To most people, all small rodents are virtually indistinguishable from each other, and as such, they are lumped together and considered to be mice of one kind or another. In Webster’s Third New International Dictionary, one finds the following definition for a mouse: " any of numerous small rodents typically resembling diminutive rats with pointed snout, rather small ears, elongated body and slender hairless or sparsely haired tail, including all the small members of the genus Mus and many members of other rodent genera and families having little more in common than their relatively small size". In fact, the order Rodentia (in the kingdom Animalia, phylum Chordata, and subphylum Vertebrata) is very old and highly differentiated with 28 separate families, numerous genera, and over 1500 well-defined species accounting for 40% of all mammalian species known to be in existence today (Corbet and Hill, 1991). All families, subfamilies and genera in this order that contain animals commonly referred to as mice are listed in Table 2.1. The family Muridae encompasses over 1000 species by itself including mice, rats, voles, gerbils, and hamsters. Within this family is the subfamily Murinae which contains over 300 species of old world mice and rats, and within this subfamily is the genus Mus. The Mus genus has been divided into four subgenera, of which one is also called Mus. This subgenus contains all of the "true old world mice" including the house mouse M. musculus — the main focus of this book. A humorous view of mouse evolution is reproduced in figure 2.1, and a more serious phylogenetic tree with all extant members of the Mus subgenus is presented in figure 2.2.

There is still a great deal of confusion in the field of rodent systematics, and the proper classification of species into and among genera is now undergoing serious revision with the results of new molecular analyses. Just recently, it was suggested that the guinea pig is not a rodent at all, contrary to long-held beliefs (Graur et al., 1991). And in other studies (based on DNA-DNA hybridization and quantitative immunological cross-reactivity), a series of African species known as "spiny mice" were found to be more closely related to gerbils than to true old world mice (Wilson et al., 1987; Chevret et al., 1993).

The major reason for the confusion is that classical systematics has always been dependent on taxonomy, and taxonomy has always been dependent on the demonstration of distinct morphological differences — measurable on a macroscopic scale — that can be used to distinguish different species. Unfortunately, many small rodent species have developed gross morphological characteristics that are convergent with those present in other relatively distant species. Thus, traditional taxonomy can fail to provide an accurate systematic description of mice. (An illustration of the close similarity of Mus species can be seen in figure 3.3). Fortunately, the tools of molecular phylogenetics — and in particular, DNA sequence comparisons — have proven highly effective at sorting out the evolutionary relationships that exist among different mouse groups. With continued molecular analysis, it should be possible to clear up all of the confusion that now exists in the field.

Excellent sources of information concerning the systematics and phylogeny of Mus and related species are the proceedings from two conferences, The Wild Mouse in Immunology (Potter et al., 1986) and The Fifth International Theriological Congress (Berry and Corti, 1990) as well as a review by the Montpellier group (Boursot et al., 1993). A concise description of Mus systematics is provided by Bonhomme and Guénet (Bonhomme and Guénet, 1989).

The common ancestor to mice and humans was an inconspicuous rodent-like mammal that scurried along the surface of the earth some 65 million years (myr) before present (bp). It had to be inconspicuous because the earth was ruled by enormous dinosaurs, many of whom would have eaten any small mammal that could be caught. The glorious age of the dinosaurs came to an abrupt end with the collision of one or a few large extraterrestrial objects — perhaps asteroids or comets — into the earth’s surface over a relatively short period of time (Alvarez and Asaro, 1990; Sheehan et al., 1991). Possible sites at which these impacts may have occurred have been identified in the Yucatan peninsula of Mexico and the state of Iowa (Kerr, 1991; Kerr, 1992; Kerr, 1993). It has been hypothesized that the impact resulted in the formation of a thick cloud of dust that dispersed and shrouded the earth for a period of years, leading to a nuclear-winter-like scenario with the demise of all green life, and with that, all large animals that depended either directly on plants for survival or indirectly on the animals that ate the plants. At least a small number of our rodent-like ancestors were presumably able to survive this long sunless winter as a consequence of their small size which allowed them to "get by" eating seeds alone. When the sun finally returned, the seeds lying dormant on the ground sprung to life and the world became an extremely fertile place. In the absence of competition from the dinosaurs, mammals were able to become the dominant large animal group, and they radiated out into numerous species that could take advantage of all the newly unoccupied ecological niches. It was in this context that the demise of the dinosaurs brought forth both humans and mice as well as most other mammalian species on earth today.

The Muridae family of rodents, which includes both "true" mice and rats, originated in the area across present-day India and Southeast Asia. Phylogenetic and palaeontological data suggest that mice and rats diverged apart from a common ancestor 10 to 15 myr bp (Jaeger et al., 1986), and by six myr bp, the genus Mus was established. The Mus genus has since diverged into a variety of species (listed in figure 2.2) across the Indian subcontinent and neighboring lands.

At the beginning of the Neolithic transition some 10,000 years ago, the progenitors to the house mouse (collectively known as Mus musculus, as discussed later in this chapter) had already undergone divergence into four separate populations that must have occupied non-overlapping ranges in and around the Indian subcontinent. Present speculation is that the domesticus group was focused along the steppes of present-day Pakistan to the west of India (Auffray et al., 1990); the musculus group may have been in Northern India (Horiuchi et al., 1992; Boursot et al., 1993); the castaneus group was in the area of Bangladesh, and the founder population — bactrianus — remained in India proper.

The house mouse could only begin its commensal association with humans after agricultural communities had formed. Once this leap in civilization had occurred, mice from the domesticus group in Pakistan spread into the villages and farms of the fertile crescent as illustrated in figure 1.2 (Auffray et al., 1990); mice from the musculus group may have spread to a second center of civilization in China (Horiuchi et al., 1992); and finally, bactrianus and castaneus animals went from the fields to nearby communities established in India and Southeast Asia respectively.

Much later (~4000 yrs bp), the domesticus and musculus forms of the house mouse made their way to Europe. The domesticus animals moved with migrating agriculturalists from the Middle East across Southwestern Europe (Sokal et al., 1991) and the development of sea transport hastened the sweep of both mice and people through the Mediterranean basin and North Africa. Invasion of Europe by musculus animals occurred by a separate route from the East. Chinese voyagers brought these mice along in their carts and wagons, and they migrated along with their hosts across Russia and further west to present-day Germany where their spread was stopped by the boundary of the domesticus range (figure 2.3). Finally, it is only within the last millennium that mice have spread to all inhabited parts of the world including sub-Saharan Africa, the Americas, Australia, and the many islands in-between.

One interesting sidelight of the stowaway tendency of mice is that it is sometimes possible to observe the origin of human populations within the context of the mice that have come along with them. A clear example of this concordance is seen in the domesticus mice that have colonized all of North America, South America, Australia, and sub-Saharan Africa in conjunction with their Western European human partners (figure 2.3). A more complex example is observed in the Japanese islands where the native mice were long thought to be a separate subspecies or species group referred to in the literature as Mus molossinus. In fact, molecular phylogenetic studies have demonstrated that Japanese mice do not represent a distinct evolutionary line at all. Instead, they appear to have been derived by hybridization of two other house mouse groups on the mainland nearby — musculus in China and castaneus in Southeast Asia (Yonekawa et al., 1988, figure 2.3). The hybrid character of the mice parallels the hybrid origin of the Japanese people themselves.

Finally, there is the interesting observation of a pocket of mice from the castaneus group that has recently been uncovered in Southern California (Gardner et al., 1991). This is the only documented example of an established natural house mouse population in the Americas that is not derived from the Western European domesticus group. This finding is a testament to the strong wave of twentieth century Asian migration to the West Coast of the United States.

Animals that are members of the genus Mus can be further classified according to their relationship to humankind. The house mouse represents one group within this genus that is characterized by its ability to live in close association with people. Animals dependent on human shelter and/or activity for their survival are referred to as commensal animals. As discussed later in this chapter, all commensal mice appear to be members of a single species — Mus musculus — that can be subdivided into four distinct subspecies groups with different geographical ranges.

Although the success of M. musculus throughout the world is dependent on its status as a commensal species, in some regions with appropriate environmental conditions, animals have reverted back to a non-commensal state, severing their dependence on humankind. Such mice are referred to as feral. The return to the wild can occur most readily with a mild climate, sufficient vegetation or other food source, and weak competition from other species. Feral mice have successfully colonized small islands off Great Britain and in the South Atlantic (Berry et al., 1987), and in Australia, M. musculus has replaced some indigenous species. Although feral populations exist in North America and Europe as well, here they seem to be at a disadvantage relative to other small indigenous rodents such as Apodemus (field mice in Europe), Peromyscus (American deer mice), and Microtus (American voles). In some geographical areas, individual house mice will switch back and forth from a feral to a commensal state according to the season — in mid-latitude temperate zones, human shelters are much more essential in the winter than in the summertime.

None of the remaining species in the genus Mus (indicated in figure 2.2) have the ability to live commensally. These animals are not, and their ancestors never have been, dependent on humans for survival. Such animals are referred to as aboriginal.

Although the average person cannot distinguish a field mouse from a house mouse, taxonomists have gone in the opposite direction describing numerous types of house mouse species. In the book The Genetics of the Mouse published in 1943, Grünberg wrote "The taxonomy of the musculus group of mice is in urgent need of revision. About fifty names of reputed ‘good species’, sub-species, local varieties and synonyms occur in the literature, all of which refer to members of this group." (Grüneberg, 1943). M. brevirostris, M. poschiavinus, M. praetextus, and M. wagneri are among the 114 species names for various house mice present in the literature by 1981 (Marshall, 1981). One reason for this early confusion was the high level of variation in coat color and tail length that exists among house mice from different geographical regions. In particular, the belly can vary in color from nearly white to dark gray (Sage, 1981). A second reason for more recent taxonomic subdivisions was the discovery of a large variation in chromosome number among different European populations (discussed in chapter 5). These differences and others led traditional taxonomists to conclude the existence of numerous house mouse species.

Over the last decade, the power of molecular biology has been combined with a more detailed investigation of breeding complementarity to sort out the true systematics of the house mouse group [see review by Boursot et al. (1993)]. Much of the credit for this comprehensive analysis goes to two groups of researchers — one at Berkeley including Sage, Wilson, and their colleagues (Sage, 1981; Ferris et al., 1983b), and the second in Montpellier including Thaler, Bonhomme, and their colleagues (Bonhomme et al., 1978; Bonhomme et al., 1978; Britton and Thaler, 1978; Bonhomme et al., 1984; Bonhomme and Guénet, 1989; Auffray et al., 1991). Moriwaki and his colleagues have also contributed to this analysis (Yonekawa et al., 1981; Yonekawa et al., 1988). The accumulated data clearly demonstrate the existence of four primary forms of the house mouse — domesticus, musculus, castaneus, and bactrianus (figure 2.2). Two of these four groups — domesticus and musculus — are each relatively homogenous at the genetic level whereas the other two are not (Boursot et al., 1993). In particular, mice from the bactrianus group show a high level of genetic heterogeneity. The Montpellier team has interpreted these findings as strong supporting evidence for the hypothesis that the Indian subcontinent represents the ancestral home of all house mice and that bactrianus animals are descendants of this very old founder population. In contrast, the musculus and domesticus groups have more recent founders that derive from the ancestral bactrianus population (Boursot et al., 1993).

Although the four groups can be distinguished morphologically and molecularly, and have different non-overlapping ranges around the world (figure 2.3), it is clear at the DNA level that individuals within all these groups are descendants of a common ancestor that lived between 800,000 and one million years ago. Individuals representing pure samples from each of the four groups can interbreed readily in the laboratory to produce fertile male and female offspring. The high level of morphologic and karyotypic variation that has been observed among house mice from different regions must be a consequence of rapid adaptation to aspects of the many varied environments in which the house mouse can survive and thrive. The previously identified "false species" M. brevirostris, M. poschiavinus, and M. praetextus are not distinguishable genetically and are all members of the domesticus group.

Although mouse systematicists have reached a consensus on the structure of the Mus musculus group — with the existence of only four well-defined subgroups — there is still a question as to whether each of these subgroups represents a separate species, or whether each is simply a subspecies, or race, within a single all-encompassing house mouse species. The very fact that this question is not simply answered attests to the clash that exists between (1) those who would define two populations as separate species only if they could not produce fully viable and fertile hybrid offspring, whether in a laboratory or natural setting, and (2) those who believe that species should be defined strictly in geographical and population terms, based on the existence of a natural barrier (of any kind) to gene flow between the two populations (Barton and Hewitt, 1989).

The first question to be asked is whether this is simply a semantical argument between investigators without any bearing on biology. At what point in the divergence of two populations from each other is the magic line crossed when they become distinct species? Obviously, the line must be fuzzy. Perhaps, the house mouse groups are simply in this fuzzy area at this moment in evolutionary time, so why argue about their classification? The answer is that an understanding of the evolution of the Mus group in particular, and the entire definition of species in general, is best served by pushing this debate as far as it will go, which is the purpose of what follows.

Each of the four primary house mouse groups occupies a distinct geographical range as shown in figure 2.3. Together, these ranges have expanded out to cover nearly the entire land mass on the globe. In theory, it might be possible to solve the species versus sub-species debate by examining the interactions that occur between different house mouse groups whose ranges have bumped-up against each other. If all house mice were members of the same species, barriers to interbreeding might not exist, and as such, one might expect boundaries between ranges to be extremely diffuse with broad gradients of mixed genotypes. This would be the prediction of laboratory observations, where members of both sexes from each house mouse group can interbreed readily with individuals from all other groups to produce viable and fertile offspring of both sexes that appear to be just as fit in all respects as offspring derived from matings within a group.

However, just because productive interbreeding occurs in the laboratory does not mean that it will occur in the wild where selective processes act in full force. It could be argued that two populations should be defined as separate species if the offspring that result from interbreeding are less fit in the real world than offspring obtained through matings within either group. It is known that subtle effects on fitness can have dramatic effects in nature and yet go totally unrecognized in captivity. If this were the case with hybrids formed between different house mouse groups, the dynamics of interactions between different populations would be quite different from the melting-pot prediction described above. In particular, since inter-specific crosses would be "non-productive," genotypes from the two populations would remain distinct. Nevertheless, if the two populations favored different ecological niches, their ranges could actually overlap even as each group (species) maintained its genetic identity — such species are considered to be sympatric. Examples of sympatric species within the context of the broader Mus genus are described in section 2.3.5.

Species that have just recently become distinct from each other would be more likely to demand the same ecological niches. In this case, ranges would not overlap since all of the niches in each range would already be occupied by the species members that got there first. Instead, the barrier to gene flow would result in the formation of a distinct boundary between the two ranges. Boundary regions of this type are called hybrid zones because along these narrow geographical lines, members of each population can interact and mate to form viable hybrids, even though gene flow across the entire width of the hybrid zone is generally blocked (Barton and Hewitt, 1989).

The best-characterized house mouse hybrid zone runs through the center of Europe and separates the domesticus group to the West from the musculus group to the East (figure 2.3). If, as the one-species protagonists claim, musculus and domesticus mice simply arrived in Europe and spread toward the center by different routes — domesticus from the southwest and musculus from the east — then upon meeting in the middle, the expectation would be that they would readily mix together. This should lead to a hybrid zone which broadens with time until eventually it disappears. In its place initially, one would expect a continuous gradient of the characteristics present in the original two groups.

In contrast to this expectation, the European hybrid zone does not appear to be widening. Rather, it appears to be stably maintained at a width of less than 20 kilometers (Sage et al., 1986). Since hybridization between the two groups of mice does occur in this zone, what prevents the spreading of most genes beyond it? The answer seems to be that hybrid animals in this zone are less fit than those with pure genotypes on either side. One manner in which this reduced fitness is expressed is through the inability of the hybrids to protect themselves against intestinal parasites. Sage (Sage, 1986) has shown through direct studies of captured animals that hybrid zone mice with mixed genotypes carry a much larger parasitic load, in the form of intestinal worms. This finding has been independently confirmed (Moulia et al., 1991). Superficially, these "wormy mice" do not appear to be less healthy than normal; however, one can easily imagine a negative effect on reproductive fitness through a reduced life span and other changes in overall vitality.

Nevertheless, for a subset of genes and gene complexes, the hybrid zone does not act as a barrier to transmission across group lines. In particular, there is evidence for the flow of mitochondrial genes from domesticus animals in Germany to musculus animals in Scandinavia (Ferris et al., 1983a; Gyllensten and Wilson, 1987) with the reverse flow observed in Bulgaria and Greece (Boursot et al., 1984; Vanlerberghe et al., 1988; Bonhomme and Guénet, 1989). An even more dramatic example of gene flow can be seen with a variant form of chromosome 17 — called a t haplotype — that has passed freely across the complete ranges of all four groups (Silver et al., 1987; Hammer et al., 1991).

In contrast to the stable hybrid zone in Europe, other boundaries between different house mouse ranges are likely to be much more diffuse. The extreme form of this situation is the complete mixing of two house mouse groups — castaneus and musculus — that has taken place on the Japanese islands (Yonekawa et al., 1988, see figure 2.3). So thorough has this mixing been that the hybrid group obtained was considered to be a separate group unto itself — with the name Mus molossinus — until DNA analysis showed otherwise.

In the end, there is no clear solution to the one species versus multiple species debate and it comes down to a matter of taste. However, the consensus has been aptly summarized by Bonhomme: "None of the four main units is completely genetically isolated from the other three, none is able to live sympatrically with any other. In those locations where they meet, there is evidence of exchange ranging from differential introgression . . . to a complete blending. It is therefore necessary to keep all these taxonomical units, whose evolutionary fate is unpredictable, within a species framework" (Bonhomme and Guénet, 1989). Thus, in line with this consensus, I will describe the four house mouse groups by their subspecies names M. m. musculus, M. m. domesticus, M. m. castaneus, and M. m. bactrianus. I will use M. musculus as a generic term in general discussions of house mice, where the specific subspecies is unimportant or unknown.

As presented in chapter one, the original inbred strains were derived almost exclusively from the fancy mice purchased by geneticists from pet mouse breeders like Abbie Lathrop and others at the beginning of the twentieth century. Mouse geneticists have always been aware of the multi-facted derivation of the fancy mice from native animals captured in Japan, China, and Europe. Thus, it is not surprising that none of the original inbred strains are truly representative of any one house mouse group, but rather each is a mosaic of M. m. domesticus, M. m. musculus, M. m. castaneus, and perhaps M. m. bactrianus as well (Bonhomme et al., 1987). Nevertheless, the accumulated data suggest that the most prominent component of this mosaic is M. m. domesticus.

In early comparative DNA studies carried out with the use of restriction enzymes, the classical inbred lines were analyzed to determine the derivation of two particular genomic components — the mitochondrial chromosome and the Y chromosome. The findings were surprising. First, all of the classical inbred strains were found to carry mitochondria derived exclusively from domesticus (Yonekawa et al., 1980; Ferris et al., 1982). Even more surprising was the fact that the mitochondrial genomes present in all of the inbred strains were identical, implying a common descent along the maternal line back to a female who could have lived as recently as 1920.

The Y chromosome results also showed a limited ancestry, but, in contrast to the mitochondrial results, the great majority of the classical inbred strains have a common paternal-line ancestor that came from musculus (Bishop et al., 1985; Tucker et al., 1992). Again, a large number of what-are-thought-to-be independent inbred strains (including B6, BALB/c, LP, LT, SEA, 129, and others) carry indistinguishable Y chromosomes (Tucker et al., 1992). Ferris and colleagues (Ferris et al., 1982) suggest that, contrary to the published records, early inter-strain contaminations may have been responsible for a much closer relationship among many of the inbred lines than had been previously assumed. It was, in fact, the absence of sufficient inter-strain variation that served as the impetus to use more novel approaches to linkage analysis in the mouse such as the interspecific crosses described in the next section and in more detail in chapter 9. Atchley and Fitch (1991) have constructed a phylogenetic tree that shows the relative overall genetic relatedness among 24 common inbred strains.

For many biological studies, use of the classical inbred strains is perfectly acceptable even though they are not actually representative of any race found in nature. However, in some cases, especially in studies that impact on aspects of evolution or population biology, it obviously does make a difference to use animals with genomes representative of naturally-occurring populations. It is only in the last decade that a major effort has been devoted to the generation of new inbred lines directly from wild mice certified to represent particular M. musculus subgroups. It is now possible to purchase inbred lines representative of M. m. domesticus, M. m. musculus, and M. m. castaneus (as well as the M. m. molossinus hybrid race) from the Jackson Laboratory. Many other inbred lines have been derived from mice captured in particular localities and a list of investigators that maintain such lines has been published (Potter et al., 1986).

A phylogenetic tree showing the relationships that exist among close relatives of the house moues M. musculus is presented in figure 2.2. All Mus species have the same basic karyotype of 40 acrocentric chromosomes. The three closest known relatives of Mus musculus are aboriginal species with restricted ranges within and near Europe. All three species — M. spretus, M. spicilegus, and M. macedonicus — are sympatric with M. musculus but interspecific hybrids are not produced in nature. Thus, there is a complete barrier to gene flow between the house mice and each of these aboriginal species. The ability of two animal populations to live sympatrically — with overlapping ranges — in the absence of gene flow is the clearest indication that the two populations represent different species. Nevertheless, in the forced, confined environment of a laboratory cage, Bonhomme and colleagues were able to demonstrate the production of interspecific F1 hybrids between each of these aboriginal species and M. musculus (Bonhomme et al., 1978; Bonhomme et al., 1984).

The best characterized of the aboriginal species is Mus spretus, a western Mediterranean short-tailed mouse with a range across the most southwestern portion of France, through most of Spain and Portugal, and across the North African coast above the Sahara in Morocco, Algeria, and Tunisia (Bonhomme and Guénet, 1989). M. spretus is sympatric with the M. m. domesticus group across its entire range. In 1978, Bonhomme and his colleagues reported the landmark finding that M. spretus males and laboratory strain females could be bred to produce viable offspring of both sexes (Bonhomme et al., 1978). Although all male hybrids are sterile, the female hybrid is fully fertile and can be backcrossed to either M. musculus or M. spretus males to obtain fully viable second generation offspring.

In a series of subsequent papers, Bonhomme and colleagues demonstrated the power of the interspecific cross for performing multi-locus linkage analysis with molecular and biochemical makers (Bonhomme et al., 1979; Bonhomme et al., 1982; Avner et al., 1988; Guenet et al., 1990). With the large evolutionary distance that separates the two parental species, it is possible to readily find alternative DNA and biochemical alleles at nearly every locus in the genome. This finding stands in stark contrast to the high level of non-polymorphism observed at the majority of loci examined within the classical inbred lines. The significance of the interspecific cross for mouse genetics cannot be understated: it was the single most important factor in the development of a whole genome linkage map based on molecular markers during the last half of the 1980s. A detailed discussion of the actual protocols involved in such a linkage analysis will be presented in chapter 9.

Two other well-defined aboriginal species have non-overlapping ranges in Eastern Europe. Mus spicilegus (previously known as M. hortulanus or species 4B) is commonly referred to as the mound-building mouse. Its range is restricted to the steppe grassland regions north and west of the Black Sea in current-day Bulgaria, Romania, and Ukraine (Bonhomme et al., 1978; Sage, 1981; Bonhomme et al., 1983). Mus macedonicus (previously known as M. abbotti, M. spretoides, or species 4A) is restricted in range to the eastern Mediterranean across Greece and Turkey; this very short-tailed species is the Eastern European equivalent of M. spretus in terms of ecological niches. M. spicilegus and M. macedonicus are an interesting pair of species in that they are barely distinguishable from each other morphologically, and yet they fail to interbreed in the wild, and successful attempts at interbreeding in the laboratory have yet to be published. Nevertheless, males from both species can be bred with M. musculus to give an outcome identical to that obtained with the M. spretus-M. musculus cross — both male and female hybrid offspring are fully viable, however, only the females are fertile (Bonhomme et al., 1984).

Presumably, both of these interspecific hybrid types could be used for linkage analysis in the same manner as that described above. However, in general, these crosses would not provide any obvious advantage over the spretus-musculus cross. The one exception to this statement would be in chromosomal regions where spretus and musculus were distinguished by an inversion polymorphism that did not distinguish musculus from either macedonicus or spiciligus. The presence of an inversion polymorphism will prevent recombination in F1 hybrids and can lead to false estimates of gene distances. In only one instance to date has such a polymorphism between spretus and musculus been demonstrated — in the proximal region of chromosome 17 (Hammer et al., 1989). This inversion can cause a suppression of recombination over a chromosomal region that extends far beyond the inverted region itself (Himmelbauer and Silver, 1993). In the case of this particular chromosomal region, musculus and macedonicus have been shown to share the same gene order leading to the occurrence of normal recombination in the macedonicus-musculus F1 hybrid (Hammer et al., 1989).

The failure to find other inversion polymorphisms does not mean that they do not exist. Inversions can only be demonstrated formally by creating a linkage map for M. spretus by itself and comparing the gene order on this map to the gene order on a M. musculus map. This has not been done for any chromosome other than the seventeenth. Nevertheless, a recent comparison of linkage maps constructed from the spretus-musculus cross and an intersubspecific domesticus-castaneus cross points to several additional regions where inversion polymorphisms are implicated based on the observation of localized recombination suppression in the interspecific cross only (Copeland et al., 1993). Cryptic inversions could have serious consequences for those using linkage map distances as means for estimating the physical length of DNA that must be walked from a cloned marker to a gene of interest as discussed more fully in chapter 10.

Other more-distant members of the genus Mus have evolved in and around India. These include M. caroli, M. cooki, M. cervicolor, M. booduga, and M. dunni. None of these species can produce interspecific hybrids with any representatives of the M. musculus complex under normal laboratory conditions. However, with artificial insemination, Chapman and colleagues were able to demonstrate fertilized embryos representing F1 hybrids between M. musculus and M. caroli, M. cervicolor, or M. dunni (West et al., 1977). However, the embryos formed with M. musculus and either M. dunni or M. cervicolor never gave rise to live-born animals, with most cervicolor-musculus hybrids failing to undergo even the first cleavage division, and most dunni-musculus hybrids failing at the blastocyst stage. Although most caroli-musculus embryos also died prenatally, a small number actually made it through to a live birth. These interspecific hybrids were all delivered by Caesarian Section; they were usually small and only a few survived after fostering to nursing mothers. None were shown to be fertile, although the sample size was exceedingly small.

Inbred lines developed from a number of different Mus species, including M. spretus and M. spicilegus (M. hortulanus) are available for purchase from the Jackson Laboratory. In addition, outbred stocks representing most of the other Mus species are maintained by individual investigators [listed in (Potter et al., 1986)].

Mus musculus can live in an incredible variety of different habitats. Commensal animals can live in all types of human-made structures including houses, buildings, barns, haystacks, ruins, and in coal mines, 1800 feet below the ground. But the possibilities are virtually unlimited — animals have been found in climates as different as frozen-food lockers and central heating ducts (Bronson, 1984). Feral animals can live in agricultural fields, meadows, and scrublands (Sage, 1981). In most places, they do not normally live in woodlands or forest, but even this is possible in areas — such as islands — where natural predators do not exist (Berry and Jakobson, 1974; Berry et al., 1987). The survival of feral mice is often dependent on the production of nests and burrow systems which act to ameliorate the prevailing air temperatures (Sage, 1981). Both sexes construct nests which can range from very simple to highly complex enclosed structures used for food storage as well as nesting. Feral animals can display a highly developed homing behavior and are capable of returning to their nests after long distance (250 m) displacement (Sage, 1981). Mice can eat almost anything — cereals, grass, seeds, roots and stems of various plants, adult insects, and even larvae (Rowe, 1981). Animals can also subsist with very little water, especially if their food is high in moisture content (Grüneberg, 1943). In many locations, the morning dew can probably provide much of the daily water requirement (Rowe, 1981). These traits provide the house mouse with great adaptability and have played an important role in their dispersion among many different habitats, both commensal and feral.

The paradigm population structure for animals living under commensal conditions is that of independent, relatively stable demes, or families. The classic deme will have a single dominant male who patrols a well-defined home range and sires most of the young; up to ten breeding female members of the deme will confine their own ranges to that of the single dominant male. Different dominant males will have mutually exclusive territories. Males will tolerate their own offspring, but will kill offspring born to females that belong to other demes. In highly structured populations of this type, the level of interdemic migration is very low, even between nesting sites located within a few meters of each other (Sage, 1981).

In reality, the picture of demes presented above is an idealized situation that may actually define the structure of some populations but not others, and at some points in times, but not others. In the presence of an ample food supply and in the absence of predators or competitors, populations appear to retain a higher level of structure. However, demes can vary in size from two animals to at least 100; the amount of interdemic migration can vary between none and all; and the detailed structure of a population can change drastically in response to changes in the environment.

Under optimal environmental conditions with plenty of food and nesting material, commensal mice living inside temperature-controlled buildings can breed throughout the year (Rowe, 1981; Sage, 1981). In strictly feral populations in temperate climates, breeding activity tends to be seasonal, from spring to early autumn (Rowe, 1981). The average litter size has been found to vary from as few as three pups to as many as nine. Although mice from some laboratory lines can survive as long as three years, free-living wild animals are likely to die much earlier from disease, competition, or predators.

The usual structure of feral populations may be very different from that of commensal populations in that animals living outdoors appear to move over much larger distances, and deme structures appear to be much less stable (Berry and Jakobson, 1974). However, the ability and desire of mice to migrate over long distances is complex and highly variable. Many animals appear to live their entire lives in very small and well-defined home ranges (defined as the area in which an animal spends the vast majority of its time) of less than 10 meters across. Others will move constantly over much larger distances, traveling kilometers daily, and some will migrate long distances between home ranges that are very small. All possible permutations are possible, and the distribution of animals in each class varies greatly among different populations. The lifestyle of the house mouse has been described aptly by Berry: "The house mouse is a weed: quick to exploit opportunity, and able to withstand local adversity . . . A consequence of the repeated formation of new populations by small numbers of founders is that every population is likely to be unique." (Berry, 1981).

The incredible adaptability of M. musculus to new environments can be accounted for almost entirely by the enormous plasticity that exists in its behavioral traits (Bronson, 1984). In the case of nearly all other species, specific behaviors are highly defined by genomes, and adaptability to new environments can occur only slowly with changes in behavior as well as physiology and/or morphology driven by natural selection. In contrast, the house mice can disembark from ships in subantarctic islands or in equatorial Africa, and adapt immediately to survive and prosper. "To be introduced into a radically new environment is one thing; to be able to reproduce there and so to establish a new population is quite another. The planet-wide spread of the house mouse in both manmade and natural habitats suggests an extreme reproductive adaptability, probably the most extreme among the mammals" (Bronson, 1984). Only humans are as adaptable (some would say less so).

Thus, the defining characteristic of the species M. musculus is the de-coupling of genetics and behavior. At some point during evolution, the ancestral house mouse population broke away from its previous behavioral constraints and once this occurred, the success of the species was assured. With men and women as chauffeurs and guides, the global conquest of the house mouse began.