TY - JOUR TI - Limited role of generation time changes in driving the evolution of the mutation spectrum in humans AU - Gao, Ziyue AU - Zhang, Yulin AU - Cramer, Nathan AU - Przeworski, Molly AU - Moorjani, Priya A2 - Messer, Philipp W A2 - Perry, George H A2 - Duret, Laurent VL - 12 PY - 2023 DA - 2023/02/13 SP - e81188 C1 - eLife 2023;12:e81188 DO - 10.7554/eLife.81188 UR - https://doi.org/10.7554/eLife.81188 AB - 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. KW - mutation spectrum KW - generation time KW - demography KW - biased gene conversion KW - natural selection JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -