Project description:Chromatin accessibility is a hallmark of active regulatory function in the genome and variation of chromatin accessibility across individuals has been shown to contribute to complex traits and disease susceptibility. However, the mechanisms responsible for chromatin variation among different individuals and how this variation contributes to phenotypic diversity remain poorly understood. We examined chromatin accessibility variation in liver tissue from seven strains of adult mice that have phenotypic diversity in response to a high-fat/high-sucrose diet. Remarkably, nearly 40% of the loci with the greatest degree of chromatin variability across the strains are associated with transposable elements (TEs), with evolutionarily younger TEs being particularly enriched for regions of chromatin variation. We found that evolutionary younger and older TEs have differential chromatin accessibility profiles and are enriched for binding sites of different transcription factors, indicating the role of TEs in the evolution of regulatory networks in the liver. We also demonstrate that TE polymorphisms and epigenetic regulation of TEs contribute to regulatory variation across different strains through providing binding sites for liver transcription factors. Intriguingly, variable chromatin loci that are associated with liver metabolism are primarily TE-associated. We demonstrate that TEs contribute to regulatory variation in liver and have downstream effects on metabolism. Our data reveal TEs as a novel and important contributor to regulatory and phenotypic variation in the liver and suggest that regulatory variation at TEs is a major contributor to phenotypic variation in populations. Examination of chromatin accessibility with FAIRE-seq in livers of male mice (A/J, AKR/J, BALB/cJ, C57BL/6J, C3H/HeJ, CBA/J, DBA/2J, BXH2/TyJ, and BXH19/TyJ) fed a high-fat, high-sucrose diet.
Project description:To characterize the genetic basis of hybrid male sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL - but not cis eQTL - were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
Project description:To investigate the differences in microRNA expression profiles between fibrotic and normal livers, we performed microRNA microarrays for total RNA extracts isolated from mouse livers treated with carbontetrachloride (CCl4) or corn-oil for 10 weeks (n=3/group). MicroRNAs were considered to have significant differences in expression level when the expression difference showed more than two-fold change between the experimental and control groups at p<0.05. We found that 12 miRNAs were differentially expressed in CCl4-induced fibrotic liver.
Project description:Analysis of gene expression profiles is an attractive method for discovering how animals respond to environmental challenges in nature. Compared to low altitudes, high altitudes are characterized by reduced partial pressures of oxygen (hypoxia) and cooler ambient temperatures To better understand how mammals cope with high altitudes, we trapped wild house mice (Mus musculus domesticus) from 3 populations in La Paz, Bolivia (3000 - 3600 m) and 3 populations in Lima, Peru (0 – 200 m). Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays were use to measure mRNA abundance in the livers of these mice.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
Project description:The replication timing program, or the order in which DNA is duplicated during S-phase, is associated with various features of chromosome structure and function, including gene expression, histone modifications, and 3-D compartmentalization of chromatin.
Project description:Analysis of gene expression profiles is an attractive method for discovering how animals respond to environmental challenges in nature. Compared to low altitudes, high altitudes are characterized by reduced partial pressures of oxygen (hypoxia) and cooler ambient temperatures To better understand how mammals cope with high altitudes, we trapped wild house mice (Mus musculus domesticus) from 3 populations in La Paz, Bolivia (3000 - 3600 m) and 3 populations in Lima, Peru (0 M-bM-^@M-^S 200 m). Affymetrix GeneChipM-BM-. Mouse Genome 430 2.0 Arrays were use to measure mRNA abundance in the livers of these mice. Eighteen male house mice were trapped from three different locations (3 mice per location)at high alttiude (La Paz, Bolivia, 3600 m) and from three locations at low altiditude (Lima, Peru, 100 m). Total mRNA was extracted from the livers and used for hybridization of Affymetrix GeneChip Mouse expression set 420.
Project description:Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.