Fine haplotype structure of a chromosome 17 region in the laboratory and wild mouse

Abstract

Extensive linkage disequilibrium among classical laboratory strains represents an obstacle in the high-resolution haplotype mapping of mouse quantitative trait loci (QTL). To determine the potential of wild-derived mouse strains for fine QTL mapping, we constructed a haplotype map of a 250-kb region of the t-complex on chromosome 17 containing the Hybrid sterility 1 (Hst1) gene. We resequenced 33 loci from up to 80 chromosomes of five mouse (sub)species. Trans-species single-nucleotide polymorphisms (SNPs) were rare between Mus m. musculus (Mmmu) and Mus m. domesticus (Mmd). The haplotypes in Mmmu and Mmd differed and therefore strains from these subspecies should not be combined for haplotype-associated mapping. The haplotypes of t-chromosomes differed from all non-t Mmmu and Mmd haplotypes. Half of the SNPs and SN indels but only one of seven longer rearrangements found in classical laboratory strains were useful for haplotype mapping in the wild-derived M. m. domesticus. The largest Mmd haplotype block contained three genes of a highly conserved synteny. The lengths of the haplotype blocks deduced from 36 domesticus chromosomes were in tens of kilobases, suggesting that the wild-derived Mmd strains are suitable for fine interval-specific mapping.

Figure 1.—

Phylogenetic history of the Hst1 region. A neighbor-joining tree of selected mice and strains was constructed from 339 SNPs (pairwise gap removal, observed divergence). The tree was rooted by genotypes derived from the rat assembly. All laboratory strains are shown on a lightly shaded background; classical laboratory strains are underlined. Wild-derived mice and strains are indicated: M. m. domesticus, wavy underlining; t-haplotype t^w12, italics; M. m. musculus and M. m. molossinus, underlining; M. m. castaneus, darkly shaded background; M. spretus, shaded letters.

Figure 2.—

Haplotype map of M. m. domesticus in the 250-kb Hst1 region of chromosome 17. The map was constructed using 22 loci encompassing differences with a MAF >15% from 36 Mmd chromosomes. Genes are shown as arrows pointing in the direction of transcription. RBCS, reused breakpoint of conserved synteny. The squared correlation coefficient between two loci r² = 1 (perfect LD) is indicated by solid diamonds; r² = 0, open diamonds; 0 < r² < 1, various shading. Haplotype blocks are indicated as lines with their length indicated to the right (in kilobases); they were computed using three methods: confidence intervals (solid line), solid spine of LD (dashed), and four-gamete rule (dot-and-dash).

Figure 3.—

Haplotype map of human Chr6qter. Genes are shown as arrows pointing in the direction of transcription. CEU, Caucasian population; JPT, Japanese population; 0 < r² < 1, various shading; r² = 1, solid.