High-Resolution Genetic Mapping Using the Mouse Diversity Outbred Population

The JAX Diversity Outbred population is a new mouse resource derived from partially inbred Collaborative Cross strains and maintained by randomized outcrossing. As such, it segregates the same allelic variants as the Collaborative Cross but embeds these in a distinct population architecture in which each animal has a high degree of heterozygosity and carries a unique combination of alleles. Phenotypic diversity is striking and often divergent from phenotypes seen in the founder strains of the Collaborative Cross. Allele frequencies and recombination density in early generations of Diversity Outbred mice are consistent with expectations based on simulations of the mating design. We describe analytical methods for genetic mapping using this resource and demonstrate the power and high mapping resolution achieved with this population by mapping a serum cholesterol trait to a 2-Mb region on chromosome 3 containing only 11 genes. Analysis of the estimated allele effects in conjunction with complete genome sequence data of the founder strains reduced the pool of candidate polymorphisms to seven SNPs, five of which are located in an intergenic region upstream of the Foxo1 gene.

[1]  J. Cheverud.  Genetics and analysis of quantitative traits , 1999 .

[2]  D. Hartl,et al.  Principles of population genetics , 1981 .

[3]  Gary A. Churchill,et al.  A New Standard Genetic Map for the Laboratory Mouse , 2009, Genetics.

[4]  Carol J. Bult,et al.  The mouse as a model for human biology: a resource guide for complex trait analysis , 2007, Nature Reviews Genetics.

[5]  Frank Dudbridge,et al.  Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. , 2004, American journal of human genetics.

[6]  Catherine E. Welsh,et al.  Subspecific origin and haplotype diversity in the laboratory mouse , 2011, Nature Genetics.

[7]  W. Silvers.  The Coat Colors of Mice , 1979, Springer New York.

[8]  C. Haley,et al.  A simple regression method for mapping quantitative trait loci in line crosses using flanking markers , 1992, Heredity.

[9]  Russell A. Wilke,et al.  Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges , 2007, Nature Reviews Drug Discovery.

[10]  Nengjun Yi,et al.  The Collaborative Cross, a community resource for the genetic analysis of complex traits , 2004, Nature Genetics.

[11]  M. Pushkareva,et al.  Biosynthesis of leukotriene B4 in human polymorphonuclear leukocytes: regulation by cholesterol and other lipids , 2008, Journal of immunotoxicology.

[12]  S. Mohan,et al.  Identification of quantitative trait loci that regulate obesity and serum lipid levels in MRL/MpJ × SJL/J inbred mice Published, JLR Papers in Press, October 27, 2005. , 2006, Journal of Lipid Research.

[13]  Elissa J. Chesler,et al.  The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics , 2008, Mammalian Genome.

[14]  David Higgins,et al.  Haplotype analysis in multiple crosses to identify a QTL gene. , 2004, Genome research.

[15]  W. Russell,et al.  A Study of the Physiological Genetics of Coat Color in the Mouse by Means of the Dopa Reaction in Frozen Sections of Skin. , 1948, Genetics.

[16]  A. Skol,et al.  QTLRel: an R Package for Genome-wide Association Studies in which Relatedness is a Concern , 2011, BMC Genetics.

[17]  Thomas M. Keane,et al.  Mouse genomic variation and its effect on phenotypes and gene regulation , 2011, Nature.

[18]  D. Moore,et al.  Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice. , 2009, Biochimica et biophysica acta.

[19]  Lisa E. Gralinski,et al.  The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population , 2012, Genetics.

[20]  R. Mott,et al.  Bayesian Quantitative Trait Locus Mapping Using Inferred Haplotypes , 2010, Genetics.

[21]  J. Harrow,et al.  A conditional knockout resource for the genome-wide study of mouse gene function , 2011, Nature.

[22]  S. Mohan,et al.  Mapping genetic loci that regulate lipid levels in a NZB/B1NJ×RF/J intercross and a combined intercross involving NZB/B1NJ, RF/J, MRL/MpJ, and SJL/J mouse strains Published, JLR Papers in Press, May 13, 2007. , 2007, Journal of Lipid Research.

[23]  W. Silvers,et al.  The Effects of Genotype and Cell Environment on Melanoblast Differentiation in the House Mouse. , 1956, Genetics.

[24]  B. Stranger,et al.  Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics , 2011, Genetics.

[25]  Yueming Ding,et al.  A customized and versatile high-density genotyping array for the mouse , 2009, Nature Methods.

[26]  Mark Abney,et al.  Genome-Wide Association Studies and the Problem of Relatedness Among Advanced Intercross Lines and Other Highly Recombinant Populations , 2010, Genetics.

[27]  K. Svenson,et al.  A General Bayesian Approach to Analyzing Diallel Crosses of Inbred Strains , 2012, Genetics.

[28]  M. Lynch,et al.  Genetics and Analysis of Quantitative Traits , 1996 .

[29]  Martin S. Taylor,et al.  Genome-wide genetic association of complex traits in heterogeneous stock mice , 2006, Nature Genetics.