Imputation of Single-Nucleotide Polymorphisms in Inbred Mice Using Local Phylogeny

Abstract

We present full-genome genotype imputations for 100 classical laboratory mouse strains, using a novel method. Using genotypes at 549,683 SNP loci obtained with the Mouse Diversity Array, we partitioned the genome of 100 mouse strains into 40,647 intervals that exhibit no evidence of historical recombination. For each of these intervals we inferred a local phylogenetic tree. We combined these data with 12 million loci with sequence variations recently discovered by whole-genome sequencing in a common subset of 12 classical laboratory strains. For each phylogenetic tree we identified strains sharing a leaf node with one or more of the sequenced strains. We then imputed high-and medium-confidence genotypes for each of 88 nonsequenced genomes. Among inbred strains, we imputed 92% of SNPs genome-wide, with 71% in high-confidence regions. Our method produced 977 million new genotypes with an estimated per-SNP error rate of 0.083% in high-confidence regions and 0.37% genome-wide. Our analysis identified which of the 88 nonsequenced strains would be the most informative for improving full-genome imputation, as well as which additional strain sequences will reveal more new genetic variants. Imputed sequences and quality scores can be downloaded and visualized online.

Deconstructing Mus gemischus: advances in understanding ancestry, structure, and variation in the genome of the laboratory mouse

“…Fortunately, recent advances in genotype imputation methods (Wang 2012a, Box 1) have made a large fraction of the complete catalog of genetic variants available to any strain at the relatively affordable cost of array genotyping.…”

“…The high degree of population structure in classical strains means that in most regions of the mouse genome, a local phylogenetic tree based on dense genotypes has a small number of branches, and the strains located at each leaf of the tree are essentially identical to each other (excluding private mutations that have arisen in the 100 years since their derivation). In 88 classical strains for which only MDA genotypes were available, Wang et al (2012a, b) were able to identify an appropriate reference among 12 strains sequenced by the Sanger project across an average of 92 % of the genome. In those regions, they were able to impute 977M new genotypes (11.1M per strain on average) with an error rate of ~0.4 %.…”

“…The missing haplotypes in those regions probably originated from the small number of Asian ( M. m. molossinus ) or Swiss fancy mice that have contributed to the classical strain genome (Nagamine et al 1992). Those regions have highlighted gaps in our knowledge of the genome of the laboratory mouse and identified the strains for which whole-genome sequencing would provide the most information (Wang et al 2012a). …”

Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

“…Constant acquisition of information on the genetic variability among inbred mouse strains has made the mouse a powerful model to facilitate rapid evaluation of the genetic basis of human physiology and pathophysiology (23)(24)(25)(26)(27)(28)(29)(30)(31). Recently, nextgeneration whole genome sequencing information has been obtained on 17 mouse strains (29), which has strengthened the existing single nucleotide polymorphism (SNP) database for over 40 mouse strains (29)(30)(31).…”

“…Recently, nextgeneration whole genome sequencing information has been obtained on 17 mouse strains (29), which has strengthened the existing single nucleotide polymorphism (SNP) database for over 40 mouse strains (29)(30)(31). Using a genetically diverse panel of >40 inbred mouse strains, we previously conducted functional genomic analyses of acrolein-induced (32,33) and chlorine-induced (34) ALI.…”