Hybrid Mouse diversity Panel Liver Expression Profile
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE16780 | GEO | 2009/12/07
SECONDARY ACCESSION(S): PRJNA117535
REPOSITORIES: GEO
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Project description:Novel, systems-based approach to mouse genetics. Expression Profiles from 99 strains of inbred and recombinant inbred mice. Most assayed in triplicate. Two of 288 chips were excluded from the final analysis due to low QC scores.
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Project description:Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis was used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal and femoral BMD revealed four significant associations (-log10P > 5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12 and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism though which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression gene module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cell of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits.
2011-02-25 | GSE27483 | GEO
Project description:Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis was used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal and femoral BMD revealed four significant associations (-log10P > 5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12 and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism though which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression gene module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cell of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits. RNA from cortical bone (femoral diaphysis free of marrow) were profiled from 99 Hybrid Mouse Diversity Panel strains were profiled. Sixteen-week old male mice were used in this study. A total of 1-3 mice per strain were arrayed.
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Project description:We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5% of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase. In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches.
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Project description:Transcriptomes performed on left ventricular heart samples from mice of the hybrid mouse diversity panel, a set of over a hundred inbred strains of mice. In this project, the strains were challenged with Isoproterenol, a beta-adrenergic agonist to induce cardiac hypertrophy and failure. Results are useful for the analysis of heart-related traits in mice
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Project description:Transcriptomes performed on left ventricular heart samples from mice of the hybrid mouse diversity panel, a set of over a hundred inbred strains of mice. In this project, the strains were challenged with Isoproterenol, a beta-adrenergic agonist to induce cardiac hypertrophy and failure. Results are useful for the analysis of heart-related traits in mice Mice were given three weeks of ISO @ 20ug/g/day for three weeks, then sacrificed. Left ventricles from these mice and matched controls were used for transcripome analysis.
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Project description:Cocaine self-administration is a complexly determined trait, with a substantial proportion of individual differences being determined by genetic variation. However, the relevant genetic variants that drive heritable differences in cocaine use remain undiscovered. Cocaine intravenous self-administration (IVSA) procedures in laboratory animals provide opportunities to prospectively investigate neurogenetic influences on the acquisition of voluntary cocaine use. Here, we provide information on cocaine (or saline-as a control) IVSA in 84 members of the hybrid mouse diversity panel (HMDP), an array of genetically distinct classical or recombinant inbred strains. We found cocaine IVSA to be substantially heritable in this population, with strain-level intake ranging for near 0 to >25 mg/kg/session. Though saline IVSA was also found to be heritable, a modest genetic correlation between cocaine and saline IVSA indicates that operant responding for the cocaine reinforcer was influenced, at least in part, by unique genetic variants. Genome-wide association studies (GWAS) of infusions earned in cocaine and saline groups revealed significant quantitative trait loci (QTL) on Chromosomes 3 and 14 for cocaine, but not saline, IVSA. Positional candidates were further prioritized through use of bulk RNA sequencing data that revealed genes with cis-eQTL and genetic correlation to number of infusions. Additionally, these data identify reference strains with extreme cocaine IVSA phenotypes, revealing them as polygenic models of risk and resilience to cocaine reinforcement. This work is part of an ongoing effort to characterize genetic variation that moderates cocaine IVSA that may, in turn, provide a more comprehensive understanding of cocaine risk genetics and neurobiology.
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