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:Genome-wide gene expression studies may provide a comprehensive insight in gene activities and biological pathways differing between individuals and tissues (even closely related tissues building complex organs such as the brain). Our research addressed both kinds of gene expression variation – between brain regions and between individuals – by expression profiling in brain tissues derived from eight brain regions and blood from 12 vervet monkeys (Chlorocebus aethiops sabaeus). We employed the non-human primate model to assure tissue quality and to enhance the probability of precise dissection of the brain tissues, which is difficult to realize in human subjects. We characterized brain regional differences in gene expression levels which may relate to specific functions of brain tissues including disease symptoms affecting specific brain regions. We focused on inter-individual variability of brain transcript levels in different regions that correlates well between blood and brain tissues and therefore could be further reliably studied in easily accessible blood samples. Applying very stringent transcript selection criteria including 1). considerable similarities between brain and blood tissues, 2). consistent repeat measurements in blood, 3). higher inter-individual than intra-individual variability and 4). detection in all tissue samples, allowed us to identify transcripts in which inter-individual variation in brain expression profiles indicates possible genetic factors regulating gene transcript levels. High heritabilities of these transcript levels indicated that our approach focusing on transcripts showing higher inter-individual variability than intra-individual variability identifies transcripts with a strong genetic component.
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. Gene expression was measured in whole testis from males aged 62-86 days. Samples include 190 first generation lab-bred male offspring of wild-caught mice from the Mus musculus musculus - M. m. domesticus hybrid zone.
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:The inter-patient variability of tumor proteomes has been investigated on a large scale but many tumors display also intra-tumoral heterogeneity (ITH) regarding morphological and genetic features. To what extent the local proteome of tumors intrinsically differs remains largely unknown. Here, we used hepatocellular carcinoma (HCC) as a model system, to quantify both inter- and intra-tumor heterogeneity across human patient specimens with spatial resolution. We first defined proteomic features that robustly distinguish neoplastic from the directly adjacent non-neoplastic tissue by integrating proteomic data from human patient samples and genetically defined mouse models with available gene expression data. We then demonstrated the existence of intra-tumoral variations in protein abundance that re-occur across different patient samples, and affect clinically relevant proteins, even in the absence of obvious morphological differences or genetic alterations. Our work demonstrates the suitability and the benefits of using mass spectrometry based proteomics to analyze diagnostic tumor specimens with spatial resolution