Molecular phylogeny of the genus Mus (Rodentia: Murinae) based on mitochondrial and nuclear data

The genus Mus encompasses at least 38 species divided into four subgenera: Mus , Pyromys , Nannomys and Coelomys . The subgenus Mus , which comprises the house mouse and related species, is by far the most extensively studied, although the subgenus Nannomys is the most speciose. Although the relationships within the subgenus Mus are rather well characterized, those between subgenera are still unclear. In the present study, phylogenetic analyses of the whole genus were performed using a larger species sample of Nannomys than in previous studies, and a nuclear gene (IRBP) in addition to mitochondrial data (cytochrome b and 12S rRNA). Members of the Acomyinae and Murinae were used as outgroups. Separate and combined analyses were performed with maximum parsimony, maximum likelihood and Bayesian methods, and divergence times were estimated. The results showed that the monophyly of the genus Mus and of each subgenus was strongly supported by the three genes and the combined analysis. The phylogenies derived from the three genes were on the whole congruent; however, several conflicting topologies were observed such as the relationships between the three Asian species of the subgenus Mus ( caroli , cervicolor and cookii ). Increasing the taxonomic sampling of Nannomys did not satisfactorily improve the resolution of relationships between the four subgenera. In addition, molecular calibrations indicate that the Mus and Nannomys radiation coincided with major environmental changes.  © 2005 The Linnean Society of London, Biological Journal of the Linnean Society , 2005, 84 , 417–427.     

Mouse biodiversity in the genomic era

Comparative genomics has developed by comparison of distantly related genomes, for which the link between the reported evolutionary changes and species development/physiology/ecology is not obvious. It is argued that the mouse (genus Mus) is an optimal model for microevolutionary genomics in vertebrates. This is because the mouse genome sequence, physical and genetic map have been completed, because mouse genetics, morpho-anatomy, pathology, behavior and ecology are well-studied, and because the Mus genus is a diverse, well- documented taxon, allowing comparative studies at the level of individual, population, subspecies, and species. The potential of the interaction between mouse genome and mouse biodiversity is illustrated by recent studies of speciation in the house mouse Mus musculus, and studies about the evolution of isochores, the peculiar pattern of GC-content variation across mammalian genomes.     

Phylogenetic relationships in the genus mus,based on paternally,maternally, and biparentally inherited characters

Several species in the rodent genus Mus are used as model research organisms, but comparative studies of these mice have been hampered by the lack of a well-supported phylogeny. We used DNA sequences from six genes representing paternally, maternally, and biparentally inherited regions of the genome to infer phylogenetic relationships among 10 species of Mus commonly used in laboratory research. Our sample included seven species from the subgenus Mus; one species each from the subgenera Pyromys, Coelomys, and Nannomys; and representatives from three additional murine genera, which served as outgroups in the phylogenetic analyses. Although each of the six genes yielded a unique phylogeny, several clades were supported by four or more gene trees. Nodes that conflicted between trees were generally characterized by weak support for one or both of the alternative topologies, thus providing no compelling evidence that any individual gene, or part of the genome, was misleading with respect to the evolutionary history of these mice. Analysis of the combined data resulted in a fully resolved tree that strongly supports monophyly of the genus Mus, monophyly of the subgenus Mus, division of the subgenus Mus into Palearctic (M. musculus, M. macedonicus, M. spicilegus, and M. spretus) and Asian (M. cervicolor, M. cookii, and M. caroli) clades, monophyly of the house mice (M. m. musculus, "M. m. molossinus," M. m. castaneus, and M. m. domesticus), and a sister-group relationship between M. macedonicus and M. spicilegus. Other clades that were strongly supported by one or more gene partitions were not strongly supported by the combined data. This appears to reflect a localized homoplasy in one partition obscuring the phylogenetic signal from another, rather than differences in gene or genome histories.     

Evolutionary systematics of the Indian mouse Mus famulus Bonhote, 1898: molecular (DNA/DNA hybridization and 12S rRNA sequences) and morphological evidence

The genus Mus encompasses 38 species of mice divided into four subgenera: Mus , Pyromys , Nannomys and Coelomys . Each of these four taxa is characterized by discrete morphological as well as biochemical traits. We used two different molecular approaches to determine the relationships between these subgenera: DNA/DNA hybridization and 12S rRNA mitochondrial sequences. We compared the resulting phylogenies from each method and with phylogenies derived from morphological data. The degree of resolution of each molecular approach is discussed. The two molecular studies indicate that Mus , Pyromys , Nannomys and Coelomys are clearly distinct monophyletic groups, as previously indicated by morphological data and other biochemical and molecular approaches. There is one divergence between previous morphological and the molecular and morphological studies presented here: the position of the Indian species Mus famulus . This taxon, which was formerly included in the subgenus Coelomys , is demonstrated here to belong to the subgenus Mus. We also propose the following relationships within Mus sensu lato : Mus and Pyromys are the closest relatives, followed by Nannomys and Coelomys , whose relationships are still unclear. This arrangement is more robustly supported by DNA/DNA hybridization than by 12S rRNA data. A molecular time scale for the evolution within Mus sensu lato is proposed, using as a reference the Mus/Rattus divergence estimated by the fossil record at around 12 mya.  © 2003 The Linnean Society of London, Zoological Journal of the Linnean Society , 2003, 137 , 385–401.     

A pronounced evolutionary shift of the pseudoautosomal region boundary in house mice

The pseudoautosomal region (PAR) is essential for the accurate pairing and segregation of the X and Y chromosomes during meiosis. Despite its functional significance, the PAR shows substantial evolutionary divergence in structure and sequence between mammalian species. An instructive example of PAR evolution is the house mouse Mus musculus domesticus (represented by the C57BL/6J strain), which has the smallest PAR among those that have been mapped. In C57BL/6J, the PAR boundary is located just ~700 kb from the distal end of the X chromosome, whereas the boundary is found at a more proximal position in Mus spretus, a species that diverged from house mice 2-4 million years ago. In this study we used a combination of genetic and physical mapping to document a pronounced shift in the PAR boundary in a second house mouse subspecies, Mus musculus castaneus (represented by the CAST/EiJ strain), ~430 kb proximal of the M. m. domesticus boundary. We demonstrate molecular evolutionary consequences of this shift, including a marked lineage-specific increase in sequence divergence within Mid1, a gene that resides entirely within the M. m. castaneus PAR but straddles the boundary in other subspecies. Our results extend observations of structural divergence in the PAR to closely related subspecies, pointing to major evolutionary changes in this functionally important genomic region over a short time period.     

Molecular phylogeny of the African pygmy mice, subgenus Nannomys (Rodentia, Murinae, Mus): implications for chromosomal evolution

Molecular phylogenies based on sequences of mitochondrial cytochrome b and nuclear IRBP genes are assessed on a comprehensive taxonomic sampling of African pygmy mice (subgenus Nannomys of the genus Mus). They represent a taxonomically diversified group of morphologically similar species, and exhibit an important chromosomal diversity, particularly involving sex-autosome translocations, one of the rarest and most deleterious chromosomal changes among mammals. The results show that the species sampled are genetically well differentiated, and that chromosomal rearrangements offer accurate diagnostic characters for discriminating most species. Furthermore, the species carrying different sex-autosome translocations appear monophyletic, suggesting that a genome modification allowing a higher rate of occurrence and/or fixation of such translocations took place, leading to the emergence of this lineage. In addition to taxonomic and biogeographical clarifications, we provide a temporal framework within which patterns of genic and chromosomal evolution are discussed.     

The uncharacterized gene 1700093K21Rik and flanking regions are correlated with reproductive isolation in the house mouse,Mus musculus

Reproductive barriers exist between the house mouse subspecies, Mus musculus musculus and M. m. domesticus, members of the Mus musculus species complex, primarily as a result of hybrid male infertility, and a hybrid zone exists where their ranges intersect in Europe. Using single nucleotide polymorphisms (SNPs) diagnostic for the two taxa, the extent of introgression across the genome was previously compared in these hybrid populations. Sixty-nine of 1316 autosomal SNPs exhibited reduced introgression in two hybrid zone transects suggesting maladaptive interactions among certain loci. One of these markers is within a region on chromosome 11 that, in other studies, has been associated with hybrid male sterility of these subspecies. We assessed sequence variation in a 20 Mb region on chromosome 11 flanking this marker, and observed its inclusion within a roughly 150 kb stretch of DNA showing elevated sequence differentiation between the two subspecies. Four genes are associated with this genomic subregion, with two entirely encompassed. One of the two genes, the uncharacterized 1700093K21Rik gene, displays distinguishing features consistent with a potential role in reproductive isolation between these subspecies. Along with its expression specifically within spermatogenic cells, we present various sequence analyses that demonstrate a high rate of molecular evolution of this gene, as well as identify a subspecies amino acid variant resulting in a structural difference. Taken together, the data suggest a role for this gene in reproductive isolation.     

Temporal, spatial, and ecological modes of evolution of Eurasian Mus based on mitochondrial and nuclear gene sequences

We sequenced mitochondrial (cytochrome b, 12S rRNA) and nuclear (IRBP, RAG1) genes for 17 species of the Old World murine genus Mus, drawn primarily from the Eurasian subgenus Mus. Phylogenetic analysis of the newly and previously available sequences support recognition of four subgenera within Mus (Mus, Coelomys, Nannomys, and Pyromys), with an unresolved basal polytomy. Our data further indicate that the subgenus Mus contains three distinct 'species groups': (1) a Mus booduga Species Group, also including Mus terricolor and Mus fragilicauda (probably also Mus famulus); (2) a Mus cervicolor Species Group, also including Mus caroli and Mus cookii; and (3) a Mus musculus Species Group, also including Mus macedonicus, Mus spicilegus, and Mus spretus. Species diversity in Eurasian Mus is probably explicable in terms of several phases of range expansion and vicariance, and by a propensity within the group to undergo biotope transitions. IRBP and RAG1 molecular clocks for Mus date the origin of subgenera to around 5-6 mya and the origin of Species Groups within subgenus Mus to around 2-3 mya. The temporal pattern of evolution among Eurasian Mus is more complex than that within the Eurasian temperate genus Apodemus.     

Long-range restriction site mapping of a syntenic segment conserved between human chromosome 1 and mouse chromosome 3

A linkage map determined from segregation analysis of 338 meiotic events in an interspecific mouse cross was utilized to help investigate genomic organization of a linkage group conserved between human chromosome 1p and mouse chromosome 3. Using pulsed-field gel electrophoresis, the genes encoding the lymphocyte adhesion molecule human CD2/murine Ly-37, the alpha 1-subunit of Na, K-ATPase, the beta-subunit of thyrotropin, the beta-subunit of nerve growth factor, and muscle adenylate deaminase were similarly positioned on long-range restriction maps in both species. These studies indicate that the development of detailed genetic maps using interspecific Mus crosses facilitates rapid analysis of murine genomic organization and may enable physical mapping of syntenic regions within the human genome. Moreover, the data suggest profound conservation of genomic organization during mammalian evolution.     

Evolution of a 6-200 Mb long-range repeat cluster in the genus Mus

By fluorescence in situ hybridization, we mapped the location of genes associated with the Sp100-rs cluster, a long-range repeat cluster in chromosome 1 of the house mouse, Mus musculus. The cluster comprises between 60 and 2000 repeats and extends over 6-200 Mb of the M. musculus genome, depending on the source of the cluster. The cluster evolved during the last two million years in the genus Mus in the lineage to which M. musculus belongs. The Asiatic mouse species M. caroli is not in this lineage and does not possess the cluster. M. caroli represents the ancestral genomic organization of the cluster source components Sp100, Csprs and Ifi75: they are located close to each other in the same chromosome band (1D). However, Sp100-rs, the principal gene of the cluster, is not present in the M. caroli genome. It is a chimeric M. musculus gene that arose by fusion of Csprs and the 5' part of Sp100. Sp100-rs and Ifi75 are homogeneously distributed throughout the cluster while Sp100 and Csprs in its original sequence context flank the cluster on opposite sides. Our results suggest a model for the origin and evolution of the long-range repeat cluster by duplication, gene fusion and amplification.     

Fingerprinting genomes by use of PCR with primers that encode protein motifs or contain sequences that regulate gene expression

PCR primers of arbitrary nucleotide sequence have identified DNA polymorphisms useful for genetic mapping in a large variety of organisms. Although technically very powerful, the use of arbitrary primers for genome mapping has the disadvantage of characterizing DNA sequences of unknown function. Thus, there is no reason to anticipate that DNA fragments amplified by use of arbitrary primers will be enriched for either transcribed or promoter sequences that may be conserved in evolution. For these reasons, we modified the arbitrarily primed PCR method by using oligonucleotide primers derived from conserved promoter elements and protein motifs. Twenty-nine of these primers were tested individually and in pairwise combinations for their ability to amplify genomic DNA from a variety of species including various inbred strains of laboratory mice and Mus spretus. Using recombinant inbred strains of mice, we determined the chromosomal location of 27 polymorphic fragments in the mouse genome. The results demonstrated that motif sequence-tagged PCR products are reliable markers for mapping the mouse genome and that motif primers can also be used for genomic fingerprinting of many divergent species.     

小家鼠的遗传与进化研究进展

小家鼠作为重要的模式生物,近20年来对其遗传与进化领域的研究取得很大进展,通过现代遗传学的各种遗传标记（蛋白质电泳,mtDNA,rDNA,Y染色体等）,不仅更深入地探讨了共栖小家鼠间的遗传差异和系统关系以及与野生种的关系;进而还对小家鼠的分类系统进行了修正,提出小家鼠种组（species complex)由domesticus,musculus,castaneus 和bactrianus 4个共栖种以及spicilegus,macedonicus和spretus3个野生种组成;并且进一步阐明了小家鼠的起源和进化问题,目前主要有离心模型和顺序模型2种起源假说,然而对中国小家鼠的遗传分化,亚种分类尚缺乏系统的研究。     

The complex history of a gene proposed to participate in a sexual isolation mechanism in house mice

Previous behavioral experiments showed that mouse salivary androgen-binding protein (ABP) was involved in interindividual recognition and might play a role in sexual isolation between house mouse (Mus musculus) subspecies. The pattern of evolution of Abpa, the gene for the alpha subunit of ABP, was found to be consistent with this hypothesis. Abpa apparently diverged rapidly between species and subspecies with a large excess of nonsynonymous substitutions, a lack of exon polymorphism within each of the three subspecies, and a lack of intron polymorphism in the one subspecies studied (M. musculus domesticus). Here we characterized the intron and exon sequence variations of this gene in house mouse populations from central Eurasia, a region yet unsampled and thought to be close to the cradle of the radiation of the subspecies. We also determined the intron and exon sequences in seven other species of the genus Mus. We confirmed the general pattern of rapid evolution by essentially nonsynonymous substitutions, both inter- and intraspecifically, supporting the idea that Darwinian selection has driven the evolution of this gene. We also observed a uniform intron sequence in five samples of M. musculus musculus, suggesting that a selective sweep might have occurred for that allele. In contrast to previous results, however, we found extensive intron and exon polymorphism in some house mouse populations from central Eurasia. We also found evidence for secondary admixture of the subspecies-specific alleles in regions of transition between the subspecies in central Eurasia. Furthermore, an abnormal intron phylogeny suggested that interspecific exchanges had occurred between the house mouse subspecies and three other Palearctic species. These observations appear to be at variance with the simple hypothesis that Abpa is involved in reproductive isolation. Although we do not rule out a role in recognition, the situation appears to be more complex than previously thought. Thus the selective mechanism behind the evolution of Abpa remains to be resolved, and we suggest that it may have changed during the recent colonization history of the house mouse.     

Town Mouse, Country Mouse: adaptation and adaptability in Mus domesticus (M. musculus domesticus)

The generally accepted idea that the house mouse is a single, world-wide species which owes its success largely to commensalism with man is wrong. There are at least five European and two Asian species lumped together under the name Mus musculus, plus another fourteen Asian species in the same genus. The house mouse of western Europe is the one that has been introduced to the Americas and Australasia, as well as being domesticated in the laboratory and ‘fancy’ strains; it is properly described as Mus domesticus. A complication of this particular species is the existence of chromosomal races involving the fusion of pairs of chromosomes, apparently at random. These races seem to be reproductively isolated from normal (2n = 40) mice. They have been described in southern Europe and northern Britain. Genetical studies of wild-living mice have shown the operation of powerful natural selection, contrary to earlier assumptions that most of the polymorphic variation in the species (especially that revealed by electrophoresis) was neutral. The effects of such selection are reduced (but not eliminated) by the deme structure of established mouse populations; this social structure is much less rigid than some laboratory experiments have suggested, because of opportunism by individual mice in replacing dead or debilitated animals, and filling new niches as these become available. Virtually every mouse population is unique, since a population tends to be founded by a small group of animals drawn from a genetically variable ancestral population. This differentiation has allowed laboratory workers to develop inbred strains with characteristic properties; it has also resulted in over 130 sub-species being described from wild caught animals. A substantial proportion of these latter have probably arisen by instant sub-speciation through the founder effect. This is well illustrated by the mice of the Faroe islands, which are often quoted as standard examples of extremely rapid evolution. The adaptive properties of the house mouse that have made it such an effective pest and such a good laboratory animal have enabled it to colonize habitats as different as Antarctic tundra and tropical atolls. The species is an ideal one for the general biological task of dissecting the traits that contribute to this adaptability; the material is largely available for this task in the diversity of local forms established in different habitats and characterized genetical varieties maintained in the laboratory. More is known about M. domesticus than any other mammal, except possibly man; the time is ripe for fusing laboratory work on reproduction, mortality, and behaviour with the information increasingly coming from field studies of wild-living animals.     

Isolation and Characterization of a Mouse Y Chromosomal Repetitive Sequence

The Y chromosome plays a dominant role in mammalian sex determination, and characterization of this chromosome is essential to understand the mechanism responsible for testicular differentiation. Male mouse genomic DNA fragments, cloned into pBR322, were screened for the presence of Bkm (a female snake satellite DNA)-related sequences, and we obtained a clone (AC11) having a DNA fragment from the mouse Y chromosome. In addition to a Bkm-related sequence, this fragment contained a Y chromosomal repetitive sequence. DNA isolated from the XX sex-reversed male genome produced a hybridization pattern indistinguishable to that obtained with normal female DNA, suggesting that the AC11 sequence is not contained within the Y chromosomal DNA present in the sex-reversed male genome. Based on the hybridization patterns against mouse Y chromosomal DNA, AC11 classified 16 inbred laboratory strains into two categories; those with the Mus musculus musculus type Y chromosome and those with the M.m. domesticus type Y chromosome. Three European subspecies of Mus musculus (M.m. brevirostris, M.m. poschiavinus and M.m. praetextus) possessed the M.m. domesticus type Y chromosome, whereas the Japanese mouse, M.m. molossinus, had the M.m. musculus type Y chromosome. The survey was also extended to six other species that belong to the genus Mus, of which M. spretus and M. hortulamus showed significant amounts of AC11-related sequences in their Y chromosomes. The male-specific accumulation of AC11-related sequences was not found in M. caroli, M. cookii, M. pahari or M. platythrix. This marked difference among Mus species indicates that the amplification of AC11-related sequences in the mouse Y chromosome was a recent evolutionary event.     

Large-scale genomic correlations in Arabidopsis thaliana relate to chromosomal structure

Background

The genome of classical laboratory strains of mice is an artificial mosaic of genomes originated from several mouse subspecies with predominant representation (>90%) of the Mus m. domesticus component. Mice of another subspecies, East European/Asian Mus m. musculus, can interbreed with the classical laboratory strains to generate hybrids with unprecedented phenotypic and genotypic variations. To study these variations in depth we prepared the first genomic large insert BAC library from an inbred strain derived purely from the Mus m. musculus-subspecies. The library will be used to seek and characterize genomic sequences controlling specific monogenic and polygenic complex traits, including modifiers of dominant and recessive mutations.

Results

A representative mouse genomic BAC library was derived from a female mouse of the PWD/Ph inbred strain of Mus m. musculus subspecies. The library consists of 144 768 primary clones from which 97% contain an insert of 120 kb average size. The library represents an equivalent of 6.7 × mouse haploid genome, as estimated from the total number of clones carrying genomic DNA inserts and from the average insert size. The clones were arrayed in duplicates onto eight high-density membranes that were screened with seven single-copy gene probes. The individual probes identified four to eleven positive clones, corresponding to 6.9-fold coverage of the mouse genome. Eighty-seven BAC-ends of PWD/Ph clones were sequenced, edited, and aligned with mouse C57BL/6J (B6) genome. Seventy-three BAC-ends displayed unique hits on B6 genome and their alignment revealed 0.92 single nucleotide polymorphisms (SNPs) per 100 bp. Insertions and deletions represented 0.3% of the BAC end sequences.

Conclusion

Analysis of the novel genomic library for the PWD/Ph inbred strain demonstrated coverage of almost seven mouse genome equivalents and a capability to recover clones for specific regions of PWD/Ph genome. The single nucleotide polymorphism between the strains PWD/Ph and C57BL/6J was 0.92/100 bp, a value significantly higher than between classical laboratory strains. The library will serve as a resource for dissecting the phenotypic and genotypic variations between mice of the Mus m. musculus subspecies and classical laboratory mouse strains.     

Recombination rate variation in mice from an isolated island

Recombination rate is a heritable trait that varies among individuals. Despite the major impact of recombination rate on patterns of genetic diversity and the efficacy of selection, natural variation in this phenotype remains poorly characterized. We present a comparison of genetic maps, sampling 1212 meioses, from a unique population of wild house mice (Mus musculus domesticus) that recently colonized remote Gough Island. Crosses to a mainland reference strain (WSB/EiJ) reveal pervasive variation in recombination rate among Gough Island mice, including subchromosomal intervals spanning up to 28% of the genome. In spite of this high level of polymorphism, the genomewide recombination rate does not significantly vary. In general, we find that recombination rate varies more when measured in smaller genomic intervals. Using the current standard genetic map of the laboratory mouse to polarize intervals with divergent recombination rates, we infer that the majority of evolutionary change occurred in one of the two tested lines of Gough Island mice. Our results confirm that natural populations harbour a high level of recombination rate polymorphism and highlight the disparities in recombination rate evolution across genomic scales.     

Novel arenavirus sequences in Hylomyscus sp. and Mus (Nannomys) setulosus from Côte d'Ivoire: implications for evolution of arenaviruses in Africa

This study aimed to identify new arenaviruses and gather insights in the evolution of arenaviruses in Africa. During 2003 through 2005, 1,228 small mammals representing 14 different genera were trapped in 9 villages in south, east, and middle west of C?te d'Ivoire. Specimens were screened by pan-Old World arenavirus RT-PCRs targeting S and L RNA segments as well as immunofluorescence assay. Sequences of two novel tentative species of the family Arenaviridae, Menekre and Gbagroube virus, were detected in Hylomyscus sp. and Mus (Nannomys) setulosus, respectively. Arenavirus infection of Mus (Nannomys) setulosus was also demonstrated by serological testing. Lassa virus was not found, although 60% of the captured animals were Mastomys natalensis. Complete S RNA and partial L RNA sequences of the novel viruses were recovered from the rodent specimens and subjected to phylogenetic analysis. Gbagroube virus is a closely related sister taxon of Lassa virus, while Menekre virus clusters with the Ippy/Mobala/Mopeia virus complex. Reconstruction of possible virus-host co-phylogeny scenarios suggests that, within the African continent, signatures of co-evolution might have been obliterated by multiple host-switching events.     

Diversity of mammary tumor viral genes within the genus Mus, the species Mus musculus, and the strain C3H.

Proviral sequences complementary to the C3H mouse mammary tumor virus RNA genome are present in the DNA of early occurring mammary tumors of C3H/HeN mice and are absent from apparently normal C3H/HeN tissues; these sequences are non-germ line transmitted in C3H/HeN mice and have been termed tumor-associated sequences; (W. Drohan et al., J. Virol. 21:986-995, 1977). We report here that tumor-associated sequences are present in the DNA of spontaneous mammary tumors that occur early in the life of several inbred, high-tumor-incidence mouse strains but are absent in mammary tumors that occur later in life in low- and moderate-tumor-incidence strains. These sequences are also absent in apparently normal organs tested from numerous laboratory mouse strains, feral mice, Mus musculus subspecies, and other Mus species. Sequences represented in tumor-associated sequence RNA, however, are present as endogenous provirus in GR mice (at approximately four copies per haploid genome) and in two of five substrains of C3H mice tested (at approximately one copy per haploid genome). The two substrains of C3H mice positive for endogenous tumor-associated sequence provirus were recently (circa 1930) separated from the negative substrains of C3H mice. The results may be explained by the unlikely chance segregation of proviral sequences or by the recent integration of viral genes (within the last few decades). Whereas radioactively labeled mouse mammary tumor virus 60-70S RNA or complementary DNA detected mouse mammary tumor virus-related proviral information in all laboratory mouse strains, feral mice, subspecies of M. musculus, and other species of Mus, the use of tumor-associated sequence RNA clearly revealed the genetic diversity that may exist between different colonies or substrains of "inbred" laboratory mice commonly used in cancer research.