Recent studies have suggested that the human germline mutation rate and spectrum evolve rapidly. Variation in generation time has been linked to these changes, though its contribution remains unclear. We develop a framework to characterize temporal changes in polymorphisms within and between populations, while controlling for the effects of natural selection and biased gene conversion. Application to the 1000 Genomes Project dataset reveals multiple independent changes that arose after the split of continental groups, including a previously reported, transient elevation in TCC>TTC mutations in Europeans and novel signals of divergence in C>Gand T>A mutation rates among population samples. We also find a significant difference between groups sampled in and outside of Africa in old T>C polymorphisms that predate the out-of-Africa migration. This surprising signal is driven by TpG>CpG mutations and stems in part from mis-polarized CpG transitions, which are more likely to undergo recurrent mutations. Finally, by relating the mutation spectrum of polymorphisms to parental age effects on de novo mutations, we show that plausible changes in the generation time cannot explain the patterns observed for different mutation types jointly. Thus, other factors - genetic modifiers or environmental exposures - must have had a non-negligible impact on the human mutation landscape.
Keywords: biased gene conversion; demography; evolutionary biology; generation time; genetics; genomics; human; mutation spectrum; natural selection.
Each human has 23 pairs of chromosomes, one set inherited from each parent. But the child's chromosomes are not an exact copy of their parents' chromosomes. Spontaneous changes or mutations in the DNA during the formation of the egg or sperm cells, or early development of the embryo, can change a small fraction of the nucleotides or ‘letters’ that make up the DNA. These modifications are an important source of genetic diversity in human populations and contribute to the evolution of new traits. Each genetic variant in present-day human populations represents a mutation in one of their ancestors. The types and frequencies of variants vary across human populations and have changed over time, suggesting that mutation patterns have evolved in the past. But the processes driving these population-level differences remain elusive. One possible factor may be changes in the average age of reproduction or the generation time in a population . For example, older parents contribute more – and also different types of – new mutations to their children than younger parents do. Populations, where it is customary to have children at older ages, may therefore have a different mutation landscape. To find out if this is indeed the case, Gao et al. used computer algorithms to analyze the genomes of hundreds of people living on three continents who participated in ‘the 1,000 Genomes Project’. The analysis identified differences in mutation patterns across continental groups and estimated when these changes occurred. Further, they showed that although the age of reproduction had an impact on the mutation landscape, differences in generation time alone could not explain the observed changes in the human mutation spectrum. Factors other than generation time, such as environmental exposures, may have played a role in shifting these patterns. The study provides new insights into the changes in the mutation landscape over the course of human evolution. Mapping these patterns in humans worldwide may help scientists understand the causes underlying these changes. The techniques used by Gao et al. may also help analyze changes in mutation patterns in other organisms.
© 2023, Gao et al.