Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice

Abstract

The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10 −9 (95% confidence interval = 4.6 × 10 −9 -6.5 × 10 −9 ) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population.

Direct estimate of the rate of germline mutation in a bird

“…Kong et al 2012), halving α would give a rate of 6.6 × 10 −9 , and if there were no male excess, the rate would only be 4.5 × 10 −9 , i.e., essentially identical to our avian estimate. A strong paternal age effect in man may also explain why the per-generation mutation rate in mice (5.4 × 10 −9 ) (Uchimura et al 2015), in which α is about two (Sandstedt and Tucker 2005), is more similar to our estimate for birds than to the estimates for humans and chimpanzee. If annual rates are considered, the estimate we obtained for flycatchers (2.3 × 10 −9 per site per year) is much higher than that in humans (4.4 × 10…”

Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes

“…This ratio of generation time (40-60) is much higher than the observed ratio of evolutionary rate (6-7), suggesting an important contribution from factors other than generation time (Bromham 2009) predicting either a faster rate in Hominidae or a lower rate in Muridae. We can reduce the effect of generation time by half by considering the increased rate of mutation accumulation per generation in the genome of Hominidae (Uchimura et al 2015). A further consideration is the effective population size, which is at least one order of magnitude larger in the Muridae compared to the Hominidae (Geraldes et al 2011;Schrago 2014).…”

Genome instability: a conserved mechanism of ageing?

“…Based on the first information on the actual numbers of base substitutions in a typical somatic cell and the observed age-related increase of various types of mutations, it is no longer reasonable to consider any age-related adverse effects of somatic mutagenesis limited to only cancer [65]. With the disposable nature of the ageing genome underscored by the dramatically higher frequency of mutations in the soma as compared with the germline (Table 1) [51,66,67,68], the observed base substitution loads in a typical single cell, in combination with as yet not quantified other types of mutations, such as CNV and genome structural variation, suggest that somatic mutations can adversely affect normal gene expression.…”