Genomic resources for wild populations of the house mouse, Mus musculus and its close relative Mus spretus.
ABSTRACT: Wild populations of the house mouse (Mus musculus) represent the raw genetic material for the classical inbred strains in biomedical research and are a major model system for evolutionary biology. We provide whole genome sequencing data of individuals representing natural populations of M. m. domesticus (24 individuals from 3 populations), M. m. helgolandicus (3 individuals), M. m. musculus (22 individuals from 3 populations) and M. spretus (8 individuals from one population). We use a single pipeline to map and call variants for these individuals and also include 10 additional individuals of M. m. castaneus for which genomic data are publically available. In addition, RNAseq data were obtained from 10 tissues of up to eight adult individuals from each of the three M. m. domesticus populations for which genomic data were collected. Data and analyses are presented via tracks viewable in the UCSC or IGV genome browsers. We also provide information on available outbred stocks and instructions on how to keep them in the laboratory.
Project description:A LINE-1 element, LIC105, was found in the Mus musculus domesticus inbred strain, C57BL/6J. Upon sequencing, this element was found to belong to a M. spretus LINE-1 subfamily originating within the last 0.2 million years. This is the second spretus-specific LINE-1 subfamily found to be represented in C57BL/6J. Although it is unclear how these M. spretus LINE-1s transferred from M. spretus to M. m. domesticus, it is now clear that at least two different spretus LINE-1 sequences have recently transferred. The limited divergence between the C57BL/6J spretus-like LINE-1s and their closest spretus ancestors suggests that the transfer did not involve an exceptionally long lineage of sequential transpositions.
Project description:BACKGROUND: Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL) mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5) on chromosome 12, shows strong linkage in one cross. RESULTS: To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice. CONCLUSION: Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.
Project description:BACKGROUND:Populations and subspecies of the house mouse Mus musculus were able to invade new regions worldwide in the wake of human expansion. Here we investigate the origin and colonization history of the house mouse inhabiting the small island of Heligoland on the German Bight - Mus musculus helgolandicus. It was first described by Zimmermann in 1953, based on morphological descriptions which were considered to be a mosaic between the subspecies M. m. domesticus and M. m. musculus. Since mice on islands are excellent evolutionary model systems, we have focused here on a molecular characterization and an extended phenotype analysis. RESULTS:The molecular data show that the mice from Heligoland are derived from M. m. domesticus based on mitochondrial D-loop sequences as well as on four nuclear diagnostic markers, including one each from the sex-chromosomes. STRUCTURE analysis based on 21 microsatellite markers assigns Heligoland mice to a distinct population and D-loop network analysis suggests that they are derived from a single colonization event. In spite of mice from the mainland arriving by ships, they are apparently genetically refractory against further immigration. Mutation frequencies in complete mitochondrial genome sequences date the colonization age to approximately 400 years ago. Complete genome sequences from three animals revealed a genomic admixture with M. m. musculus genomic regions with at least 6.5% of the genome affected. Geometric morphometric analysis of mandible shapes including skull samples from two time points during the last century suggest specific adaptations to a more carnivorous diet. CONCLUSIONS:The molecular and morphological analyses confirm that M. m. helgolandicus consists of a distinct evolutionary lineage with specific adaptations. It shows a remarkable resilience against genetic mixture with mainland populations of M. m. domesticus despite major disturbances in the past century and a high ship traffic. The genomic admixture with M. m. musculus genetic material may have contributed to the genomic distinction of the Heligoland mice. In spite of its young age, M. m. helgolandicus may thus be considered as a true subspecies of Mus, whose evolution was triggered through fast divergence on a small island.
Project description:The mammalian vomeronasal organ (VNO) expresses two G-protein coupled receptor gene families that mediate pheromone responses, the V1R and V2R receptor genes. In rodents, there are ~150 V1R genes comprising 12 subfamilies organized in gene clusters at multiple chromosomal locations. Previously, we showed that several of these subfamilies had been extensively modulated by gene duplications, deletions, and gene conversions around the time of the evolutionary split of the mouse and rat lineages, consistent with the hypothesis that V1R repertoires might be involved in reinforcing speciation events. Here, we generated genome sequence for one large cluster containing two V1R subfamilies in Mus spretus, a closely related and sympatric species to Mus musculus, and investigated evolutionary change in these repertoires along the two mouse lineages.We describe a comparison of spretus and musculus with respect to genome organization and synteny, as well as V1R gene content and phylogeny, with reference to previous observations made between mouse and rat. Unlike the mouse-rat comparisons, synteny seems to be largely conserved between the two mouse species. Disruption of local synteny is generally associated with differences in repeat content, although these differences appear to arise more from deletion than new integrations. Even though unambiguous V1R orthology is evident, we observe dynamic modulation of the functional repertoires, with two of seven V1Rb and one of eleven V1Ra genes lost in spretus, two V1Ra genes becoming pseudogenes in musculus, two additional orthologous pairs apparently subject to strong adaptive selection, and another divergent orthologous pair that apparently was subjected to gene conversion.Therefore, eight of the 18 (~44%) presumptive V1Ra/V1Rb genes in the musculus-spretus ancestor appear to have undergone functional modulation since these two species diverged. As compared to the rat-mouse split, where modulation is evident by independent expansions of these two V1R subfamilies, divergence between musculus and spretus has arisen more by mutations within coding sequences. These results support the hypothesis that adaptive changes in functional V1R repertoires contribute to the delineation of very closely related species.
Project description:BACKGROUND: Due to their high level of genotypic and phenotypic variability, Mus spretus strains were introduced in laboratories to investigate the genetic determinism of complex phenotypes including quantitative trait loci. Mus spretus diverged from Mus musculus around 2.5 million years ago and exhibits on average a single nucleotide polymorphism (SNP) in every 100 base pairs when compared with any of the classical laboratory strains. A genoproteomic approach was used to assess polymorphism of the major milk proteins between SEG/Pas and C57BL/6J, two inbred strains of mice representative of Mus spretus and Mus musculus species, respectively. RESULTS: The milk protein concentration was dramatically reduced in the SEG/Pas strain by comparison with the C57BL/6J strain (34 ± 9 g/L vs. 125 ± 12 g/L, respectively). Nine major proteins were identified in both milks using RP-HPLC, bi-dimensional electrophoresis and MALDI-Tof mass spectrometry. Two caseins (? and ?s1) and the whey acidic protein (WAP), showed distinct chromatographic and electrophoresis behaviours. These differences were partly explained by the occurrence of amino acid substitutions and splicing variants revealed by cDNA sequencing. A total of 34 SNPs were identified in the coding and 3'untranslated regions of the SEG/Pas Csn1s1 (11), Csn2 (7) and Wap (8) genes. In addition, a 3 nucleotide deletion leading to the loss of a serine residue at position 93 was found in the SEG/Pas Wap gene. CONCLUSION: SNP frequencies found in three milk protein-encoding genes between Mus spretus and Mus musculus is twice the values previously reported at the whole genome level. However, the protein structure and post-translational modifications seem not to be affected by SNPs characterized in our study. Splicing mechanisms (cryptic splice site usage, exon skipping, error-prone junction sequence), already identified in casein genes from other species, likely explain the existence of multiple ?s1-casein isoforms both in SEG/Pas and C57BL/6J strains. Finally, we propose a possible mechanism by which the hallmark tandem duplication of a 18-nt exon (14 copies) may have occurred in the mouse genome.
Project description: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.
Project description:In Mus spretus, the chloride channel 4 gene Clcn4-2 is X-linked and dosage compensated by X up-regulation and X inactivation, while in the closely related mouse species Mus musculus, Clcn4-2 has been translocated to chromosome 7. We sequenced Clcn4-2 in M. spretus and identified the breakpoints of the evolutionary translocation in the Mus lineage. Genetic and epigenetic differences were observed between the 5'ends of the autosomal and X-linked loci. Remarkably, Clcn4-2 introns have been truncated on chromosome 7 in M. musculus as compared with the X-linked loci from seven other eutherian mammals. Intron sequences specifically preserved in the X-linked loci were significantly enriched in AT-rich oligomers. Genome-wide analyses showed an overall enrichment in AT motifs unique to the eutherian X (except for genes that escape X inactivation), suggesting a role for these motifs in regulation of the X chromosome.
Project description:BACKGROUND: Insights into the micro-evolutionary patterns of morphological traits require an assessment of the natural variation of the trait within and between populations and closely related species. The mouse mandible is a particularly suitable morphological trait for such an analysis, since it has long been used as a model to study the quantitative genetics of shape. In addition, many distinct populations, sub-species and closely related species are known for the house mouse. However, morphological comparisons among wild caught animals require an assessment in how far environmental and technical factors could interfere with the shape change measurements. RESULTS: Using geometric morphometrics, we have surveyed mandible shapes in 15 natural populations of the genus Mus, with a focus on the subspecies Mus musculus domesticus. In parallel we have carefully assessed possibly confounding technical and biological factors. We find that there are distinct differences on average between populations, subspecies and species, but these differences are smaller than differences between individuals within populations. Populations from summer-dry regions, although more ancestral, are less distinct from each other than are populations from the more recently colonized northern areas. Populations with especially distinct shapes occur in an area of sympatry of M. m. domesticus and M. spretus and on recently colonized sub-antarctic islands. We have also studied a number of inbred strains to assess in how far their mandible shapes resemble those from the wild. We find that they fall indeed into the shape space of natural variation between individuals in populations. CONCLUSIONS: Although mandible shapes in natural populations can be influenced by environmental variables, these influences are insufficient to explain the average extent of shape differences between populations, such that evolutionary processes must be invoked to explain this level of diversity. We discuss that adaptive evolution may contribute to shape changes between populations, in particular in newly colonized areas. A comparison between inbred strains and wild mice suggests that the laboratory environment has no major systematic effect on the mandible shape and that such strains can be used as representatives of the natural shape differences between individuals.
Project description:North Africa is now recognized as a major area for the emergence and dispersal of anatomically modern humans from at least 315?kya. The Mediterranean Basin is thus particularly suited to study the role of climate versus human-mediated changes on the evolutionary history of species. The Algerian mouse (Mus spretus Lataste) is an endemic species from this basin, with its distribution restricted to North Africa (from Libya to Morocco), Iberian Peninsula and South of France. A rich paleontological record of M. spretus exists in North Africa, suggesting hypotheses concerning colonization pathways, and the demographic and morphologic history of this species. Here we combined genetic (3 mitochondrial DNA loci and 18 microsatellites) and climatic niche modeling data to infer the evolutionary history of the Algerian mouse. We collected 646 new individuals in 51 localities. Our results are consistent with an anthropogenic translocation of the Algerian mouse from North Africa to the Iberian Peninsula via Neolithic navigators, probably from the Tingitane Peninsula. Once arrived in Spain, suitable climatic conditions would then have favored the dispersion of the Algerian mice to France. The morphological differentiation observed between Spanish, French and North African populations could be explained by a founder effect and possibly local adaptation. This article helps to better understand the role of climate versus human-mediated changes on the evolutionary history of mammal species in the Mediterranean Basin.
Project description:We evaluated the suitability of high-throughput transcriptomics approach to monitor terrestrial ecosystems. Free-living Mus spretus from several polluted sites of Huelva (Andalusia, SW Spain) were compared with mice from Doñana Biological Reserve (“Santa Olalla” lagoon (SOL) used as negative control). As most popular bioindicators, M. spretus is poorly represented in gene databases, therefore limiting the use of genomics in ecotoxicological studies. To solve this problem, we used microarrays produced from mRNAs of M. musculus. Specifically we used the One-Color Gene Expression Platform commercialized by Agilent. Overall design: Gene expression in Mus spretus liver was assessed in mice from 5 sites of the Spanish Southwest. Five independent experiments were performed. The arrays were hybridized with labelled cRNA samples made from pooled livers of 9 mice per sampling site. We made 4 technichal repetitions per sample.