Selection shapes the landscape of functional variation in wild house mice

Background Through human-aided dispersal over the last ~ 10,000 years, house mice (Mus musculus) have recently colonized diverse habitats across the globe, promoting the emergence of new traits that confer adaptive advantages in distinct environments. Despite their status as the premier mammalian model system, the impact of this demographic and selective history on the global patterning of disease-relevant trait variation in wild mouse populations is poorly understood. Results Here, we leveraged 154 whole-genome sequences from diverse wild house mouse populations to survey the geographic organization of functional variation and systematically identify signals of positive selection. We show that a significant proportion of wild mouse variation is private to single populations, including numerous predicted functional alleles. In addition, we report strong signals of positive selection at many genes associated with both complex and Mendelian diseases in humans. Notably, we detect a significant excess of selection signals at disease-associated genes relative to null expectations, pointing to the important role of adaptation in shaping the landscape of functional variation in wild mouse populations. We also uncover strong signals of selection at multiple genes involved in starch digestion, including Mgam and Amy1. We speculate that the successful emergence of the human-mouse commensalism may have been facilitated, in part, by dietary adaptations at these loci. Finally, our work uncovers multiple cryptic structural variants that manifest as putative signals of positive selection, highlighting an important and under-appreciated source of false-positive signals in genome-wide selection scans. Conclusions Overall, our findings highlight the role of adaptation in shaping wild mouse genetic variation at human disease-associated genes. Our work also highlights the biomedical relevance of wild mouse genetic diversity and underscores the potential for targeted sampling of mice from specific populations as a strategy for developing effective new mouse models of both rare and common human diseases.

Extensive variation in the intelectin gene family in laboratory and wild mouse strains

Intelectins are a family of multimeric secreted proteins that bind microbe-specific glycans. Both genetic and functional studies have suggested that intelectins have an important role in innate immunity and are involved in the etiology of various human diseases, including inflammatory bowel disease. Experiments investigating the role of intelectins in human disease using mouse models are limited by the fact that there is not a clear one-to-one relationship between intelectin genes in humans and mice, and that the number of intelectin genes varies between different mouse strains. In this study we show by gene sequence and gene expression analysis that human intelectin-1 (ITLN1) has multiple orthologues in mice, including a functional homologue Itln1; however, human intelectin-2 has no such orthologue or homologue. We confirm that all sub-strains of the C57 mouse strain have a large deletion resulting in retention of only one intelectin gene, Itln1. The majority of laboratory strains have a full complement of six intelectin genes, except CAST, SPRET, SKIVE, MOLF and PANCEVO strains, which are derived from different mouse species/subspecies and encode different complements of intelectin genes. In wild mice, intelectin deletions are polymorphic in Mus musculus castaneus and Mus musculus domesticus. Further sequence analysis shows that Itln3 and Itln5 are polymorphic pseudogenes due to premature truncating mutations, and that mouse Itln1 has undergone recent adaptive evolution. Taken together, our study shows extensive diversity in intelectin genes in both laboratory and wild-mice, suggesting a pattern of birth-and-death evolution. In addition, our data provide a foundation for further experimental investigation of the role of intelectins in disease.

Intranasal oxytocin reduces pre-courtship aggression and increases paternal response in California mice (Peromyscus californicus)

Oxytocin (OXT) is a neuropeptide that can facilitate prosocial behavior and decrease social stress and anxiety. We investigated whether acute pulses of intranasal (IN) OXT influenced social behavior during social challenges that are likely to occur throughout the lifespan of a wild mouse. To test this, we examined the acute effects of IN OXT in the male California mouse (Peromyscus californicus), a monogamous, biparental, and territorial rodent, using a within-subjects longitudinal design. Social challenges included a pre-courtship male-female encounter conducted during the initial aggressive and not the following affiliative phase of courtship, same-sex resident intruder test, and parental care test, with each test and dose separated by at least two weeks. Males were treated with intranasal infusions of 0.8 IU/kg OXT or saline controls 5-min before each behavioral test, receiving a total of three treatments of either IN OXT or saline control. We predicted that IN OXT would 1) decrease aggression and increase affiliation during the pre-courtship aggression phase, 2) increase aggression during resident intruder paradigms and 3) increase paternal care and vocalizations during a paternal care test. As predicted, during pre-courtship aggression with a novel female, IN OXT males displayed less contact aggression than control males, although with no change in affiliative behavior. However, post-pairing, during the resident intruder test, IN OXT males did not differ from control males in contact aggression. During the paternal care test, IN OXT males were quicker to approach their pups than control males but did not differ in vocalizations produced, unlike our previous research demonstrating an effect on vocalizations in females. In summary, during pre-courtship aggression and the paternal care test, IN OXT promoted prosocial approach; however, during the resident intruder test IN OXT did not alter social approach. These data suggest that IN OXT promotes prosocial approach specifically in social contexts that can lead to affiliation.

THE ROLE AND SIGNIFICANCE OF MORPHOLOGICAL CHANGES IN INTRAORGAN VESSELS IN ANIMALS DURING PATHOGENESIS OF BABESIOSIS

The aim of this study is to investigate morphological changes in intraorgan vessels and their role in susceptible animals in the pathogenesis of babesiosis. The material of the study included the intraorgan vessels of domestic dogs with clinically and laboratory confirmed babesiosis and wild mouse-like rodents from latent foci of babesiosis in Volyn, Zhitomir, Kiev, Poltava, Sumy, Kharkov, Chernigov regions. For histological study, we used standard fixation in a 12% aqueous formalin solution in phosphate buffer (pH = 7.0-7.2). After the post-fixation and dehydration, the samples were placed into paraffin blocks; then a series of histological slices (5 μm) were prepared. The preparations were stained with hematoxylin and eosin, according to Van Gieson technique. All test animals, regardless of the species taxonomy, were divided into two groups. The control group included clinically healthy animals (∑ = 36). The group under clinical study consisted of animals with clinically and laboratory confirmed babesiosis (∑ = 91). Histological changes in intraorgan vessels in the control group corresponded to the anatomical and functional parameters in the health. The preparations taken from the group with basesiosis demonstrate that microvessels are branched, different in size, spasmodic; their walls have signs of delamination and through lesions. Delamination developed gradually, started with the detachment of a small horizontal fragment of the outer layer. Defects in the integrity of microvessels resulted in penetrations; there was an active diapedesis of erythrocytes into the periovascular space. The accumulation of erythrocytes directed to the areas of connective tissue, branching of blood vessels, and fatty fragments. Hemorrhages were local in nature, concentrated in the form of small blurred foci of irregular shape. In the pathogenesis of babesiosis, the defects in the walls of blood vessels with their further penetration and dissection, hemorrhages, microvesiculation of the endothelium, and its desquamation play a critical role. Other manifestations included the development of intravascular blood coagulation, thrombosis, stasis, microcirculation disorders followed by ischemia, destructive and degenerative changes in the walls of blood vessels.

Selection shapes the landscape of functional variation in wild house mice

Background Through human-aided dispersal, house mice have recently colonized new and diverse habitats across the globe, promoting the emergence of new traits that confer adaptive advantages in distinct environments. Despite their status as the premiere mammalian model system, the impact of this demographic and selective history on the global patterning of disease-relevant trait variation in wild mouse populations is poorly understood. Results Here, we leveraged 154 whole-genome sequences from diverse wild house mouse populations, subspecies, and species to survey the geographic organization of functional variation and systematically identify signals of positive selection. We show that a significant proportion of wild mouse variation is private to single populations, including numerous predicted functional alleles. In addition, we report strong signals of positive selection at numerous genes associated with both complex and Mendelian diseases in humans. Notably, we detect a significant excess of selection signals at disease-associated genes relative to null expectations, pointing to the important role of adaptation in shaping the landscape of functional variation in wild mouse populations. We also uncover strong signals of selection at multiple genes involved in starch digestion, including Mgam and Amy1. We speculate that the successful emergence of the human-mouse commensalism may have been facilitated, in part, by dietary adaptations at these loci. Finally, our work uncovers multiple cryptic structural variants that manifest as putative signals of positive selection, highlighting an important and under-appreciated source of false-positive signals in genome-wide selection scans. Conclusions Overall, our findings underscore the role of adaptation in shaping wild mouse genetic variation at human disease-associated genes. Our work highlights the biomedical relevance of wild mouse genetic diversity and underscores the potential for targeted sampling of mice from specific populations as a strategy for developing effective new mouse models of both rare and common human diseases.

Radiocesium contamination in wild mouse in Fukushima, Japan

<div><span>The large Japanese field mouse (<em>Apodemus speciosus</em>) which endemic wild mice living in Japanese forest, was monitored after the Fukushima nuclear power plant released a large amount of radioactive materials due to accident. We will introduce current status of radiocesium contamination, estimated radiation dose, and effect in the field mouse. According to calculation of radiation dose using Monte Carlo electron-photon transport code EGS5, it was clarified that dose rate level of the field mouse fall under derived consideration reference level determined by ICRP. Analysis of the oxidative stress in male mice testis revealed the damage in testicular cells of mice collected in 2012, when monitoring began.</span></div>

The Japanese Wild-Derived Inbred Mouse Strain, MSM/Ms in Cancer Research

MSM/Ms is a unique inbred mouse strain derived from the Japanese wild mouse, Mus musculus molossinus, which has been approximately 1 million years genetically distant from standard inbred mouse strains mainly derived from M. m. domesticus. Due to its genetic divergence, MSM/Ms has been broadly used in linkage studies. A bacterial artificial chromosome (BAC) library was constructed for the MSM/Ms genome, and sequence analysis of the MSM/Ms genome showed approximately 1% of nucleotides differed from those in the commonly used inbred mouse strain, C57BL/6J. Therefore, MSM/Ms mice are thought to be useful for functional genome studies. MSM/Ms mice show unique characteristics of phenotypes, including its smaller body size, resistance to high-fat-diet-induced diabetes, high locomotive activity, and resistance to age-onset hearing loss, inflammation, and tumorigenesis, which are distinct from those of common inbred mouse strains. Furthermore, ES (Embryonic Stem) cell lines established from MSM/Ms allow the MSM/Ms genome to be genetically manipulated. Therefore, genomic and phenotypic analyses of MSM/Ms reveal novel insights into gene functions that were previously not obtained from research on common laboratory strains. Tumorigenesis-related MSM/Ms-specific genetic traits have been intensively investigated in Japan. Furthermore, radiation-induced thymic lymphomas and chemically-induced skin tumors have been extensively examined using MSM/Ms.

Family dynamics reveal that female house mice preferentially breed in their maternal community

Whether females breed in their natal group is an important factor in the evolution of extended families in animal sociality. Breeding in natal groups comes with clear costs and benefits, depending on size of the group and presence of older relatives, including mothers. Studying individual decisions about whether to stay or leave can provide insight into the mechanisms and trade-offs governing the formation and structure of family groups. We investigated the family dynamics of a large population of free-ranging commensal house mice. Using dynamic community detection on long term datasets, we determined which females first bred in their natal group. We then looked at how this influenced breeding success. We found most females (77%) exhibited strong philopatry, breeding in their natal groups. Whether a female bred elsewhere was only predictable when natal groups were extremely small and related or large and unrelated. Despite this preference, breeding elsewhere made no difference in how quickly and successfully a female bred. However, presence of their mother did lead females to breed sooner when born during high breeding activity, when competition over reproduction is high. Based on these results, potential loss of fitness does not seem to be the main driver of philopatry in female house mice. The effect of the presence of mothers may indicate retaining prior social connections is an important benefit of breeding in the natal group. Mothers providing benefits also suggests lack of conflict between generations, which is likely an important attribute in the development of extended family groups.Lay summaryWhether animals breed in the group they are born in influences how they form extended family groups. Whether females stay will depend on properties such as presence of older relatives, including mothers. Using long-term wild mouse data, we track groups and which group females bred in. Most stayed, but leaving didn’t reduce breeding success. Presence of mother, who generally stayed, did lead to earlier breeding. This might be a key advantage to remaining to breed.

Naturally Acquired Mouse Kidney Parvovirus Infection Produces a Persistent Interstitial Nephritis in Immunocompetent Laboratory Mice

Mouse kidney parvovirus (MKPV), also known as murine chapparvovirus (MuCPV), is an emerging, highly infectious agent that has been isolated from laboratory and wild mouse populations. In immunocompromised mice, MKPV produces severe chronic interstitial nephropathy and renal failure within 4 to 5 months of infection. However, the course of disease, severity of histologic lesions, and viral shedding are uncertain for immunocompetent mice. We evaluated MKPV infections in CD-1 and Swiss Webster mice, 2 immunocompetent stocks of mice. MKPV-positive CD-1 mice ( n = 30) were identified at approximately 8 weeks of age by fecal PCR (polymerase chain reaction) and were subsequently housed individually for clinical observation and diagnostic sampling. Cage swabs, fecal pellets, urine, and blood were evaluated by PCR at 100 and 128 days following the initial positive test, which identified that 28 of 30 were persistently infected and 24 of these were viremic at 100 days. Histologic lesions associated with MKPV in CD-1 ( n = 31) and Swiss mice ( n = 11) included lymphoplasmacytic tubulointerstitial nephritis with tubular degeneration. Inclusion bodies were rare; however, intralesional MKPV mRNA was consistently detected via in situ hybridization within tubular epithelial cells of the renal cortex and within collecting duct lumina. In immunocompetent CD-1 mice, MKPV infection resulted in persistent shedding of virus for up to 10 months and a mild tubulointerstitial nephritis, raising concerns that this virus could produce study variations in immunocompetent models. Intranuclear inclusions were not a consistent feature of MKPV infection in immunocompetent mice.