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The house mouse is a powerful model to dissect the genetic basis of phenotypic variation, and serves as a model to study human diseases. Despite a wealth of discoveries, most classical laboratory strains have captured only a small fraction of genetic variation known to segregate in their wild progenitors, and existing strains are often related to each other in complex ways. Inbred strains of mice independently derived from natural populations have the potential to increase power in genetic studies with the addition of novel genetic variation. Here, we perform exome-enrichment and high-throughput sequencing (~8× coverage) of 26 wild-derived strains known in the mouse research community as the "Montpellier strains." We identified 1.46 million SNPs in our dataset, approximately 19% of which have not been detected from other inbred strains. This novel genetic variation is expected to contribute to phenotypic variation, as they include 18,496 nonsynonymous variants and 262 early stop codons. Simulations demonstrate that the higher density of genetic variation in the Montpellier strains provides increased power for quantitative genetic studies. Inasmuch as the power to connect genotype to phenotype depends on genetic variation, it is important to incorporate these additional genetic strains into future research programs.

Transcaucasia comprises a key region for understanding the history of both the hybrid zone between house mouse lineages and the dispersal of the Neolithic way of life outside its Near Eastern cradle. The opportunity to document the colonization history of both men and mice in Transcaucasia was made possible by the discovery of mouse remains accumulated in pits from a 6000-year-old farming village in the Nakhchivan (Autonomous Republic of Nakhchivan, Azerbaijan). The present study investigated their taxonomy and most likely dispersal path through the identification of the Mus lineage to which they might belong using a geometric morphometric approach of dental traits distances between archaeological and modern populations of the different Mus lineages of South-West Asia. We demonstrate that the mouse remains trapped in the deep storage pits of the dwelling belong to the Mus musculus domesticus from the Near East, with dental shapes similar to current populations in Northern Syria. These results strongly suggest that the domesticus lineage was dispersed into Transcaucasia from the upper Euphrates valley by Neolithic migration, some time between the 7th and 5th millennium BC, providing substantial evidence to back up the scenario featuring near-eastern stimuli in the emergence of agriculture in the South Caucasus. The domesticus mitochondrial DNA signature of the current house mouse in the same location 5000 years later, as well as their turnover towards a subspecies musculus/castaneus phenotype, suggests that early domesticus colonizers hybridized with a later musculus (and maybe castaneus) dispersal originating from south of the Caspian Sea and/or Northern Caucasia. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 108, 917-928.

Accurate knowledge of the biogeographic history and precise characterization of the genetic make-up of a taxon are essential to investigate speciation processes and achieve sound evolutionary comparisons. A case in point is the house mouse Mus musculus and its three parapatric subspecies, which have become a model for such studies. However, although Mus musculus domesticus and Mus musculus musculus constitute genetically well-characterized homogeneous entities, the case of Mus musculus castaneus remains poorly documented. Using mtDNA control region variation in a sample of 402 individuals, covering much of the distribution range of this subspecies, we identify four haplogroups that show largely non-overlapping geographic distributions. They appear to have undergone post-Neolithic expansions, presumably through commensalism with humans, but exhibit a much more ancient divergence. These results point towards a strong past subdivision and a vicariant origin of the different haplogroups, with each retaining a subfraction of the total variability. The genomic consequences of this spatial heterogeneity on the present taxonomic partition will have to be appraised, and may challenge the use of this subspecies as a single entity in evolutionary studies. © 2012 The Linnean Society of London, Biological Journal of the Linnean Society, 2012, ••, ••–••.

Two morphological forms of black rats (Rattus cf. rattus) were found living in sympatry in high-altitude dense forests of the Nilgiri Mountains, South India. The 1st one, often brown- or gray-bellied, also is found commensal in lowland settlements and represents Rattus rattus cf. rufescens (Gray 1837), with a diploid number (2N) of 38 chromosomes. The 2nd form, which has most often a pure white belly, has 2N = 42 chromosomes and is referable to Rattus r. satarae Hinton, 1918, based on morphological comparison with the holotype. A multidisciplinary study indicates that these 2 forms are characterized by clear-cut differences in biochemistry (electrophoresis of homologous isozymes), molecular sequences (mitochondrial and nuclear DNA), and chromosomes (detailed banding analysis). All these data, coupled to diagnostic morphological characteristics, support the hypothesis that Rattus satarae and Rattus rattus are separate, sympatric species, with no gene flow between them. Their similar external mor...

Interspecific hybridization in mammals causes hybrid dysgenesis effects, such as sterility and abnormal placentation. Here, we describe a novel obesity syndrome caused by interspecific hybridization in the genus Mus and show that this obesity, appearing sporadically in F1 littermates derived from inbred strains, has an epigenetic basis. Mus hybrids from various strains of M. musculus and M. spretus were generated and the sporadic obese phenotype was confirmed through assessment of physiological and biochemical parameters in littermates. To understand the underlying mechanisms, large-scale and candidate gene expression assays, global DNA methylation assays and allelic expression analysis were performed. Studies showed that obese hybrids are similar to other known models of obesity. While increased axial growth indicated a defect in POMC pathway, comparison of global gene expression patterns in brain of obese F1 and obese Pomc mutant mice showed little similarity. In F1 obese mice many genes involved in the maintenance of epigenetic states, as well as several imprinted genes, were differentially expressed. Global DNA methylation analysis in brain showed that increased methylation levels were associated with obesity. The imprinted gene Gnasxl, known to be important in lipid homeostasis, was found over expressed in the obese hybrids. Allelic expression and methylation analysis of Gnasxl showed that alterations of epigenetic marks underlying F1 obesity are probably many and multi-factorial. Conclusions: This model of obesity, which is both spontaneous and epigenetic, may be a useful tool to address the epigenetic aspects of clinical obesity.

Few genetic data document the postglacial history of the western house mouse, Mus musculus domesticus. We address this by studying a sample from the southeastern tip of the Fertile Crescent in the Iranian province of Ahvaz. Including other published and unpublished data from France, Germany, Italy, Bulgaria, Turkey and other places in Iran, altogether 321 mitochondrial D-loop sequences are simultaneously analysed. The patterns of coalescence obtained corroborate the classical proposal according to which the Fertile Crescent is where commensalism with humans has started in the Western Hemisphere, and from where the subspecies has expanded further west. Our data also clearly show that despite multiple colonisations and long-range transportation, there is still a rather high PhiST of 0.39. The original expansion signal is still recognisable, with two well-separated derived clades, allowing us to propose a hypothetical scenario in which expansion toward Europe and Asia Minor took at least two routes, tentatively termed the Mediterranean and the Bosphorus/Black Sea routes. This scenario resembles that of another domesticated species, the goat, and fits with the known progression of Neolithic culture. Given the concomitance of both phenomena around 12,000 years ago, we propose a recalibration of the D-loop mutation rate to a much faster tick of approximately 40% per site per million years (Myr). This value should be used for intrasubspecific polymorphism, while the interspecific rate in Mus is presently estimated at 6-10%/site/Myr. This is in keeping with the now well recognised fact that only a subfraction of segregating mutations go to fixation.

This work presents a study of the distribution and pattern of variation throughout the ranges of three free-living mouse species of the genus Mus-M. macedonicus, M. spicilegus, and a M. cypriacus - based on sequencing of two segments of the mitochondrial DNA (mtDNA) control region. The study shows a similar level of variability in the three species and suggests their recent population expansion. The highest proportion of variation is found within populations indicating low genetic structuring. Phylogenetic analysis confirms the significant divergence of a mitochondrial lineage of M. macedonicus from Israel, recently described as a new subspecies, M. macedonicus spretoides. Conversely, no genetic hiatus is revealed between European and Asian populations of M. macedonicus macedonicus. Although phylogenetic relationships among M. spicilegus populations could not be unravelled precisely, the results suggest a recent westward expansion of the species. The mtDNA divergence between M. macedonicus and M. spicilegus is 7.3%, suggesting their split between c. 700,000 and 1 million years ago. These dates correspond with a coalescent estimate about 720,000 years ago. On the other hand, M. cypriacus appeared almost twice as divergent from the former species (4.5%) as from the latter (8.8%) suggesting a divergence of c. 430,000-610,000 years ago (coalescent approximately 490,000 years ago) and 830,000-1.2 million years ago (coalescent approximately 780,000 years ago), respectively. Approximate times of population expansion have also been estimated for all taxa and groups of populations. Existence of several glacial refuges and various colonization scenarios are discussed; since all estimated divergence times fall within interglacial periods it seems that climatic oscillations did not play a crucial role in the evolution of the three species.

Most members of the large family of rhodopsin-like G-protein-coupled receptors possess an evolutionarily conserved Asp-Arg-Tyr (DRY) motif in the C-terminal region of the third transmembrane domain. Mutations of residues within this motif usually abolish receptor function and, when they occur naturally, can even cause human diseases. By analyzing over 100 mammalian orthologs of the chemoattractant receptor GPR33 we identified several polymorphic and fixed sequence variations within the DRY motif. Unexpectedly, the naturally occurring mutation of Arg(3.50) to His in mouse GPR33 showed no difference from the wild-type receptor in several functional tests. Sequence analysis of GPR33 from Asian house mice revealed the polymorphic existence of Arg(3.50) and His(3.50) alleles in wild-trapped populations, further supporting the functional equivalence of both allelic variants. In contrast, the Arg(3.50) to Gly mutation found in hamster GPR33 inactivates the receptor and may have contributed to pseudogenization of this gene in this species. Functional data with GPR33 variants indicate different receptor- and context-specific consequences of DRY mutations. Our study also reveals GPR33 as a new example illustrating missense mutations as a first step in the pseudogenization process.

We analysed the patterns of allele frequency change for ten diagnostic autosomal allozyme loci in the hybrid zone between the house mouse subspecies Mus musculus domesticus and M. m. musculus in central Jutland. After determining the general orientation of the clines of allele frequencies, we analysed the dine shapes along the direction of maximum gradient. Eight of the ten clines are best described by steep central steps with coincident positions and an average width of 8.9 km (support limits 7.6-12.4) flanked by tails of introgression, indicating the existence of a barrier to gene flow and only weak selection on the loci studied. We derived estimates of migration from linkage disequilibrium in the centre of the zone, and by applying isolation by distance methods to microsatellite data from some of these populations. These give concordant estimates of σ = 0.5-0.8 km generation -1/2 . The barrier to gene flow is of the order of 20 km (support limits 14-28), and could be explained by selection of a few per cent at 43-120 under-dominant loci that reduces the mean fitness in the central populations to 0.45. Some of the clines appear symmetrical, whereas others are strongly asymmetrical, and two loci appear to have escaped the central barrier to gene flow, reflecting the differential action of selection on different parts of the genome. Asymmetry is always in the direction of more introgression into musculus, indicating either a general progression of domesticus into the musculus territory, possibly mediated by differential behaviour, or past movement of the hybrid zone in the opposite direction, impeded by potential geographical barriers to migration in domesticus territory.

This study analysed patterns of mate choice based on different types of laboratory test, and points out the advantages of combined methods to assess mate preference. We compared dyadic encounters and two-way choice tests involving a pair of mice or their urinary signature. Preference was assessed in males and females of the two European subspecies of the house mouse Mus musculus that share a secondary hybrid zone. A preference was deduced from directional choice or behavioural discrimination in favour of a mouse. Our results show discrepancies between the outcomes of the different types of test, which we discuss in terms of the quality of the stimuli involved, and of physical access to the information carried by those stimuli. Despite variation, our results indicate that M. m. domesticus did not show a preference, but could discriminate between stimuli of the two subspecies and tended to direct sexual behaviour assortatively. In contrast, both male and female M. m. musculus showed positive discrimination and preference for potential mates and signals carried by their own subspecies. Additionally, our results confirm that subspecies informative signals are present in mouse urine and suggest that they may be molecules of low volatility, necessitating contact for preference to be displayed.

Mammalian interspecies hybrids exhibit parent-of-origin effects in that offspring of reciprocal matings, even though genetically identical, frequently exhibit opposite phenotypes, especially in growth. This was also observed in hybridization with the genus Mus. These parent-of-origin effects suggested that imbalance in the expression of imprinted genes, which are expressed differentially, depending on their transmission through the maternal or paternal germline, and/or differential loss-of-imprinting (LOI) could underlie these opposite growth phenotypes in reciprocal mammalian hybrids. Here we report that tissue-specific LOI occurs in adult Mus hybrids. Contrary to expectations, LOI patterns were not consistent with a direct influence of altered expression levels of imprinted genes on growth. Bisulfite sequencing revealed that reactivation of maternal alleles of Peg3 and Snrpn in specific tissues was accompanied by partial demethylation at their potential imprinting control regions. We propose that abnormal reprogramming after fertilization and during preimplantation development is in part responsible for hybrid dysgenesis, for which a strong epigenetic basis has been demonstrated.

A mitochondrial and nuclear gene analysis allowed us to precise the taxonomical position of the two sympatric species of mice known to be present on Cyprus. One of them is the commensal house mouse M. m. domesticus, and the other revealed to be a new taxon that is a sister species of M. spicilegus and M. macedonicus. The new species is equidistant from each of these, the divergence dating around 0.5-1 Myr. Its origin either results from an ancient accidental colonisation of the island or from a recent transportation by the first epipalaeolithic settlers. In this last eventuality, the new species would also exist somewhere else in Asia Minor.

Interspecific hybridization in the rodent genera Peromyscus and Mus results in abnormal placentation. In the Peromyscus interspecies hybrids, abnormal allelic interaction between an X-linked locus and the imprinted paternally expressed Peg3 locus was shown to cause the placental defects. In addition, loss-of-imprinting (LOI) of Peg3 was positively correlated with increased placental size. As in extreme cases this placental dysplasia constitutes a post-zygotic barrier against interspecies hybridization, this finding was the first direct proof that imprinted genes may be important in speciation and thus in evolution. In the Mus interspecies hybrids, a strong role of an X-linked locus in placental dysplasia has also been detected. However, here we show by backcross and allele specific expression analyses that neither LOI of Peg3 nor abnormal interactions between Peg3 and an X-linked locus are involved in generating placental dysplasia in Mus hybrids, although the placental phenotypes observed in the two genera seem to be identical. In contrast to this, another dysgenesis effect common to Peromyscus and Mus hybrids, altered foetal growth, is caused at least in part by the same X-chromosomal regions in both genera. These findings first underline the strong involvement of the X-chromosome in the genetics of speciation. Secondly, they indicate that disruption of epigenetic states, such as LOI, at specific loci may be involved in hybrid dysgenesis effects in one group, but not in another. Thus, we conclude that even in closely related groups divergent molecular mechanisms may be involved in the production of phenotypically similar post-zygotic barriers against hybridization.

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.

As part of a population genetics survey of the hybrid zone between mouse subspecies Mus musculus domesticus and M. m. musculus, we identified and characterized the t haplotypes in 1068 mice from 186 different populations in a 2500 km2 area in central Jutland. On the basis of two t-specific PCR markers, 130 mice possessed this haplotype. The allele frequencies at six microsatellites on the third and fourth chromosomal inversions of the t region were sufficiently different between t-bearing and non-t-bearing mice, and linkage disequilibria sufficiently marked on the t haplotype, to be able to reconstitute the genotype of most t haplotypes. A total of three frequent and 15 rarer haplotypes were identified. These haplotypes resemble each other more than they resemble a panel of known haplotypes from a wide range of geographical regions, except for tw73, which was also extracted from Jutland. The patterns of variation at the microsatellite loci suggest that the Jutland haplotypes were derived from a small number of haplotypes, followed by recombination between complementing haplotypes. Further evidence of recombination came from complementation tests that we performed, showing the lack of concordance between the degrees of complementation and of molecular resemblance between haplotypes. This study shows that it is possible to characterize the presence and variation of t haplotypes by a population genetics approach using simple molecular markers. However recombination between t haplotypes has occurred frequently enough to obscure the links between this variation and the biological properties of distortion and lethality of the haplotypes that originally colonized Jutland.

The plague has been present for a century in Madagascar; the only known reservoir is the black rat, which is also the main victim of this disease. Whereas the two plague foci are restricted to an altitude above 800 m, the black rat is distributed over the whole island, the only morphological variation being a within-site variability in belly colour. To resolve these apparent contradictions, an analysis of the different belly colour morphs and of populations living in different habitats and altitudes was undertaken. An allozymic study demonstrated that sympatric white- and grey-bellied rats (N = 26) living within the plague foci, all belonged to the same species: Rattus rattus. This specific assignment was confirmed by a chromosomal analysis which showed that all 90 individuals studied presented the same diploid number, 2n = 38, whatever the habitat and altitude. This study indicates that all specimens investigated in Madagascar could be referred to the same black rat species. Survival of rat populations, despite a century of coexistence with the plague, is most likely related to their high reproductive and recolonization potential, as well as selection of plague resistant genotypes. As the altitudinal limit of the plague foci does not seem to be related to characteristics of the rodent reservoir, investigations concerning the vectors are now essential. © 2003 The Linnean Society of London, Biological Journal of the Linnean Society, 2003, 78, 335–341.

119–127.Molecular, chromosomal and morphometric analyses of wild-caught mice of subgenus Musfrom the central plain of Thailand are presented. These specimens are distinct from all speciespreviously described in the literature. This has led to the characterization of Mus fragilicaudasp. n., a new member of the set of closely related species encompassed by the subgenus . Whilethis species may be considered as a sibling and sympatric species of the Asian M. cervicolor,M. fragilicauda sp. n. is phylogenetically closer to the M. musculus complex of species and tothe other European species of Mus.Jean-Christophe Auffray & Josette Catalan, Institut des Sciences de l’Evolution, UMR 5554CNRS, CC064, Universite Montpellier 2, 34095 Montpellier cedex, France. E-mail:auffray@isem.univ-montp2.fr.Annie Orth, Eric Desmarais & Francois Bonhomme, Laboratoire Genome, Populations, Interactions,UMR 5000 CNRS, CC063, Universite Montpellier 2, 34095 Montpellier cedex 05, France.Jean-Paul Gonzalez, IRD, Research Center for Emerging Viral Diseases, CVD, Institute of Sciencesand Technology for Development, Mahidol University at Salaya, 25/25 Phutthamonthon 4, Nakhon-pathom 73170, Thailand

Background The phylogeography of the house mouse (Mus musculus L.), an emblematic species for genetic and biomedical studies, is only partly understood, essentially because of a sampling bias towards its most peripheral populations in Europe, Asia and the Americas. Moreover, the present-day phylogeographic hypotheses stem mostly from the study of mitochondrial lineages. In this article, we complement the mtDNA studies with a comprehensive survey of nuclear markers (19 microsatellite loci) typed in 963 individuals from 47 population samples, with an emphasis on the putative Middle-Eastern centre of dispersal of the species. Results Based on correspondence analysis, distance and allele-sharing trees, we find a good coherence between geographical origin and genetic make-up of the populations. We thus confirm the clear distinction of the three best described peripheral subspecies, M. m. musculus, M. m. domesticus and M. m. castaneus. A large diversity was found in the Iranian populations, which have had an unclear taxonomic status to date. In addition to samples with clear affiliation to M. m. musculus and M. m. domesticus, we find two genetic groups in Central and South East Iran, which are as distinct from each other as they are from the south-east Asian M. m. castaneus. These groups were previously also found to harbor distinct mitochondrial haplotypes. Conclusion We propose that the Iranian plateau is home to two more taxonomic units displaying complex primary and secondary relationships with their long recognized neighbours. This central region emerges as the area with the highest known diversity of mouse lineages within a restricted geographical area, designating it as the focal place to study the mechanisms of speciation and diversification of this species. Electronic supplementary material The online version of this article (doi:10.1186/s12862-015-0306-4) contains supplementary material, which is available to authorized users.

A survey of 77 individuals covering the range of Mus macedonicus from Georgia in the East to Greece and Bulgaria in the West and Israel in the South has shown the existence of two deeply divergent mitochondrial clades. The southern clade was until now undetected and characterises mice from Israel. Nuclear genes also show some amount of regional differentiation tending to separate the southern M. macedonicus from the northern ones. These results point towards the fact that the eastern Mediterranean short-tailed mouse, which was seen as a fairly homogeneous monotypic species, has in fact a more complex phylogeographic history than has been suspected, and that it warrants the existence of two subspecies. The reasons for this non-uniformity probably ought to be looked for in the history of faunal movements linked to glacial periods, underlining the possible existence of at least two refugia south of the Caucasus.

Various subspecies of the house mouse (Mus musculus sensu lato) are known to have contributed to its worldwide expansion. However, the origin of mice on some larger islands such as Madagascar has remained unknown, with several sources being possible. In order to classify the Malagasy house mouse, individuals were trapped in 13 different localities distributed throughout the island. For 33 individuals the control region (D-Loop) of the mitochondrial DNA was partially sequenced and 21 males were typed for a Zfy-2 polymorphism of the Y chromosome. Malagasy mt DNA lineages constitute a narrow monophyletic group which suggests a recent and probably single origin, and are very close to the gentilulus mitochondrial lineages from Yemen. This was supported by the fact that all the males have the domesticus type Y chromosome, like gentilulus. From these results, it can be inferred that the Malagasy house mice originate probably from the Arabian peninsula in a single colonisation wave, unlike its human population. Our results provide a better molecular description of the Yemeni-Malagasy mitochondrial clade which clearly belongs to the Mus musculus radiation.

It has been shown previously that abnormal placental growth occurs in crosses and backcrosses between different mouse (Mus) species. In such crosses, late gestation placentas may weigh between 13 and 848 mg compared with a mean placental weight of approximately 100 mg in late gestation M. musculus intraspecific crosses. A locus on the X-chromosome was shown to segregate with placental dysplasia. Thus in the (M. musculus × M. spretus)F1 × M. musculus backcross, placental hyperplasia cosegregates with a M. spretus derived X-chromosome. Here we have investigated whether increased cell proliferation and aberrant expression of two genes that are involved in placental growth control, Igf2 and Esx1, may cause, or contribute to placental hyperplasia. Increased bromodeoxyuridine labeling of nuclei, reflecting enhanced proliferation, was indeed observed in hyperplastic placentas when compared with normal littermate placentas. Also, increased expression of Igf2 was seen in giant cells and spongiotrophoblast. However, when M. musculus × M. spretus F1 females were backcrossed with males that were heterozygous for a targeted mutation of the Igf2 gene, placentas that carried a M. spretus derived X-chromosome and were negative for a functional Igf2 allele exhibited an intermediate placental phenotype. Furthermore, in early developmental stages of placental hyperplasia, we observed a decreased expression of the X-chromosomal Esx1 gene. This finding suggests that abnormal expression of both Igf2 and Esx1 contributes to abnormal placental development in mouse interspecific hybrids. However, Esx1 is not regulated by IGF2. © 2002 Wiley-Liss, Inc.

Using protein loci and DNA markers, we show by a multilocus genetic analysis that certain populations of the two sympatric mouse species Mus musculus domesticus and Mus spretus show clear signs of partial introgression. Given the sterility of F1 males and the known partial genetic incompatibilities between the genomes of the two species, our finding does not invalidate the biological species complex, but allows to think that very limited genetic exchanges remain possible even long after the divergence of taxa. This may have some consequences on the dynamics of certain kinds of invasive or advantageous DNAs like transposable elements or pathogen resistance genes.

A multiplex PCR assay was developed for the identification of polymorphic microsatellite loci (18) for the Algerian mouse, Mus spretus, using 454 GS-FLX Titanium pyrosequencing. The utility of these markers was evaluated in 184 individuals from for different Moroccan populations. Number of alleles per locus ranged from 10 to 39, with expected and observed heterozygosities ranging from 0.256 to 0.947 and from 0.259 to 0.926 respectively. None departures from Hardy–Weinberg equilibrium were observed at all loci. These markers will be valuable tools for population genetic studies in conservation management.

It has been shown previously that abnormal placental growth, i.e., hyper- and hypoplasia, occurs in crosses and backcrosses between different mouse (Mus) species. A locus that contributes to this abnormal development has been mapped to the X chromosome. Unexpectedly, an influence of fetal sex on placental development has been observed, in that placentas attached to male fetuses tended to exhibit a more pronounced phenotype than placentas attached to females. Here, we have analyzed this sex dependence in more detail. Our results show that differences between male and female placental weights are characteristic of interspecific matings and are not observed in intraspecific Mus musculus matings. The effect is retained in congenic lines that contain differing lengths of M. spretus-derived X chromosome. Expression of the X-linked gene Pgk1 from the maternal allele only and lack of overall activity of two paternally inherited X-linked transgenes indicate that reactivation or lack of inactivation of the paternal X chromosome in trophoblasts of interspecific hybrids is not a frequent occurrence. Thus, the difference between male and female placentas seems not to be caused by faulty preferential X-inactivation. Therefore, these data suggest that the sex difference of placental weights in interspecific hybrids is caused by interactions with the Y chromosome.

The placenta plays a pivotal role in fetal growth control and is considered a major site of genetic conflict between maternal and paternal genomes within the conceptus and, in addition, the genome of the mother. Accordingly, placental development is a strictly controlled process, and both placental and fetal weights do not vary much in intraspecific crosses of laboratory mice (Mus musculus). In mouse interspecific crosses and backcrosses [(M. musculus x M. spretus) x M. musculus], tremendous variation of placental, but not of fetal weight was observed. We have studied trophoblast cell type distribution and differentiation, and their effect on the associated placentas and fetuses in such backcrosses. Differentiation of spongious trophoblast, but not size of materno-fetal interface, correlated with fetal weight. Giant fetuses were observed only if less than one third of the spongiotrophoblast was formed by glycogen cells. Thus, placental efficiency was inversely related to the amount of glycogen cells. This influence of a trophoblast-derived cell type on fetal growth was not anticipated. We conclude that: (1) glycogen cells are able to negatively modulate fetal growth by an as yet unidentified mechanism; (2) correlation between fetal and placental weights is weak or absent in interspecific hybrids; (3) impaired control over placental and embryonic development in hybrids may contribute to post-mating isolation of species.

Alleles at the Fv1 gene of inbred mice confer resistance to infection and spread of vertically or horizontally transmitted murine leukemia viruses (MuLV). The nucleotide sequence of Fv1 bears similarity to the gag of a human endogenous retrovirus, HERV-L, but is more closely related to the gag-coding sequence of a newly described class of HERV-L-related mouse endogenous retroviruses designated MuERV-L. Both observations suggest an origin of Fv1 from endogenous gag sequences. The molecular definition of Fv1 provided an opportunity to determine the phylogeny of the gene among wild mice and its relation to MuERV-L. PCR primers, chosen to include most of the coding region of Fv1 for both the n and b alleles, were used to amplify sequences from animals of the genus Mus, which were then sequenced. Closely related products were obtained from almost all animals examined that evolved after the separation from Rattus, in which the homologous gene was shown to be absent. A phylogenetic tree generated with Fv1 sequence data differs noticeably from that developed with sequence data from other genes. In addition, non-synonymous changes were found to be present twice as frequently as synonymous changes, a fact that departs from the standard behavior of a structural gene. These observations suggest that the Fv1 gene may have been subjected to possible horizontal transfers as well as to positive Darwinian selection.

The house mouse Mus musculus is a polytypic species, distributed worldwide, with three main subspecies: M. m. musculus in the North-East of Eurasia, M. m. castaneus in South-East Asia, and M. m. domesticus in Europe, the Near-East, and Africa. This last subspecies may also be found in Australia and the Americas, where it was brought by European colonization. Previous studies, however, have shown the presence of specific antiviral determinants of Asian origin in a mouse population at Lake Casitas, California. In this study, an analysis of the variability at 35 enzyme loci demonstrates the hybrid nature of this Californian population intermediate between M. m. castaneus and M. m. musculus. Restriction fragment length polymorphisms of two fragments of the mitochondrial DNA also confirm unambiguously the presence of two types of matrilines in comparable frequencies in our sample. Nevertheless, the study of a subspecies-specific Y chromosome microdeletion in the Zfy2 gene reveals only theM. m. domesticus haplotype at Lake Casitas, a phenomenon comparable with the one observed in other hybrid zones of the M. musculus complex. These findings testify once more that genetic exchanges between subspecies inside the broader M. musculus gene pool are still possible.

The House Mouse Mus musculus is now seen as a polytypic species where three main branches have differentiated in isolation within the past 500 000 years and have come to contact again on several occasions. It is almost invariably considered as being constituted of three subspecies, Mus musculus castaneus being considered as more polymorphic, with a larger effective population size and as having retained more ancestral polymorphisms than the other two. Yet, it is the less, well-studied component, and its geographical origin and genetic makeup disserve more careful attention since a recent reappraisal was indeed shown that the House Mouse populations in the region ranging from Middle-East to Southeast Asia classically assigned to M. m. castaneus are indeed much more diverse than previously thought. Since the House Mouse is often taken as a model species, this may have important bearings on our understanding of the context in which genome evolution and speciation occurs.

Archaeological and historical records indicate that mice were already bred as pets three millennia ago: it was then logical that these small mammals should be used by early scientists for performing their experiments. Even if this choice may retrospectively appear relatively opportunistic, it nevertheless turned out to be an excellent one in the modern context of biomedical research, especially in genetics, where the mouse has become an emblematic model. Because they are all derived from a relatively small pool of ancestors, laboratory mice exhibit a rather limited amount of genetic polymorphism. For this reason, strains of mice recently derived from different species of the genus Mus have been developed that represent an interesting addition to the arsenal of mouse geneticists, because some of them can be crossed with classical laboratory strains to produce viable and fertile offspring segregating for a large number of polymorphisms of natural origin. These strains are helpful for making genome annotations because they make it possible to establish high-resolution/high-density genetic maps that, in turn, allow establishing refined genotype–phenotype correlations. In this chapter, we describe the origins of laboratory mice and their phylogenetic relationships with other mammalian species. We also discuss the advantage of strains established from wild specimens as an almost unlimited source of polymorphisms.

The molecular signatures of the recent expansion of the western house mouse,Mus musculus domesticus, around the Mediterranean basin are investigated through the study of mitochondrial D-loop polymorphism on a 1313 individual dataset. When reducing the complexity of the matrilineal network to a series of haplogroups (HGs), our main results indicate that: (i) several HGs are recognized which seem to have almost simultaneously diverged from each other, confirming a recent expansion for the whole subspecies; (ii) some HGs are geographically delimited while others are widespread, indicative of multiple introductions or secondary exchanges; (iii) mice from the western and the eastern coasts of Africa harbour largely different sets of HGs; and (iv) HGs from the two shores of the Mediterranean are more similar in the west than in the east. This pattern is in keeping with the two-step westward expansion proposed by zooarchaeological data, an early one coincident with the Neolithic progression and limited to the eastern Mediterranean and a later one, particularly evident in the western Mediterranean, related to the generalization of maritime trade during the first millennium BC and onwards. The dispersal of mice along with humans, which continues until today, has for instance left complex footprints on the long ago colonized Cyprus or more simple ones on the much more recently populated Canary Islands.

Interferon-gamma plays a key role in the immune response against intracellular pathogens. Its gene is located inside a cluster of cytokines from the interleukin-10 family. A comparison of the coding sequences in the mammalian Glire lineage indicates a possible action of positive Darwinian selection promoting rapid amino-acid changes in the branch leading to murine rodents represented by Mus and Rattus. Looking at genomic diversity of this gene inside the genus Mus, we could propose that a recent selective sweep has affected M. m. domesticus, this subspecies harbouring predominantly a single Ifng haplotype that differs from that of the other subspecies by a unique amino-acid difference in a key position of the molecule. The sweep seems to have affected a region of at most 50 kb as recombinants could be found at flanking conserved non-coding sequences. Functional differences were clearly apparent in cis-regulation of Ifng transcription between the domesticus and the musculus-type haplotypes. As the presence of the musculus haplotype in a predominantly domesticus background seems to promote susceptibility to chronic infection by Theiler's virus, these findings open interesting avenues for documenting immune system gene co-evolution.

Few genetic data document the postglacial history of the western house mouse, Mus musculus domesticus. We address this by studying a sample from the southeastern tip of the Fertile Crescent in the Iranian province of Ahvaz. Including other published and unpublished data from France, Germany, Italy, Bulgaria, Turkey and other places in Iran, altogether 321 mitochondrial D-loop sequences are simultaneously analysed. The patterns of coalescence obtained corroborate the classical proposal according to which the Fertile Crescent is where commensalism with humans has started in the Western Hemisphere, and from where the subspecies has expanded further west. Our data also clearly show that despite multiple colonisations and long-range transportation, there is still a rather high PhiST of 0.39. The original expansion signal is still recognisable, with two well-separated derived clades, allowing us to propose a hypothetical scenario in which expansion toward Europe and Asia Minor took at least two routes, tentatively termed the Mediterranean and the Bosphorus/Black Sea routes. This scenario resembles that of another domesticated species, the goat, and fits with the known progression of Neolithic culture. Given the concomitance of both phenomena around 12,000 years ago, we propose a recalibration of the D-loop mutation rate to a much faster tick of approximately 40% per site per million years (Myr). This value should be used for intrasubspecific polymorphism, while the interspecific rate in Mus is presently estimated at 6-10%/site/Myr. This is in keeping with the now well recognised fact that only a subfraction of segregating mutations go to fixation.

International audience; Oligoadenylate synthetases (OASs) are interferon-inducible enzymes that participate in the first line of defense against a wide range of viral infection. Recent studies have determined that Oas1b, a member of the OAS gene family in the house mouse (Mus musculus), provides specific protection against flavivirus infection (e.g., West Nile virus, dengue fever virus, and yellow fever virus). We characterized the nucleotide sequence variation in coding and noncoding regions of the Oas1b gene for a large number of wild-derived strains of M. musculus and related species. Our sequence analyses determined that this gene is one of the most polymorphic genes ever described in any mammal. The level of variation in noncoding regions of Oas1b is an order of magnitude higher than the level reported for other regions of the mouse genome and is significantly different from the level of intraspecific variation expected under neutrality. Furthermore, a phylogenetic analysis of intronic sequences demonstrated that Oas1b alleles are ancient and that their divergence predates several speciation events, resulting in transspecific polymorphisms. The amino acid sequence of Oas1b is also extremely variable, with 1 out of 7 amino acid positions being polymorphic within M. musculus. Oas1b alleles are comparatively more divergent at synonymous positions than most autosomal genes and the ratio of nonsynonymous to synonymous substitution is remarkably high, suggesting that positive selection has been acting on Oas1b. The ancestry of Oas1b polymorphisms and the high level of amino acid polymorphisms strongly suggest that the allelic variation at Oas1b has been maintained in mouse populations by long-term balancing selection.

RésuméLa présente étude porte sur la taille et la forme des dents et sur la morphologie crânienne d'individus en provenance d'Europe sud-occidentale et d'Afrique du Nord caractérisés génétiquement comme appartenant aux espèces Mus spretus et Mus musculus domesticus . Une révision des caractères diagnostiques des dents et du crâne utilisés pour la détermination de l'appartenance spécifique des spécimens a été faite. La révision porte sur 17 caractères métriques et 14 caractères morphologiques. Une application à un matériel fossile inédit d'âge pléistocène supérieur du Maroc a ensuite été tentée. La détermination de ces restes fossiles représentés par des molaires inférieures de souris du gisement de Doukkala II, près de Rabat, permet de conclure à la présence d'une souris très proche de l'actuelle M. spretus . La présence dans le Pléistocène supérieur d'une souris, différente de la souris domestique, est ainsi démontrée dans le nord de l'Afrique, l'arrivée de la souris domestique dans ce secteur restant à préciser.

A mitochondrial and nuclear gene analysis allowed us to precise the taxonomical position of the two sympatric species of mice known to be present on Cyprus. One of them is the commensal house mouse M. m. domesticus, and the other revealed to be a new taxon that is a sister species of M. spicilegus and M. macedonicus. The new species is equidistant from each of these, the divergence dating around 0.5-1 Myr. Its origin either results from an ancient accidental colonisation of the island or from a recent transportation by the first epipalaeolithic settlers. In this last eventuality, the new species would also exist somewhere else in Asia Minor.

To obtain a deeper insight into the genes and gene networks involved in the development of placentopathies, we have assessed global gene expression in three different models of placental hyperplasia caused by interspecies hybridization (IHPD), cloning by nuclear transfer, and mutation of the Esx1 gene, respectively. Comparison of gene expression profiles of approximately 13,000 expressed sequence tags (ESTs) identified specific subsets of genes with changed expression levels in IHPD, cloned, and Esx1 mutant placentas. Of interest, only one gene of known function and one EST of unknown function were found common to all three placentopathies; however, a significant number of ESTs were common to IHPD and cloned placentas. In contrast, only one gene was shared between IHPD and Esx1 mutant, and cloned and Esx1 mutant placentas, respectively. These genes common to different abnormal placental growth genotypes are likely to be important in the occurrence of placentopathy.

Interspecific hybridization in the genus Mus results in several hybrid dysgenesis effects, such as male sterility and X-linked placental dysplasia (IHPD). The genetic or molecular basis for the placental phenotypes is at present not clear. However, an extremely complex genetic system that has been hypothesized to be caused by major epigenetic changes on the X chromosome has been shown to be active. We have investigated DNA methylation of several single genes, Atrx, Esx1, Mecp2, Pem, Psx1, Vbp1, Pou3f4, and Cdx2, and, in addition, of LINE-1 and IAP repeat sequences, in placentas and tissues of fetal day 18 mouse interspecific hybrids. Our results show some tendency toward hypomethylation in the late gestation mouse placenta. However, no differential methylation was observed in hyper- and hypoplastic hybrid placentas when compared with normal-sized littermate placentas or intraspecific Mus musculus placentas of the same developmental stage. Thus, our results strongly suggest that generalized changes in methylation patterns do not occur in trophoblast cells of such hybrids.

It has been shown previously that abnormal placental growth occurs in crosses and backcrosses between different mouse (Mus) species. In such crosses, late gestation placentas may weigh between 13 and 848 mg compared with a mean placental weight of approximately 100 mg in late gestation M. musculus intraspecific crosses. A locus on the X-chromosome was shown to segregate with placental dysplasia. Thus in the (M. musculus x M. spretus)F1 x M. musculus backcross, placental hyperplasia cosegregates with a M. spretus derived X-chromosome. Here we have investigated whether increased cell proliferation and aberrant expression of two genes that are involved in placental growth control, Igf2 and Esx1, may cause, or contribute to placental hyperplasia. Increased bromodeoxyuridine labeling of nuclei, reflecting enhanced proliferation, was indeed observed in hyperplastic placentas when compared with normal littermate placentas. Also, increased expression of Igf2 was seen in giant cells and spongiotrophoblast. However, when M. musculus x M. spretus F1 females were backcrossed with males that were heterozygous for a targeted mutation of the Igf2 gene, placentas that carried a M. spretus derived X-chromosome and were negative for a functional Igf2 allele exhibited an intermediate placental phenotype. Furthermore, in early developmental stages of placental hyperplasia, we observed a decreased expression of the X-chromosomal Esx1 gene. This finding suggests that abnormal expression of both Igf2 and Esx1 contributes to abnormal placental development in mouse interspecific hybrids. However, Esx1 is not regulated by IGF2.

Using protein loci and DNA markers, we show by a multilocus genetic analysis that certain populations of the two sympatric mouse species Mus musculus domesticus and Mus spretus show clear signs of partial introgression. Given the sterility of F1 males and the known partial genetic incompatibilities between the genomes of the two species, our finding does not invalidate the biological species complex, but allows to think that very limited genetic exchanges remain possible even long after the divergence of taxa. This may have some consequences on the dynamics of certain kinds of invasive or advantageous DNAs like transposable elements or pathogen resistance genes.

This study characterises the extent of the susceptibility to parasites (first demonstrated with helminths) of hybrids between Mus musculus domesticus and Mus musculus musculus . Experimental infections with Trypanosoma musculi of M. m . domesticus, M. m. musculus and their natural hybrids have been performed to compare their level of resistance/susceptibility. It appears that contrary to the results with helminths, hybrid mice present the same level of resistance/susceptibility to the trypanosome as M. m. musculus and M. m. domesticus individuals. This result is interpreted in the light of the modalities of host–parasite interactions and leads us to hypothesise on the role of parasitism in the evolution of the house mouse hybrid zone.

Interspecific hybridization in the genus Mus results in male sterility and X-linked placental dysplasia. We have generated several congenic laboratory mouse lines (Mus musculus) in which different parts of the maternal X chromosome were derived from M. spretus. A strict positive correlation between placental weight and length of the M. spretus-derived part of the X chromosome was shown. Detailed analysis was carried out with one congenic strain that retained a M. spretus interval between 12.0 and 30.74 cM. This strain consistently produced hyperplastic placentas that exhibited an average weight increase of 180% over the weight of control placentas. In derived subcongenic strains, however, increased placental weight could no longer be observed. Morphometric analysis of these placentas revealed persistence of abnormal morphology. Fully developed placental hyperplasia could be reconstituted by recombination of proximal and central M. spretus intervals with an intervening M. musculus region. These results may suggest that placental dysplasia of interspecific mouse hybrids is caused by multiple loci clustered on the X chromosome that act synergistically. Alternatively, it is possible that changes in chromatin structure in interspecific hybrids that influence gene expression are dependent on the length of the alien chromosome.

It has previously been shown that abnormal placental development, i.e., hyper- and hypoplasia, occurs in crosses and backcrosses between different mouse (Mus) species. These defects are caused mainly by abnormal growth of the spongiotrophoblast. The precise genetic basis for these placental malformations has not been determined. However, a locus that contributes to the abnormal development (Ihpd: interspecific hybrid placental dysplasia) has been mapped to the X chromosome. The X-chromosomal location of Ihpd and its site of action, that is the spongiotrophoblast, mean that normally only the maternally inherited Ihpd locus is active even in female fetuses. However, by making use of the X-chromosomal inversion In(X)1H, we have produced interspecific hybrid Xp0, in which the active X chromosome was inherited from Mus macedonicus males. In contrast to XX female and XY male conceptuses from this cross, which have hypoplastic placentas, the Xp0 female conceptuses have hyperplastic placentas. This finding supports the view that it is expression of the M. macedonicus Ihpd locus in the spongiotrophoblast that leads to hyperplasia due to an abnormal interaction with M. musculus autosomal loci.

Sixteen laboratory and 7 wild-derived strains of mice were infected with the pinworm Aspiculuris tetraptera in order to compare their resistance levels estimated by the intestinal parasite loads. It appears that (i) in 4 strains out of 23, females and males harbour different parasite loads; (ii) wild and laboratory mice display a broad range of infection levels when compared independently; (iii) the laboratory strains are more resistant than the wild ones. We suggest that (i) compared to sex, the strain (i.e. genetic) effect is the main parameter which determines the levels of infection; (ii) resistance was selected in laboratory strains during their breeding because of the parasite pressure present in captivity.

Interspecific hybridization between closely related species is commonly associated with decreased fertility or viability of F1 hybrids. Thus, in mouse interspecific hybrids, several different hybrid sterility genes that impair gametogenesis of the male hybrids have been described. We describe a novel effect in hybrids between different mouse species that manifests itself in abnormal growth of the placenta. Opposite phenotypes, that is, placental hypotrophy versus hypertrophy, are observed in reciprocal crosses and backcrosses. The severity of the phenotype, which is mainly caused by abnormal development of the spongiotrophoblast, is influenced by the sex of the conceptus. In general, placental hypertrophy is associated with increased fetal growth. Hypotrophy of the placenta frequently leads to growth impairment or death of the fetus. One of the major genetic determinants of placental growth maps to the proximal part of the mouse X chromosome.

The traditional approach to fluctuating asymmetry (FA) is compared with an application of the Procrustes superposition method. This comparison was performed on wild-derived and random bred strains of two house mouse subspecies, Mus musculus domesticus and M. m. musculus, originated from Denmark, and their hybrids in a controlled experiment. Results obtained with the Procrustes method show a decrease of FA for the hybrid sample, which is consistent with what was expected from previous FA studies on wild populations. However, no trend was detectable using the traditional approach in that specific case. Additionally, the observed levels of FA compared with those found in wild populations of the hybrid zone in Denmark suggest that the latter are under higher environmental stress than are laboratory-reared animals.