Genetic analysis of a switch in cell specificity of P lysozyme expression in molossinus mice.

An electrophoretic survey of concentrations of lysozymes M and P was carried out with seven species in the house mouse group (spretus, hortulanus, abbotti, musculus, castaneus, domesticus and molossinus). In most species M is the predominant lysozyme in all tissues tested, except the small intestine, where P predominates if present. In inbred strains of molossinus mice P is more abundant than M in all tissues tested. The phenotypes of high expression of P lysozyme and low expression of M lysozyme in peritoneal and alveolar macrophages were examined genetically. Results of interspecific crosses and backcrosses to domesticus mice support the model that the phenotypes are caused by mutation(s) tightly linked to the lysozyme locus. Alleles at the regulatory loci show additive inheritance.     

Genetic differences in the histochemically defined structure of oligosaccharides in mice

A wide range of tissues from three interfertile species of mice and an interspecific hybrid was examined with lectins conjugated to peroxidase to localize specifically glycoconjugates containing terminal alpha-N-acetylgalactosamine, alpha-galactose, and alpha-fucose, and the terminal disaccharide galactose-(beta 1----3)-N-acetylgalactosamine. This battery of lectins disclosed marked heterogeneity of glycoconjugates in different histological sites in a given animal and even between cells in a presumably homogeneous cell population within an organ. No variation with any lectin was observed between individuals of two closely related inbred strains of Mus domesticus at any specific histological or cytological site. In contrast, littermates of an outbred strain of Mus castaneus differed in binding of certain lectins at various sites, attesting to a genetic basis for individual variation. Hybrids between castaneus and domesticus mice also showed individual variation. Moreover, extensive differences between the mouse species were demonstrable with every lectin in glycoconjugates of stored secretions, Golgi cisternae, and apical or basolateral plasmalemma in many cell types. Totaling the differences in tabulated staining intensities for each possible species pair gave a measure of the overall extent of difference at 53 histological sites. According to this measure, the three species are about equally divergent from one another. Some differences between species appeared to depend on histological rather than histochemical variation, as, for example, a greater abundance of granular duct cells in the sublingual and submandibular glands in Mus hortulanus. Other differences were apparently derived from pathological change, as exemplified by casts and lymphoid infiltrates in kidney and structurally atypical submandibular gland lobules in Mus castaneus, and possibly by infiltrating cells in intestinal lamina propria and epithelium in Mus castaneus and hortulanus.     

Mitochondrial DNA Sequence Variation in the Eastern House Mouse, Mus Musculus: Comparison with Other House Mice and Report of a 75-Bp Tandem Repeat

The control region and flanking tRNAs were sequenced from 139 Mus musculus mitochondrial DNAs (mtDNAs) from mice collected at 44 localities extending from Germany to Japan. Among the 36 types of M. musculus mtDNA resolved, five have an added 75-bp direct repeat; the two copies within an individual differ by two to four base substitutions. Among 90 M. domesticus mtDNAs sequenced, 12 new types were found; 96 M. domesticus types have now been identified by sequencing this segment. Representative mtDNAs from M. castaneus, M. macedonicus, M. spicilegus and M. spretus were also sequenced. A parsimony tree for the M. musculus mtDNAs is about half as deep as the tree for the M. domesticus mtDNAs, which is consistent with the idea that M. musculus is genetically less diverse and younger than M. domesticus. The patterns of variation as a function of position are similar but not identical in M. musculus and M. domesticus mtDNAs. M. castaneus and M. musculus mtDNAs are allied, at a tree depth about three times as great as the start of intra-M. musculus divergence. The coalescence of the M. musculus and M. castaneus mtDNAs is about half as deep as their coalescence with the M. domesticus mtDNA lineages. The mtDNAs of the aboriginal M. macedonicus and M. spicilegus are each other's closest relatives, at a tree depth greater than the deepest intracommensal node. The mtDNA results support the view that the aboriginal M. spretus is the sister group of the other five species.     

The diverse origins of New Zealand house mice

Molecular markers and morphological characters can help infer the colonization history of organisms. A combination of mitochondrial (mt) D-loop DNA sequences, nuclear DNA data, external measurements and skull characteristics shows that house mice (Mus musculus) in New Zealand and its outlying islands are descended from very diverse sources. The predominant genome is Mus musculus domesticus (from western Europe), but Mus musculus musculus (from central Europe) and Mus musculus castaneus (from southern Asia) are also represented genetically. These subspecies have hybridized to produce combinations of musculus and domesticus nuclear DNA coupled with domesticus mtDNA, and castaneus or musculus mtDNA with domesticus nuclear DNA. The majority of the mice with domesticus mtDNA that we sampled had D-loop sequences identical to two haplotypes common in Britain. This is consistent with long-term British-New Zealand cultural linkages. The origins of the castaneus mtDNA sequences widespread in New Zealand are less easy to identify.     

Genetic differentiation of house mice in the south of the Soviet Far East

Electrophoretic analysis of 24 loci specifying a number of enzymatic and non-enzymatic proteins was carried out in populations of Primorye house mice. No variability in Ldh-B, Ldh of testis, fumarase, alpha-Gpd, Aat-2, Sod-2, Gp-1, GP-3 was found. Distribution of the same main variant in all samples is represented by Sdh, Mor-1, Mor-2, Ldh-A, GP-2, Est-D, Gpd-x, Pgl, Ldr and alb. The second variant of these loci was found in one or two animals. Two and more variants encountered with significant frequency were detected for Id-1, Hbb, Aat-1, Est-1, Est-2, Mod-2. Hybrid origin of the Primorye house mouse is assumed. Genogeography of Id-1, Hbb, Aat-1 and Est-1 points to involvement of the Mus-2C castaneus form in development of their gene pool, the effect of Mus-2A musculus being not excluded. Genogeography of Sod-1 confirms the involvement of both castaneus and musculus. Intensive mutual penetration of these forms (more than 300 km from north to south) indicates that they did not achieve the level characteristic of musculus and domesticus in the course of their differentiation.     

Hybrid origin of Japanese mice "Mus musculus molossinus": evidence from restriction analysis of mitochondrial DNA

The Japanese mouse, Mus musculus molossinus, has long been considered an independent subspecies of the house mouse. A survey of restriction- site haplotypes of mitochondrial DNA (mtDNA) showed that Japanese mice have two main maternal lineages. The most common haplotype is closely related to the mtDNA of the European subspecies M. m. musculus. The other common haplotype and two minor ones are closely related to each other and to the mtDNA of an Asiatic subspecies, M. m. castaneus. Two other rare variants are probably the result of recent contamination by European M. m. domesticus. The musculus type of mtDNA is found in the southern two-thirds of Japan, whereas the common castaneus type is found in the northern third and the minor variants are found sporadically throughout Japan. The castaneus mtDNA lineage had a few minor variants, whereas the musculus lineage was completely monomorphic. By contrast, the native population of M. m. castaneus and the Chinese and Korean musculus populations were highly polymorphic. These results suggest that M. m. molossinus is a hybrid between ancestral colonies, possibly very small, of M. m. musculus and M. m. castaneus, rather than an independent subspecies.      

Higher differentiation among subspecies of the house mouse (Mus musculus) in genomic regions with low recombination

In the early stages of reproductive isolation, genomic regions of reduced recombination are expected to show greater levels of differentiation, either because gene flow between species is reduced in these regions or because the effects of selection at linked sites within species are enhanced in these regions. Here, we study the patterns of DNA sequence variation at 27 autosomal loci among populations of Mus musculus musculus, M. m. domesticus, and M. m. castaneus, three subspecies of house mice with collinear genomes. We found that some loci exhibit considerable shared variation among subspecies, while others exhibit fixed differences. We used an isolation-with-gene-flow model to estimate divergence times and effective population sizes (N(e) ) and to disentangle ancestral variation from gene flow. Estimates of divergence time indicate that all three subspecies diverged from one another within a very short period of time approximately 350,000 years ago. Overall, N(e) for each subspecies was associated with the degree of genetic differentiation: M. m. musculus had the smallest N(e) and the greatest proportion of monophyletic gene genealogies, while M. m. castaneus had the largest N(e) and the smallest proportion of monophyletic gene genealogies. M. m. domesticus and M. m. musculus were more differentiated from each other than either were from M. m. castaneus, consistent with greater reproductive isolation between M. m. domesticus and M. m. musculus. F(ST) was significantly greater at loci experiencing low recombination rates compared to loci experiencing high recombination rates in comparisons between M. m. castaneus and M. m. musculus or M. m. domesticus. These results provide evidence that genomic regions with less recombination show greater differentiation, even in the absence of chromosomal rearrangements.     

Mouse subspecies differentiation and H-2 polymorphism

Four major groups of Mus musculus subspecies are analysed from the genetical view point. A number of genetic traits exhibited polymorphism. Most were common among domesticus, bactrianus and castaneus subspecies, while others were musculus subspecies-specific. This suggests that the earliest differentiation was between domesticus and musculus . Mouse class I MHC was compared in these two lines. Immunological and molecular analyses of H-2K molecules indicated that these two groups of mouse have several common haplotypes of class I molecules. Phenotype frequencies of these haplotypes are considerably different in each subspecies. "Overdominance selection" in class I H-2 is one of the possible explanations for this.     

Mosaic genealogy of the Mus musculus genome revealed by 21 nuclear genes from its three subspecies

Patterns of genetic variation provide insight into the evolutionary history of a species. Mouse (Mus musculus) is a good model for this purpose. Here we present the analysis of genealogies of the 21 nuclear loci and one mitochondrial DNA region in M. musculus based on our nucleotide sequences of nine inbred strains from three M. musculus subspecies (musculus, domesticus, and castaneus) and one M. spicilegus strain as an outgroup. The mitochondrial DNA gene genealogy of those strains confirmed the introgression pattern of one musculus strain. When all the nuclear DNA data were concatenated to produce a phylogenetic tree of nine strains, musculus and domesticus strains formed monophyletic clusters with each other, while the two castaneus strains were paraphyletic. When each DNA region was treated independently, the phylogenetic networks revealed an unnegligibly high level of subspecies admixture and the mosaic nature of their genome. Estimation of ancestral and derived population sizes and migration rates suggests the effects of ancestral polymorphism and gene flow on the pattern of genetic variation of the current subspecies. Gene genealogies of Fut4 and Dfy loci also suggested existence of the gene flow between M. musculus and M. spicilegus or other distant species.     

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.     

Frequency and distribution of t-haplotypes in the Southeast Asian house mouse (Mus musculus castaneus) in Taiwan

t-haplotypes are a meiotic drive system found on the 17th chromosome of the house mouse (Mus musculus). They can be found in wild populations of all four genetically differentiated subspecies. The drive phenomenon is male-specific, such that heterozygous males (+/t) show non-Mendelian transmission and transmit the t-chromosome to > 90% of their offspring. So far the most comprehensive studies on the frequencies of t-haplotypes in natural populations have been on just one of the subspecies (M. musculus domesticus). We applied molecular methods to accurately screen t-haplotypes in a large number of populations of a second subspecies (M. musculus castaneus) distributed in Taiwan. We found that the overall t-haplotype frequency is low in M. m. castaneus (0.108), and the chromosomes are patchily distributed among its populations, closely resembling the situation found in M. m. domesticus. Further, we found the frequencies of t-haplotypes in our sample did not differ in relation to the sex or age of mice. This resemblance in the frequency and distribution among populations of the two distinct subspecies suggests that similar general mechanisms might be responsible for the low frequencies in both subspecies.     

Diverse wild mouse origins of xenotropic, mink cell focus-forming, and two types of ecotropic proviral genes

We analyzed wild mouse DNAs for the number and type of proviral genes related to the env sequences of various murine leukemia viruses (MuLVs). Only Mus species closely related to laboratory mice carried these retroviral sequences, and the different subclasses of viral env genes tended to be restricted to specific taxonomic groups. Only Mus musculus molossinus carried proviral genes which cross-reacted with the inbred mouse ecotropic MuLV env gene. The ecotropic viral env sequence associated with the Fv-4 resistance gene was found in the Asian mice M. musculus molossinus and Mus musculus castaneus and in California mice from Lake Casitas (LC). Both M. musculus castaneus and LC mice carried many additional Fv-4 env-related proviruses, two of which are common to both mouse populations, which suggests that these mice share a recent common ancestry. Xenotropic and mink cell focus-forming (MCF) virus env sequences were more widely dispersed in wild mice than the ecotropic viral env genes, which suggests that nonecotropic MuLVs were integrated into the Mus germ line at an earlier date. Xenotropic MuLVs represented the major component of MuLV env-reactive genes in Asian and eastern European mice classified as M. musculus molossinus, M. musculus castaneus, and Mus musculus musculus, whereas Mus musculus domesticus from western Europe, the Mediterranean, and North America contained almost exclusively MCF virus env copies. M. musculus musculus mice from central Europe trapped near the M. musculus domesticus/M. musculus musculus hybrid zone carried multiple copies of both types of env genes. LC mice also carried both xenotropic and MCF viral env genes, which is consistent with the above conclusion that they represent natural hybrids of M. musculus domesticus and M. musculus castaneus.     

Genetics and evolution of hybrid male sterility in house mice

Comparative genetic mapping provides insights into the evolution of the reproductive barriers that separate closely related species. This approach has been used to document the accumulation of reproductive incompatibilities over time, but has only been applied to a few taxa. House mice offer a powerful system to reconstruct the evolution of reproductive isolation between multiple subspecies pairs. However, studies of the primary reproductive barrier in house mice-hybrid male sterility-have been restricted to a single subspecies pair: Mus musculus musculus and Mus musculus domesticus. To provide a more complete characterization of reproductive isolation in house mice, we conducted an F(2) intercross between wild-derived inbred strains from Mus musculus castaneus and M. m. domesticus. We identified autosomal and X-linked QTL associated with a range of hybrid male sterility phenotypes, including testis weight, sperm density, and sperm morphology. The pseudoautosomal region (PAR) was strongly associated with hybrid sterility phenotypes when heterozygous. We compared QTL found in this cross with QTL identified in a previous F(2) intercross between M. m. musculus and M. m. domesticus and found three shared autosomal QTL. Most QTL were not shared, demonstrating that the genetic basis of hybrid male sterility largely differs between these closely related subspecies pairs. These results lay the groundwork for identifying genes responsible for the early stages of speciation in house mice.     

Origin of the house mice (superspecies complex Mus musculus sensu lato) from the Transcaucasian region: A new look at dispersal routes and evolution

We analyzed our results and literature evidence on variability of nuclear protein genes in 39 populations of eight synanthropic and wild species of house mice (superspecies complexes Mus musculus and M. spicilegus) from Transcaucasia, Eastern and Western Europe, Near and Middle East, Central, South, and East Asia, and Cuba. These data were for the first time ever combined into a single database by unification of nomenclature of 21 loci examined by different authors in 39 populations. Analysis of geographical allele distribution have shown that populations of domestic Transcaucasian mice are close to Indo-Pakistani populations of form oriental of the species M. castaneus, which preserved a high level of ancestral polymorphism. We concluded that a very heterogeneous, rich gene pool of house mice from Transcaucasia could not develop only by secondary contacts of differentiated M. musculus s. str. and M. domesticus forms, since it is similar to the ancestral gene pool of the superspecies complexes M. musculus and M. spicilegus. In this context, unique characteristics of some Central Asian populations were examined; these populations may have served as a "transit station" in the dispersal of synanthropic house mice forms. We suggest that the Transcaucasian populations are genealogically closely related to an early Near East form of M. musculus, which, as M. domesticus and M. castaneus, split from the common ancestor and preserved nondifferentiated pool of ancestral alleles of protein genes. This hypothesis admits the involvement of differentiated species M. musculus s. str. and M. domesticus in the ultimate formation of the gene pool of Transcaucasian house mice. Apparently, these populations resulted from alternation and (or) "overlapping" of different evolutionary processes. A scenario suggesting that hybrid events having occurred in Transcaucasia at different times, were "superposed" on the gene pool of the ancient autochtonous population of house mice from this region seems most plausible. Analysis of allozyme variability in the modern Transcaucasian Mus populations could not always distinguish between ancestral polymorphism and hybridization consequences.     

Altered Turnover of Hypoxanthine Phosphoribosyltransferase in Erythroid Cells of Mice Expressing Hprt a and Hprt b Alleles

We have previously shown that mice expressing Hprt a allele(s) have erythrocyte hypoxanthine phosphoribosyltransferase (HPRT) levels that are approximately 25-fold (Mus musculus castaneus) and 70-fold (Mus spretus) higher than in mice that express the Hprt b allele (Mus musculus domesticus; C57BI/6J; C3H/HeHa), and that these differences in erythrocyte HPRT levels are due to differences in the turnover rates of the HPRT A and B proteins as reticulocytes mature to erythrocytes. We show here that: the taxonomic subgroups of the genus Mus are essentially monomorphic for the occurrence of either the Hprt a or the Hprt b allele, with Hprt a being common in the aboriginal species (M. spretus, Mus hortulanus and Mus abbotti) and in several commensal species (Mus musculus musculus, M. m. castaneus, Mus musculus molossinus), while Hprt b is common in feral M. m. domesticus populations as well as in all inbred strains of mice tested; in all these diverse Mus subgroups there is a strict association of Hprt a with high and Hprt b with low levels of erythrocyte HPRT; and, the association between the occurrence of the Hprt a allele and elevated erythrocyte HPRT levels is retained following repeated backcrosses of wild-derived Hprt a allele(s) into the genetic background of inbred strains of mice with the Hprt b allele. Collectively, these observations indicate that the elevated and low levels of erythrocyte HPRT are specified by differences in the Hprt a and b structural genes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Structural organization and evolution of t-complex in Mus genus

Modern data on the structure and evolution of the t complex are discussed. The t complex is a series of inversions in the proximal region of murine chromosome 17; it contains a set of genes that determine its predominant transmission to the offspring of heterozygous males. Variants of structural organization of this genetic system (t haplotypes) have been found in wild populations of four species of genus Mus (M. domesticus, M. musculus, M. molossinus, and M. castaneus), but not in representatives of other, evolutionarily remote species of this genus. The so-called vertical, horizontal, and introgressive hypotheses are discussed of the origin and evolution of the t complex. Based on population genetic studies and molecular analysis a new hypothesis on the origin of the t-complex is put forward. This hypothesis is a synthesis between the vertical and horizontal models and assumes that all known t haplotypes had a common ancestral chromosome 17 carrying a proximal inversion.     

Rapid, large-scale and inexpensive genotype differentiation of Mus musculus castaneus and domesticus sub-species

A robust rapid method is described for differentiating Mus musculus castaneus and domesticus sub-species based on the analysis of restriction fragment length polymorphisms in three regions of the mtDNA genome.     

Reduced nucleotide variability at an androgen-binding protein locus (Abpa) in house mice: evidence for positive natural selection.

Previous work has shown that the gene for the alpha subunit of androgen-binding protein, Abpa, may be involved in premating isolation between different subspecies of the house mouse, Mus musculus. We investigated patterns of DNA sequence variation at Abpa within and between species of mice to test several predictions of a model of neutral molecular evolution. Intraspecific variation among 10 Mus musculus domesticus alleles was compared with divergence between M. m. domesticus and M. caroli for Abpa and two X-linked genes, Glra2 and Amg. No variation was observed at Abpa within M. m. domesticus. The ratio of polymorphism to divergence was significantly lower at Abpa than at Glra2 and Amg, despite the fact that all three genes experience similar rates of recombination. Interspecific comparisons among M. m. domesticus, Mus musculus musculus, Mus musculus castaneus, Mus spretus, Mus spicilegus, and Mus caroli revealed that the ratio of nonsynonymous substitutions to synonymous substitutions on a per-site basis (Ka/Ks) was generally greater than one. The combined observations of no variation at Abpa within M. m: domesticus and uniformly high Ka/Ks values between species suggest that positive directional selection has acted recently at this locus.     

Genetic variation in mouse apolipoprotein A-IV due to insertion and deletion in a region of tandem repeats.

We have detected three unique apolipoprotein A-IV (apoA-IV) charge isoforms in strains of commensal mice. The cDNA sequences for one representative of each isoform (Mus domestesticus strains C57BL/6J and 129/J and Mus castaneus) revealed a polymorphism within a series of four imperfect repeats encoding the sequence Glu-Gln-Ala/Val-Gln. Insertions or deletions of 12 nucleotides within this repetitive region have given rise to three genotypes characterized by three (129), four (C57BL/6), or five (M. castaneus) copies of the repeat unit. To ascertain the extent of this variation among other species of the Mus genus, we sequenced this region of apoA-IV cDNAs from eight additional M. domesticus inbred strains and from five wild-derived Mus species. All eight additional M. domesticus strains examined had four repeat units, as found in C57BL/6. Among wild-derived mice, however, one species (Mus spretus) had three repeats, two species (Mus cookii and Mus cervicolor) had four repeats, and two species (Mus hortulanus and Mus minutoides) had five repeats. A lack of correlation between the number of repeat units and the phylogeny of Mus species indicates that independent mutations may have occurred throughout the evolution of specific mouse lineages. We suggest that the repetitive nature of the polymorphic sequence may predispose this region to slippage errors during DNA replication, resulting in frequent deletion/insertion mutations.