Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference (1999)

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Genetic Background and Phenotypes in Animal Models of Human Diseases Kazuo Moriwaki Vice President, The Graduate University for Advanced Studies Kanagawa-ken, Japan DEVELOPMENT OF EXPERIMENTAL MOUSE STRAINS In the field of mammalian genetics including human genetics, the effect of genetic background on the expression of a particular gene for a given biological function or disease has long been a well-known but unresolved subject. More than two decades ago, Goodenough and Levine (Goodenough and Levine 1974) foresaw that a particular gene product would normally operate in the presence of countless different combinations of other gene products. Because we did not have a dependable method of mapping multiple genes, considerable effort was invested in developing experimental strains with the same genetic background as the chromosomal region to be analyzed. The most valuable contribution was the establishment of H2 congenic mouse strains (Snell and others 1976), in which the structure and immunological function of mouse major histocompatibility com- plex (MHC) could be clearly demonstrated. These findings have also resulted in very useful models of human MHC, particularly the structures and functions relevant to human diseases. As a result of recent remarkable developments in the technology of both gene and embryo manipulation, we can now isolate genes for a biological func- tion or human or mouse diseases as DNA molecules and inject them into the mouse in an early embryo stage to observe their expression in the whole body. The successful establishment of embryonic stem (ES) cell lines has also made it possible to knock out a given gene in the embryo that later develops to adulthood. 44 

KUZUO MORIWAKI 45 TRANSGENIC AND KNOCKOUT MICE The development of modern technology has shed light on the rather classical problem of genetic background. Of the large number of reports that have been published recently on transgenic and knockout experiments in mice, many have described significant effects of genetic background (that is, strain specificity). Threadgill and his colleagues (Threadgill and others 1995) demonstrated the effect of strain difference on the embryonic lethality in the EGFR gene-targeted mouse. The CF-1 strain with the targeted gene died at a much earlier stage that the CD-1 strain. Sibilia and Wagner (Sibilia and Wagner 1995) showed the strain-dependent epithelial defects in mice lacking epidermal growth factor re- ceptor (EGFR). Those mice with 129/Sv genetic background died at the mid- gestation stage, whereas those with 129/Sv × B/6 × MF/1 survived to postnatal 20 days. Wolf and Henderson (Wolf and Henderson 1998) recently reported the effect of strain difference in the transgenic introduction of the human P450 gene in mouse, which can be expressed in the C3H strain but not in the BALB strain. RECOMBINANT INBRED STRAINS Recombinant inbred (RI) strains have been developed for mapping of a specific gene that has different alleles between the two parental strains based on the strain distribution pattern. Bailey (Bailey 1971) first conceived the useful- ness of RI strains for analyzing multiple genes controlling biological functions and diseases. When he established CXB RI strains, however, he learned that the number of marker gene loci was not enough to map one or more genes precisely. Many RI strains have been developed recently, and they can be used for mapping multiple gene loci by use of microsatellite DNA primers, the polymerase chain reaction technique, and computer software for quantitative trait locus [QTL] analysis. Although these technical advances have also made it possible to map multiple gene loci by conventional backcrosses, more accurate mapping (and complete homozygosity in their recessive alleles) can be done by employing RI strains, as discussed by Silver (Silver 1995). Nishimura and colleagues (Nishimura and others 1995) have established the new 21 SMXA RI strains from SM/J and A/J progenitor strains. By using those RI strains, Pataer and colleagues (Pataer and others 1997) recently identified a new gene locus for the resistance to urethan-induced pulmonary adenomas. Sus- ceptibility to the pulmonary adenoma has so far been considered to be controlled by at least four genes (Festing and others 1994): (1) Pas1 linked to Kras2 on number 6 chromosome, (2) Pas2 to MHC on number 17, (3) Pas3 to D9Mit11 on number 9, and (4) Pas4 to D19Mit16 on number 19. Moreover, two dominant resistant genes, Par 1 on number 11 and Par2 on number 18, have been reported (Manenti and others 1996; Obata and others 1996). 

46 MICROBIAL AND PHENOTYPIC DEFINITION OF RATS AND MICE COMMON DISEASE MODELS Development of the modern mapping techniques described above has also made it possible to map multiple genes causing common adulthood model dis- eases in mice (for example, diabetes in non-obese diabetes [NOD] strain). From those studies, it is assumed that although most mutations have mild effects, a specific combination of them can facilitate the expression of an ethnological mutation. Because common adulthood (life-style) diseases such as diabetes and cancer appear to be caused by the specific combination of many normal variant genes and, in many cases, etiological genes, the animal models for them should replicate human disease states. A broader study of gene loci related to diseases requires more variant alleles in mice for analyzing the molecular mechanism of gene manifestation. Asian mice are useful for that purpose because they are genetically more remote from laboratory mice and have plenty of variant alleles. We were able to conduct a DNA analysis using 60 marker DNA loci with Asian mice (Moriwaki and others 1999). The finding that variant genes contained in the Asian wild mice sometimes have a long evolutionary history is biologically important to investigate the mechanism of gene function. It is not possible to select for long evolutionary history in fancy mice and laboratory mice. As seen in the NOD experiment conducted by Wakana and colleagues (Wakana and others 1997), genetic introduction of a genetically remote allele of Idd-4 in Asian wild-derived MSM strain (established from wild mice collected in Mishima) exhibited a significant increase in frequency of diabetes. This strain should be a useful model to analyze Idd-4 function, which cannot be observed by the introduction of BALB/c or C57BL/6 alleles. Another example of the characteristic function of Asian wild-derived alleles is the expression of the Rim4 mutant phenotype, polydactyly, which was com- pletely suppressed in the Asian wild-derived genetic background (Masuya and others 1997). One might expect some “dominant negative” structural change in the gene product. CONCLUSION Animal models of common adulthood diseases such as diabetes and cancer have indicated that these diseases are apparently caused by the specific combi- nation of many normal variant genes and possibly some etiological genes. To further our knowledge requires additional animal models so that we can identify a large number of variant alleles that vary within the normal range. For this purpose, Asian wild-derived genes are useful not only for the number of vari- ations, but also for the large differences in the genome structure, which sometimes give rise to a “dominant negative” effect. These characteristics are useful for analyzing the mechanism of normal gene functions as seen in the case of Rim4 mouse. 

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