Variation in the Spectrum of New Mutations among Inbred Strains of Mice

Abstract

The mouse serves as a mammalian model for understanding the nature of variation from new mutations, a question that has both evolutionary and medical significance. Previous studies suggest that the rate of single-nucleotide mutations (SNMs) in mice is ∼50% of that in humans. However, information largely comes from studies involving the C57BL/6 strain, and there is little information from other mouse strains. Here, we study the mutations that accumulated in 59 mouse lines derived from four inbred strains that are commonly used in genetics and clinical research (BALB/cAnNRj, C57BL/6JRj, C3H/HeNRj, and FVB/NRj), maintained for eight to nine generations by brother-sister mating. By analyzing Illumina whole-genome sequencing data, we estimate that the average rate of new SNMs in mice is ∼μ = 6.7 × 10-9. However, there is substantial variation in the spectrum of SNMs among strains, so the burden from new mutations also varies among strains. For example, the FVB strain has a spectrum that is markedly skewed toward C→A transversions and is likely to experience a higher deleterious load than other strains, due to an increased frequency of nonsense mutations in glutamic acid codons. Finally, we observe substantial variation in the rate of new SNMs among DNA sequence contexts, CpG sites, and their adjacent nucleotides playing an important role.

Keywords: Mus musculus; mutation accumulation; mutation rate; mutation spectrum.

Fig. 1.

Rates of de novo SNM in MA samples of the mouse strains BALBC, BL6, C3H, and FVB shown as points and boxplots. Points represent individual MA lines. Mutation rates were estimated assuming no mutation clustering.

Fig. 2.

Spectrum of SNMs in four different mouse strains. The heights of the bars represent the median mutation rate (μ) for each type of mutation and strain (in colors). Mutation rates for each SNM type were calculated while adjusting the number of callable sites by their GC content. Error bars represent 95% confidence intervals.

Fig. 3.

Proportion of mutations simulated in coding sites, grouped by their predicted effect using SnpEff. Median proportions are plotted with error bars showing 95% confidence intervals. a) Proportions for mutations with low, moderate and high effect sizes. b) Proportion of high effect size mutations in Glu codons.