A comparison of humans and baboons suggests germline mutation rates do not track cell divisions

Abstract

In humans, most germline mutations are inherited from the father. This observation has been widely interpreted as reflecting the replication errors that accrue during spermatogenesis. If so, the male bias in mutation should be substantially lower in a closely related species with similar rates of spermatogonial stem cell divisions but a shorter mean age of reproduction. To test this hypothesis, we resequenced two 3-4 generation nuclear families (totaling 29 individuals) of olive baboons (Papio anubis), who reproduce at approximately 10 years of age on average, and analyzed the data in parallel with three 3-generation human pedigrees (26 individuals). We estimated a mutation rate per generation in baboons of 0.57×10 −8 per base pair, approximately half that of humans. Strikingly, however, the degree of male bias in germline mutations is approximately 4:1, similar to that of humans-indeed, a similar male bias is seen across mammals that reproduce months, years, or decades after birth. These results mirror the finding in humans that the male mutation bias is stable with parental ages and cast further doubt on the assumption that germline mutations track cell divisions. Our mutation rate estimates for baboons raise a further puzzle, suggesting a divergence time between apes and Old World monkeys of 65 million years, too old to be consistent with the fossil record; reconciling them now requires not only a slowdown of the mutation rate per generation in humans but also in baboons.

De novomutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations

“…The spectrum of mutations in the cat was remarkably similar to those found in most primates, with a preponderance of C>T and A>G transitions (Kong et al 2012;Venn et al 2014;Thomas et al 2018;Besenbacher et al 2019;Bergeron et al 2020;Wang et al 2020;Wu et al 2020;see Campbell et al 2020 for an exception in the mouse lemur). We showed that differences in the mutation spectrum between the cat and the human can in large part be explained by differences in age according to a model of reproductive longevity.…”

“…Assuming the average parental age in our sample (3.8 years) is representative of the average age of reproduction in the cat, we estimate a per-year mutation rate of 2.2 × 10 -9 per bp. This is much higher than the human rate of 0.43 × 10 -9 per bp per year (Jónsson et al 2017), or the per-year rate from any reported primate (Besenbacher et al 2019;Campbell et al 2020;Wang et al 2020;Wu et al 2020). This higher rate is driven by the similar number of mutations at puberty, but a much shorter generation time in the cat.…”

Temperature-dependence of spontaneous mutation rates

“…Several studies are lending support for the GL: in primates μ can be predicted via the reproductive longevity 15 and the mammalian male mutation bias is higher for species with long generation times 43 . There is evidence that this effect does not depend on the absolute number of cell divisions 44 . Also in invertebrates there is significant evidence for a correlation between rates of molecular evolution and generation times 11 .…”

Meiosis and beyond – understanding the mechanistic and evolutionary processes shaping the germline genome

“…Nucleotide substitutions occur roughly 10 times more frequently than indels during germline cell replication. Genome-wide studies place the germline de novo mutation rate per nucleotide per generation at 1.2 × 10 −8 in humans, and 5.7 × 10 −9 in mice (Milholland et al, 2017 Processes shaping the germline genome germline mutational signaturesan increased proportion of paternally inherited versus maternally inherited mutationsis in part explicable as a consequence of the greater number of cell divisions involved in male reproduction (Haldane, 1947;Wilson Sayres & Makova, 2011;Jónsson et al, 2017;Wu et al, 2020; but see also Gao et al, 2018).…”

“…This is based on the observation that the yearly mutation rate estimated from human pedigree studies is almost half the rate inferred by looking at sequence divergence between human and chimpanzee (Pan troglodytes) genomes, suggesting a potential slowdown in mutation rate in humans (Scally & Durbin, 2012;Besenbacher et al, 2019). By contrast, in olive baboons (Papio anubis) the mutation rate appears to be lower than in humans (Wu et al, 2020).…”