Project description:Survey of gene expression in 7 brain regions at 6-8wks of age in 20 inbred strains of laboratory mice. Autism is a highly heritable neurodevelopmental disorder with no consistent neuropathological hallmarks, diagnosed through behavioral inventory rather than a biomarker. The genetic etiology of autism is complex and likely has a significant interaction with the environment. To investigate the molecular and genetic nature of autism, we modeled the core symptom of social deficits in inbred strains of mice. Using gene expression profiles and behavioral phenotyping relevant to social deficits, we have identified basic cellular functions that may be dysregulated in the brain in autism. Correlations between these two complex datasets indicate cell morphology, proliferation, and migration may be perturbed in disorders of altered social behavior. Furthermore, these data in the mouse show significant overlap with published expression profiling in lymphoblastoid lines from autistic individuals. Keywords: Comparison between inbred strains and brain regions.
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:Survey of gene expression in ten common inbred strains of laboratory mouse. Seven brain regions examined: amygdala, basal ganglia, cerebellum, frontal cortex, hippocampus, cingulate cortex, olfactory bulb. Keywords: Genetic background and brain region Sample data tables were removed because the ID_REF identifiers did not match the platform IDs
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 M-bM-^@M-^Xhotspots,M-bM-^@M-^Y 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 M-bM-^@M-^XfertileM-bM-^@M-^Y 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. Gene expression was measured in whole testis in males aged 70(M-BM-15) days. Samples include 294 WSB/EiJ x PWD/PhJ F2s, 11 PWD/PhJ x WSB/EiJ F2s, 8 WSB/EiJ, 8 PWD/PhJ, 6 PWD/PhJ x WSB/EiJ F1s and 4 WSB/EiJ x PWD/PhJ F1s.
Project description:The collaborative cross (CC) founder strains include five classical inbred laboratory strains (129S1/SvlmJ, A/J, C57BL/6J (B6), NOD/ShiLtJ, and NZO/HILtJ) and three wild-derived strains (CAST/EiJ, PWK/PhJ (PWK) and WSB/EiJ) The strains encompass 89% of the genetic diversity available in Mus musculus and about 10 to 20 times more genetic diversity than found in Homo sapiens. For more than 60 years the B6 strain has been used as the model strain for high ethanol preference/high consumption. However, another one of the CC founder strains, PWK, was identified as a high ethanol preference/high consumption strain. The current study determined how the transcriptomes of the B6 and PWK strains differed from the 6 low preference CC strains across 3 nodes of the brain addiction circuit. RNA-Seq data were collected from the central nucleus of the amygdala, the nucleus accumbens core and the prelimbic cortex. Differential expression (DE) analysis was performed in each of these brain regions for all 28 possible pairwise comparisons of the CC founder strains. Unique genes for each strain were identified by selecting for genes that differed significantly (false discovery rate (FDR) < 0.05) from all other strains in the same direction. B6 was identified as the most distinct inbred laboratory strain, having the highest number of total differently expressed genes (DEGs) and DEGs with high log fold change, and unique genes compared to other CC strains. Less than 50 unique DEGs were identified in common between B6 and PWK within all three brain regions, indicating the strains potentially represent two distinct genetic signatures for risk for high ethanol-preference. 238 DEGs were found to be commonly different between B6, PWK and the average expression of the remaining CC strains within all three regions. The commonly different up-expressed genes were significantly enriched (FDR < 0.001) among genes associated with neuroimmune function. These data compliment the observation that neuroimmune signaling is key to understanding alcohol use disorder and and support use of these 8 strains and the highly heterogeneous mouse populations derived from them to identify alcohol-related brain mechanisms and treatment targets.
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:Survey of gene expression in ten common inbred strains of laboratory mouse. Seven brain regions examined: amygdala, basal ganglia, cerebellum, frontal cortex, hippocampus, cingulate cortex, olfactory bulb. Experiment Overall Design: Tissue from three animals was pooled on each array. Three biological replicates per strainxregion condition. Animals were 4-5 weeks of age.
Project description:SILAC based protein correlation profiling using size exclusion of protein complexes derived from seven Mus musculus tissues (Heart, Brain, Liver, Lung, Kidney, Skeletal Muscle, Thymus)
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.