Significant Strain Variation in the Mutation Spectra of Inbred Laboratory Mice.

Mutation provides the ultimate source of all new alleles in populations, including variants that cause disease and fuel adaptation. Recent whole genome sequencing studies have uncovered variation in the mutation rate among individuals and differences in the relative frequency of specific nucleotide changes (the mutation spectrum) between populations. Although parental age is a major driver of differences in overall mutation rate among individuals, the causes of variation in the mutation spectrum remain less well understood. Here, I use high-quality whole genome sequences from 29 inbred laboratory mouse strains to explore the root causes of strain variation in the mutation spectrum. My analysis leverages the unique, mosaic patterns of genetic relatedness among inbred mouse strains to identify strain private variants residing on haplotypes shared between multiple strains due to their recent descent from a common ancestor. I show that these strain-private alleles are strongly enriched for recent de novo mutations and lack signals of widespread purifying selection, suggesting their faithful recapitulation of the spontaneous mutation landscape in single strains. The spectrum of strain-private variants varies significantly among inbred mouse strains reared under standardized laboratory conditions. This variation is not solely explained by strain differences in age at reproduction, raising the possibility that segregating genetic differences affect the constellation of new mutations that arise in a given strain. Collectively, these findings imply the action of remarkably precise nucleotide-specific genetic mechanisms for tuning the de novo mutation landscape in mammals and underscore the genetic complexity of mutation rate control

Variation in the CENP-A sequence association landscape across diverse inbred mouse strains.

Centromeres are crucial for chromosome segregation, but their underlying sequences evolve rapidly, imposing strong selection for compensatory changes in centromere-associated kinetochore proteins to assure the stability of genome transmission. While this co-evolution is well documented between species, it remains unknown whether population-level centromere diversity leads to functional differences in kinetochore protein association. Mice (Mus musculus) exhibit remarkable variation in centromere size and sequence, but the amino acid sequence of the kinetochore protein CENP-A is conserved. Here, we apply k-mer-based analyses to CENP-A chromatin profiling data from diverse inbred mouse strains to investigate the interplay between centromere variation and kinetochore protein sequence association. We show that centromere sequence diversity is associated with strain-level differences in both CENP-A positioning and sequence preference along the mouse core centromere satellite. Our findings reveal intraspecies sequence-dependent differences in CENP-A/centromere association and open additional perspectives for understanding centromere-mediated variation in genome stability

Rapid Evolution of the Fine-scale Recombination Landscape in Wild House Mouse (Mus musculus) Populations.

Meiotic recombination is an important evolutionary force and an essential meiotic process. In many species, recombination events concentrate into hotspots defined by the site-specific binding of PRMD9. Rapid evolution of Prdm9\u27s 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 \u3e150 alleles identified to date, and pose a particularly powerful system for addressing this open question. We employed a coalescent-based approach to construct broad- and 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 M. musculus and underscore the functional impact of Prdm9 allelic variation in wild mouse populations

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

Population and subspecies diversity at mouse centromere satellites.

BACKGROUND: Mammalian centromeres are satellite-rich chromatin domains that execute conserved roles in kinetochore assembly and chromosome segregation. Centromere satellites evolve rapidly between species, but little is known about population-level diversity across these loci. RESULTS: We developed a k-mer based method to quantify centromere copy number and sequence variation from whole genome sequencing data. We applied this method to diverse inbred and wild house mouse (Mus musculus) genomes to profile diversity across the core centromere (minor) satellite and the pericentromeric (major) satellite repeat. We show that minor satellite copy number varies more than 10-fold among inbred mouse strains, whereas major satellite copy numbers span a 3-fold range. In contrast to widely held assumptions about the homogeneity of mouse centromere repeats, we uncover marked satellite sequence heterogeneity within single genomes, with diversity levels across the minor satellite exceeding those at the major satellite. Analyses in wild-caught mice implicate subspecies and population origin as significant determinants of variation in satellite copy number and satellite heterogeneity. Intriguingly, we also find that wild-caught mice harbor dramatically reduced minor satellite copy number and elevated satellite sequence heterogeneity compared to inbred strains, suggesting that inbreeding may reshape centromere architecture in pronounced ways. CONCLUSION: Taken together, our results highlight the power of k-mer based approaches for probing variation across repetitive regions, provide an initial portrait of centromere variation across Mus musculus, and lay the groundwork for future functional studies on the consequences of natural genetic variation at these essential chromatin domains

A first genetic portrait of synaptonemal complex variation.

The synaptonemal complex (SC) is a proteinaceous scaffold required for synapsis and recombination between homologous chromosomes during meiosis. Although the SC has been linked to differences in genome-wide crossover rates, the genetic basis of standing variation in SC structure remains unknown. To investigate the possibility that recombination evolves through changes to the SC, we characterized the genetic architecture of SC divergence on two evolutionary timescales. Applying a novel digital image analysis technique to spermatocyte spreads, we measured total SC length in 9,532 spermatocytes from recombinant offspring of wild-derived mouse strains with differences in this fundamental meiotic trait. Using this large dataset, we identified the first known genomic regions involved in the evolution of SC length. Distinct loci affect total SC length divergence between and within subspecies, with the X chromosome contributing to both. Joint genetic analysis of MLH1 foci-immunofluorescent markers of crossovers-from the same spermatocytes revealed that two of the identified loci also confer differences in the genome-wide recombination rate. Causal mediation analysis suggested that one pleiotropic locus acts early in meiosis to designate crossovers prior to SC assembly, whereas a second locus primarily shapes crossover number through its effect on SC length. One genomic interval shapes the relationship between SC length and recombination rate, likely modulating the strength of crossover interference. Our findings pinpoint SC formation as a key step in the evolution of recombination and demonstrate the power of genetic mapping on standing variation in the context of the recombination pathway

Loss of TRP53 (p53) accelerates tumorigenesis and changes the tumor spectrum of SJL/J mice.

Known as the guardian of the genome, transformation-related protein 53 (TRP53) is a well -known tumor suppressor. Here, we describe a novel TRP53 deficient mouse model on a tumor prone background-SJL/J mice. The absence of TRP53 (TRP53 nullizygosity) leads to a shift in the tumor spectrum from a non-Hodgkin\u27s-like disease to thymic lymphomas and testicular teratomas at a very rapid tumor onset averaging ~12 weeks of age. In haplotype studies, comparing tumor prone versus tumor resistant Trp53 null mouse strains, we found that other tumor suppressor, DNA repair and/or immune system genes modulate tumor incidence in TRP53 null strains, suggesting that even a strong tumor suppressor such as TRP53 is modulated by genetic background. Due to their rapid development of tumors, the SJL/J TRP53 null mice generated here can be used as an efficient chemotherapy or immunotherapy screening mouse model

Sexual dimorphism in the meiotic requirement for PRDM9: A mammalian evolutionary safeguard.

In many mammals, genomic sites for recombination are determined by the histone methyltransferase PRMD9. Some mouse strains lacking PRDM9 are infertile, but instances of fertility or semifertility in the absence of PRDM9 have been reported in mice, canines, and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain fertility. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that, in the absence of PRDM9, a PRDM9-independent recombination system is compatible with female meiosis and fertility, suggesting sex-specific regulation of meiotic recombination, a finding with implications for speciation

Prospective Evaluation over 15 Years of Six Breast Cancer Risk Models.

Prospective validation of risk models is needed to assess their clinical utility, particularly over the longer term. We evaluated the performance of six commonly used breast cancer risk models (IBIS, BOADICEA, BRCAPRO, BRCAPRO-BCRAT, BCRAT, and iCARE-lit). 15-year risk scores were estimated using lifestyle factors and family history measures from 7608 women in the Melbourne Collaborative Cohort Study who were aged 50-65 years and unaffected at commencement of follow-up two (conducted in 2003-2007), of whom 351 subsequently developed breast cancer. Risk discrimination was assessed using the C-statistic and calibration using the expected/observed number of incident cases across the spectrum of risk by age group (50-54, 55-59, 60-65 years) and family history of breast cancer. C-statistics were higher for BOADICEA (0.59, 95% confidence interval (CI) 0.56-0.62) and IBIS (0.57, 95% CI 0.54-0.61) than the other models (p-difference ≤ 0.04). No model except BOADICEA calibrated well across the spectrum of 15-year risk (p-value < 0.03). The performance of BOADICEA and IBIS was similar across age groups and for women with or without a family history. For middle-aged Australian women, BOADICEA and IBIS had the highest discriminatory accuracy of the six risk models, but apart from BOADICEA, no model was well-calibrated across the risk spectrum.This work was primarily supported by grant 1129136 from the Australian National Health and Medical Research Council (NHMRC) (https://www.nhmrc.gov.au/). MCCS cohort recruitment was funded by Cancer Council Victoria (https://www.cancervic.org.au/) and VicHealth (https://www.vichealth.vic.gov.au/). The MCCS was further supported by Australian NHMRC grants 209057, 396414 and 1074383, and ongoing follow-up and data management has been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database.TN-D is a recipient of a Career Development Fellowship from the National Breast Cancer Foundation (Australia). JLH and MCS are Senior Principal and Senior Research Fellows of the National Health and Medical Research Council (Australia), respectively. ACA and AJL are supported by grants from Cancer Research UK (C12292/A20861 and PPRPGM19 Nov20\100002)