Fine mapping in 94 inbred mouse strains using a high-density haplotype resource

Abstract

The genetics of phenotypic variation in inbred mice has for nearly a century provided a primary weapon in the medical research arsenal. A catalog of the genetic variation among inbred mouse strains, however, is required to enable powerful positional cloning and association techniques. A recent whole-genome resequencing study of 15 inbred mouse strains captured a significant fraction of the genetic variation among a limited number of strains, yet the common use of hundreds of inbred strains in medical research motivates the need for a high-density variation map of a larger set of strains. Here we report a dense set of genotypes from 94 inbred mouse strains containing 10.77 million genotypes over 121,433 single nucleotide polymorphisms (SNPs), dispersed at 20-kb intervals on average across the genome, with an average concordance of 99.94% with previous SNP sets. Through pairwise comparisons of the strains, we identified an average of 4.70 distinct segments over 73 classical inbred strains in each region of the genome, suggesting limited genetic diversity between the strains. Combining these data with genotypes of 7570 gap-filling SNPs, we further imputed the untyped or missing genotypes of 94 strains over 8.27 million Perlegen SNPs. The imputation accuracy among classical inbred strains is estimated at 99.7% for the genotypes imputed with high confidence. We demonstrated the utility of these data in high-resolution linkage mapping through power simulations and statistical power analysis and provide guidelines for developing such studies. We also provide a resource of in silico association mapping between the complex traits deposited in the Mouse Phenome Database with our genotypes. We expect that these resources will facilitate effective designs of both human and mouse studies for dissecting the genetic basis of complex traits.

Figure 1.—

Classification of 94 strains used in the Mouse HapMap projects on the basis of the availability in other resources, including 8.27 million NIEHS/Perlegen resequencing-based SNPs, WTCHG SNPs, and additional gap-filling SNPs. (C57BL/6J is not included in the 15 resequenced strains, but it is the reference strain that has been fully resequenced.)

Figure 2.—

A histogram of the fractions of genome covered by shared segments with one of the 12 classical inbred strains over 78 nonresequenced Mouse HapMap strains. The classical inbred strains are in blue, the hybrid strains in red, and the wild-derived strains in green.

Figure 3.—

A phylogeny of the 94 Mouse HapMap strains. The domesticus wild-derived strains are in blue, and the non-domesticus wild-derived strains are in red. The reference strain is in green. SOD1/EiJ and RBA/DnJ are hybrid strains.

Figure 4.—

A histogram of the fractions of shared genomic segments between each of 4371 pairs among the 94 strains.

Figure 5.—

Distribution of the fraction of phenotypic variation explained by population structure among the strains over 180 quantitative phenotypes deposited in the MPD with ≥30 strains.

Figure 6.—

Number of phenotypes with multiple genomic regions with significant associations illustrating the degree of inflated false positives over 180 quantitative phenotypes deposited in the MPD with ≥30 strains.

Figure 7.—

Comparison of genomic control “inflation factors” between t-test and linear mixed model across 180 MPD phenotypes.