History, Development and Genetics of the Mouse As a Laboratory Model

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P ART 1 History, Development and Genetics of the Mouse as a Laboratory Model

Contents

CHAPTER 1 Origin of the Laboratory Mouse and Related Subspecies ...... 3

CHAPTER 2 Historical Foundations ...... 15

CHAPTER 3 Strains, Stocks, and Mutant Mice ...... 25

CHAPTER 4 Mouse Genomics ...... 47

CHAPTER 5 Generation of Mouse Mutants by Sequence Information Driven and Random Mutagenesis ...... 85

CHAPTER 6 The Mouse as an Animal Model for Human Diseases ...... 97

CHAPTER 7 The Mouse in Preclinical Safety Studies ...... 111 Hedrich-ch01.qxd 12/7/04 12:46 PM Page 2 Hedrich-ch01.qxd 12/7/04 12:46 PM Page 3

C HAPTER 1 O Origin of the Laboratory THE OF RIGIN Mouse and Related L Subspecies ABORATORY M OUSE

Jean-Louis Guénet Institut Pasteur, Unité de Génétique des Mammifères, Paris, France 3 François Bonhomme D

Université Montpellier II, CNRS UMR 5000, Laboratoire THE OF EVELOPMENT Génome, Populations, Interactions, Montpellier, France

Introduction Mice are easy to keep. Because they are rodents, they eat a rather large quantity of food but do not have

very specific or expensive nutritional requirements. They M

Based on paleontological data it seems that men and breed all year round, with a short generation time; they A AS OUSE mice have been in contact since the early Pleistocene deliver relatively large progenies and tolerate inbreeding (Berry, 1970), which means for over a million years rather well compared to other mammalian species. With (Myrs), and numerous historical records (Keeler, 1931; the passing years, hundreds of mutations, most of them

Staats, 1966; Morse, 1978; Berry, 1987; Moriwaki with deleterious alleles, have been collected that all have L et al., 1994) indicate that mice were already bred as pets contributed and still contribute to the identification of ABORATORY 3 millennia ago: it was then logical that these small genes by their function(s), and several programs of mammals, as well as the rat and some small sized pet- intensive mutagenesis have been developed worldwide to birds, be used by scientists of the early days for perform- increase further this invaluable resource. Another very

ing their experiments. However, if this choice was more important advantage to be credited to the mouse is that it M

opportunistic rather than based on scientific considera- seems to be one of the rare, maybe the only species, where ODEL tions, it nevertheless appears to be an excellent one in it is possible to grow totipotent embryonic stem (ES) cells the context of modern biomedical research where the in vitro, which can be genetically engineered in a number house mouse has become a model of predilection. of ways and still retain the capacity to participate in

the formation of the germ line once re-injected into a 1993). The establishment of the evolutionary systemat- developing embryo. Finally, and this is not the slightest ics in this group has also been disputed but, this time, it of the advantages, the complete sequence of the mouse was because many mammals in this family are very simi- genome is now available (Waterston et al., 2002), which lar in size and shape. Here again studies making use of will allow comparisons with other mammalian genomes DNA sequences of various types (Michaux et al., 2001; and annotations concerning the function of the genes to Lundrigan et al., 2002) have greatly contributed to clar- be made. In short, the mouse is the only mammalian ify the situation and Figure 1.2 represents the evolution- species whose genomic sequence is known and for which ary relationships among a sample of 21 rodent species technical procedures exist for the generation of a anchored into the broader phylogeny of eutherian mam- virtually unlimited number of genetic alterations. mals. The divergence between the Mus and Rattus genus In this chapter we will describe the origins of lab- has been estimated at around 10–15 Myrs ago ( Jaeger

OUSE oratory mice, starting with their phylogenetic rela- et al., 1986; Murphy et al., 2001), while the divergence of

M tionships with the other mammalian species. We will these two genera with Peromyscus maniculatus, the deer also discuss the advantage of strains established from mouse (subfamily Sigmodontinae), occurred at around recently trapped wild specimens as a source of poly- 25 Myrs ago. This is to be remembered because deer morphisms for scientific research. mice, which are abundantly used as laboratory models, are often considered close relatives of the laboratory mice

ABORATORY while, in fact, they are no more related to them than L hamsters. The phylogenetic Systematics in the genus Mus relationships of the Figure 1.3 (Guénet and Bonhomme, 2003 and refer- RIGIN OF THE ences therein) summarizes the phylogenetic relation- O house mouse ships within the genus Mus (subfamily Murinae). The individualization of the subgenus Mus sensu stricto 4 The position of rodents among occurred around 5 Myrs ago with the split of three other different subgenera, the African Nannomys and mammalian species the Asian Coelomys and Pyromys.

ODEL Mice are rodents. They belong to the most abundant The subgenus Mus comprises several species that

M (around 40%) and diversified order of living placental are extremely similar in size and shape but never mammals, with slightly over 2000 species grouped in hybridize in the wild. Among the Asian species are Mus 28 families (Huchon et al., 2002). Because of their great cervicolor, Mus cookii, and Mus caroli as well as the diversity, the phylogenetic relationships between the group of Indian pigmy mice related to Mus dunni. Mus different species of this order has been a matter of con- famulus from India should also be cited as well as the ABORATORY

L troversy for many years, especially when morphological recently discovered species Mus fragilicauda (Auffray markers were the only criteria available for the establish- et al., 2003) from Thailand. ment of phylogeny. Nowadays, with the use of various Mus spicilegus and Mus macedonicus are short tailed molecular (mostly DNA) markers and possible refer- mice that are found in central Europe and the eastern OUSE AS A ences to the complete genomic sequence of numerous Mediterranean, respectively, while mice belonging to M orthologous genes, the situation is much clarified and the species Mus spretus are common in the western Figure 1.1 represents the most likely phylogenetic tree Mediterranean regions (south east France, Spain, Portugal for a sample of 40 different eutherian mammals. Based and North Africa). on comparisons at the level of nuclear DNA sequences, Mice of the Mus musculus complex are closely the divergence between man and murid rodents (Mus or related. They have their evolutionary origins in the Rattus genus) has been set somewhere between 65 and Indian subcontinent (Bonhomme et al., 1994) but are 75 Myrs ago (Waterston et al., 2002). now spread over the five continents. The best known rep-

EVELOPMENT OF THE resentatives of the complex are the three Mus musculus D Mice among rodents subspecies: Mus m. domesticus, common in western Europe, Africa, the near-East, and transported by man to The rodent family of Muridae encompasses at least 1326 the Americas and Australia; Mus m. musculus, whose species grouped in 281 genera (Musser and Carleton, habitat spans from eastern Europe to Japan, across Hedrich-ch01.qxd 12/7/04 12:46 PM Page 5

Bradypus (sloth) Orycteropus (aardvark) Dugong (dugong) Procavia (hyrax) Cynopterus (bat) Erinaceus (hedgehog) Felis (cat) Manis (pangolin) ~100 Equus (horse) Myrs Lama (lama) Sus (pig)

Bos (cow) O

Physeter (sperm whale) THE OF RIGIN ~75–90 Tupaia (tree shrew) Myrs Homo (human) Cynocephalus (flying lemur) Ochotona (pika) Lepus (hare)

Oryctolagus (rabbit) L ~70–85 Marmota (woodchuck) ABORATORY Myrs Aplodontia (mountain beaver) Dryomys (forest dormouse) Glis (fat dormouse) ~65–80 Anomalurus (scaly-tailed flying squirrel) Myrs Castor (beaver) M Dipodomys (kangaroo-rat) OUSE Thomomys (pocket mouse) ~60–75 Myrs Dipus (jerboa) Tachyoryctes (mole rat) Mus (mouse) Rattus (rat) 5 Massoutiera (gundi) Trichys (Old-World porcupine) D Bathyergus (naked mole rat) VLPETO THE OF EVELOPMENT Thryonomys (cane rat) Petromus (dassie rat) Echimys (spiny rat) Cavia (Guinea pig) Erethizon (New-World porcupine) Chinchilla (chinchilla) Figure 1.1 Evolutionary tree concerning 40 mammalian species including 21 rodent species, with an estimated time of divergence in Myrs (from Huchon et al. (2002). Mol.Biol.Evol. 19, 1053–1065). M UEA A AS OUSE

Russia, and northern China, and Mus m. castaneus, which have never been reported and probably never occur. is found from Sri Lanka to south east Asia including the Hybrids between wild mice of the species Mus 1

Indo-Malayan archipelago. Various molecular criteria cervicolor, Mus caroli, Mus dunni and mice of the Mus L discriminate easily between these different species musculus complex have never been found in the ABORATORY (Figure 1.4; Boursot et al., 1993; Moriwaki et al., 1994) wild but hybrids between the former three wild species and laboratory mice have been produced by artifi- cial insemination (West et al., 1977). In these experi-

Mouse interspecific ments, hybrids generated by insemination of female M laboratory mice with Mus cervicolor sperms failed to ODEL complete more than a few cleavage divisions. Hybrids hybridization generated from Mus dunni sperms and laboratory female oocytes implanted but died in utero at a very Hybrids between mice of the genus Mus and mice of the subgenera Nannomys, Coelomys or Pyromys 1See legend to Figure 1.3. Hedrich-ch01.qxd 12/7/04 12:46 PM Page 6

Sicista betulina Allactaga elater Dipus sagitta Jaculus jaculus Spalacinae Rhizomyinae Macrotarsomys ingens Nesomys rufus Mystromys albicaudatus Cricetomys gamblanus Saccostomus sp. Dendromus mystacalis Steatomys sp. Calomyscus mystax Clethrionomys glareolus

OUSE Dicrostonyx sp.

M Neotoma sp. Peromyscus leucopus Cricetulus migratorius Mesocricetus auratus Phodopus roborovskii Myospalax sp.

ABORATORY Tatera gambiana L Gerbillus henleyi Lophuromys sp. Deomys ferrugineus Uranomys ruddi Acomys cahirinus Rattus norvegicus Micromys minutus RIGIN OF THE Otomys irroratus O Mus musculus

6 Figure 1.2 Phylogenetic relationships between 32 species of rodents representing 14 subfamilies of Muridae (redrawn from Michaux et al. (2001). Mol.Biol.Evol. 18, 2017–2031).

ODEL 54321 Mus musculus M domesticus musculus molossinus castaneus bactrianus spretus ABORATORY subgenus Mus L spicilegus

macedonicus fragilicauda

OUSE AS A famulus

M caroli cooki cervicolor

dunni other subgenera Pyromys

Coelomys

EVELOPMENT OF THE Nannomys D

Figure 1.3 Evolutionary tree of the genus Mus (the time scale is in Myrs).The exact branching for Mus dunni is not precisely known.The four species at the origin of the classical laboratory strains are highlighted in bold (from Guénet, J.L. and Bonhomme, F.(2003). Trends Genet. 19,24–31). Hedrich-ch01.qxd 12/7/04 12:46 PM Page 7

musculus

domesticus molossinus

Himalayas central domesticus populations

castaneus O II FTHE OF RIGIN

gentilulus L ABORATORY

domesticus M OUSE colonization routes for the various species zones of secondary contacts M. spretus M. spicilegus M. macedonicus 7 Figure 1.4 Geographical distribution of the different species of the genus Mus and routes of colonization. Mice of the American and Australian continents were imported by man during colonization (from Guénet, J.L. and Bonhomme, F.(2003). D Trends Genet.19,24–31). THE OF EVELOPMENT

early developmental stage. Hybrids generated from the a relatively small number of genes since fertile males same laboratory females and sperm from Mus caroli are frequently observed in the backcross progeny of completed fetal development and a very low percent- F1 females with a male of either of the parental species age of them even survived to maturity but none (Guénet et al., 1990; Forejt, 1996; Pilder et al., 1997; M reproduced. Elliott et al., 2001). UEA A AS OUSE Although they share the same range (they are Mice of the Mus musculus complex are not geneti- sympatric) with some Mus musculus subspecies, the cally isolated and, in those locations where they meet, short tailed species Mus spretus, Mus spicilegus and Mus there is evidence of gene exchanges ranging from limited

macedonicus rarely produce hybrids in nature. However, introgression to complete blending (Boursot et al., L evidence from studies on mtDNA (Orth et al., 2002) 1993). The best-documented cases of such gene ABORATORY and LINE transposable elements (Greene-Till et al., exchanges are those occurring between M. m. musculus 2000) indicate that exchanges can occur sporadically and M. m. domesticus in Europe, along a narrow hybrid that would allow alleles with a selective advantage to zone, and between M. m. musculus and Mus m. castaneus

circulate outside the species in which they originated. in Japan. In this archipelago, the two subspecies have M

The three species mentioned above produce viable off- hybridized extensively, giving rise to a unique popu- ODEL spring with laboratory mice but male offspring of these lation often referred to as Mus m. molossinus (Yonekawa crosses are sterile in compliance with Haldane’s rule. et al., 1988). These gene exchanges, which indicate that Male hybrids born from a Mus musculus Mus spretus the speciation process is in progress but not yet completed, cross, for example, are invariably sterile regardless of explain the use of Latin trinomens for the designation of the direction of the cross. This sterility is controlled by the different subspecies in the M. musculus complex. Hedrich-ch01.qxd 12/7/04 12:46 PM Page 8

other species as well as for other genetic traits by The house mouse G. Bateson, E.R. Saunders, A. Garrod, W.E. Castle and C.C. Little (Paigen, 2003a). as a laboratory Even if mice have been extensively used during the twentieth century in most areas of biomedical model: a historical research, animals of this species have played an instrumental role in research in immunology, oncology, perspective and genetics because the breeding systems2 which are used to produce them allow the establishment of highly standardized strains whose characteristics are Mice, rats and other small vertebrates have been used precisely known and monitored generation after

OUSE in biomedical research since the middle of the sixteenth generation. Most laboratory strains have their origins

M century when biology progressively shifted from a from a few pet dealers who progressively became descriptive to an experimental science. Morse (1981), suppliers of ‘laboratory’ mice. For many years, most of reported that William Harvey used mice for his funda- the albino strains used in laboratories were collectively mental studies on reproduction and blood circulation designated ‘Swiss’ mice to recapitulate their Helvetian and, according to Berry (1987), the earliest record of origin.

ABORATORY the use of mice in scientific research seem to have been Strain DBA/2 (formerly dba, then DBA) is the L in England, in 1664, when Robert Hooke used mice to most ancient of all inbred strains since it was established study the biological consequences of an increase in air by C.C. Little in 1909 (Russell, 1978), by intercrossing pressure. Much later, Joseph Priestly (1733–1804) and mice homozygous for the coat color markers non his intellectual successor, Antoine Lavoisier (1743–94), agouti (a), brown (formerly b now Tyrp1), and dilute both used mice repeatedly in their experiments on (formerly d and now Myo5a). About 10 years later, RIGIN OF THE respiration.

O strain C57BL/6 was established by Miss Lathrop During the nineteenth century several fanciers in (Granby, Massachusetts, USA) intercrossing the ‘black’ 8 Europe and the United States were breeding and offspring of her female 57, while strains C3H, CBA, exchanging pet mice segregating for a variety of coat and A were created by L.C. Strong, a cancer geneticist color or behavioral mutations. According to Grüneberg established at Cold Spring Harbor Laboratory (Strong, (1957), one of these fanciers, M. Coladon, who was 1978). At this point, it is interesting to note that,

ODEL established as a pharmacist in Geneva, reported results among the strains established by L.C. Strong, strains

M from his breeding experiments that were in perfect CBA and C3H stemmed from the offspring of an out- agreement with the Mendelian expectations … but cross with a few wild specimens trapped in a pigeon this was 36 years before the publication of Mendel’s coop in Cold Spring Harbor. This explains how the own results on peas. As mentioned by Paigen (2003a,b) wild allele at the agouti locus (A) was re-introduced in in his notes about a century of mouse genetics, it seems laboratory strains. ABORATORY

L that Mendel’s first experiments on the transmission of With a few exceptions, historical records concern- characters were made using mice segregating for coat ing the genealogy of most laboratory inbred strains color markers but Mendel was rapidly asked by his are well documented and several interesting reviews on ecclesiastical superior to stop breeding in his cellule this subject are available (Morse, 1978; Festing, 1979).

OUSE AS A awfully smelly creatures that, in addition, had sex and A chart concerning the genealogy of these strains, M copulated. Mendel changed his experimental material including the recently established ones, has been for peas and published in 1866 his observations in a published (Beck et al., 2000) and regularly up-dated botanical journal where they had a much lower impact information is available at the website http://www. and remained virtually ignored until the very begin- informatics.jax.org. ning of the twentieth century. Once rediscovered In addition to its contribution to the re-discovery by De Vries, Correns and von Tschermark, the three of Mendel’s laws, the mouse has been closely associated of them working independently with plants, it was with many important discoveries in biology during the

EVELOPMENT OF THE really tempting to check whether the so-called twentieth century. To cite just a few among the most

D Mendel’s laws were also valid for animals and experiments were published in 1902 by L. Cuénot (1902), 2Among the genetically standardized strains, inbred strains are the most widely used. They result from the systematic and uninterrupted mating indicating that this was indeed the case. Cuénot’s of brothers to their sisters, which leads to complete homozygosity for the observations were shortly confirmed and extended to same allele at all loci. Hedrich-ch01.qxd 12/7/04 12:46 PM Page 9

experiments performed by J. McGrath and D. Solter (1984) and M.A. Surani and co-workers (1984), who demonstrated that a normal mouse embryo can only result from the fusion of a male and a female pronu- cleus, while B.M. Cattanach and M. Kirk (1985) demonstrated that the parental origin for the two elements of a given chromosome pair was sometimes not genetically equivalent. The first transgenic mammal created by pronuclear injection of a cloned DNA, was a

mouse (Gordon et al., 1980; Brinster et al., 1981; O

Costantini and Lacy, 1981; Gordon and Ruddle, 1981; THE OF RIGIN Harbers et al., 1981; Wagner et al., 1981a,b) and the first in vitro genetically engineered mammalian organism was also a mouse (Kuehn et al., 1987). Only the first cloned Figure 1.5 Mice of the Mus spretus species (left, with an mammal was not a mouse although this type of uni- agouti coat color) and C57BL/6 (right, with a non agouti or

parental procreation has been achieved also in the L

solid black coat color). In spite of their great similarity in ABORATORY size and body shape these mice are distantly related mouse (Wakayama and Yanagimachi, 1999). species but can still produce viable and fertile hybrids Information concerning many aspects of the biol- (female only). Mice of the Mus spretus species have been ogy of the mouse considered as a laboratory model, in extensively used for the development of the mouse particular about its genetics, has been published in the genetic map. (See also Color Plate 1.) 95 issues of the Mouse News Letters. First issued in 1949 3 M

and published regularly every semester till 1997, this OUSE informal publication, edited by the scientists from important, we could say that our understanding of the the MRC at Harwell and distributed at low cost, has genetic determinism underlying the success or failure been for several decades the major medium for the of tissue transplantations is a consequence of the many dissemination of information among the community 9 experiments performed with inbred mouse strains by of mouse geneticists. In this sense, the Mouse News

P.A. Gorer (Gorer et al., 1948), then by G.D. Snell and Letters will for ever remain the best place to get infor- D

co-workers (Snell, 1978) who developed a series of con- mation about the history of mouse genetics, and in par- THE OF EVELOPMENT genic resistant strains, which were all genetically identi- ticular, about the history and location of most inbred cal to the C57BL/10Sn background strain, with the strains, the progressive development and refinement exception of single short-sized chromosomal regions of the linkage map and the discovery of hundreds of determining graft rejection. The discovery and genetic spontaneous mutations. interpretation of the phenomenon of X-inactivation in The Jackson Laboratory (the JAX-Lab), which was female mammals, by M.F. Lyon (Lyon, 1961), has been founded in Bar Harbor (Maine, USA), in 1929, by facilitated by the existence and use of several X-linked C.C. Little, has played a pivotal role in the promotion M mutations in the mouse and the observation of variega-

of the mouse as a laboratory model and still is a unique A AS OUSE tion in the coat color. The first chimeric organisms pro- center for mouse genetics. The Jax-Lab, a non-profit duced by A.K. Tarkowski, in Warsaw (Tarkowski, organization entirely dedicated to basic research on the 1961), and B. Mintz, in Philadelphia (Mintz, 1962), genetics of mammals, is nowadays almost exclusively

were mice. The observation of a particularly high fre- dedicated to the mouse. It is, at the same time, a top L quency of testicular terato-carcinomas in strain 129 ranked research institution, a meeting place where ABORATORY (Stevens and Little, 1954; Stevens, 1970) and the in courses and conferences are organized on the various vitro culture of cell lines derived from these tumors, aspects of mouse genetics, and the world largest gene- which represented for almost a decade a material of tic repository where a great variety of genotypes and

choice for investigating the processes at work in tissue biological samples of all kind are stored, under the form M

differentiation ( Jacob, 1983), undoubtedly opened of frozen embryos or sperm cells, for distribution to ODEL the way to the establishment of the so-called embry- the community. Several other Institutions, like the onic stem (ES) cells, by G.R. Martin (1981) and, simultaneously, by M.J. Evans and M.H. Kaufman 3The name Mouse News Letter was changed for Mouse Genome in 1990 when this publication became a peer reviewed journal. From 1998, (1981). The discovery of parental imprinting of Mouse Genome and Mammalian Genome have merged in one and a single some chromosomal regions has been a consequence of journal. Hedrich-ch01.qxd 12/7/04 12:46 PM Page 10

Oak Ridge National Laboratory in Tennessee (USA) and in well-defined geographical areas and belonging to the MRC center at Harwell in England have also played well characterized species, have been established in var- a very important role in the development of the mouse ious laboratories. A list of the strains that are com- as a laboratory model for researches in genetics, oncology pletely inbred, i.e. that have been propagated by strictly and immunology. Recently, the European Union has unrelaxed brother sister matings for more than decided to support the establishment of a network of 20 generations, is given in Bonhomme and Guénet genetic repositories (the so-called European Mouse (1996). Other useful stocks of wild mice are also main- Mutant Archive or EMMA), with major nodes in Italy tained in various laboratories and a complete descrip- (EMMA head quarters is in Monteretondo, near tion of these stocks has been published by Potter Roma), in England (Harwell), in France (Orléans-la- (1986). These ‘new’ inbred strains have been extremely Source) and in Germany (Munich). Finally, more important over these last years because they represent a

OUSE recently, Japan has established a bio-resource center at virtually unlimited reservoir of genetic polymorphisms.

M the RIKEN, in Tsukuba. More information about all Wild mice have been useful in providing geneticists these centers is available at the websites provided at the with polymorphisms such as electrophoretic variants, end of this chapter. restriction fragment length polymorphisms (RFLPs), or more generally single nucleotide polymorphisms (SNPs) that were much less numerous in standard

ABORATORY inbred strains. With the introduction of strains derived L The house mouse from wild progenitors, in particular, from Mus spretus, the genetic map of mouse has dramatically increased its and its wild relatives resolution (Guénet, 1986). Comparisons of non-coding orthologous regions at the sequence level indicate that any inbred strain derived from Mus spretus exhibits, on RIGIN OF THE As discussed above, the classical laboratory inbred

O average, one SNP at every 80 –100 bp when compared strains of mouse have many advantages that are related with any of the classical laboratory strains. This means to their great genetic homogeneity. After all, a popula- 10 that virtually any DNA sequence of 100 –200 bp, can be tion of F1 hybrid mice, born from an intercross set used as a molecular marker in assays such as denaturing between two highly inbred strains, can be considered gradient gel electrophoresis (DGGE) or single strand identical from the genetic point of view to a population confirmation polymorphism (SSCP). This high density

ODEL of cloned mice. Unfortunately, the coin has another of polymorphisms represents a considerable advantage

M side and these inbred strains, because they are derived in experiments when the aim is positional cloning of a from a relatively small pool of ancestors do not exhibit gene identified only by phenotype because it allows an a great variety of genetic polymorphisms of natural ori- accurate delineation of the targeted locus. In fact, one gin. This relative genetic homogeneity is well reflected can consider that there is no upper limit to the density in the fact that most of the classical strains possess the in molecular markers when a genetic map is established ABORATORY

L same maternally inherited molecule of mitochondrial from an interspecific or intersubspecific cross (Breen DNA (Yonekawa, 1980; Ferris et al., 1982) and rela- et al., 1994). The high density of polymorphisms turns tively reduced polymorphisms for the Y chromosome out to be an even greater advantage when quantitative (Bishop et al., 1985; Tucker et al., 1992). Aside from traits are mapped, because every animal with a relevant

OUSE AS A this relative genetic homogeneity, a careful analysis of phenotype can be genotyped for a very large number of M the genetic polymorphism also indicates that laboratory markers. In this respect, the mouse is unique since the strains have a mosaic genome derived from more than frequency of SNPs between humans is roughly one order one species (Bonhomme et al., 1987; Wade et al., of magnitude lower than that of Mus spretus compared to 2002) and today’s classical laboratory strains should be laboratory strains (Flint and Mott, 2001; Matin and regarded as interspecific recombinant strains derived (in Nadeau, 2001). The high frequency of SNPs in coding unequal percentages) from three parental components: regions means that the genome of Mus spretus or Mus m. domesticus, Mus m. musculus and Mus m. casta- Mus m. musculus is full of ready-made ‘quantitative trait

EVELOPMENT OF THE neus. For this reason, and to point to a relatively unnat- loci (QTL)-point mutations’ waiting for functional

D ural genetic constitution, it would probably be more genomic studies! appropriate to designate them as Mus m. ‘laboratorius’! Wild mice have also been invaluable in providing Over the last 20 years a variety of strains, derived cytogeneticists with a large collection of Robertsonian from small breeding nuclei of wild specimens, trapped translocations (or centric fusions) recovered from the Hedrich-ch01.qxd 12/7/04 12:46 PM Page 11

many populations of Mus m. domesticus where they Similar phenotypes of resistance/susceptibility occur in homozygous conditions (Gropp and Winking, have also been reported for a variety of pathogens 1981). These translocations are characterized by the (Sebastiani et al., 2000; Lengeling et al., 2001) and, fusion of two acrocentric chromosomes by their cen- even if in most instances genetic differences have been tromeres and they often interfere with the normal observed among classical laboratory strains, these dif- process of meiosis resulting in the production of ferences also exist between laboratory and wild derived gametes with an aneuploid (unbalanced) complement. strains making the genetic analysis much easier. Wild Using carefully designed crosses involving these centric animals also proved particularly useful for investigating fusions, it has been possible to produce and study tri- the biology of murine leukemia viruses and both new

somies and monosomies for all mouse chromosomes Fv loci and new alleles at the Fv1 and Fv2 loci have O

(Epstein, 1986). been discovered in wild mice (Gardner et al., 1991; THE OF RIGIN In addition to their homogeneity in terms of chro- Qi et al., 1998). mosome morphology, laboratory strains have only long The comments addressed concerning the suscepti- telomeres while, for instance, strains of Mus spretus bility of mice to infectious diseases also apply to origins, have both long and short telomeres (Coviello- carcinogenesis and comparisons between classical labo-

McLaughlin and Prowse, 1997; Zhu et al., 1998). ratory strains allowed the complex influences of genetic L This peculiarity might be helpful for investigating the background on tumor susceptibility to be unraveled ABORATORY significance of the still mysterious variations in telom- and several genes modifying tumor susceptibility have ere size found in mammalian cells. been identified. However, while the phenotype of F1 When infectious agents of various kinds are hybrids between any two classical laboratory strains injected into mice it is common to observe that some is generally intermediate between the two parental M

strains are more susceptible than others and that wild strains, it is often identical to the phenotype of the wild OUSE derived strains are in general more resistant than classi- parent when crosses are performed with wild inbred cal laboratory strains. A commonly accepted explana- strains, indicating dominance of the wild derived allele. tion, although not demonstrated, is that some alleles of (Nagase et al., 2001). laboratory strains, which are essential for determining Besides their use in mapping, interspecific crosses 11 innate or acquired mechanisms of defense, have been also offer an opportunity for analyzing the effects of

by chance replaced by a defective mutant allele without bringing together the products of genes separated by D

any consequences for the mice because these animals divergent evolution in the cells of an offspring. This can THE OF EVELOPMENT are kept in protected environments. Even if in most help identify the genetic functions that are subject to cases the level of susceptibility or resistance is con- rapid divergence and to pinpoint the functions that trolled by several genes interacting together (QTLs) or eventually promote speciation. Those functions that having an additive effect, the situation is sometimes are mostly unaffected during the evolution of the taxa under the control of a single gene making its analysis are most likely to be basic functions that are under more relatively simple. This is the case, for example, when constraint. This last point will be important in the com- mice of most laboratory strains die after an injection parison of orthologous regions between human and M

with an appropriate dose of orthomyxoviruses while mouse genomes now that sequencing is completed for A AS OUSE most wild strains are resistant (Haller et al., 1998). both species. This phenotype is controlled by a single gene (Mx1 – Questions concerning epistatic interactions can chromosome 16) with two alleles: Mx1 (resistant, also be addressed by investigating offspring of inter-

dominant) and Mx1 (susceptible, recessive) and the specific crosses at the genomic level. So far, we have no L discrepancy between wild mice and laboratory mice in clear answers to this question but data exist indicating ABORATORY terms of susceptibility indicates that the mutated allele that some combinations of alleles are strongly counter- of Mx1 is over-represented in laboratory strains, proba- selected in the offspring of some interspecific crosses bly due to a sampling effect. A similar example exists (Montagutelli et al., 1996).

with experimental flavivirus infections where all labora- A less dramatic but still very interesting situation is M

tory inbred strains, except strain PL/J, are susceptible frequently observed when wild mice are used for the ODEL while most wild derived inbred strains are resistant mapping of mutations with deleterious phenotypic (Sangster et al., 1998). Here again, it seems that Flvs, effects. In this case, the interspecific offspring, homozy- the allele responsible for susceptibility at the Flv locus gous for the mutant allele, often exhibit a wide range of (chromosome 5), has been fortuitously selected in lab- variations in the degree of severity of their phenotypes oratory strains while it is rare or absent in wild mice. with severe forms and weaker ones. In these cases, Hedrich-ch01.qxd 12/7/04 12:46 PM Page 12

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