High-Resolution Maps of Mouse Reference Populations

Abstract

Genetic reference panels are widely used to map complex, quantitative traits in model organisms. We have generated new high-resolution genetic maps of 259 mouse inbred strains from recombinant inbred strain panels (C57BL/6J × DBA/2J, ILS/IbgTejJ × ISS/IbgTejJ, and C57BL/6J × A/J) and chromosome substitution strain panels (C57BL/6J-Chr#<A/J>, C57BL/6J-Chr#<PWD/Ph>, and C57BL/6J-Chr#<MSM/Ms>). We genotyped all samples using the Affymetrix Mouse Diversity Array with an average intermarker spacing of 4.3 kb. The new genetic maps provide increased precision in the localization of recombination breakpoints compared to the previous maps. Although the strains were presumed to be fully inbred, we found residual heterozygosity in 40% of individual mice from five of the six panels. We also identified de novo deletions and duplications, in homozygous or heterozygous state, ranging in size from 21 kb to 8.4 Mb. Almost two-thirds (46 out of 76) of these deletions overlap exons of protein coding genes and may have phenotypic consequences. Twenty-nine putative gene conversions were identified in the chromosome substitution strains. We find that gene conversions are more likely to occur in regions where the homologous chromosomes are more similar. The raw genotyping data and genetic maps of these strain panels are available at http://churchill-lab.jax.org/website/MDA.

Keywords: chromosome substitution strains; gene conversions; mouse diversity genotyping array; recombinant inbred strains.

Figure 1

Number of founder haplotype blocks in RIS panels. The number of founder blocks for each strain is indicated as a point, with jitter for clarity. The boxplot indicates median and quartiles of each panel. Results for the BXD panel are broken down by three breeding epochs (I, II, and III); the increased number of recombination event in epoch III reflects additional generation of outbreeding used in the derivation of these strains.

Figure 2

Sister strains in RIS panels. Side-by-side comparison of sister strains AXB6 vs. AXB12 (red, B6; blue, A) and LXS94 vs. LXS107 (red, L; blue, S) illustrates the extent of shared haplotype blocks.

Figure 3

Gene conversion in a CSS strain. Strain B6.PWD13 has an unexpected founder genotype at marker JAX00357227 marker (Chr 13: 47,505,217 bp). Average and contrast signal intensities are plotted for all B6.PWD strains. Numbers indicate the CSS strains by substituted chromosome with B6. PWD13 is highlighted by the red circle. Also indicated on the plot are founder strains B6, and PWD and their F1 hybrids. The B.PWD13 data should be similar to PWD but is actually close to B6, indicating a putative gene conversion. Gray letters indicate genotype calls for 1902 additional samples in the MDA database (A, B6 allele homozygous; B, PWD allele homozygous; H, heterozygous; V, vino; N, no call).