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Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits.

ABSTRACT: 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.

SUBMITTER: Ghazalpour A

PROVIDER: S-EPMC3586763 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits.

Ghazalpour Anatole A Rau Christoph D CD Farber Charles R CR Bennett Brian J BJ Orozco Luz D LD van Nas Atila A Pan Calvin C Allayee Hooman H Beaven Simon W SW Civelek Mete M Davis Richard C RC Drake Thomas A TA Friedman Rick A RA Furlotte Nick N Hui Simon T ST Jentsch J David JD Kostem Emrah E Kang Hyun Min HM Kang Eun Yong EY Joo Jong Wha JW Korshunov Vyacheslav A VA Laughlin Rick E RE Martin Lisa J LJ Ohmen Jeffrey D JD Parks Brian W BW Pellegrini Matteo M Reue Karen K Smith Desmond J DJ Tetradis Sotirios S Wang Jessica J Wang Yibin Y Weiss James N JN Kirchgessner Todd T Gargalovic Peter S PS Eskin Eleazar E Lusis Aldons J AJ LeBoeuf Renée C RC

Mammalian genome : official journal of the International Mammalian Genome Society 20120815 9-10

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) strain ...[more]

PMID: 22892838

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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. 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.

Dataset Information

Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits.

Publications

Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits.

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