title: Commercially available outbred mice for genome-wide association studies.
abstract: Genome-wide association studies using commercially available outbred mice can detect genes involved in phenotypes of biomedical interest. Useful populations need high-frequency alleles to ensure high power to detect quantitative trait loci (QTLs), low linkage disequilibrium between markers to obtain accurate mapping resolution, and an absence of population structure to prevent false positive associations. We surveyed 66 colonies for inbreeding, genetic diversity, and linkage disequilibrium, and we demonstrate that some have haplotype blocks of less than 100 Kb, enabling gene-level mapping resolution. The same alleles contribute to variation in different colonies, so that when mapping progress stalls in one, another can be used in its stead. Colonies are genetically diverse: 45% of the total genetic variation is attributable to differences between colonies. However, quantitative differences in allele frequencies, rather than the existence of private alleles, are responsible for these population differences. The colonies derive from a limited pool of ancestral haplotypes resembling those found in inbred strains: over 95% of sequence variants segregating in outbred populations are found in inbred strains. Consequently it is possible to impute the sequence of any mouse from a dense SNP map combined with inbred strain sequence data, which opens up the possibility of cataloguing and testing all variants for association, a situation that has so far eluded studies in completely outbred populations. We demonstrate the colonies' potential by identifying a deletion in the promoter of H2-Ea as the molecular change that strongly contributes to setting the ratio of CD4+ and CD8+ lymphocytes.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Binnaz
authors.initials: B
authors.lastname: Yalcin
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nicod
authors.forename: Amarjit
authors.initials: A
authors.lastname: Bhomra
authors.forename: Stuart
authors.initials: S
authors.lastname: Davidson
authors.forename: James
authors.initials: J
authors.lastname: Cleak
authors.forename: Laurent
authors.initials: L
authors.lastname: Farinelli
authors.forename: Magne
authors.initials: M
authors.lastname: Østerås
authors.forename: Adam
authors.initials: A
authors.lastname: Whitley
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Xiangchao
authors.initials: X
authors.lastname: Gan
authors.forename: Martin
authors.initials: M
authors.lastname: Goodson
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Ansu
authors.initials: A
authors.lastname: Satpathy
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Richard
authors.initials: R
authors.lastname: Mott
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
mesh_terms: D000818:Animals; D000830:Animals, Laboratory / Q000235:genetics; D021461:Animals, Outbred Strains / Q000235:genetics*; D002874:Chromosome Mapping; D040961:Genetic Drift; D005819:Genetic Markers; D014644:Genetic Variation / Q000235:genetics; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D007178:Inbreeding; D015810:Linkage Disequilibrium / Q000235:genetics; D051379:Mice; D010641:Phenotype; D010802:Phylogeny; D040641:Quantitative Trait Loci / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D005819:Genetic Markers