Widespread over-expression of the X chromosome in sterile F1 hybrid mice
Ontology highlight
ABSTRACT: We used a reciprocal cross of Mus musculus and M. domesticus in which F1 males are sterile in one direction and fertile in the other direction, in order to associate expression differences with sterility. Four different crosses were performed. A cross between two strains within each mouse species (M. musculus, PWK/PhJ and CZECHII/EiJ; M. domesticus, LEWES/EiJ and WSB/EiJ). And two reciprocal crosses between a domesticus (LEWES/EiJ) and a musculus (PWK/PhJ) strain. The cross between a musculus female and a domesticus male produces sterile male offspring - whereas all other crosses produced fertile male offspring. Testis tissue from three male mice (60 days old) from all four crosses were analysed on the Affymetrix MG 430.2. Array.
ORGANISM(S): Mus musculus musculus x M. m. domesticus
Project description:We performed RNaseq of liver, hypothalamus and vomeronasal organ crosses between inbred stains of M. m. domesticus (strain WSB/EiJ) and M. m. musculus (PWD/PhJ). We also sequenced RNA from the same tissues from parental M. m. musculus (PWD/PhJ).
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:To determine if genetic background can modulate severity of an infection, we studied the host responses to influenza infections in the eight genetically highly diverse Collaborative Cross (CC) founder mice. The CC founder (C57BL/6J, 129S1/SvlmJ, CAST/EiJ, PWK/PhJ) were intranasally infected with influenza A/HK/01/68 (H3N2) with 20μl virus solution (1x101 ffu) or mock infected (with PBS). After infection lung was collected at different time points (mock_d3), d3, d5).
Project description:To determine if genetic background can modulate severity of an infection, we studied the host responses to influenza infections in the eight genetically highly diverse Collaborative Cross (CC) founder mice. The CC founder (C57BL/6J, 129S1/SvlmJ, CAST/EiJ, PWK/PhJ) were intranasally infected with influenza A/HK/01/68 (H3N2) with 20μl virus solution (1x101 ffu) or mock infected (with PBS). After infection lung was collected at different time points (mock_d3), d3, d5).
Project description:This is the proteomics component of a multi-omics analysis of the aging murine retina. Age is a critical risk factor for vision-threatening retinopathies. Susceptibility to age-related retinal neurodegeneration is genetically influenced, however, no studies have addressed molecular retinal aging signatures across genetically diverse populations. Here, we profile retinal proteomics in an array of genetically diverse mice with age. Proteomics were employed to profile retinal aging signatures in C57BL/6J (B6), 129S1/SvImJ, NZO/HlLtJ (NZO), WSB/EiJ (WSB), CAST/EiJ, PWK/PhJ, NOD/ShiLtJ, A/J, and BALB/cJ mouse strains at 4, 12, and 18M. These data were collated into a publicly available resource.
Project description:Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene–environment interactions. We tested the susceptibility of seven mouse strains to develop NASH. The severity of the clinical phenotypes observed varied widely across strains. PWK/PhJ mice were the most prone to develop hepatic inflammation and the only strain to progress to NASH with extensive fibrosis, while CAST/EiJ mice were completely resistant. Levels of mitochondrial transcripts and proteins as well as mitochondrial function were robustly reduced specifically in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, the NASH gene expression profile of PWK/PhJ mice had the highest overlap with the human NASH signature. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model with features of the human NASH.
Project description:Collaborative Cross (CC) mouse embryonic fiborolasts (MEF) cells obtained from the eight Founder animals [PWK/PhJ, NZO/HILtJ, NOD/ShiLtJ, WSB/EiJ, A/J, CAST, C57BL/6J, and 129/SvlmJ] were immortalized and the cell lines used to assess differences in transcriptional responses following treatment with type I, II and III recombinant mouse interferon.
Project description:Transcription profiling by high throughput sequencing of a Diversity Outbred mice population and the eight founder strains: A/J, 129S1/SvImJ, C57BL/6J, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ
Project description:We performed an inter-species comparison of murine spermatogenesis using the inbred strains C57B6J, CAST/EiJ and CAROLI/EiJ to investigate the cell type-specific evolution of gene expression levels among closely related species. We also used F1 crosses of C57B6J and CAST/EiJ to investigate context-specific regulatory effects on gene expression in cis and trans by measuring allele-specific expression (Goncalves et al. 2012; Wittkopp et al. 2021). To this end, single-cell RNA-Sequencing data was generated from dissociated testicular tissue in each mouse strain using the 10x Genomics scRNA-Seq platform.
Project description:Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer’s disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were characterized using metabolic, functional, neuropathological and transcriptional assays. Strain-, sex- and genotype-specific differences were observed in cognitive ability, neurodegeneration, plaque load, cerebrovascular health and cerebral amyloid angiopathy. Analyses of brain transcriptional data showed strain was the greatest driver of variation. We identified significant variation in myeloid cell numbers in wild type mice of different strains as well as significant differences in plaque-associated myeloid responses in APP/PS1 mice between the strains. Collectively, these data support the use of wild-derived strains to better model the complexity of human AD.