title: Quantitative trait locus mapping methods for diversity outbred mice.
abstract: Genetic mapping studies in the mouse and other model organisms are used to search for genes underlying complex phenotypes. Traditional genetic mapping studies that employ single-generation crosses have poor mapping resolution and limit discovery to loci that are polymorphic between the two parental strains. Multiparent outbreeding populations address these shortcomings by increasing the density of recombination events and introducing allelic variants from multiple founder strains. However, multiparent crosses present new analytical challenges and require specialized software to take full advantage of these benefits. Each animal in an outbreeding population is genetically unique and must be genotyped using a high-density marker set; regression models for mapping must accommodate multiple founder alleles, and complex breeding designs give rise to polygenic covariance among related animals that must be accounted for in mapping analysis. The Diversity Outbred (DO) mice combine the genetic diversity of eight founder strains in a multigenerational breeding design that has been maintained for >16 generations. The large population size and randomized mating ensure the long-term genetic stability of this population. We present a complete analytical pipeline for genetic mapping in DO mice, including algorithms for probabilistic reconstruction of founder haplotypes from genotyping array intensity data, and mapping methods that accommodate multiple founder haplotypes and account for relatedness among animals. Power analysis suggests that studies with as few as 200 DO mice can detect loci with large effects, but loci that account for <5% of trait variance may require a sample size of up to 1000 animals. The methods described here are implemented in the freely available R package DOQTL.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gatti
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Svenson
authors.affiliation: Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Andrey
authors.initials: A
authors.lastname: Shabalin
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Long-Yang
authors.initials: LY
authors.lastname: Wu
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: William
authors.initials: W
authors.lastname: Valdar
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Petr
authors.initials: P
authors.lastname: Simecek
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Neal
authors.initials: N
authors.lastname: Goodwin
authors.affiliation: Division of Plant Sciences, Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Riyan
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pomp
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois 60637.
authors.forename: Abraham
authors.initials: A
authors.lastname: Palmer
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Chesler
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Karl W
authors.initials: KW
authors.lastname: Broman
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609 gary.churchill@jax.org.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D003198:Computer Simulation; D005838:Genotype; D007958:Leukocyte Count; D051379:Mice; D008957:Models, Genetic; D009504:Neutrophils / Q000166:cytology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012984:Software
keywords: MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); Multiparental populations; diversity outbred; haplotype reconstruction; quantitative trait locus mapping