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A Panel of Inbred Mouse Strains Suitable for Analysis of Complex Genetic Traits

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A Panel of Inbred Mouse Strains Suitable for Analysis of Complex Genetic Traits Mamm Genome DOI 10.1007/s00335-012-9411-5 Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits Anatole Ghazalpour • Christoph D. Rau • Charles R. Farber • Brian J. Bennett • Luz D. Orozco • Atila van Nas • Calvin Pan • Hooman Allayee • Simon W. Beaven • Mete Civelek • Richard C. Davis • Thomas A. Drake • Rick A. Friedman • Nick Furlotte • Simon T. Hui • J. David Jentsch • Emrah Kostem • Hyun Min Kang • Eun Yong Kang • Jong Wha Joo • Vyacheslav A. Korshunov • Rick E. Laughlin • Lisa J. Martin • Jeffrey D. Ohmen • Brian W. Parks • Matteo Pellegrini • Karen Reue • Desmond J. Smith • Sotirios Tetradis • Jessica Wang • Yibin Wang • James N. Weiss • Todd Kirchgessner • Peter S. Gargalovic • Eleazar Eskin • Aldons J. Lusis • Rene´e C. LeBoeuf Received: 29 March 2012 / Accepted: 4 July 2012 Ó Springer Science+Business Media, LLC 2012 Abstract We have developed an association-based approach strains for a variety of clinical traits as well as intermediate using classical inbred strains of mice in which we correct for phenotypes and have shown that the HMDP has sufficient population structure, which is very extensive in mice, using an power to map genes for highly complex traits with resolution efficient mixed-model algorithm. Our approach includes inbred that is in most cases less than a megabase. In this essay, we parental strains as well as recombinant inbred strains in order to review our experience with the HMDP, describe various capture loci with effect sizes typical of complex traits in mice ongoing projects, and discuss how the HMDP may fit into the (in the range of 5 % of total trait variance). Over the last few larger picture of common diseases and different approaches. years, we have typed the hybrid mouse diversity panel (HMDP) Anatole Ghazalpour, Christoph D. Rau, Charles R. Farber, Brian J. Bennett, Luz D. Orozco, and Atila van Nas contributed equally to this work. A. Ghazalpour Á M. Civelek Á R. C. Davis Á S. T. Hui Á S. W. Beaven B. W. Parks Á A. J. Lusis Division of Digestive Diseases, Department of Medicine, Department of Medicine, David Geffen School of Medicine, David Geffen School of Medicine, University of California, University of California, Los Angeles, CA, USA Los Angeles, CA, USA C. D. Rau Á J. N. Weiss Á A. J. Lusis T. A. Drake Department of Microbiology, Immunology and Molecular Department of Pathology and Laboratory Medicine, Genetics, University of California, Los Angeles, CA, USA David Geffen School of Medicine, University of California, Los Angeles, CA, USA C. R. Farber Departments of Medicine and Biochemistry and Molecular R. A. Friedman Genetics, and Center for Public Health Genomics, University Department of Otology/Skull Base Surgery, of Virginia, Charlottesville, VA, USA House Research Institute, Los Angeles, CA, USA B. J. Bennett N. Furlotte Á E. Kostem Á E. Y. Kang Á E. Eskin Department of Genetics, and Nutrition Research Institute, Department of Computer Sciences, University of California, University of North Carolina, Chapel Hill, NC, USA Los Angeles, CA, USA L. D. Orozco Á A. van Nas Á C. Pan Á J. W. Joo Á J. D. Jentsch L. J. Martin Á K. Reue Á J. Wang Á E. Eskin Á A. J. Lusis Department of Psychology & Behavioral Neuroscience and Department of Human Genetics, David Geffen School of Psychiatry & Biobehavioral Sciences, David Geffen School Medicine, University of California, Los Angeles, CA, USA of Medicine, University of California, Los Angeles, CA, USA H. Allayee H. M. Kang Department of Preventive Medicine, Keck School of Medicine, Department of Biostatistics, School of Public Health, University of Southern California, Los Angeles, CA, USA University of Michigan, Ann Arbor, MI, USA 123 A. Ghazalpour et al.: Hybrid mouse diversity panel Introduction To address these limitations, we have developed an association-based approach using classical inbred strains of The human genome-wide association studies (GWAS) of mice (Bennett et al. 2010). We follow previous attempts to the last several years have provided the first unbiased views apply association in mice (Cervino et al. 2007; Grupe et al. of the genetics of common complex diseases, such as 2001; Guo et al. 2007; Liao et al. 2004; Liu et al. 2007; coronary artery disease, diabetes, and cancer. Many of the Pletcher et al. 2004) with two differences. First, we correct loci contain novel genes not previously connected to their for population structure, which is very extensive in mice, respective disease, indicating that there is great potential to using an efficient mixed-model algorithm (EMMA) (Kang discover new pathways and new targets for therapeutic et al. 2008). Second, to capture loci with effect sizes typical intervention. These GWAS do, however, have some of complex traits in mice (in the range of 5 % of total trait important limitations. First, human GWAS are not well variance), we supplemented the population with recombi- powered to study genetic interactions, such as gene-by-gene nant inbred (RI) strains. or gene-by-environment interactions (Zuk et al. 2012). Over the last few years, we have typed the hybrid mouse Second, it will be difficult to move from locus to a disease diversity panel (HMDP) strains for a variety of clinical pathway directly in humans (Altshuler et al. 2008). And traits as well as intermediate phenotypes, and have shown third, for most diseases, GWAS have identified only a small that the HMDP has sufficient power to map genes for fraction of the total genetic contributions and, thus, there is a highly complex traits with resolution that is in most cases great deal more to be discovered (Altshuler et al. 2008; less than a megabase. In this essay, we review our expe- Manolio et al. 2009). rience with the HMDP, describe various ongoing projects, To simplify genetic analysis, natural variations relevant and discuss how the HMDP may fit into the larger picture to disease have been studied in mice and rats (Ahlqvist of common diseases and different approaches. et al. 2011; Flint and Mackay 2009; Keane et al. 2011). This has generally involved traditional linkage mapping methods with crosses between different strains to identify Overview of the HMDP quantitative trait loci (QTLs). An important problem with such analysis has been poor mapping resolution because The hybrid mouse diversity panel (HMDP) consists of a the QTLs generally contain hundreds of genes, making the population of over 100 inbred mouse strains selected for identification of the causal genes difficult. usage in systematic genetic analyses of complex traits J. W. Joo S. Tetradis Á A. J. Lusis Bioinformatics Program, David Geffen School of Medicine, Division of Diagnostic and Surgical Science, School of University of California, Los Angeles, CA, USA Dentistry, University of California, Los Angeles, CA, USA V. A. Korshunov J. Wang Department of Medicine, Aab Cardiovascular Research Institute, Department of Medicine/Cardiology, David Geffen School University of Rochester School of Medicine and Dentistry, of Medicine, University of California, Los Angeles, CA, USA Rochester, NY, USA Y. Wang R. E. Laughlin Division of Molecular Medicine, Department of Anesthesiology, Semel Institute for Neuroscience and Human Behavior, Physiology and Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA University of California, Los Angeles, CA, USA J. D. Ohmen T. Kirchgessner Á P. S. Gargalovic Department of Cell Biology and Genetics, Department of Cardiovascular Drug Discovery, House Research Institute, Los Angeles, CA, USA Bristol-Myers Squibb Co, Pennington, NJ, USA M. Pellegrini R. C. LeBoeuf (&) Department of Molecular, Cell and Developmental Biology, Division of Metabolism, Endocrinology and Nutrition, University of California, Los Angeles, CA, USA Department of Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109-4725, USA D. J. Smith e-mail: [email protected] Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA S. Tetradis Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA 123 A. Ghazalpour et al.: Hybrid mouse diversity panel (Table 1). Our goals in selecting the strains were to (1) greater than 5 % minor allele frequency (mean and median increase resolution of genetic mapping, (2) have a renew- minor allele frequency of 28 and 31 %) and are polymor- able resource that is available to all investigators world- phic between the strains. Using 0.8 as the r2 cutoff to define wide, and (3) provide a shared data repository that would LD, there are a total of 13,706 LD blocks with the median allow the integration of data across multiple scales, including size of 42.8 kb per block (mean of 143.3 kb per block) genomic, transcriptomic, metabolomic, proteomic, and scattered throughout the genome (Fig. 1). Since LD blocks clinical phenotypes. The core of our panel for association are more likely to define the window in which a candidate mapping (Bennett et al. 2010; Cervino et al. 2007; Grupe gene for a locus resides, the presence of small LD in the et al. 2001) consists of 29 classic parental inbred strains HMDP suggests that the number of causal candidate genes which are a subset of a group of mice commonly called the will be on average fewer than five genes per locus. This is a mouse diversity panel. We settled on our strains by elimi- considerable improvement over mapping resolution in nating closely related strains and removing wild-derived traditional linkage studies and/or in outbred stock mice strains. The decision to remove wild-derived stains is based where, on average, the number of candidate genes for each on the tradeoff between statistical power and genetic diver- locus ranges from 10 to 50. Large blocks (defined as LD sity. While we were sacrificing the genetic diversity by blocks[1 Mb) are also present in the HMDP panel but not leaving out wild-derived strains, our panel increased the frequently.
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