Meta-populational demes constitute a reservoir for large MHC allele diversity in wild house mice (Mus musculus).

BACKGROUND: The MHC class I and II loci mediate the adaptive immune response and belong to the most polymorphic loci in vertebrate genomes. In fact, the number of different alleles in a given species is often so large that it remains a challenge to provide an evolutionary model that can fully account for this. RESULTS: We provide here a general survey of MHC allele numbers in house mouse populations and two sub-species (M. m. domesticus and M. m. musculus) for H2 class I D and K, as well as class II A and E loci. Between 50 and 90% of the detected different sequences constitute new alleles, confirming that the discovery of new alleles is indeed far from complete. House mice live in separate demes with small effective population sizes, factors that were proposed to reduce, rather than enhance the possibility for the maintenance of many different alleles. To specifically investigate the occurrence of alleles within demes, we focused on the class II H2-Aa and H2-Eb exon 2 alleles in nine demes of M. m. domesticus from two different geographic regions. We find on the one hand a group of alleles that occur in different sampling regions and three quarters of these are also found in both sub-species. On the other hand, the larger group of different alleles (56%) occurs only in one of the regions and most of these (89%) only in single demes. We show that most of these region-specific alleles have apparently arisen through recombination and/or partial gene conversion from already existing alleles. CONCLUSIONS: Demes can act as sources of alleles that outnumber the set of alleles that are shared across the species range. These findings support the reservoir model proposed for human MHC diversity, which states that large pools of rare MHC allele variants are continuously generated by neutral mutational mechanisms. Given that these can become important in the defense against newly emerging pathogens, the reservoir model complements the selection based models for MHC diversity and explains why the exceptional diversity exists.

Genetic differentiation of hypothalamus parentally biased transcripts in populations of the house mouse implicate the Prader-Willi syndrome imprinted region as a possible source of behavioral divergence.

Parentally biased expression of transcripts (genomic imprinting) in adult tissues, including the brain, can influence and possibly drive the evolution of behavioral traits. We have previously found that paternally determined cues are involved in population-specific mate choice decisions between two populations of the Western house mouse (Mus musculus domesticus). Here, we ask whether this could be mediated by genomically imprinted transcripts that are subject to fast differentiation between these populations. We focus on three organs that are of special relevance for mate choice and behavior: The vomeronasal organ (VNO), the hypothalamus, and the liver. To first identify candidate transcripts at a genome-wide scale, we used reciprocal crosses between M. m. domesticus and M. m. musculus inbred strains and RNA sequencing of the respective tissues. Using a false discovery cutoff derived from mock reciprocal cross comparisons, we find a total of 66 imprinted transcripts, 13 of which have previously not been described as imprinted. The largest number of imprinted transcripts were found in the hypothalamus; fewer were found in the VNO, and the least were found in the liver. To assess molecular differentiation and imprinting in the wild-derived M. m. domesticus populations, we sequenced the RNA of the hypothalamus from individuals of these populations. This confirmed the presence of the above identified transcripts also in wild populations and allowed us to search for those that show a high genetic differentiation between these populations. Our results identify the Ube3a-Snrpn imprinted region on chromosome 7 as a region that encompasses the largest number of previously not described transcripts with paternal expression bias, several of which are at the same time highly differentiated. For four of these, we confirmed their imprinting status via single nucleotide polymorphism-specific pyrosequencing assays with RNA from reciprocal crosses. In addition, we find the paternally expressed Peg13 transcript within the Trappc9 gene region on chromosome 15 to be highly differentiated. Interestingly, both regions have been implicated in Prader-Willi nervous system disorder phenotypes in humans. We suggest that these genomically imprinted regions are candidates for influencing the population-specific mate-choice in mice.

Paternal imprinting of mating preferences between natural populations of house mice (Mus musculus domesticus).

The evolutionary divergence of cues for mate recognition can contribute to early stages of population separation. We compare here two allopatric populations of house mice (Mus musculus domesticus) that have become separated about 3000 years ago. We have used paternity assignments in semi-natural environments to study the degree of mutual mate recognition according to population origin under conditions of free choice and overlapping generations. Our results provide insights into the divergence of mating cues, but also for the mating system of house mice. We find frequent multiple mating, occurrence of inbreeding and formation of extended family groups. In addition, many animals show strong mate fidelity, that is, frequent choice of the same mating partners in successive breeding cycles, indicating a role for familiarity in mating preference. With respect to population divergence, we find evidence for assortative mating, but only under conditions where the animals had time to familiarize themselves with mating partners from their own population. Most interestingly, the first-generation offspring born in the enclosure showed a specific mating pattern. Although matings between animals of hybrid population origin with animals of pure population origin should have occurred with equal frequency with respect to matching the paternal or maternal origin, paternal matching with mates from their own populations occurred much more often. Our findings suggest that paternally imprinted cues play a role in mate recognition between mice and that the cues evolve fast, such that animals of populations that are separated since not more than 3000 years can differentially recognize them.

Long-term balancing selection at the blood group-related gene B4galnt2 in the genus Mus (Rodentia; Muridae).

Recent surveys of the human genome have highlighted the significance of balancing selection in relation to understanding the evolutionary origins of disease-associated variation. Cis-regulatory variation at the blood group-related glycosyltransferase B4galnt2 is associated with a phenotype in mice that closely resembles a common human bleeding disorder, von Willebrand disease. In this study, we have performed a survey of the 5' flanking region of the B4galnt2 gene in several Mus musculus subspecies and Mus spretus. Our results reveal a clear pattern of trans-species polymorphism and indicate that allele classes conferring alternative tissue-specific expression patterns have been maintained for >2.8 My in the genus Mus. Furthermore, analysis of B4galnt2 expression patterns revealed the presence of an additional functional class of alleles, supporting a role for gastrointestinal phenotypes in the long-term maintenance of expression variation at this gene.

Genomic resources for wild populations of the house mouse, Mus musculus and its close relative Mus spretus.

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.

Genome-wide quantitative analysis of histone H3 lysine 4 trimethylation in wild house mouse liver: environmental change causes epigenetic plasticity.

In mammals, exposure to toxic or disease-causing environments can change epigenetic marks that are inherited independently of the intrauterine environment. Such inheritance of molecular phenotypes may be adaptive. However, studies demonstrating molecular evidence for epigenetic inheritance have so far relied on extreme treatments, and are confined to inbred animals. We therefore investigated whether epigenomic changes could be detected after a non-drastic change in the environment of an outbred organism. We kept two populations of wild-caught house mice (Mus musculus domesticus) for several generations in semi-natural enclosures on either standard diet and light cycle, or on an energy-enriched diet with longer daylight to simulate summer. As epigenetic marker for active chromatin we quantified genome-wide histone-3 lysine-4 trimethylation (H3K4me3) from liver samples by chromatin immunoprecipitation and high-throughput sequencing as well as by quantitative polymerase chain reaction. The treatment caused a significant increase of H3K4me3 at metabolic genes such as lipid and cholesterol regulators, monooxygenases, and a bile acid transporter. In addition, genes involved in immune processes, cell cycle, and transcription and translation processes were also differently marked. When we transferred young mice of both populations to cages and bred them under standard conditions, most of the H3K4me3 differences were lost. The few loci with stable H3K4me3 changes did not cluster in metabolic functional categories. This is, to our knowledge, the first quantitative study of an epigenetic marker in an outbred mammalian organism. We demonstrate genome-wide epigenetic plasticity in response to a realistic environmental stimulus. In contrast to disease models, the bulk of the epigenomic changes we observed were not heritable.