (B7/CD28 interaction)". Certain aspects of the invention are described in greater detail in the non-limiting Examples that follow. EXAMPLES EXAMPLE 1:Porcine Heavy Chain Targeting and Generation of Porcine Animals that Lack Expression of Heavy Chain A portion of the porcine Ig heavy-chain locus was isolated from a 3X redundant porcine BAC library. In general, BAC libraries can be generated by fragmenting pig total genomic DNA, which can then be used to derive a BAC library representing at least three times the genome of the whole animal. BACs that contain porcine heavy chain immunoglobulin can then be selected through hybridization of probes selective for porcine heavy chain immunoglobulin as described herein. Sequence from a clone (Seq ID 1) was used to generate a primer complementary to a portion of the J-region (the primer is represented by Seq ID No. 2). Separately, a primer was designed that was complementary to a portion of Ig heavy-chain mu constant region (the promer 162 is represented by Seq ID No. 3). These primers were used to amplify a fragment of porcine Ig heavy-chain (represented by Seq ID No. 4) that led the functional joining region (J-region) and sufficient flanking region to design and build a targeting vector. To maintain this fragment and subicones of this fragment in a native state, the E. coli (Stable 2, Invitrogen cat #1026-019) that .harbored these fragments was maintained at 30*C. Regions of Seq. ID No. 4 were subcloned and used to assemble a targeting vector as shown in Seq. ID No. 5. This vector was transfected into porcine fetal fibroblasts that were subsequently subjected to selection with G418. Resulting colonies were screened by PCR to detect potential targeting events (Seq ID No. 6 and Seq ID. No. 7, 5' screen prmers; and Seq ID No. 8 and Seq ID No. 9, 3' screen primers). See Figure 1. for a schematic illustrating the targeting. Targeting was confirmed by southern blotting. Piglets were generated by nuclear transfer using the targeted fetal fibroblasts as nuclear donors. Nuclear Transfer. The targeted fetal fibroblasts were used as nuclear donor cells. Nuclear transfer was performed by methods that are well.known.in the.art (see,.e.g., Dai et al., Nature Biotechnology 20: 251-255, 2002; and Polejaeva et al., Nature 407:86-90, 2000). Oocytres were collected 46-54 h after the hCG injection by reverse flush of the oviducts using pre-warmed Dulbecco's phosphate buffered saline (PBS) containing bovine serum albumin (BSA; 4 g r') (as described in Polejaeva, I.A., et al. (Nature 407, 86-90 (2000)). Enucleation of in vitro-matured oocytes (BioMed, Madison, WI) was begun between 40 and 42 hours post maturation as described in Polejaeva, I.A., et al. (Nature 407, 86-90 (2000)). Recovered oocytes were washed in PBS containing 4 gl 1 BSA at 38 0 C, and transferred to calcium-free phosphate buffered NCSU-23 medium at 38 0 C for transport to the laboratory. For. enucleation, we incubated the oocytes in calcium-free phosphate-buffered NCSU-23 medium containing 5 pig ml cytochalasin B (Sigma) and 7.5 pg ml- 1 Hoechst 33342 (Sigma) at 38 0 C for 20 min. A small amount of cytoplasm from directly beneath the first polar body was then aspirated using an 18 pM glass pipette (Humagen, Charlottesville, Virginia). We exposed the aspirated karyoplast to ultraviolet light to confirm the presence of a metaphase plate. For nuclear transfer, a single fibroblast cell was placed under the zona pellucida in contact with each enucleated oocyte. Fusion and activation were induced by application of an AC pulse of 5 V for 5 s followed by two DC pulses of 1.5 kV/cm for 60 ps each using an ECM2001 Electrocell Manipulator (BTX Inc., San Diego, CA). Fused embryos were cultured in 163 NCSU-23 medium for 1-4 h at 38.6 0 C in a humidified atmosphere of 5% CO 2 , and then transferred to the oviduct of an estrus-synchronized recipient gilt. Crossbred gilts (large white/Duroc/landrace) (280-400 lbs) were synchronized as recipients by oral administration of 18-20 mg Regu-Mate (Altrenogest, Hoechst, Warren, NJ) mixed into their feed. Regu-Mate was fed for 14 consecutive days. Human chorionic. gonadotropin (hCG, 1,000 units; Intervet America, Millsboro, DE) was administered intra-muscularly 105 h after the last Regu-Mate treatment. Embryo transfers were done 22-26 h after the hCG injection. Nuclear transfer produced 18 healthy piglets from four litters. These animals have one functional wild-type Ig heavy-chain locus and one disrupted Ig heavy chain locus. Seq ID 2: primer from ggccagacttcctcggaacagctca Butler subclone to amplify Ito C heavychain (637Xba5') Seq ID 3: primer for C to ttccaggagaaggtgacggagct amplify J to C heavychain (JMlL) Seq ID 6: heavychain 5'. tctagaagacgctggagagaggccag primer for 5' screen (HCKOXba5'2) Seq ID 7: heavychain 3' taaagcgcatgctccagactgcctt primer for 5' screen (5'arm5') Seq ID 8: heavychain 5' catcgccttctatcgccttctt primer for 3' screen (NE04425) Seq ID 9: heavychain 3' Aagtacttgccgcctctcagga primer for 3' screen (650+CA) _ Southern blot analysis of cell and pig tissue samples. Cells or tissue samples were lysed overnight at 60*C in lysis buffer (10mM Tris, pH 7.5, 10mM EDTA, 10mM NaCl, 0.5% (w/v) Sarcosyl, I mg/ml proteinase K) and the DNA precipitated with ethanol. The DNA was then 164 digested with NcoI or XbaI, depending on the probe to be used, and separated on a 1% agarose gel. After electrophoresis, the DNA was transferred to a nylon membrane and probed with digoxigenin-labeled probe (SEQ ID No 41 for NcoI digest, SEQ ID No 40 for XbaI digest). Bands were detected using a chemiluminescent substrate system (Roche Molecular Biochemicals). Probes for Heavy Chain Southern: HC J Probe (used with Xba I digest) CTCTGCACTCACTACCGCCGGACGCGCACTGCCGTGCTGCCCATGGACCA CGCTGGGGAGGGGTGAGCGGACAGCACGTTAGGAAGTGTGTGTGTGCGCG TGGGTGCAAGTCGAGCCAAGGCCAAGATCCAGGGGCTGGGCCCTGTGCCC AGAGGAGAATGGCAGGTGGAGTGTAGCTGGATTGAAAGGTGGCCTGAAGG GTGGGGCATCCTGTTTGGAGGCTCACTCTCAGCCCCAGGGTCTCTGGTTC CTGCCGGGGTGGGGGGCGCAAGGTGCCTACCACACCCTGCTAGCCCCTCG TCCAGTCCCGGGCCTGCCTCTTCACCACGGAA AGATAAGCCAGGCTGC -AGGCTTCATGTGCGCCGTGGAGAACCCAGTTCGGCCCTTGGAGG (Seq ID No 40) HC Mu Probe (used with Ncol digest) GGCTGAAGTCTGAGGCCTGGCAGATGAGCTTGGACGTGCGCTGGGGAGTA CTGGAGAAGGACTCCCGGGTGGGGACGAAGATGTTCAAGACGGGGGGCTG CTCCrCTACGACTGCAGGCAGGAACGGGGCGTCACTGTGCCGGCGGCACC CGGCCCCGCCCCCGCCACAGCCACAGGGGGAGCCCAGCTCACCTGGCCCA GAGATGGACACGGACTTGGTGCCACTGGGGTGCTGGACCTCGCACACCAG GAAGGCCTCTGGGTCCTGGGGGATGCTCACAGAGGGTAGGAGCACCCGGG AGGAGGCCAAGTACTTGCCGCCTCTCAGGACGG (Seq ID No 41) EXAMPLE 2: Porcine Kappa Light Chain Targeting and Generation of Porcine Lacking Expression of Kappa Light Chain A portion of the porcine Ig kappa-chain locus was isolated from a 3X redundant porcine BAC library. in general, BAC libraries can be generated by fragmenting pig total genomic DNA, which can then be used to derive a BAC library representing at least three times the 165 genome of the whole animal. BACs that contain porcine kappa chain immunoglobulin can then be selected through hybridization of probes selective for porcine kappa chain immunoglobulin as described herein. A fragment of porcine Ig light-chain kappa was amplified using a primer complementary to a portion of the J-region (the primer is represented by Seq ID No. 10) and a primer complementary to a region of kappa C-region (represented by Seq I) No. 11). The resulting amplimer was cloned into a plasmid vector and maintained in Stable2 cells at 30*C ( Seq ID No. 12). See Figure 2 for a schematic illustration. Separately, a fragment of porcine Ig light-chain kappa was amplified using a primer complementary. to a portion of the C-region (Seq ID No. 13) and a primer complementary to a region of the kappa enhancer region (Seq ID No. 14). The resulting amplimer was fragmented by restriction enzymes and DNA fragments that were produced were cloned, maintained in Stable2 cells at 30 degrees C and sequenced. As a result of this sequencing, two non overlapping contigs were assembled ( Seq ID No. 15,.5' portion of amplimer; and Seq ID No. 16, 3'.portion of amplimer). Sequence from the downstream contig (Seq ID No. 16) was used to design a set of primers (Seq ID No. 17 and Seq ID No. 18) that were used to amplify a contiguous fragment near the enhancer (Seq ID No. 19). A subclone of each Seq ID No. 12 and Seq ID No. 19 were used to build a targeting vector (Seq ID No. 20). This vector was transfected into porcine fetal fibroblasts that were subsequently subjected to selection with G418. Resulting colonies were screened by PCR to detect potential targeting events (Seq ID No. 21 and Seq ID No. 22, 5' screen primers; and Seq ID No. 23 and Seq Id No 43, 3' screen primers, and Seq ID No. 24 and Seq Id No 24, endogenous screen primers). Targeting was confirmed by southern blotting. Southern blot strategy design was facilitated by cloning additional kappa sequence, it corresponds to the template for germline kappa transcript (Seq ID No. 25). Fetal pigs were generated by nuclear transfer. Nuclear Transfer. The targeted fetal fibroblasts were used as nuclear donor cells. Nuclear transfer was performed by methods that are well known in the art (see, e.g., Dai et al., Nature Biotechnology 20: 251-255, 2002; and Polejaeva et al., Nature 407:86-90, 2000). Oocytres were collected 46-54 h after the hCG injection by reverse flush of the oviducts using pre-warmed Dulbecco's phosphate buffered saline (PBS) containing bovine serum albumin 166 (BSA; 4 g~') (as described in Polejaeva, I.A., et al. (Nature 407, 86-90 (2000)). Enuclcation of in vitro-matured oocytes (BioMed, Madison, WI) was begun between 40 and 42 hours post maturation as described in Polejaeva, I.A., et al. (Nature 407, 86-90 (2000)). Recovered oocytes were washed in PBS containing 4 gl' BSA at 38 0 C, and transferred to calcium-free phosphate buffered NCSU-23 medium at 38"C for transport to the laboratory. For enucleation, we incubated the oocytes in calcium-free phosphate-buffered NCSU-23 medium containing 5 pg ml-U cytochalasin B (Sigma) and 7.5 Ig ml-1 Hoechst 33342 (Sigma) at 38 0 C for 20 min. A small amount of cytoplasm from directly beneath the first polar body was then aspirated using an 18 pM glass pipette (Humagen, Charlottesville, Virginia). We exposed the aspirated karyoplast to ultraviolet light to confirm the presence of a metaphase plate. For nuclear transfer, a single fibroblast cell was placed under the zona pellucida in contact with each enucleated oocyte. Fusion and activation were induced by application of an AC pulse of 5 V for 5 s followed by two DC pulses of 1.5 kV/cm for 60 ps each using an ECM2001 Electrocell Manipulator (BTXIic., San Diego, CA). Fused embryos were cultured in NCSU-23 medium for 1-4h at 38.6*C in a humidified atmosphere of 5% CO 2 , and then transferred to the oviduct of an estrus-synchronized recipient gilt. Crossbred gilts (large white/Duroc/landrace) (280-400 lbs) were synchronized as recipients by oral administration of 18-20 mg Regu-Mate (Altrenogest, Hoechst, Warren, NJ) mixed into their feed. Regu-Mate was fed for 14 consecutive days. Human chorionic gonadotropin (hCG, 1,000 units; Intervet America, Millsboro, DE) was administered intra-muscularly 105 h after the last Regu-Mate treatment. Embryo transfers were done 22-26 h after the hCG injection. Nuclear transfer using kappa targeted cells produced 33 healthy pigs from 5 litters. These pigs have one functional wild-type allele of porcine Ig light-chain kappa and one disrupted Ig light-chain kappa allele. Seq ID 10: kappa J to C caaggaqaccaagctggaactc 5' primer (kic5'l) Seq ID 11: kappa J to C tgatcaagcacaccacagagacag 3' primer (kjc3'2) Seq ID 13: 5' primer for gatgccaagccatccgtcttcatc Kappa C to E (porKCS 1) 167 Seq ID 14: 3' primer for tgaccaaagcagtgtgacggttgc Kappa C to E (porKCA1) Seq ID 17: kappa 5' ggatcaaacacgcatcctcatggac primer for amplification -of enhancer region (K3'arm1S) Seq ID 18: kappa 3' ggtgattggggcatggttgagg primer for amplification of enhancer region (K3'arm1A) Seq ID 21: kappa screen, cgaacccctgtgtatatagtt 5' primer, 5' (kappa5armS) Seq ID 22: kappa screen, gagatgaggaagaggagaaca 3' primer, 5' (kappaNeoA) Seq ID 23: kappa screen, gcattgtctgagtaggtgtcatt 5' primer, 3' (kappaNeoS) Seq ID 24: kappa screen, cgcttcttgcagggaacacgat 3' primer, 5' (kappa5armProbe3') Seq ID No 43, Kappa GTCTTTGGTTTGCTGAGGGTT screen, 3' primer (kappa3armiA2) Southern blot analysis of cell and pig tissue samples. Cells or tissue samples were lysed overnight at 60*C in lysis buffer (10mM Tris, pH 7.5, 10mM EDTA, 10mM NaCl, 0.5% (w/v) Sarcosyl, 1 mg/ml proteinase K) and the DNA precipitated with ethanol. The DNA was then digested with SacI and separated on a 1% agarose gel. After electrophoresis, the DNA was transferred to a nylon membrane and probed with digoxigenin-labeled probe (SEQ ID No 42). Bands were detected using a chemiluminescent substrate system (Roche Molecular Biochemicals). Probe for Kapna Southern: 168 Kappa5ArmProbe 5'/3' gaagtgaagccagccagttctcctgggcaggtggccaaaattacagtg acccctcctggttggtgaaccttgcccatatggtgacagccatctgg ccagggcccaggtctCccttgaagctttgggaggagagggagagtggC tggcccgatcacagatgcggaaggggctgactcctcaaccggggtgcaga ctctgcagggtgggtctgggcccaacacacccaaagcacgcccaggaagg aaaggcagcttggtatcactgcccagagctaggagaggcaccgggaaaat gatctgtccaagacccgttcttgcttctaaactccgagggggtcagatga agtggttttgtttcttggcctgaagcatcgtgttccctgcaagagCgg (SEQ ID No 42) EXAMPLE 3 Characterization of the Porcine Lambda Gene Locus To disrupt or disable porcine lambda, a targeting strategy has been devised that allows for the. removal or disruption of the region of the lambda locus that includes a concatamer of J to C expression cassettes. -BAC clones that contain portions of the porcine genome can be generated. A portion of the porcine Ig lambda-chain locus was isolated from a 3X redundant porcine BAC library. In general, BAC libraries can be generated by fragmenting pig total genomic DNA, which can. then be used to derive a BAC library representing at least three times the genome of the whole animal. BACs that contain porcine lambda chain immunoglobulin can then be selected through hybridization of probes selective for porcine lambdachain immunoglobulin as described herein. BAC clones containing a lambda J-C flanking region (see Figure 3), ran be independently fragmented and subcloned into a plasmid vector. Individual subclones have been screened by PCR for the presence of a portion of the J to C intron. We have cloned several of these cassettes by amplifying from one C region to the next C region. This amplification was accomplished by using primers that are oriented to allow divergent extension within any one C region (Seq ID 26 and Seq ID 27). To obtain successful amplification, the extended products converge with extended products originated from adjacent C regions (as opposed to the same C region). This strategy produces primarily amplimers that extend from one C to the adjacent C. However, some amplimers are the result of amplification across the adjacent C and into the next C which lies beyond the adjacent C. These multi-gene amplimers contain a portion of a C, both the J and C region of the next J-C unit, the J region of the third J-C unit, and a portion of the C 169 region of the third J-C unit. Seq ID 28 is one such amplimer and represents sequence that must be removed or disrupted. Other porcine lambda sequences that have been cloned include: Seq ID No. 32, which includes 5' flanking sequence to the first lambda J/C region of the porcine lambda light chain genomic sequence; Seq ID No. 33, which includes 3' flanking sequence to the J/C cluster region of the porcine lambda light chain genomic sequence, from approximately 200 base pairs downstream of lambda J/C; Seq ID No. 34, which includes 3' flanking sequence to the J/C cluster region of the porcine lambda light chain genomic sequence, approximately 11.8 Kb downstream of the J/C cluster, near the enhancer; Seq ID No. 35, which includes approximately 12 Kb downstream of lambda, including the enhancer region; Seq ID No. 36, which includes approximately 17.6 Kb downstream of lambda; Seq ID No. 37, which includes approximately 19.1 Kb downstream of lambda; Seq ID No. 38, which includes approximately 21.3 Kb downstream of lambda; and Seq ID No. 39, which includes approximately 27 Kb downstream of lambda. Seq ID 26: 5'primer for ccttcctcctgcacctgtcaac lambda C to C amplimer (lamC5') Seq ID 27: 3' primer for tagacacaccagggtggccttg lambda C to C amplimer (lamC3') . Example 4 Production of Targeting Vectors for the Lambda Gene In one example, a vector has been designed and built with one targeting arm that is homologous to a region upstream of J1 and the other arm homologous to a region that is downstream of the last C (see Figure 4). One targeting vector is designed to target upstream of Ji. This targeting vector utilizes a selectable marker that can be selected for or against. Any combination of positive and negative selectable markers described herein or known in the art can be used. A fusion gene composed of the coding region of Herpes simplex thymidine kinase (TK) and the Tn5 aminoglycoside phosphotransferase (Neo resistance) genes is used. This fusion 170 gene is flanked by recognition sites for any site specific recombinase (SSRRS) described herein or known in the art, such as lox sites. Upon isolation of targeted cells through the use of G418 selection, Cre is supplied in trans to delete the marker gene (See Figure 5). Cells that have deleted the marker gene are selected by addition of any drug known in the art that can be metabolized by TK into a toxic product, such as ganciclovir. The resulting genotype is then targeted with a second vector. The second targeting vector (Figure 6) is designed to target downstream of last C and uses a positive/negative selection system that is flanked on only one side by a specific recombination site (lox). The recombination site is placed distally in relation. to the first targeting event. Upon isolation of the targeted genotype, Cre is again supplied in trans to mediate deletion from recombination site provided in the first targeting-event to the recombination site delivered in the second targeting event. The entire J to C cluster will be removed. The appropriate genotype is again selected by administration of ganciclovir. In another example, insertional targeting vectors are used to disrupt each C regions independently... An. insertional targeting_.yector will be designed and assembled to disrupt individual C region genes. There are at least 3 J to C regions in the J-C cluster. We will begin the process by designing vectors to target the first and last C regions and will include in the targeting vector site-specific recombination sites. Once both insertions have been made, the intervening region will be deleted with the site-specific recombinase. Example 5: Crossbreeding of Heavy chain single knockout with Kappa single knockout pigs. To produce pigs that have both one disrupted Ig heavy chain locus and one disrupted Ig light-chain kappa allele, single knockout animals were crossbred. The first pregnancy yielded four fetuses, two of which screened positive by both PCR and Southern for both heavy-chain and kappa targeting events (see examples 1 and 2 for primers). Fetal fibroblasts were isolated, expanded and frozen. A second pregnancy resulting from the mating of a kappa single knockout with a heavy chain single knockout produced four healthy piglets. Fetal fibroblast cells that contain a heavy chain single knockout and a kappa chain single knockout will be used for further targeting. Such cells will be used to target the lambda locus via the methods and compositins described herein. The resulting offspring will be hereozygous 171 knockouts for heavy chain, kappa chain and lambda chain. These animals will be further crossed with animals containing the human Ig genes as decsibed herein and then crossbred with other single Ig knockout animals to produce porcine Ig double knockout animals with human Ig replacement genes. This invention has been described with reference to its preferred embodiments. Variations and modifications of the invention, will be-obvious to those skilled in the art from the foregoing detailed description of the invention. 172

Claims (114)

1. A transgenic ungulate that lacks any expression of functional endogenous immunoglobulins.

2. The transgenic ungulate of claim 1, wherein the ungulate lacks any expression of endogenous heavy chain immunoglobulins.

3. The transgenic ungulate of claim 1, wherein the ungulate lacks any expression of endogenous light chain immunoglobulins.

4. The transgenic ungulate of claim 3, wherein the ungulate lacks any expression of endogenous kappa chain immunoglobulin.

5. The transgenic ungulate of claim 3, wherein the ungulate lacks any expression of endogenous lambda chain immunoglobulin.

6. The transgenic ungulate of claim 1, wherein the ungulate is selected from the group consisting of a porcine, bovine, ovine and caprine.

7. The transgenic ungulate of claim 6, wherein the ungulate is a porcine.

8. The transgenic ungulate of claim 1, wherein the ungulate is produced via nuclear transfer.

9. *The transgenic ungulate of claim 1, wherein the ungulate expresses an exogenous immunoglobulin loci.

10. The transgenic ungulate of claim 9, wherein the exogeous immunoglobulin loci is a heavy chain immunoglobulin or fragment thereof.

11. The transgenic ungulate of claim 9, wherein the exogeous immunoglobulin loci is a light chain immunoglobulin or fragment thereof.

12. The transgenic ungulate of claim 11, wherein the light chain locus is a kappa chain locus or fragment thereof.

13. The transgenic ungulate of claim 11, wherein the light chain locus is a lambda chain locus or fragment thereof.

14. The transgenic ungulate of claim 9, wherein the xenogenous locus is a human immunoglobulin locus or fragment thereof.

15. The transgenic ungulate of claim 9, wherein an artificial chromosome contains the xenogenous immunoglobulin. 173 15. The transgenic ungulate of claim 15, wherein the artificial chromosomes comprise a mammalian artificial chromosome.

16. The transgenic ungulate of claim 15, wherein the mammalian artificial chromosome comprises one or more of human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof.

17. A transgenic mammal that lacks any expression of an endogenous lambda chain immunoglobulin.

18. A transgenic ungulate that expresses a xenogenous immunoglobulin loci or fragment thereof, wherein the immunoglobulin is expressed from an immunoglobulin locus that is integrated within an endogenous ungulate chromosome.

19. The transgenic ungulate of claim 18, wherein the xenogenous immunoglobulin is a human immunoglobulin or fragment thereof.

20. The transgenic ungulate of claim 18, wherein the xenogenous immunoglobulin locus is inherited by offspring.

21. The transgenic ungulate of claim 18, wherein the xenogenous immunoglobulin locus is inherited through the male germ line by offspring.

22. The transgenic ungulate of claim 18, wherein the ungulate is a porcine, sheep, goat or cow.

23. The transgenic ungulate of claim 22, wherein the ungulate is a porcine.

24. The transgenic ungulate of claim 18, wherein the ungulate is produced through nuclear transfer.

25. The transgenic ungulate of claim 18, wherein the immunoglobulin loci are expressed in B cells to produce xenogenous immunoglobulin in response to exposure to one or more antigens.

26. The transgenic ungulateof claim 18, wherein an artificial chromosome comprises the xenogenous immunoglobulin.

27. The transgenic ungulate of claim 18, wherein the artificial chromosome comprises a mammalian artificial chromosome.

28. The transgenic ungulate of claim 27, wherein the artificial chromosomes comprises a yeast artificial chromosome. 174

29. The transgenic ungulate of claim 26, wherein the artificial chromosome comprises one or more of human chromosome 14, human chromosome 2, and human chromosome 22 or fragment thereof.

30. A transgenic ungulate cell, tissue or organ derived from the transgenic ungulate of claim 1.

31. A transgenic ungulate cell, tissue or.organ derived from the transgenic ungulate of claim 18.

32. The cell of claim 30 or 31, wherein the cell is a somatic, reproductive or germ cell.

33. The cell of claim 32, wherein the cell is a B cell.

34. The cell of claim 33, wherein the cell is a fibroblast cell.

35. A porcine animal comprising a xenogenous immunoglobulin locus.

36. The porcine of claim 35, wherein an artificial chromosome contains the xenogenous locus.

37. The porcine of claim 36, wherein the artificial chromosome comprises one or more xenogenous immunoglobulin loci that undergo rearrangement and can produce a xenogenous immunoglobulin in response to exposure to one or more antigens.

38. The procine cell derived from the animal of claim 35.

39. The procine cell of claim 36, wherein the cell is a somatic cell, a B cell or a fibroblast.

40. The porcine of claim 35, wherein the xenogenous immunoglobulin is a human immunoglobulin.

41. The porcine of claim 36, wherein the one or more artificial chromosomes comprise a mammalian artificial chromosome.

42. The porcine of claim 41, wherein the mammalian artificial chromosome comprises one or more of human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof.

43 A method of producing xenogenous antibodies, the method comprising the steps of: (a) administering one or more antigens of interest to an ungulate whose cells comprise one or more artificial chromosomes and lack any expression of functional endogenous immunoglobulin, each artificial chromosome comprising one or more xenogenous immunoglobulin loci that undergo rearrangement, resulting in production of xenogenous antibodies against the one or more antigens; and (b) recovering the xenogenous antibodies from the ungulate. 175

44. The method of claim 43, wherein the immunoglobulin loci undergo rearrangement in a.B cell.

45. The method of claim 43, wherein the exogeous immunoglobulin loci is a heavy chain immunoglobulin or fragment thereof.

46. The method of claim 43, wherein the exogeous immunoglobulin loci is a light chain immunoglobulin or fragment thereof.

47. . The method of claim 43, wherein the xenogenous locus is a human immunoglobulin locus or fragment thereof.

48. The method of claim 43, wherein an artificial chromosome contains the xenogenous immunoglobulin.

49. The method of claim 48, wherein the artificial chromosomes comprise a mammalian artificial chromosome.

50. The method of claim 49, wherein the mammalian artificial chromosome comprises one or more of human chromosome 14, human chromosome 2, and human chromosome 22 or fragments thereof.

51. An isolated nucleotide sequence comprising porcine heavy chain immunoglobulin or fragment thereof, wherein the heavy chain immunoglobulin includes at least one joining region and at least one constant immunoglobulin region.

52. The nucleotide sequence of claim 51, wherein the heavy chain immunoglobulin comprises at least one variable region, at least two diversity regions, at least four joining regions and at least one constant region.

53. The nucleotide sequence of claim 52, wherein the heavy chain immunoglobulin comprises Seq ID No. 29.

54. The nucleotide sequence of claim 51, wherein the heavy chain immunoglobulin comprises Seq ID No. 4.

55. The nucleotide sequence of claim 53 or 54, wherein the sequence is at least 80, 85, 90, 95, 98. or 99% homologous to Seq ID Nos 4 or 29.

56. The nucleotide sequence of claim 53 or 54, wherein the sequence contains at least 17, 20, 25 or 30 contiguous nucleotides of Seq ID No 4 or residues 1- 9,070 of Seq ID No 29.

57. The nucleotide sequence of claim 53 or 54, wherein the sequence comprises residues 9,070-11039 of Seq ID No 29. 176

58. An isolated nucleotide sequences that hybridizes to Seq ID No 4 or 29.

59. A targeting vector comprising: (a) a first nucleotide sequence comprising at least 17 contiguous nucleic acids . homologous to SEQ ID No 29; (b) a selectable marker gene; and (c) a second nucleotide sequence comprising at least 17 contiguous nucleic acids homologous to SEQ ID No 29, which does not overlap with the first nucleotide sequence.

60. The targeting vector of claim 59 wherein the selectable marker comprises an antibiotic resistence gene.

61. The targeting vector of claim 59 wherein the first nucleotide sequence represents the 5' recombination arm.

62. The targeting vector of claim 59 wherein the second nucleotide sequence represents the 3' recombination arm.

63. A cell transfected with the targeting vector of claim 59.

.64. The cell of claim 63 wherein at least one allele of a porcine heavy chain immunoglobulin locus has been rendered inactive.

65. A porcine animal comprising the cell of claim 64.

66. An isolated nucleotide sequence comprising an ungulate kappa light chain immunoglobulin locus or fragment thereof.

67. The nucleotide sequence of claim 66, wherein the ungulate is a porcine.

68. The nucleotide sequence of claim 66, wherein the ungulate kappa light chain imnimunoglobulin locus comprises at least one joining region, one constant region and/or one enhancer region.

69. The nucleotide sequence of claim 66, wherein the nucleotide sequence comprises at least five joining regions, one constant region and one enhancer region.

70. The nucleotide sequence of claim 69 comprising Seq ID No. 30.

71. The nucleotide sequence of claim 69 comprising Seq ID No. 12.

72. The nucleotide sequence of claim 70 or 71, wherein the sequence contains at least 17, 20, 25 or 30 contiguous nucleotides of Seq ID No 12 or 30.

73. An isolated nucleotide sequences that hybridizes to Seq ID No 12 or 30.

74. A targeting vector comprising: 177 (a) a first nucleotide sequence comprising at least 17 contiguous nucleic acids homologous to SEQ ID No 30; (b) a selectable marker gene; and (c) a second nucleotide sequence comprising at least 17 contiguous nucleic acids homologous to SEQ ID No 30, which does not overlap with the first nucleotide sequence.

75. The targeting vector of claim 74 wherein the selectable marker comprises an antibiotic resistence gene.

76. The targeting vector of claim 74 wherein the first nucleotide sequence represents the 5' recombination arm.

77. The targeting vector of claim 74 wherein the second nucleotide sequence represents the 3' recombination arm.

78. A cell transfected with the targeting vector of claim 74.

79. The.cell of claim 78 wherein at least one allele of a kappa chain immunoglobulin locus has beenrendered inactive.

80. . A porcine animal comprising the cell of claim 79.

81. An isolated nucleotide sequence comprising an ungulate lambda light chain immunoglobulin locus.

82. The nucleotide sequence of claim 81, wherein the ungulate -is a porcine.

83. The nucleotide sequence of claim 81, wherein the ungulate is a bovine.

84. The nucleotide sequence of claim 81, wherein the ungulate lambda light chain immunoglobulin locus comprises a concatamer of J to C units.

85. The nucleotide sequence of claim 81, wherein the ungulate lambda light chain immunoglobulin locus comprises at least one joining region-constant region pair and/or at least one variable region, for example, as represented by Seq ID No. 31

86. The nucleotide sequence of claim 82 comprising Seq ID No. 28.

87. The nucleotide sequence of claim 83 comprising Seq ID No. 31.

88. The nucleotide sequence of claim 86 or 87, wherein the sequence contains at least 17, 20, 25 or 30 contiguous nucleotides of Seq ID No 28 or 31.

89. An isolated nucleotide sequences that hybridizes to Seq ID No 28 or 31.

90. A targeting vector comprising: 178 (a) a first nucleotide sequence comprising at least 17 contiguous nucleic acids homologous to SEQ ID No 28 or 31; (b) a selectable marker gene; and (c) a second nucleotide sequence comprising at least 17 contiguous nucleic acids homologous to SEQ ID No 28 or 31, which does not overlap with the first nucleotide sequence.

91. The targeting vector of claim 90 wherein the selectable marker comprises an antibiotic. resistence gene.

92. The targeting vector of claim 90 wherein the first nucleotide sequence represents the 5' recombination arm.

93. The targeting vector of claim 90 wherein the second nucleotide sequence represents the 3' recombination arm.

94. A cell transfected with the targeting vector of claim 90.

95. The cell of claim 94 wherein at least one allele of a lambda chain immunoglobulin locus has been rendered inactive.

96. A porcine animal comprising the cell of claim 95.

97. A method to circularize at least 100 kb of DNA, wherein the DNA can then be integrated into a host genome via a site specific recombinase.

98.- The method of claim 97, wherein at least 100, 200, 300, 400, 500, 1000, 2000, 5000, 10,000 kb of DNA can be circularized.

99. The method of claim 97, wherein the circularization of the DNA can be accomplished by attaching site specific recombinase target sites at each end of the DNA sequence and then applying a site specific recombinase to the DNA sequence.

100. The method of claim 97, wherein the site specific recombinase target site is Lox.

101. The method of claim 97, wherein an artificial chromosome contains the DNA sequence.

102. The method of claim 101, wherein the artificial chromosome is a yeast artificial chromosome or a mammalian artificial chromosome.

103. The method of claim 101, wherein the artificial chromosome comprises a DNA sequence that encodes a human immunoglobulin locus or fragment thereof.

104. The method of claim 103, the human immunoglobulin locus or fragment thereof comprises human chromosome 14, human chromosome 2, and/ or human chromosome 22. 179

105. A transgenic ungulate that lacks expression of at least one allele of an endogenous immunoglobulin wherein the immunoglobulin is selected from the group consisting of heavy chain, kappa light chain and lambda light chain or any combination thereof.

106. The transgenic ungulate of claim 105, wherein xenogenous immunoglobulin is expressed.

107. A method to produce the transgenic ungulate. of claim 106, wherein a transgenic ungulate that lacks expression of at least one allele of an endogenous immunoglobulin wherein the immunoglobulin is selected from the group consisting of heavy chain, kappa light chain and lambda light chain or any combination thereof is bred with an ungulate that expresses an xenogenous immunoglobulin.

108. The transgenic ungulate of any of claims 105-107, wherein the ungulate is a porcine.

109. The transgenic ungulate of claim 106 or 107, wherein the xenogenous immunoglobulin is a human immunoglobulin locus or fragment thereof.

110. The transgenic ungulate of claim 109, wherein an artificial chromosome contains the human immunoglobulin locus or fragment thereof.

111. A cell derived from the ungulate of claim 105.

112. The transgenic ungulate of claim 1, 18, 105 or 106, further comprising an additional genetic modifications to eliminate the expression of a xenoantigen.

113. The transgenic ungulate of claim 112, wherein the ungulate lacks expression of at least one allele of the alpha-1,3-galactosyltransferase gene.

114. The transgenic ungulate of claim 112, wherein the ungulate is a porcine. 180