History,Development and Genetics of the Mouse as a ...

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ContentsCHAPTER 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

P A R T

History, Development andGenetics of the Mouse as a Laboratory Model

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IntroductionBased on paleontological data it seems that men andmice have been in contact since the early Pleistocene(Berry, 1970), which means for over a million years(Myrs), and numerous historical records (Keeler, 1931;Staats, 1966; Morse, 1978; Berry, 1987; Moriwakiet al., 1994) indicate that mice were already bred as pets3 millennia ago: it was then logical that these smallmammals, as well as the rat and some small sized pet-birds, be used by scientists of the early days for perform-ing their experiments. However, if this choice was moreopportunistic rather than based on scientific considera-tions, it nevertheless appears to be an excellent one inthe context of modern biomedical research where thehouse mouse has become a model of predilection.

Mice are easy to keep. Because they are rodents, theyeat a rather large quantity of food but do not havevery specific or expensive nutritional requirements. Theybreed all year round, with a short generation time; theydeliver relatively large progenies and tolerate inbreedingrather well compared to other mammalian species. Withthe passing years, hundreds of mutations, most of themwith deleterious alleles, have been collected that all havecontributed and still contribute to the identification ofgenes by their function(s), and several programs ofintensive mutagenesis have been developed worldwide toincrease further this invaluable resource. Another veryimportant advantage to be credited to the mouse is that itseems to be one of the rare, maybe the only species, whereit is possible to grow totipotent embryonic stem (ES) cellsin vitro, which can be genetically engineered in a numberof ways and still retain the capacity to participate in

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1C H A P T E R

Origin of the LaboratoryMouse and RelatedSubspecies

Jean-Louis GuénetInstitut Pasteur, Unité de Génétique des Mammifères,Paris, France

François BonhommeUniversité Montpellier II, CNRS UMR 5000, LaboratoireGénome, Populations, Interactions, Montpellier,France

The Laboratory MouseCopyright 2004 ElsevierISBN 0-1233-6425-6 All rights of production in any form reserved


the formation of the germ line once re-injected into adeveloping embryo. Finally, and this is not the slightestof the advantages, the complete sequence of the mousegenome is now available (Waterston et al., 2002), whichwill allow comparisons with other mammalian genomesand annotations concerning the function of the genes tobe made. In short, the mouse is the only mammalianspecies whose genomic sequence is known and for whichtechnical procedures exist for the generation of avirtually unlimited number of genetic alterations.

In this chapter we will describe the origins of lab-oratory mice, starting with their phylogenetic rela-tionships with the other mammalian species. We willalso discuss the advantage of strains established fromrecently trapped wild specimens as a source of poly-morphisms for scientific research.

The phylogeneticrelationships of thehouse mouseThe position of rodents amongmammalian speciesMice are rodents. They belong to the most abundant(around 40%) and diversified order of living placentalmammals, with slightly over 2000 species grouped in28 families (Huchon et al., 2002). Because of their greatdiversity, the phylogenetic relationships between thedifferent species of this order has been a matter of con-troversy for many years, especially when morphologicalmarkers were the only criteria available for the establish-ment of phylogeny. Nowadays, with the use of variousmolecular (mostly DNA) markers and possible refer-ences to the complete genomic sequence of numerousorthologous genes, the situation is much clarified andFigure 1.1 represents the most likely phylogenetic treefor a sample of 40 different eutherian mammals. Basedon comparisons at the level of nuclear DNA sequences,the divergence between man and murid rodents (Mus orRattus genus) has been set somewhere between 65 and75 Myrs ago (Waterston et al., 2002).

Mice among rodentsThe rodent family of Muridae encompasses at least 1326species grouped in 281 genera (Musser and Carleton,

1993). The establishment of the evolutionary systemat-ics in this group has also been disputed but, this time, itwas because many mammals in this family are very simi-lar in size and shape. Here again studies making use ofDNA sequences of various types (Michaux et al., 2001;Lundrigan et al., 2002) have greatly contributed to clar-ify the situation and Figure 1.2 represents the evolution-ary relationships among a sample of 21 rodent speciesanchored into the broader phylogeny of eutherian mam-mals. The divergence between the Mus and Rattus genushas been estimated at around 10–15 Myrs ago ( Jaegeret al., 1986; Murphy et al., 2001), while the divergence ofthese two genera with Peromyscus maniculatus, the deermouse (subfamily Sigmodontinae), occurred at around25 Myrs ago. This is to be remembered because deermice, which are abundantly used as laboratory models,are often considered close relatives of the laboratory micewhile, in fact, they are no more related to them thanhamsters.

Systematics in the genus MusFigure 1.3 (Guénet and Bonhomme, 2003 and refer-ences therein) summarizes the phylogenetic relation-ships within the genus Mus (subfamily Murinae). Theindividualization of the subgenus Mus sensu strictooccurred around 5 Myrs ago with the split of threeother different subgenera, the African Nannomys andthe Asian Coelomys and Pyromys.

The subgenus Mus comprises several species thatare extremely similar in size and shape but neverhybridize in the wild. Among the Asian species are Muscervicolor, Mus cookii, and Mus caroli as well as thegroup of Indian pigmy mice related to Mus dunni. Musfamulus from India should also be cited as well as therecently discovered species Mus fragilicauda (Auffrayet al., 2003) from Thailand.

Mus spicilegus and Mus macedonicus are short tailedmice that are found in central Europe and the easternMediterranean, respectively, while mice belonging tothe species Mus spretus are common in the westernMediterranean regions (south east France, Spain, Portugaland North Africa).

Mice of the Mus musculus complex are closelyrelated. They have their evolutionary origins in theIndian subcontinent (Bonhomme et al., 1994) but arenow spread over the five continents. The best known rep-resentatives of the complex are the three Mus musculussubspecies: Mus m. domesticus, common in westernEurope, Africa, the near-East, and transported by man tothe Americas and Australia; Mus m. musculus, whosehabitat spans from eastern Europe to Japan, across

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Russia, and northern China, and Mus m. castaneus, whichis found from Sri Lanka to south east Asia including theIndo-Malayan archipelago. Various molecular criteriadiscriminate easily between these different species(Figure 1.4; Boursot et al., 1993; Moriwaki et al., 1994)

Mouse interspecifichybridizationHybrids between mice of the genus Mus and miceof the subgenera Nannomys, Coelomys or Pyromys

have never been reported and probably never occur.Hybrids between wild mice of the species Muscervicolor, Mus caroli, Mus dunni1and mice of the Musmusculus complex have never been found in thewild but hybrids between the former three wild speciesand laboratory mice have been produced by artifi-cial insemination (West et al., 1977). In these experi-ments, hybrids generated by insemination of femalelaboratory mice with Mus cervicolor sperms failed tocomplete more than a few cleavage divisions. Hybridsgenerated from Mus dunni sperms and laboratoryfemale oocytes implanted but died in utero at a very

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Bradypus (sloth)Orycteropus (aardvark)

Dugong (dugong)Procavia (hyrax)

Cynopterus (bat)Erinaceus (hedgehog)

Felis (cat)Manis (pangolin)

Equus (horse)Lama (lama)

Sus (pig)Bos (cow)

Physeter (sperm whale)Tupaia (tree shrew)

Homo (human)Cynocephalus (flying lemur)

Ochotona (pika)Lepus (hare)

Oryctolagus (rabbit)Marmota (woodchuck)

Aplodontia (mountain beaver)Dryomys (forest dormouse)

Glis (fat dormouse)Anomalurus (scaly-tailed flying squirrel)

Castor (beaver)Dipodomys (kangaroo-rat)

Thomomys (pocket mouse)Dipus (jerboa)

Tachyoryctes (mole rat)Mus (mouse)

Rattus (rat)Massoutiera (gundi)

Trichys (Old-World porcupine)Bathyergus (naked mole rat)

Thryonomys (cane rat)Petromus (dassie rat)

Echimys (spiny rat)Cavia (Guinea pig)

Erethizon (New-World porcupine)

Chinchilla (chinchilla)

~100 Myrs

~60–75 Myrs

~65–80 Myrs

~70–85 Myrs

~75–90 Myrs

Figure 1.1 Evolutionary tree concerning 40 mammalian species including 21 rodent species, with an estimated time ofdivergence in Myrs (from Huchon et al. (2002). Mol. Biol. Evol. 19, 1053–1065).

1See legend to Figure 1.3.


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musculusmolossinuscastaneus

caroli

cooki

bactrianus

spretus

domesticus

cervicolor

dunni

Pyromys

fragilicauda

famulus

Nannomys

spicilegus

macedonicus

Coelomys

5 4 3 2 1

Figure 1.3 Evolutionary tree of the genus Mus (the time scale is in Myrs).The exact branching for Mus dunni is notprecisely 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).

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

Sicista betulinaAllactaga elater

Jaculus jaculus

Steatomys sp.Dendromus mystacalis

Spalacinae

Mystromys albicaudatusCricetomys gamblanus

Saccostomus sp.

Peromyscus leucopusNeotoma sp.

Myospalax sp.

Calomyscus mystax

Uranomys ruddi

Clethrionomys glareolus

Cricetulus migratorius

Phodopus roborovskiiMesocricetus auratus

Deomys ferrugineus

Tatera gambianaGerbillus henleyi

Lophuromys sp.

Mus musculusOtomys irroratus

Dipus sagitta

Macrotarsomys ingensNesomys rufus

Acomys cahirinus

Rhizomyinae

Rattus norvegicusMicromys minutus

Dicrostonyx sp.


early developmental stage. Hybrids generated from thesame laboratory females and sperm from Mus carolicompleted fetal development and a very low percent-age of them even survived to maturity but nonereproduced.

Although they share the same range (they aresympatric) with some Mus musculus subspecies, theshort tailed species Mus spretus, Mus spicilegus and Musmacedonicus rarely produce hybrids in nature. However,evidence from studies on mtDNA (Orth et al., 2002)and LINE transposable elements (Greene-Till et al.,2000) indicate that exchanges can occur sporadicallythat would allow alleles with a selective advantage tocirculate outside the species in which they originated.The three species mentioned above produce viable off-spring with laboratory mice but male offspring of thesecrosses are sterile in compliance with Haldane’s rule.Male hybrids born from a Mus musculus � Mus spretuscross, for example, are invariably sterile regardless ofthe direction of the cross. This sterility is controlled by

a relatively small number of genes since fertile malesare frequently observed in the backcross progeny ofF1 females with a male of either of the parental species(Guénet et al., 1990; Forejt, 1996; Pilder et al., 1997;Elliott et al., 2001).

Mice of the Mus musculus complex are not geneti-cally isolated and, in those locations where they meet,there is evidence of gene exchanges ranging from limitedintrogression to complete blending (Boursot et al.,1993). The best-documented cases of such geneexchanges are those occurring between M. m. musculusand M. m. domesticus in Europe, along a narrow hybridzone, and between M. m. musculus and Mus m. castaneusin Japan. In this archipelago, the two subspecies havehybridized extensively, giving rise to a unique popu-lation often referred to as Mus m. molossinus (Yonekawaet al., 1988). These gene exchanges, which indicate thatthe speciation process is in progress but not yet completed,explain the use of Latin trinomens for the designation ofthe different subspecies in the M. musculus complex.

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domesticus

gentilulus

Himalayas

castaneus

molossinus

musculus

domesticuscentral

populations

domesticus

M. spretus

M. spicilegus

M. macedonicus

colonization routes for the various species

zones of secondary contacts

Figure 1.4 Geographical distribution of the different species of the genus Mus and routes of colonization. Mice of theAmerican and Australian continents were imported by man during colonization (from Guénet, J.L. and Bonhomme, F. (2003).Trends Genet. 19, 24–31).


The house mouse as a laboratorymodel: a historicalperspectiveMice, rats and other small vertebrates have been usedin biomedical research since the middle of the sixteenthcentury when biology progressively shifted from adescriptive to an experimental science. Morse (1981),reported that William Harvey used mice for his funda-mental studies on reproduction and blood circulationand, according to Berry (1987), the earliest record ofthe use of mice in scientific research seem to have beenin England, in 1664, when Robert Hooke used mice tostudy the biological consequences of an increase in airpressure. Much later, Joseph Priestly (1733–1804) andhis intellectual successor, Antoine Lavoisier (1743–94),both used mice repeatedly in their experiments onrespiration.

During the nineteenth century several fanciers inEurope and the United States were breeding andexchanging pet mice segregating for a variety of coatcolor or behavioral mutations. According to Grüneberg(1957), one of these fanciers, M. Coladon, who wasestablished as a pharmacist in Geneva, reported resultsfrom his breeding experiments that were in perfectagreement with the Mendelian expectations … butthis was 36 years before the publication of Mendel’sown results on peas. As mentioned by Paigen (2003a,b)in his notes about a century of mouse genetics, it seemsthat Mendel’s first experiments on the transmission ofcharacters were made using mice segregating for coatcolor markers but Mendel was rapidly asked by hisecclesiastical superior to stop breeding in his celluleawfully smelly creatures that, in addition, had sex andcopulated. Mendel changed his experimental materialfor peas and published in 1866 his observations in abotanical journal where they had a much lower impactand remained virtually ignored until the very begin-ning of the twentieth century. Once rediscoveredby De Vries, Correns and von Tschermark, the threeof them working independently with plants, it wasreally tempting to check whether the so-calledMendel’s laws were also valid for animals and experi-ments were published in 1902 by L. Cuénot (1902),indicating that this was indeed the case. Cuénot’sobservations were shortly confirmed and extended to

other species as well as for other genetic traits byG. Bateson, E.R. Saunders, A. Garrod, W.E. Castle andC.C. Little (Paigen, 2003a).

Even if mice have been extensively used duringthe twentieth century in most areas of biomedicalresearch, animals of this species have played aninstrumental role in research in immunology, oncology,and genetics because the breeding systems2 whichare used to produce them allow the establishment ofhighly standardized strains whose characteristics areprecisely known and monitored generation aftergeneration. Most laboratory strains have their originsfrom a few pet dealers who progressively becamesuppliers of ‘laboratory’ mice. For many years, most ofthe albino strains used in laboratories were collectivelydesignated ‘Swiss’ mice to recapitulate their Helvetianorigin.

Strain DBA/2 (formerly dba, then DBA) is themost ancient of all inbred strains since it was establishedby C.C. Little in 1909 (Russell, 1978), by intercrossingmice homozygous for the coat color markers nonagouti (a), brown (formerly b now Tyrp1), and dilute(formerly d and now Myo5a). About 10 years later,strain C57BL/6 was established by Miss Lathrop(Granby, Massachusetts, USA) intercrossing the ‘black’offspring of her female 57, while strains C3H, CBA,and A were created by L.C. Strong, a cancer geneticistestablished at Cold Spring Harbor Laboratory (Strong,1978). At this point, it is interesting to note that,among the strains established by L.C. Strong, strainsCBA and C3H stemmed from the offspring of an out-cross with a few wild specimens trapped in a pigeoncoop in Cold Spring Harbor. This explains how thewild allele at the agouti locus (A) was re-introduced inlaboratory strains.

With a few exceptions, historical records concern-ing the genealogy of most laboratory inbred strainsare well documented and several interesting reviews onthis subject are available (Morse, 1978; Festing, 1979).A chart concerning the genealogy of these strains,including the recently established ones, has beenpublished (Beck et al., 2000) and regularly up-datedinformation is available at the website �http://www.informatics.jax.org�.

In addition to its contribution to the re-discoveryof Mendel’s laws, the mouse has been closely associatedwith many important discoveries in biology during thetwentieth century. To cite just a few among the most

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2Among the genetically standardized strains, inbred strains are the mostwidely used. They result from the systematic and uninterrupted matingof brothers to their sisters, which leads to complete homozygosity for thesame allele at all loci.


important, we could say that our understanding of thegenetic determinism underlying the success or failureof tissue transplantations is a consequence of the manyexperiments performed with inbred mouse strains byP.A. Gorer (Gorer et al., 1948), then by G.D. Snell andco-workers (Snell, 1978) who developed a series of con-genic resistant strains, which were all genetically identi-cal to the C57BL/10Sn background strain, with theexception of single short-sized chromosomal regionsdetermining graft rejection. The discovery and geneticinterpretation of the phenomenon of X-inactivation infemale mammals, by M.F. Lyon (Lyon, 1961), has beenfacilitated by the existence and use of several X-linkedmutations in the mouse and the observation of variega-tion in the coat color. The first chimeric organisms pro-duced by A.K. Tarkowski, in Warsaw (Tarkowski,1961), and B. Mintz, in Philadelphia (Mintz, 1962),were mice. The observation of a particularly high fre-quency of testicular terato-carcinomas in strain 129(Stevens and Little, 1954; Stevens, 1970) and the invitro culture of cell lines derived from these tumors,which represented for almost a decade a material ofchoice for investigating the processes at work in tissuedifferentiation ( Jacob, 1983), undoubtedly openedthe way to the establishment of the so-called embry-onic stem (ES) cells, by G.R. Martin (1981) and,simultaneously, by M.J. Evans and M.H. Kaufman(1981). The discovery of parental imprinting ofsome chromosomal regions has been a consequence of

experiments performed by J. McGrath and D. Solter(1984) and M.A. Surani and co-workers (1984), whodemonstrated that a normal mouse embryo can onlyresult 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 ele-ments of a given chromosome pair was sometimes notgenetically equivalent. The first transgenic mammalcreated by pronuclear injection of a cloned DNA, was amouse (Gordon et al., 1980; Brinster et al., 1981;Costantini and Lacy, 1981; Gordon and Ruddle, 1981;Harbers et al., 1981; Wagner et al., 1981a,b) and the firstin vitro genetically engineered mammalian organism wasalso a mouse (Kuehn et al., 1987). Only the first clonedmammal was not a mouse although this type of uni-parental procreation has been achieved also in themouse (Wakayama and Yanagimachi, 1999).

Information concerning many aspects of the biol-ogy of the mouse considered as a laboratory model, inparticular about its genetics, has been published in the95 issues of the Mouse News Letters. First issued in 1949and published regularly every semester till 1997,3 thisinformal publication, edited by the scientists fromthe MRC at Harwell and distributed at low cost, hasbeen for several decades the major medium for thedissemination of information among the communityof mouse geneticists. In this sense, the Mouse NewsLetters will for ever remain the best place to get infor-mation about the history of mouse genetics, and in par-ticular, about the history and location of most inbredstrains, the progressive development and refinementof the linkage map and the discovery of hundreds ofspontaneous mutations.

The Jackson Laboratory (the JAX-Lab), which wasfounded in Bar Harbor (Maine, USA), in 1929, byC.C. Little, has played a pivotal role in the promotionof the mouse as a laboratory model and still is a uniquecenter for mouse genetics. The Jax-Lab, a non-profitorganization entirely dedicated to basic research on thegenetics of mammals, is nowadays almost exclusivelydedicated to the mouse. It is, at the same time, a topranked research institution, a meeting place wherecourses and conferences are organized on the variousaspects of mouse genetics, and the world largest gene-tic repository where a great variety of genotypes andbiological samples of all kind are stored, under the formof frozen embryos or sperm cells, for distribution tothe community. Several other Institutions, like the

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Figure 1.5 Mice of the Mus spretus species (left, with anagouti coat color) and C57BL/6 (right, with a non agouti orsolid black coat color). In spite of their great similarity insize and body shape these mice are distantly relatedspecies but can still produce viable and fertile hybrids(female only). Mice of the Mus spretus species have beenextensively used for the development of the mousegenetic map. (See also Color Plate 1.)

3The name Mouse News Letter was changed for Mouse Genome in 1990when this publication became a peer reviewed journal. From 1998,Mouse Genome and Mammalian Genome have merged in one and a singlejournal.


Oak Ridge National Laboratory in Tennessee (USA) andthe MRC center at Harwell in England have also playeda very important role in the development of the mouseas a laboratory model for researches in genetics, oncologyand immunology. Recently, the European Union hasdecided to support the establishment of a network ofgenetic repositories (the so-called European MouseMutant Archive or EMMA), with major nodes in Italy(EMMA head quarters is in Monteretondo, nearRoma), in England (Harwell), in France (Orléans-la-Source) and in Germany (Munich). Finally, morerecently, Japan has established a bio-resource center atthe RIKEN, in Tsukuba. More information about allthese centers is available at the websites provided at theend of this chapter.

The house mouseand its wild relativesAs discussed above, the classical laboratory inbredstrains of mouse have many advantages that are relatedto their great genetic homogeneity. After all, a popula-tion of F1 hybrid mice, born from an intercross setbetween two highly inbred strains, can be consideredidentical from the genetic point of view to a populationof cloned mice. Unfortunately, the coin has anotherside and these inbred strains, because they are derivedfrom a relatively small pool of ancestors do not exhibita great variety of genetic polymorphisms of natural ori-gin. This relative genetic homogeneity is well reflectedin the fact that most of the classical strains possess thesame maternally inherited molecule of mitochondrialDNA (Yonekawa, 1980; Ferris et al., 1982) and rela-tively reduced polymorphisms for the Y chromosome(Bishop et al., 1985; Tucker et al., 1992). Aside fromthis relative genetic homogeneity, a careful analysis ofthe genetic polymorphism also indicates that laboratorystrains have a mosaic genome derived from more thanone species (Bonhomme et al., 1987; Wade et al.,2002) and today’s classical laboratory strains should beregarded as interspecific recombinant strains derived (inunequal percentages) from three parental components:Mus m. domesticus, Mus m. musculus and Mus m. casta-neus. For this reason, and to point to a relatively unnat-ural genetic constitution, it would probably be moreappropriate to designate them as Mus m. ‘laboratorius’!

Over the last 20 years a variety of strains, derivedfrom small breeding nuclei of wild specimens, trapped

in well-defined geographical areas and belonging towell characterized species, have been established in var-ious laboratories. A list of the strains that are com-pletely inbred, i.e. that have been propagated by strictlyunrelaxed brother � sister matings for more than20 generations, is given in Bonhomme and Guénet(1996). Other useful stocks of wild mice are also main-tained in various laboratories and a complete descrip-tion of these stocks has been published by Potter(1986). These ‘new’ inbred strains have been extremelyimportant over these last years because they represent avirtually unlimited reservoir of genetic polymorphisms.Wild mice have been useful in providing geneticistswith polymorphisms such as electrophoretic variants,restriction fragment length polymorphisms (RFLPs),or more generally single nucleotide polymorphisms(SNPs) that were much less numerous in standardinbred strains. With the introduction of strains derivedfrom wild progenitors, in particular, from Mus spretus,the genetic map of mouse has dramatically increased itsresolution (Guénet, 1986). Comparisons of non-codingorthologous regions at the sequence level indicate thatany inbred strain derived from Mus spretus exhibits, onaverage, one SNP at every 80 –100 bp when comparedwith any of the classical laboratory strains. This meansthat virtually any DNA sequence of 100 –200 bp, can beused as a molecular marker in assays such as denaturinggradient gel electrophoresis (DGGE) or single strandconfirmation polymorphism (SSCP). This high densityof polymorphisms represents a considerable advantagein experiments when the aim is positional cloning of agene identified only by phenotype because it allows anaccurate delineation of the targeted locus. In fact, onecan consider that there is no upper limit to the densityin molecular markers when a genetic map is establishedfrom an interspecific or intersubspecific cross (Breenet al., 1994). The high density of polymorphisms turnsout to be an even greater advantage when quantitativetraits are mapped, because every animal with a relevantphenotype can be genotyped for a very large number ofmarkers. In this respect, the mouse is unique since thefrequency of SNPs between humans is roughly one orderof magnitude lower than that of Mus spretus compared tolaboratory strains (Flint and Mott, 2001; Matin andNadeau, 2001). The high frequency of SNPs in codingregions means that the genome of Mus spretus orMus m. musculus is full of ready-made ‘quantitative traitloci (QTL)-point mutations’ waiting for functionalgenomic studies!

Wild mice have also been invaluable in providingcytogeneticists with a large collection of Robertsoniantranslocations (or centric fusions) recovered from the

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many populations of Mus m. domesticus where theyoccur in homozygous conditions (Gropp and Winking,1981). These translocations are characterized by thefusion of two acrocentric chromosomes by their cen-tromeres and they often interfere with the normalprocess of meiosis resulting in the production ofgametes with an aneuploid (unbalanced) complement.Using carefully designed crosses involving these centricfusions, it has been possible to produce and study tri-somies and monosomies for all mouse chromosomes(Epstein, 1986).

In addition to their homogeneity in terms of chro-mosome morphology, laboratory strains have only longtelomeres while, for instance, strains of Mus spretusorigins, have both long and short telomeres (Coviello-McLaughlin and Prowse, 1997; Zhu et al., 1998).This peculiarity might be helpful for investigating thesignificance of the still mysterious variations in telom-ere size found in mammalian cells.

When infectious agents of various kinds areinjected into mice it is common to observe that somestrains are more susceptible than others and that wildderived strains are in general more resistant than classi-cal laboratory strains. A commonly accepted explana-tion, although not demonstrated, is that some alleles oflaboratory strains, which are essential for determininginnate or acquired mechanisms of defense, have beenby chance replaced by a defective mutant allele withoutany consequences for the mice because these animalsare kept in protected environments. Even if in mostcases the level of susceptibility or resistance is con-trolled by several genes interacting together (QTLs) orhaving an additive effect, the situation is sometimesunder the control of a single gene making its analysisrelatively simple. This is the case, for example, whenmice of most laboratory strains die after an injectionwith an appropriate dose of orthomyxoviruses whilemost wild strains are resistant (Haller et al., 1998).This phenotype is controlled by a single gene (Mx1 –chromosome 16) with two alleles: Mx1� (resistant,dominant) and Mx1� (susceptible, recessive) and thediscrepancy between wild mice and laboratory mice interms of susceptibility indicates that the mutated alleleof Mx1 is over-represented in laboratory strains, proba-bly due to a sampling effect. A similar example existswith experimental flavivirus infections where all labora-tory inbred strains, except strain PL/J, are susceptiblewhile most wild derived inbred strains are resistant(Sangster et al., 1998). Here again, it seems that Flvs,the allele responsible for susceptibility at the Flv locus(chromosome 5), has been fortuitously selected in lab-oratory strains while it is rare or absent in wild mice.

Similar phenotypes of resistance/susceptibilityhave also been reported for a variety of pathogens(Sebastiani et al., 2000; Lengeling et al., 2001) and,even if in most instances genetic differences have beenobserved among classical laboratory strains, these dif-ferences also exist between laboratory and wild derivedstrains making the genetic analysis much easier. Wildanimals also proved particularly useful for investigatingthe biology of murine leukemia viruses and both newFv loci and new alleles at the Fv1 and Fv2 loci havebeen discovered in wild mice (Gardner et al., 1991;Qi et al., 1998).

The comments addressed concerning the suscepti-bility of mice to infectious diseases also apply tocarcinogenesis and comparisons between classical labo-ratory strains allowed the complex influences of geneticbackground on tumor susceptibility to be unraveledand several genes modifying tumor susceptibility havebeen identified. However, while the phenotype of F1hybrids between any two classical laboratory strainsis generally intermediate between the two parentalstrains, it is often identical to the phenotype of the wildparent when crosses are performed with wild inbredstrains, indicating dominance of the wild derived allele.(Nagase et al., 2001).

Besides their use in mapping, interspecific crossesalso offer an opportunity for analyzing the effects ofbringing together the products of genes separated bydivergent evolution in the cells of an offspring. This canhelp identify the genetic functions that are subject torapid divergence and to pinpoint the functions thateventually promote speciation. Those functions thatare mostly unaffected during the evolution of the taxaare most likely to be basic functions that are under moreconstraint. This last point will be important in the com-parison of orthologous regions between human andmouse genomes now that sequencing is completed forboth species.

Questions concerning epistatic interactions canalso be addressed by investigating offspring of inter-specific crosses at the genomic level. So far, we have noclear answers to this question but data exist indicatingthat some combinations of alleles are strongly counter-selected in the offspring of some interspecific crosses(Montagutelli et al., 1996).

A less dramatic but still very interesting situation isfrequently observed when wild mice are used for themapping of mutations with deleterious phenotypiceffects. In this case, the interspecific offspring, homozy-gous for the mutant allele, often exhibit a wide range ofvariations in the degree of severity of their phenotypeswith severe forms and weaker ones. In these cases,

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genes or loci with a modifying effect can be identified,mapped and eventually cloned (Upadhya et al., 1999;Sawamura et al., 2000). Genes of this kind, which areof potentially great value cannot be recognized in ananimal with a normal genotype.

Because many different inbred strains belonging toseveral more or less related taxa of the genus Mus arenow easily available, it is possible to address questionsaimed at a better understanding of genome structureand functions. For example: are all the genes present inone strain also present in the others, or are there differ-ences and/or variations in the copy number? If theanswer is that a particular gene exists in one strain andnot in a closely related one, then what use is the gene inquestion? Examples of that kind have already beenreported (Ye et al., 2001) and have allowed fundamen-tal questions to be answered in a very elegant way.

It would also be interesting to study certain cate-gories of orthologous genes in closely related species tosee how their pattern of spatio-temporal expressionevolves and in what sort of sequence variation this evo-lution is involved. This can be particularly interestingwhen adaptive traits are concerned.

Investigations at the genomic level using inbredstrains derived from wild mice are bound to become verypopular in the near future because they can be achievedwith a high level of refinement and can be correlated in avery reliable way to the phenotype of the living animal.At this point it is no exaggeration to say that this newtype of mouse strain is bound to be of expanding interestand it is predictable that, in the future, the house mouseand its related species will be even more useful for scien-tific research than it has been over the last centuries,especially when more than one complete genome will beavailable for comparative purposes in the genus Mus.

List of relevant URLfor Mouse ResourceCenters:Mouse Genome Informatics: http://www.informatics.jax.orgMammalian Genetics Unit, Harwell, UK: http://www.mgu.har.mrc.ac.ukRIKEN Bioresource Center: http://www.brc.riken.jp/en/European Mouse Mutant Archive: http://www.emma.rm.cnr.it/

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