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Implication of Wild-derived Genes, Mitochondria, and Chromosomes in the Genetic Background of Mouse Models for Diseases and Biologic Functions

Kazuo Moriwaki

Vice President, The Graduate University for Advanced Studies

Kanagawa-Kenn, Japan

INTRODUCTION

Asian wild mouse-derived genes, mitochondria, and chromosomes are useful in the development of mouse models for biologic functions and their abnormal forms, diseases. Medical geneticists have recently recognized the effect of multiple genes on various phenotypes expressed at the whole body level. Obviously experimental analysis of these genes to include programmed mating can hardly be achieved in humans; therefore, it is advantageous to use experimental animals and, in particular, laboratory mice. For precise gene mapping in mice, several thousands of recently developed microsatellite DNA markers play an important role. However, due to limited progenitors, genetic variations detected among the current laboratory strains are rather limited. We need genetic resources with more genetic variations than those within conventional laboratory mouse strains.

GENETIC POSITION OF ASIAN WILD MICE

Since 1975, we have surveyed genetic variations in the natural populations of wild mice collected from all over the world. Taxonomically those mice have been classified into 11 subspecies based on their morphologic characters and geographic distribution (Schwarz and Schwarz 1943). However, our survey in the chromosome C-band pattern (Moriwaki and others 1985), biochemical markers (Bonhomme and others 1984; Moriwaki and others 1979), mitochondria DNA (Yonekawa and others 1981) ribosomal DNA (Suzuki and others 1986), and other genetic characters (Moriwaki and others 1986) has suggested the possibility



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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE Implication of Wild-derived Genes, Mitochondria, and Chromosomes in the Genetic Background of Mouse Models for Diseases and Biologic Functions Kazuo Moriwaki Vice President, The Graduate University for Advanced Studies Kanagawa-Kenn, Japan INTRODUCTION Asian wild mouse-derived genes, mitochondria, and chromosomes are useful in the development of mouse models for biologic functions and their abnormal forms, diseases. Medical geneticists have recently recognized the effect of multiple genes on various phenotypes expressed at the whole body level. Obviously experimental analysis of these genes to include programmed mating can hardly be achieved in humans; therefore, it is advantageous to use experimental animals and, in particular, laboratory mice. For precise gene mapping in mice, several thousands of recently developed microsatellite DNA markers play an important role. However, due to limited progenitors, genetic variations detected among the current laboratory strains are rather limited. We need genetic resources with more genetic variations than those within conventional laboratory mouse strains. GENETIC POSITION OF ASIAN WILD MICE Since 1975, we have surveyed genetic variations in the natural populations of wild mice collected from all over the world. Taxonomically those mice have been classified into 11 subspecies based on their morphologic characters and geographic distribution (Schwarz and Schwarz 1943). However, our survey in the chromosome C-band pattern (Moriwaki and others 1985), biochemical markers (Bonhomme and others 1984; Moriwaki and others 1979), mitochondria DNA (Yonekawa and others 1981) ribosomal DNA (Suzuki and others 1986), and other genetic characters (Moriwaki and others 1986) has suggested the possibility

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE that those 11 subspecies can be further grouped into four subspecies groups as follows: domesticus, bactrianus, castaneus, and musculus (Moriwaki 1994; Moriwaki and others 1990). Genetic divergence time among them has been estimated to be approximately one million years (Moriwaki and others 1979; Yonekawa and others 1981). In these studies, the genetic origin of the laboratory mice was identified as mostly European wild mice (Yonekawa and others 1982). The implication of this finding is correct, that more genetic variations should be found between the Asian wild mice and laboratory strains. The percentage of variation in the microsatellite DNA polymorphism between the Asian mice and laboratory mice was significantly greater than within laboratory mouse strains (95% vs. 48%) (Shiroishi and others, unpublished data). USE OF THE ASIAN WILD-DERIVED RECOMBINATION HOST-SPOT GENE FOR SURVEYING NOVEL GENES THAT DETERMINE SUSCEPTIBILITY TO DIABETES In 1982, Shiroishi and colleagues discovered a remarkable recombination hot-spot in a Japanese wild-derived major histocompatibility complex (MHC) chromosome. The frequency of meiotic recombination in the MHC chromosome with this hot-spot is more than 100 times greater than normal (Shiroishi and others 1982). Hattori and others (1999) introduced this hot-spot chromosome segment into the NOD diabetes model mouse and obtained various recombinants in the MHC region. Their comparison between the incidence of diabetes and the introduced chromosome segments indicates the possible presence of three genes at 5' upstream of the H2- K-I region, already reported to be important in the control of diabetes. USE OF ASIAN WILD-DERIVED MITOCHONDRIA FOR STUDYING MOUSE BEHAVIOR In 1995, Kaneda and colleagues developed mitochondria congenic strains that carry mitochondria of either the Asian wild-derived Mus musculus musculus subspecies or the European wild-derived Mus spretus species (Kaneda and others 1995). Both are genetically quite remote from laboratory mouse strains. In 1998, Nagao and colleagues demonstrated decreased physical performance of the congenic strains with a mismatch between the nuclear and mitochondrial genome, that is, the genetic background (Nagao and others 1998). USE OF ASIAN WILD-DERIVED CHROMOSOMES FOR DEVELOPING NEW CONSOMIC MOUSE STRAINS In 1999, Shiroishi and others (unpublished) attempted to develop new inter-subspecific consomic strains. Each of the 19 autosomes, X and Y chromosomes

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE of the Japanese wild-derived MSM strain, were introduced into C57B1/6J mice by repeated back-crosses. In each of the heterozygotes, donor chromosomes without recombination were selected by several microsatellite DNA markers on each chromosome. Soon they expect to establish a set of CONSOMIC strains, which will be very useful for rapidly surveying one or more unknown gene/genes in a mutant mouse that expresses the phenotype at the whole body level. If any phenotypic difference is found between the donor and recipient strains and it is controlled by a single gene, it will be possible to readily identify the chromosome responsible for the phenotypic difference because these CONSOMIC strains prevent “noise” from genetic backgrounds. These strains are also useful in identifying a modifier gene in the genetic background because the individual with modified phenotype is mated with all of the consomic strains. The several cases mentioned above are typical examples of the usefulness of Asian wild-derived mice in the analyses of gene/genes in the genetic background. REFERENCES Bonhomme, F., J. Catalan, J. Britton-Davidian, V.M. Chapman, K. Moriwaki, E. Nevo, and L. Thaler. 1984. Biochemical diversity and evolution in the genus Mus. Biochem. Genet. 22:275-303. Hattori, M., E. Yamato, N. Itoh, H. Senpuku, T. Fujisawa, M. Yoshino, M. Fukuda, E. Matsumoto, T. Toyonaga, I. Nakagawa, M. Petruzzelli, A. McMurray, H. Weiner, T. Sagai, K. Moriwaki, T. Shiroishi, R. Maron, and T. Lund. 1999. Homologus recombination of the MHC class I K region defines new MHC-linked diabetogenic susceptibility gene(s) in nonobese diabetic mice. J. Immunol. 163:1721-1724. Kaneda, H, J. Hayashi, S. Takahashi, C. Taya, K. Fischer-Lindahl, and H. Yonekawa. 1995. Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. Proc. Natl. Acad. Sci. U S A 92:4542-4546. Moriwaki, K. 1994. Wild mouse from a geneticist's viewpoint. In Moriwaki, K., T. Shiroishi and H. Yonekawa, eds. Genetics in Wild Mice. Japan Scientific Societies Press. Tokyo: Karger. p.xiii-xxv. Moriwaki, K., N. Miyashita, H. Suzuki, Y. Kurihara, and H. Yonekawa. 1986. Genetic features of major geographical isolates of Mus musculus. In M. Potter, ed. Wild Mouse in Immunology, Current Topics in Microbiology and Immunology 127, Berlin: Springer-Verlag. p. 62-67. Moriwaki, K., N. Miyashita, and H. Yonekawa. 1985. Genetic survey of the origin of laboratory mice and its implication in genetic monitoring. In Archibald, J., J. Ditchfield, and H.C. Rowsell, eds. The Contribution of Laboratory Animal Science to the Welfare of Man and Animals. Stuttgart: Gustav Fischer Verlag. p. 237-247. Moriwaki, K., T. Sagai, T. Shiroishi, F. Bonhomme, C.-H. Wang, X.-Q. He, M.-L. Jin, and Z.-G. Wu. 1990. Mouse subspecies differentiation and H-2 polymorphism. Biol. J. Linn. Soc. 41:125-139. Moriwaki, K., T. Shiroishi, M. Minezawa, T. Aotsuka, and K. Kondo. 1979. Frequency distribution of histocompatibility-2 antigenic specificities in the Japanese wild mouse genetically remote from the European subspecies . J. Immunogenet. 6:99-113. Nagao, Y., Y. Totsuka, Y. Atomi, H. Kaneda, K.F. Lindahl, H. Imai, and H. Yonekawa. 1998. Decreased physical performance of congenic mice with mismatch between the nuclear and the mitochondrial genome. Genes Genet. Syst. 73:21-27.

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE Schwarz, E., and H.K. Schwarz. 1943. The wild and commensal stocks of the house mouse, Mus musculus. J. Mammal. 24:59-72. Shiroishi, T., T. Sagai, and K. Moriwaki. 1982. A new wild-derived H-2 haplotype enhancing K-IA recombination. Nature 300:370-372. Suzuki, H., N. Miyashita, K. Moriwaki, R. Kominami, M. Muramatsu, T. Kanehisa, F. Bonhomme, M.L. Petras, Z.-C. Yu, and D.-Y. Lu. 1986. Evolutionary implication of heterogeneity of the nontranscribed spacer region of ribosomal DNA repeating units in various subspecies of Mus musculus. Mol. Biol. Evol. 3:126-137. Yonekawa, H., K. Moriwaki, O. Gotoh, J-I. Hayashi, J. Watanabe, N. Miyashita, M.L. Petras, and Y. Tagashira. 1981. Evolutionary relationships among five subspecies of Mus musculus based on restriction enzyme cleavage patterns of mitochondrial DNA . Genetics 98:801-816. Yonekawa, H., K. Moriwaki, O. Gotoh, N. Miyashita, S. Migita, F. Bonhomme, J.P. Hjorth, M.L. Petras, and Y. Tagasira. 1982. Origins of laboratory mice deduced from restriction patterns of mitochondrial DNA. Differentiation 22:222-226.