Project description:Mouse inbred strains differ in many aspects of their phenotypes, and it is known that gene expression does so too. This gives us an opportunity to isolate the genetic aspect of variation in expression and compare it to other phenotypic variables. We have investigated these issues using an eight-strain expression profile comparison with four replicates per strain on Affymetrix MGU74av2 GeneChips focusing on one well-defined brain tissue (the hippocampus). We identified substantial strain-specific variation in hippocampal gene expression, with more than two hundred genes showing strain differences by a very conservative criterion. Many such genetically driven differences in gene expression are likely to result in functional differences including differences in behaviour. A large panel of inbred strains could be used to identify genes functionally involved in particular phenotypes, similar to genetic correlation. The genetic correlation between expression profiles and function is potentially very powerful, especially given the current large-scale generation of phenotypic data on multiple strains (the Mouse Phenome Project). As an example, the strongest genetic correlation between more than 200 probe sets showing significant differences among our eight inbred strains and a ranking of these strains by aggression phenotype was found for Comt, a gene known to be involved in aggression. Keywords: mouse, inbred strains, hippocampus, genetic comparison
Project description:Mouse inbred strains differ in many aspects of their phenotypes, and it is known that gene expression does so too. This gives us an opportunity to isolate the genetic aspect of variation in expression and compare it to other phenotypic variables. We have investigated these issues using an eight-strain expression profile comparison with four replicates per strain on Affymetrix MGU74av2 GeneChips focusing on one well-defined brain tissue (the hippocampus). We identified substantial strain-specific variation in hippocampal gene expression, with more than two hundred genes showing strain differences by a very conservative criterion. Many such genetically driven differences in gene expression are likely to result in functional differences including differences in behaviour. A large panel of inbred strains could be used to identify genes functionally involved in particular phenotypes, similar to genetic correlation. The genetic correlation between expression profiles and function is potentially very powerful, especially given the current large-scale generation of phenotypic data on multiple strains (the Mouse Phenome Project). As an example, the strongest genetic correlation between more than 200 probe sets showing significant differences among our eight inbred strains and a ranking of these strains by aggression phenotype was found for Comt, a gene known to be involved in aggression. Experiment Overall Design: Total hippocampal RNA was extracted from eight inbred strains of mice and pooled within each strain (six mice/pool, one pool/strain). cDNA samples (eight) were prepared from the total hippocampal RNA and cRNA was prepared twice from cDNA. (Samples labelled 1 & 2 for each strain were from the first cRNA synthesis preparation, samples labelled 3 & 4 for each strain were from the second cRNA synthesis preparation).Each set of cRNA samples (16 in total) were then hybridized in duplicate to the Murine Genome U74Av2 Array (Chip A; Affymetrix, Santa Clara, USA). In total, 32 arrays were used; four arrays (two arrays with cRNA sample replicates in duplicate) for each of eight strains.
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:Genetic linkage analyses in rodents have unveiled numerous genomic loci contributing to a diverse array of traits, such as susceptibility to addictive behaviors and hypertension. To investigate the genetic basis of trait variation in rodents, genetic reference populations, such as the HXB/BXH recombinant inbred (RI) rat panel, have been extensively utilized. The HXB/BXH panel serves as a well-established rat model to dissect genetic variants that modulate metabolic and cardiovascular diseases. The panel has accumulated a wealth of comprehensive genotypic data, transcriptomic profiles, and phenotypic data, enabling integrative analyses to understand the pathway from genomic loci to traits. The parental strains of the HXB/BXH rat panel, SHR/OlaIpcv (SHR) and BN-Lx/Cub (BN-Lx) strains, have been completely sequenced, and sequence variants between them have been well-defined. Integrating genomics, transcriptomics, and proteomics data from these two inbred strains, have successfully identified splice events, genetic variants, and RNA editing. However, there remains a lack of proteome-wide profiling across all 30 HXB/BXH RI strains, and the genetic regulation of protein expression remains largely unexplored.
Project description:Gene-profiling of Tregs across inbred strains. There is a wide inter-individual range in the frequency of FoxP3+ Treg cells, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue accross inbred strains of mice. During this study, we established the gene expression profiles of Treg cells from the various inbred strains of mice.
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.