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G3 (Bethesda). 2014 Sep 18;4(9):1623-33. doi: 10.1534/g3.114.013748.

Quantitative trait locus mapping methods for diversity outbred mice.

Author information

1
The Jackson Laboratory, Bar Harbor, Maine 04609.
2
Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia 23298.
3
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.
4
Division of Plant Sciences, Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
5
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599.
6
Department of Human Genetics, University of Chicago, Chicago, Illinois 60637.
7
Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706.
8
The Jackson Laboratory, Bar Harbor, Maine 04609 gary.churchill@jax.org.

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.

KEYWORDS:

MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); Multiparental populations; diversity outbred; haplotype reconstruction; quantitative trait locus mapping

PMID:
25237114
PMCID:
PMC4169154
DOI:
10.1534/g3.114.013748
[Indexed for MEDLINE]
Free PMC Article

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