Exp. Anim. 60(4), 347–354, 2011 —Review— Review Series: Wild Mice in Laboratory Animal Science A New Twist on Behavioral Genetics by Incorporating Wild-Derived Mouse Strains Tsuyoshi KOIDE1, 6), Kazutaka IKEDA2), Michihiro OGASAWARA3), Toshihiko SHIROISHI4, 6), Kazuo MORIWAKI5), and Aki TAKAHASHI1, 6) 1)Mouse Genomics Resource Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, 2)Division of Psychobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585, 3)Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo 113-8421, 4)Mammalian Genetics Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, 5)RIKEN BioResource Center, Tsukuba 305-0074, and 6)Department of Genetics, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Kanagawa 240-0193, Japan Abstract: Behavior has been proven to be extremely variable among human individuals. One of the most important factors for such variations of behavior is genetic diversity. A variety of mouse strains are reportedly suitable animal models for investigating the genetic basis of large individual differences in behavior. Laboratory strains have been shown to exhibit different behavioral traits due to variations in their genetic background. However, they show low-level genetic polymorphism because the original colony used for establishing the strains comprises a relatively small number of mice. Furthermore, because the laboratory strains were derived from fancy mice, they have lost the original behavioral phenotype of wild mice. Therefore, incorporation of inbred strains derived from wild mice of different mouse subspecies for behavioral studies is a marked advantage. In the long-term process of establishing a variety of wild-derived inbred strains from wild mice captured all over the world, a number of strains have been established. We previously identified a marked variety in behavioral traits using a Mishima battery. This review reports on the usefulness of wild-derived strains for genetic analyses of behavioral phenotypes in mice. Key words: anxiety, behavior, genetic diversity, strain difference, wild mouse Introduction the course of animal domestication. Therefore, charac- terizing the mechanisms of behavioral variation is di- Behavioral differences among animals affect survival rectly related to understanding the mechanisms of evolu- in a wild environment; thus, behavior is one of the major tion and domestication, products of natural and artificial targets of natural selection. Also, behavioral phenotypes selection, respectively. A number of reports have shown that are useful for human life are often selected during that individual variation in behavior is greatly influenced (Received 18 January 2011 / Accepted 28 February 2011) Address corresponding: T. Koide, Mouse Genomics Resource Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan 348 H. Koide, ET AL. by genetic factors in many animal species. In mice, genetic admixtures between these major subspecies selective breeding experiments have shown efficient groups have been observed. In Europe, a hybrid zone selection of targeted behavior traits such as anxiety-re- from Denmark to Bulgaria separates two subspecies lated traits in several generations, suggesting the exis- groups, Domesticus and Musculus, but nonrandom tence of genetic factors related to these behavioral phe- mtDNA flow from Domesticus to Musculus was found notypes [7]. in Sweden [2, 8]. In Japanese mice, M. m. molossinus, Laboratory strains have been used as models of indi- it was shown that genetic mixing has occurred between vidual diversity as comparison of different inbred strains the Musculus and Castaneus subspecies groups [33]. reveals clear phenotypic differences in a variety of traits. Several research groups have been involved in establish- However, there is a limitation in using laboratory strains ing a variety of inbred strains from wild mice captured for studying individual variation. Most laboratory strains in different areas of the world [2, 13, 18]. The descen- originated from a relatively small group of fancy mouse dants of these wild mice were established as wild-derived colonies mostly belonging to M. m. domesticus subspe- inbred strains (wild strains) after at least 20 generations cies [2, 9, 28, 32]. Although mice in these colonies show of brother-sister mating (Table 1) [10, 14, 15, 18]. Nine some heterogeneity, genetic variation is relatively lim- strains, PGN2, BFM/2, HMI, NJL, BLG2, CHD, SWN, ited among them. In other words, many laboratory KJR, and MSM, have been established in the National strains established from these fancy mice share common Institute of Genetics, Japan. Because these wild-derived genetic polymorphisms. It is expected that the lack of strains have not been subjected to deliberate attempts at heterogeneity causes relatively limited variation in be- domestication during inbreeding, they still show the havioral phenotypes among strains. Furthermore, as characteristic behavior of wildness, such as quick move- these laboratory strains originated in breeding colonies ments, aggression, and higher responsiveness to handling of fancy mice, the behavioral phenotype is normally by humans. In addition to a series of wild-derived obedient and clearly different from that observed in wild strains, a fancy mouse-derived strain, JF1, was also es- mice. In this regard, using wild-derived mouse strains tablished. JF1 has a characteristic coat color with white may be very advantageous for studying novel behav- spotting on a black coat due to piebald mutation and is ioral phenotypes and more diverse behavior. highly obedient and easy to handle [15]. These geneti- cally defined wild- and fancy-derived strains have Wild Mice and Wild Strains proven to be useful for a variety of genetic and behav- ioral studies [14]. A panel of these wild- and fancy- Wild house mice, Mus musculus species, are distrib- derived strains including a reference laboratory strain, uted widely throughout the world where people produce C57BL/6, is now known as the Mishima battery (Table and store agricultural crops. These mice are believed to 1) [10]. The wild- and fancy-derived strains of the have originated in a region around the Indian subconti- Mishima battery except for C57BL/6 and CAST/Ei are nent and to have migrated over many generations [2]. available upon request from the National Institute of The Mus musculus species is divided into at least three Genetics (http://www.shigen.nig.ac.jp/mouse/nig/) and major subspecies groups, Domesticus, Musculus, and RIKEN BioResource Center (http://www.brc.riken.go. Castaneus, based on the genetic profiles, such as poly- jp/lab/animal/en/). These wild derived strains are dif- morphisms of biochemical markers, mtDNA, and nucle- ferent in their external characters. The body weights ar genes (Fig. 1) [2, 17, 21, 23]. Although, further markedly differ among the strains (Fig. 2). Although taxonomic subdivisions have been applied based on their males are generally heavier than females, the MSM geographical distribution and morphological character- strain, which was originally captured in Mishima City, istics, these local subspecies have been classed as het- Japan, and classified as M. m. molossinus [17], did not erogeneous with the major subspecies groups because show such a clear difference in body weight between clear genetic differences have not been identified among males and females. Laboratory strains are generally these subdivided taxonomic subspecies. Furthermore, heavier than wild-derived strains, and MSM is the small- BEHAVIOR GENETICS IN WILD MOUSE STRAINS 349 Fig. 1. Geographical distribution of subspecies groups for wild mice and the origins of wild-derived strains. Each subspecies group is categorized based on the genetic profi le of wild mice that were systemized further taxonomically. Wild-derived strains and their original capture sites are indicated. Table 1. Mouse strains in the Mishima battery Type Strain name Subspecies group Subspecifi c name Place of collection Introduction year Fancy mice C57BL/6J Domesticus Wild mice PGN2/Ms Domesticus M.m. domesticus Pigeon, Ontario, Canada 1979 Wild mice BFM/2Ms Domesticus M.m. brevirostris Montpellier, France 1980 Wild mice HMI/Ms Castaneus M.m. castaneus Heimei, Taiwan 1986 Wild mice CAST/Ei Castaneus M.m. castaneus Thailand 1989 Wild mice NJL/Ms Musculus M.m. musculus Northern Jutland, Denmark 1980 Wild mice BLG2/Ms Musculus M.m. musculus General Toshevo, Bulgaria 1981 Wild mice CHD/Ms Musculus M.m. gansuensis Chengdu, China 1981 Wild mice SWN/Ms Musculus M.m. musculus Suwon, Korea 1984 Wild mice KJR/Ms Musculus M.m. musculus Kojuri, Korea 1984 Wild mice MSM/Ms Musculus M.m. molossinus Mishima, Japan 1978 Fancy mice JF1/Ms Musculus M.m. molossinus Japan * 1987 *JF1 was found in Denmark, but characterized as a Japanese fancy mouse by a genetic study [14]. Introduction year: Year founder mice were introduced into an animal facility in the National Institute of Genetics. 350 H. KOIDE, ET AL. Fig. 2. Strain differences in body weights in the Mishima battery. Body weights were measured at 8–12 weeks of age. In each strain, 10 mice each for Fig. 3. A matrix diagram showing degrees of polymorphism based males and females were used for measurement. on SSLP typing for 104 different microsatellite markers Error bars indicate SEM. Data were taken from distributed throughout the entire genome. The values in- a previous report [10]. dicate the frequency of polymorphism between two strains. This fi gure is based on that of Koide et al. [14]. est in the Mishima battery, less than half of the body Triplet-repeat sequences, such as repeats of CAG and weight of laboratory strains of both sexes. Because three CAA, which encode polyglutamines, are frequently ob- other strains, CHD, SWN, and KJR, which originated in served in the coding regions of genes. A systematic the Far East, also showed small body weights, it is search for genes carrying CAG repeats in public data- speculated that the phenotype of a smaller body size was bases identifi ed 62 loci carrying CAG/CAA trinucleotide fi xed in the wild population during migration of the an- repeats [21].