Project description:To uncover genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP) with high mapping resolution. By integrating fear phenotypes, transcript profiling data from hippocampus and striatum and genotype information, two gene co-expression networks correlated with context-dependent immobility were identified. We prioritized the key markers and genes in these pathways using intramodular connectivity measures and structural equation modeling. We mapped 27 behavioral quantitative trait loci with a false discovery rate of 5%. We also identified two gene co-expression networks correlated with context-dependent immobility. Highly connected genes in the context fear modules included Psmd6, Ube2a and Usp33, suggesting an important role for ubiquitination in learning and memory. We surveyed the architecture of brain transcript regulation and showed preservation of gene co-expression modules in hippocampus and striatum while also highlighting important differences. Rps15a, Kif3a, Stard7, 6330503K22RIK, and Plvap were among the individual genes whose transcript abundance associated strongly with fear phenotypes.
Project description:To uncover genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP) with high mapping resolution. By integrating fear phenotypes, transcript profiling data from hippocampus and striatum and genotype information, two gene co-expression networks correlated with context-dependent immobility were identified. We prioritized the key markers and genes in these pathways using intramodular connectivity measures and structural equation modeling. We mapped 27 behavioral quantitative trait loci with a false discovery rate of 5%. We also identified two gene co-expression networks correlated with context-dependent immobility. Highly connected genes in the context fear modules included Psmd6, Ube2a and Usp33, suggesting an important role for ubiquitination in learning and memory. We surveyed the architecture of brain transcript regulation and showed preservation of gene co-expression modules in hippocampus and striatum while also highlighting important differences. Rps15a, Kif3a, Stard7, 6330503K22RIK, and Plvap were among the individual genes whose transcript abundance associated strongly with fear phenotypes. Total mRNA islolated from hippocampus and striatum of strains from Hybrid Mouse Diversity Panel and gene expression quantified using Illumina MouseRef-8 v2.0 microarrays. Submission includes gene expression data from 100 strains of HMDP for hippocampus (n=1 for each strain) and 98 strains of HMDP for striatum (n=1 for each strain).
Project description:The genetics of complex disease produce alterations in molecular interactions of cellular pathways which collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer´s disease (LOAD), we constructed gene regulatory networks in hundreds of autopsied brain tissues from LOAD patients and non-demented subjects. We demonstrate that LOAD reconfigures specific portions of the molecular interaction structure, and via an integrative network-based approach we rank ordered these sub-networks (modules) for relevance to LOAD pathology, highlighting the immune/microglia module as the top ranking. Through a Bayesian inference approach we identified multiple key causal regulators for LOAD brains.
Project description:The genetics of complex disease produce alterations in molecular interactions of cellular pathways which collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer´s disease (LOAD), we constructed gene regulatory networks in hundreds of autopsied brain tissues from LOAD patients and non-demented subjects. We demonstrate that LOAD reconfigures specific portions of the molecular interaction structure, and via an integrative network-based approach we rank ordered these sub-networks (modules) for relevance to LOAD pathology, highlighting the immune/microglia module as the top ranking. Through a Bayesian inference approach we identified multiple key causal regulators for LOAD brains.
Project description:The genetics of complex disease produce alterations in molecular interactions of cellular pathways which collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer´s disease (LOAD), we constructed gene regulatory networks in hundreds of autopsied brain tissues from LOAD patients and non-demented subjects. We demonstrate that LOAD reconfigures specific portions of the molecular interaction structure, and via an integrative network-based approach we rank ordered these sub-networks (modules) for relevance to LOAD pathology, highlighting the immune/microglia module as the top ranking. Through a Bayesian inference approach we identified multiple key causal regulators for LOAD brains.
Project description:Adolescent sensitivity to alcohol is predictive of later alcohol use and is influenced by genetic background. Data from our laboratory suggested that adolescent C57BL/6J and DBA/2J inbred mice differed in susceptibility to dorsal hippocampus-dependent contextual fear learning deficits after acute alcohol exposure. To investigate the biological underpinnings of this strain difference, we examined dorsal hippocampus gene expression via RNA-sequencing after alcohol and/or fear conditioning across male and female C57BL/6J and DBA/2J adolescents. Strains exhibited dramatic differences in dorsal hippocampal gene expression. Specifically, C57BL/6J and DBA/2J strains differed in 3526 transcripts in males and 2675 transcripts in females. We identified pathways likely to be involved in mediating alcohol’s effects on learning, including networks associated with Chrna7 and Fmr1. These findings provide insight into the mechanisms underlying strain differences in alcohol’s effects on learning and suggest that different biological networks are recruited for learning based on genetics, sex, and alcohol exposure.
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.