Biology subjects

Wooldridge, L. K.

Publications and source records attributed to Wooldridge, L. K..

4 recordsLinked to original sources

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

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↗

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↗

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↗