Biology subjects

Dumont, B. L.

Publications and source records attributed to Dumont, B. L..

At least 19 recordsLinked to original sources

bioRxiv2026

Genetically distinct microenvironment determines cancer survival and response to therapy in mice

Genetic uniqueness of the tumor microenvironment significantly influences cancer growth, survival, and response to therapy, independent of the cancer cells intrinsic properties or the adaptive immune system. Using genetically distinct Rag1-/- mouse models, this study shows that different strains exhibit varied tumor growth kinetics and survival outcomes when xenografted with identical leukemic and solid tumor cell lines. This study further highlights the critical role of the myeloid immune compartment and shows that disrupting both lymphoid and myeloid systems alters cancer progression. These results also reveal that the tumor microenvironment can permanently alter cancer cell phenotypes and significantly affect chemotherapy efficacy, as seen with Cisplatins varying effects across strains. These findings underscore the importance of considering genetic background in preclinical cancer models, suggesting that reliance upon a single mouse strain may lead to incomplete conclusions about cancer biology and treatment efficacy. SUMMARY STATEMENTPre-clinical xenograft mammalian models are used to study human diseases. Here we report that the genetic uniqueness of the tumor microenvironment, independent of the immune system, can determine the fate of cancer progression, survival, and therapy response.

cancer biology↗

bioRxiv2025

Increased rate of de novo single nucleotide mutation in house mice born through assisted reproduction

Approximately 2.6% of live births in the United States are conceived using assisted reproductive technologies (ARTs). While some ART procedures, including in vitro fertilization (IVF) and intracytoplasmic sperm injection, are known to alter the epigenetic landscape of early embryonic development, their impact on DNA sequence stability is unclear. Here, we leverage the strengths of the laboratory mouse model system to investigate whether a standard ART regimen--ovarian hyperstimulation, gamete isolation, IVF, embryo culture, and embryo transfer--affects genome stability. Age-matched cohorts of ART-derived and naturally conceived C57BL/6J inbred mice were reared in a controlled setting and whole genome sequenced to [~]50x coverage. Using a rigorous pipeline for de novo single nucleotide variant (dnSNV) discovery, we observe a [~]30% increase in the dnSNV rate in ART-compared to naturally-conceived mice. Analysis of the dnSNV mutation spectrum identified signature contributions related to germline DNA repair activity, affirming expectations and evidencing the quality of our dnSNV calls. We observed no enrichment of dnSNVs in specific genomic contexts, suggesting that the observed rate increase in ART-derived mice is a general genome-wide phenomenon. Similarly, we show that the developmental timing of dnSNVs is similar in ART- and natural-born cohorts. Together, our findings show that ART is moderately mutagenic in house mice and motivate future work to define the precise procedure(s) associated with this increased mutational vulnerability. While we caution that our findings cannot be immediately translated to humans, they nonetheless emphasize a pressing need for investigations on the potential mutagenicity of ART in our species. SIGNIFICANCE STATEMENTThis study investigates whether assisted reproductive technologies (ARTs) increase the risk of inherited genetic mutations in offspring. Using a well-controlled mouse model system, we compared the de novo mutation burden in genomes of mice conceived through ART to a naturally conceived cohort. We find a [~]30% increase in new DNA mutations in ART-conceived mice, suggesting that ART procedures have a genome destabilizing effect. This increase in mutation rate appears to be uniform across the genome, rather than attributable to specific genomic contexts. While we caution against the direct translation of our findings to humans, our work nonetheless highlights the need for further research into the genetic safety of ART in people.

genomics↗

bioRxiv2025

Recombination Rates Are Governed by Sex-Specific Evolutionary Programs in House Mice

Recombination rates vary markedly across species, populations, and sexes. In house mice (Mus musculus), this variation is particularly pronounced. Prior studies have established large differences in global recombination rates between M. musculus subspecies and inbred strains, with males exhibiting more extensive variation than females. The observation of sex-limited variation has prompted the hypothesis that male and female recombination rates may evolve by distinct evolutionary mechanisms in M. musculus. Here, we set out to formally evaluate this hypothesis in a phylogenetic framework using a dataset of cytogenetic sex-specific genome-scale crossover rate estimates from >6000 single meiotic cells from 31 genetically diverse inbred mouse strains spanning five Mus species and four M. musculus subspecies. Using phylogenetic comparative methods, we document a significant phylogenetic signal in male recombination rates, but female recombination rates show no clear phylogenetic trend. Males from M. m. musculus exhibit a large increase in recombination rate compared to other M. musculus subspecies, prompting us to explicitly test models of lineage-specific trait evolution. We show that the phylogenetic distribution of male recombination rates is best explained by an evolutionary model that allows a unique adaptive optimum along the M. m. musculus lineage, whereas female recombination rates are well-explained by a simplified model with a single global trait optimum. Taken together, our findings confirm the hypothesis that recombination rate evolution in house mice is governed by distinct sex-specific evolutionary regimes and motivate future efforts to ascertain the sex-specific selective pressures and sex-specific genetic architectures that underlie these observations. ARTICLE SUMMARYMeiotic recombination rates are highly variable between species, populations, and sexes. This variation is genetically controlled, but the underlying evolutionary processes that shape the extreme diversity of recombination rates are poorly understood. Here, we analyze sex-specific recombination rate estimates across a large panel of genetically diverse male and female house mice in an explicit phylogenetic framework. We show that recombination rates in males and females have evolved under distinct evolutionary programs, implying sex differences in the phenotypic value that optimizes evolutionary fitness. Our data point to intersexual genetic conflict driving rapid sex-specific recombination rate evolution in this system.

evolutionary biology↗

bioRxiv2025

Benchmarking Genomic Variant Calling Tools in Inbred Mouse Strains: Recommendations and Considerations

With the growing affordability of whole genome sequencing, variant identification has become an increasingly common task, but there are many challenges due to both technical and biological factors. In recent years, the number of software packages available for variant calling has rapidly increased. Understanding the benefits and drawbacks of different tools is important in setting leading practices and highlighting limitations. These considerations are crucial in model organism research, as many variant calling programs assume outbred genomes and implicit heterozygosity, which may not apply to inbred laboratory models. Here, we present an analysis of variant calling tools and their performance in the simulated genomes of the C57BL/6J inbred laboratory mouse and nine non-reference laboratory strains. Our findings reveal a tradeoff between the recall and precision of tools. Balancing these considerations, we show that an optimal call set is obtained by using an ensemble approach, but specific variant calling recommendations vary by strain and analytical goals. Further, we highlight filters improving the performance of different variant calling tools, both for the discovery of rare variants and in the discovery of strain polymorphisms. In summary, our work provides best practices for calling and filtering genomic variants in inbred organisms, particularly laboratory mice. Article SummaryIdentifying mutations and rare genetic variants is a central task for modern genomics. Many computational tools exist for variant detection, but their performance varies across diverse applications. Further, few variant calling tools have been benchmarked against inbred genomes, which are commonly used for research. To address this, we evaluated five variant calling tools using simulated data from ten diverse inbred mouse strains. We show that variant detection, recall, and precision vary across tools and mouse strains, and that an ensemble approach improves confidence in detected mutations. Our findings offer a set of best practices for variant calling in inbred organisms across diverse analytical applications.

bioinformatics↗

bioRxiv2025

Low-coverage whole-genome sequencing facilitates accurate and cost-effective haplotype reconstruction in complex mouse crosses

The search for the underlying genetic contributions to complex traits and diseases relies on accurate genetic data from populations of interest. Outbred populations, like the Diversity Outbred (DO), are commonly genotyped using commercial SNP arrays, such as the Giga Mouse Universal Genotyping Array (GigaMUGA). However, array genotypes are expensive to collect, subject to significant ascertainment bias, and too sparse to capture the genetic structure of highly recombined mouse crosses. We investigated the efficacy of sequencing-based genotyping by comparing genotyping results between the GigaMUGA, double-digest restriction-site associated DNA sequencing (ddRADseq), and low-coverage whole-genome sequencing (lcWGS). We aligned reads at [~]1X coverage and imputed segregating SNPs from the eight DO founder strains onto 48 DO genomes and reconstructed their haplotypes using R/qtl2. Haplotype reconstructions derived from all three methods were highly concordant. However, lcWGS more faithfully recapitulated crossover counts and identified more small (< 1 Mb) haplotype blocks at as low as 0.1X coverage. Over 90% of local expression quantitative trait loci identified in a set of 183 DO-derived embryoid bodies using the GigaMUGA were recalled by lcWGS at coverages as low as 0.1X. We recommend that lcWGS be adopted as the primary method of genotyping complex crosses, and cell-based resources derived from them because they are as accurate as array-based reconstructions, robust to ultra-low sequencing depths, may more accurately model haplotypes of the mouse genome that are difficult to resolve with dense reference data, and cost-effective.

genetics↗

bioRxiv2025

Young KRAB-zinc finger gene clusters are highly dynamic incubators of ERV-driven genetic heterogeneity in mice

KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. How new KZFPs emerge in response to ERV invasions is currently unknown. Using a combination of long-read sequencing technologies and genome assembly, we present a first detailed comparative analysis of young KZFP gene clusters in the mouse lineage, which has undergone recent KZFP gene expansion and ERV infiltration. Detailed annotation of KZFP genes in a cluster on Mus musculus Chromosome 4 revealed parallel expansion and diversification of this locus in different mouse strains (C57BL/6J, 129S1/SvImJ and CAST/EiJ) and species (Mus spretus and Mus pahari). Our data supports a model by which new ERV integrations within young KZFP gene clusters likely promoted recombination events leading to the emergence of new KZFPs that repress them. At the same time, ERVs also increased their numbers by duplication instead of retrotransposition alone, unraveling a new mechanism for ERV enrichment at these loci.

genetics↗

bioRxiv2024

Mapping the Global Distribution of Mus musculus: Implications for Evolutionary Genetics

House mice (Mus musculus) are a key biomedical research model and important vectors for disease transmission. In the wild, house mice are also an ecologically disruptive invasive species, and their activity is associated with significant economic and agricultural damage and cost. Despite the importance of house mice across these different contexts, the extent of their geographic distribution is not well understood. House mice are human commensals but are nonetheless sensitive to their prevailing environment, indicating that the range of human settlement cannot be used as a reliable proxy. Existing range maps for Mus musculus are based on minimum convex hulls informed by potentially biased sampling and do not 1) fully integrate large, digitized data documenting species occurrences, 2) provide insight into the likely species distribution in under-sampled regions, and 3) delineate internal structures of the range, including barriers to dispersal or unsuitable internal habitat. Consequently, we know little about the bioclimatic tolerance and environmental envelope occupied by this species. To address these unknowns, we leverage publicly available mouse sampling and biodiversity data to provide an updated range map of Mus musculus and define the environmental limits of the house mouse distribution. Using genetic data from public archives, we also model the genetic diversity of house mice across our newly updated range. Using these data, we visualize global genetic diversity trends and confirm the ancestral origins of Mus musculus to the region of the Indian subcontinent occupied by modern-day Pakistan and northwestern India. Taken together, our efforts highlight areas where house mice are predicted to be at their environmental tolerance limit, including regions where future sampling efforts may uncover mice with unique adaptive traits.

evolutionary biology↗

bioRxiv2024

Molecular evolution of the mammalian kinetochore complex

Mammalian centromeres are satellite-rich chromatin domains that serve as sites for kinetochore complex assembly. Centromeres are highly variable in sequence and satellite organization across species, but the processes that govern the co-evolutionary dynamics between rapidly evolving centromeres and their associated kinetochore proteins remain poorly understood. Here, we pursue a course of phylogenetic analyses to investigate the molecular evolution of the complete kinetochore complex across primate and rodent species with divergent centromere repeat sequences and features. We show that many protein components of the core centromere associated network (CCAN) harbor signals of adaptive evolution, consistent with their intimate association with centromere satellite DNA and roles in the stability and recruitment of additional kinetochore proteins. Surprisingly, CCAN and outer kinetochore proteins exhibit comparable rates of adaptive divergence, suggesting that changes in centromere DNA can ripple across the kinetochore to drive adaptive protein evolution within distant domains of the complex. Our work further identifies kinetochore proteins subject to lineage-specific adaptive evolution, including rapidly evolving proteins in species with centromere satellites characterized by higher-order repeat structure and lacking CENP-B boxes. Thus, features of centromeric chromatin beyond the linear DNA sequence may drive selection on kinetochore proteins. Overall, our work spotlights adaptively evolving proteins with diverse centromere-associated functions, including centromere chromatin structure, kinetochore protein assembly, kinetochore-microtubule association, cohesion maintenance, and DNA damage response pathways. These adaptively evolving kinetochore protein candidates present compelling opportunities for future functional investigations exploring how their concerted changes with centromere DNA ensure the maintenance of genome stability.

evolutionary biology↗

bioRxiv2023

Ancestral variation and its impact on wild house mouse genomes

Ancestral alleles are important contributors to adaptation and disease risk in populations. House mice emerged in and/or around the Indian subcontinent, but the genetic composition of this ancestral population and the extent to which ancestral variants contribute to contemporary global mouse diversity are poorly understood. To address these knowledge gaps, we assessed the origins and demographic patterning of global mouse diversity using a set of 169 wild mouse genome sequences from across the world. This dataset includes 37 mouse genomes from the broadly designated ancestral regions, providing crucial resources needed to evaluate the contributions and the impact of ancestral diversity on the genomic scale. We show that house mice emerged in the Indo-Pakistan region around 700 kya, with M. m. castaneus at the root of the M. musculus species. Migration out of the Indo-Pakistan homeland led to the subsequent emergence of the M. m. domesticus and M. m. musculus subspecies [~]360 and 260 kya, respectively. A modest fraction of ancestral alleles have persisted long-term across mouse populations through balancing selection, and we demonstrate that such regions are strongly enriched for genes with immune-related functions. Finally, we find widespread allele-sharing across Mus musculus lineages and show that this trend is largely due to incomplete lineage sorting, an interpretation contrary to some recent claims of pervasive subspecies introgression. Together, our work underscores the contributions of ancestral variants to contemporary house mouse diversity and adaptation, and refines our understanding of the natural evolutionary history of this important model species.

evolutionary biology↗

bioRxiv2023

Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for a century. However, laboratory mice capture a narrow subset of the genetic variation found in wild mouse populations. This consideration inherently restricts the scope of potential discovery in laboratory models and narrows the pool of potentially identified phenotype-associated variants and pathways. Wild mouse populations are reservoirs of predicted functional and disease-associated alleles, but the sparsity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently imported, sequenced, and phenotyped a set of 11 wild-derived inbred strains developed from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from five environmentally diverse locations across North and South America: Saratoga Springs, New York, USA; Gainesville, Florida, USA; Manaus, Brazil; Tucson, Arizona, USA; and Edmonton, Alberta, Canada. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the mouse reference assembly, with 42.5% of variants in the Nachman strain genomes absent from classical inbred mouse strains. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels alone. Taken together, our work introduces a novel wild-derived inbred mouse strain resource that will enable new discoveries in basic and preclinical research. These strains are currently available through The Jackson Laboratory Repository under laboratory code NachJ.

genetics↗

bioRxiv2023

Centromere Innovations Within a Mouse Species

Mammalian centromeres direct faithful genetic inheritance and are typically characterized by regions of highly repetitive and rapidly evolving DNA. We focused on a mouse species, Mus pahari, that we found has evolved to house centromere-specifying CENP-A nucleosomes at the nexus of a satellite repeat that we identified and term {pi}-satellite ({pi}-sat), a small number of recruitment sites for CENP-B, and short stretches of perfect telomere repeats. One M. pahari chromosome, however, houses a radically divergent centromere harboring [~]6 Mbp of a homogenized {pi}-sat-related repeat, {pi}-satB, that contains >20,000 functional CENP-B boxes. There, CENP-B abundance drives accumulation of microtubule-binding components of the kinetochore, as well as a microtubule-destabilizing kinesin of the inner centromere. The balance of pro and anti-microtubule-binding by the new centromere permits it to segregate during cell division with high fidelity alongside the older ones whose sequence creates a markedly different molecular composition. TeaserChromatin and kinetochore alterations arise in response to evolutionarily rapid changes to underlying repetitive centromere DNA.

genomics↗

bioRxiv2023

Fitness effects of breeding strategy: implications for life history trait evolution and mouse husbandry

Reproductive tactics can profoundly influence population reproductive success, but paradoxically, breeding strategy and female reproductive care often vary across a population. The causes and fitness impacts of this variation are not well understood. Using breeding records from the Collaborative Cross mouse population, we evaluate the effects of breeding configuration on reproductive output. Overall, we find that communal breeding in trios leads to higher output and that both trio-breeding and overlapping litters are associated with increased neonatal survival. However, we find significant strain-level variation in optimal breeding strategy and show that the tradeoff between strategies is weakly heritable. We further find that strain reproductive condition influences the ability to support multiple litters and alters the related evolutionary tradeoffs of communal breeding. Together, these findings underscore the role of genetics in regulating alternative reproductive tactics in house mice and emphasize the need to adopt animal husbandry practices tailored to strain backgrounds.

evolutionary biology↗

bioRxiv2022

Taxonomic assessment of two wild house mouse subspecies using whole genome sequencing

House mice (Mus musculus) are comprised of three primary subspecies. A large number of secondary subspecies have also been suggested on the basis of divergent morphology and molecular variation at limited numbers of markers. While the phylogenetic relationships among the primary M. musculus subspecies are well-defined, the relationships among the secondary subspecies, and their relationships to primary subspecies, remain poorly understood. Here, we integrate de novo genome sequencing of museum-stored specimens of house mice from one secondary subspecies (M. m. bactrianus) and publicly available genome sequences of house mice previously characterized as M. m. helgolandicus, with whole-genome sequences from diverse representatives of the three primary house mouse subspecies. We show that mice assigned to the secondary M. m. bactrianus and M. m. helgolandicus subspecies are not genetically differentiated from the contemporary M. m. castaneus and M. m. domesticus, respectively. Overall, our work suggests that the M. m. bactrianus and M. m. helgolandicus subspecies are not well-justified taxonomic entities, emphasizing the importance of leveraging whole-genome sequence data to inform subspecies designations. Additionally, our investigation has established experimental procedures for generating whole-genome sequences from air-dried museum specimens and provides key genomic resources to inform future genomic investigations of wild mouse diversity.

evolutionary biology↗

bioRxiv2022

Rapid evolution of the fine-scale recombination landscape in wild house mouse (Mus musculus) populations

Meiotic recombination is an important evolutionary force and essential meiotic process. In many species, recombination events concentrate into "hotspots" defined by the site-specific binding of PRMD9. Rapid evolution of PRDM9s zinc finger DNA-binding array leads to remarkably abrupt shifts in the genomic distribution of hotspots between species, but the question of how Prdm9 allelic variation shapes the landscape of recombination between populations remains less well understood. Wild house mice (Mus musculus) harbor exceptional Prdm9 diversity, with >100 alleles identified to date, and pose a particularly powerful system for addressing this open question. We employed a coalescent-based approach to construct fine-scale, sex-averaged recombination maps from contemporary patterns of linkage disequilibrium in nine geographically isolated wild house mouse populations, including multiple populations from each of three subspecies. Comparing maps between wild mouse populations and subspecies reveals several themes. First, we report weak fine- and broad-scale recombination map conservation across subspecies and populations, with genetic divergence offering no clear prediction for recombination map divergence. Second, most hotspots are unique to one population, an outcome consistent with minimal sharing of Prdm9 alleles between surveyed populations. Finally, by contrasting aggregate hotspot activity on the X versus autosomes, we uncover evidence for population-specific differences in the degree and direction of sex-dimorphism for recombination. Overall, our findings illuminate the variability of both the broad- and fine-scale recombination landscape in Mus musculus and underscore the functional impact of Prdm9 allelic variation in wild mouse populations.

genetics↗

bioRxiv2022

Strain level centromere variation influences CENP-A association dynamics and centromere function

Centromeres are rapidly evolving chromatin domains that fulfill essential roles in chromosome segregation. Rapid centromere sequence evolution imposes strong selection for compensatory changes in centromere-associated kinetochore proteins, leading to striking co-evolutionary trends across species. However, it remains unknown whether within species centromere sequence diversity leads to functional differences in kinetochore protein association. House mice (Mus musculus) exhibit significant variation in centromere satellite array size and sequence heterogeneity, but the amino acid sequence of CENP-A, a centromere-specific histone variant that specifies centromere identity, is conserved. We hypothesize that centromere satellite sequence variation leads to differences in the localization of CENP-A among house mice, with potential consequences for meiotic drive and genome stability. Using CENP-A chromatin immunoprecipitation with a customized k-mer based, reference-blind bioinformatic analysis strategy, we compare the CENP-A sequence association landscape in four diverse inbred mouse strains (C57BL/6J, CAST/EiJ, LEWES/EiJ, and PWK/PhJ). We uncover significant strain-level diversity in CENP-A associated sequences, with more closely related strains exhibiting more similar CENP-A association profiles. LEWES/EiJ and CAST/EiJ show mild association of CENP-A with the pericentromeric satellite repeat, countering the prevailing notion that functional centromere size is solely determined by the size of the minor satellite array. Strain-specific CENP-A association profiles are enriched for unique suites of transcription factor motifs, hinting at strain differences in centromere transcription. Given the importance of centromere-CENP-A association and centromere transcription for both kinetochore assembly and chromosome segregation fidelity, our findings suggest a potential mechanism for centromere-mediated variation in genome stability among inbred mouse strains.

genomics↗

bioRxiv2022

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

The BXD family of recombinant inbred mice were developed by crossing and inbreeding progeny of C57BL/6J and DBA/2J strains. This family is the largest and most extensively phenotyped mammalian experimental genetic resource. Although used in genetics for 52 years, we do not yet have comprehensive data on DNA variants segregating in the BXDs. Using linked-read whole-genome sequencing, we sequenced 152 members of the family at about 40X coverage and quantified most variants. We identified 6.25 million polymorphism segregating at a near-optimal minor allele frequency of 0.42. We also defined two other major variants: strain-specific de novo singleton mutations and epoch-specific de novo polymorphism shared among subfamilies of BXDs. We quantified per-generation mutation rates of de novo variants and demonstrate how founder-derived, strain-specific, and epoch-specific variants can be analyzed jointly to model genome-phenome causality. This integration enables forward and reverse genetics at scale, rapid production of any of more than 10,000 diallel F1 hybrid progeny to test predictions across diverse environments or treatments. Combined with five decades of phenome data, the BXD family and F1 hybrids are a major resource for systems genetics and experimental precision medicine.

genomics↗

bioRxiv2021

Patterns and Mechanisms of Sex Ratio Distortion in the Collaborative Cross Mouse Mapping Population

In species with single-locus, chromosome-based mechanisms of sex determination, the laws of segregation predict an equal ratio of females to males at birth. Here, we show that departures from this Mendelian expectation are commonplace in the 8-way recombinant inbred Collaborative Cross (CC) mouse population. More than one-third of CC strains exhibit significant sex ratio distortion (SRD) at wean, with twice as many male-biased than female-biased strains. We show that these pervasive sex biases persist across multiple breeding environments, are stable over time, are not fully mediated by maternal effects, and are not explained by sex-biased neonatal mortality. SRD exhibits a heritable component, but QTL mapping analyses and targeted investigations of sex determination genes fail to nominate any large effect loci. These findings, combined with the reported absence of sex ratio biases in the CC founder strains, suggest that SRD manifests from multilocus combinations of alleles only uncovered in recombined CC genomes. We speculate that the genetic shuffling of eight diverse parental genomes during the early CC breeding generations led to the decoupling of sex-linked drivers from their co-evolved suppressors, unleashing complex, multiallelic systems of sex chromosome drive. Consistent with this interpretation, we show that several CC strains exhibit copy number imbalances at co-evolved X-and Y-linked ampliconic genes that have been previously implicated in germline genetic conflict and SRD in house mice. Overall, our findings reveal the pervasiveness of SRD in the CC population and nominate the CC as a powerful resource for investigating sex chromosome genetic conflict in action. ARTICLE SUMMARYWe compiled breeding records from The Collaborative Cross (CC) mouse mapping population to quantify the frequency and explore potential mechanisms of sex ratio distortion. Strikingly, more than one-third of CC strains yield significantly sex-biased litters. These sex biases are not mediated by environmental effects and are moderately heritable. We conclude that the widespread sex ratio distortion in the CC manifests from multilocus permutations of selfish sex-linked elements and suppressors that are only recovered in the recombinant CC strains.

genetics↗

bioRxiv2021

Selection shapes the landscape of functional variation in wild house mice

BackgroundThrough 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. ResultsHere, 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. ConclusionsOverall, 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 unsdercores 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.

evolutionary biology↗