Mutation rates and the evolution of germline structure

Abstract

One contribution of 15 to a discussion meeting issue 'Dating species divergences using rocks and clocks'. Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which 'dark' gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates.This article is part of the themed issue 'Dating species divergences using rocks and clocks'.

Life history effects on the molecular clock of autosomes and sex chromosomes

“…If this hypothesis is true, it would suggest that the mutation rate per spermatogenic cell division (D M Þ is higher than our estimates and closer to the (considerably higher) rates per division in females, in males prepuberty (5), and in other taxa (SI Appendix, Table S2) (37). In terms of the hominine mutational model, such a revision would introduce an additional parameter for turnover, which could lead to greater variation among species in male mutation rates postpuberty (36). These refinements notwithstanding, our mutational model already suggests several predictions that align with observations.…”

“…In addition, there is still uncertainty about the number of cell divisions in the male germ line during spermatogenesis. In particular, it has been suggested that A pale cells-the stem cells from which sperm are generated-are replenished by, or experience turnover with, A dark spermatogonial stem cells throughout adulthood, resulting in fewer cell divisions in the germ line between puberty and reproduction (24,35,36). If this hypothesis is true, it would suggest that the mutation rate per spermatogenic cell division (D M Þ is higher than our estimates and closer to the (considerably higher) rates per division in females, in males prepuberty (5), and in other taxa (SI Appendix, Table S2) (37).…”

Haploid selection within a single ejaculate increases offspring fitness

“…Regardless of the exact genetic underpinning of our observations, our findings are likely to have major implications for key evolutionary processes including the rate of adaptation (30), the evolution of a sexually dimorphic recombination rate (31,32), the load of deleterious mutations (33), and the extent of inbreeding depression (34). They also may account for hitherto unexplained patterns of nonMendelian inheritance (35) and apparent discrepancies in observed mutation rates (36). In addition, our findings provide insights that are crucial for clinical and agricultural assistedfertilization techniques such as IVF and intracellular sperm injection (ICSI).…”

The mutation rate in human evolution and demographic inference

“…her offspring, and hence, seemingly present in both generations, might not be correctly identified as a de novo mutation [21][22][23]. This could be a significant factor if cellular mutation rates are particularly high in the earliest cell divisions of embryogenesis.…”