Limited role of generation time changes in driving the evolution of the mutation spectrum in humans
- University of Pennsylvania, United States
- University of California, Berkeley, United States
- Columbia University, United States
Abstract
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>G and 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.
Data availability
All data generated or analyzed during this study were based on publicly available datasets like the 1000 Genomes Project. Source data for Figures 1-4 contain the numerical data used to generate the figures. Source data for figure 1 is available at the following URL: https://doi.org/10.6078/D19B0H. (Note, For private access prior to publication, the dataset is available at the URL: https://datadryad.org/stash/share/JK1BdqPhl6azkQru6gLTi6_dA-6lobKUxzpUM7mW69Y)
Article and author information
Author details
Funding
National Institutes of Health (R35GM146810)
- Ziyue Gao
Alfred P. Sloan Foundation
- Ziyue Gao
National Institutes of Health (R35GM142978)
- Priya Moorjani
Alfred P. Sloan Foundation
- Priya Moorjani
National Institutes of Health (GM122975)
- Molly Przeworski
National Science Foundation (DGE 2146752)
- Nathan Cramer
Hellman Family Foundation
- Priya Moorjani
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Philipp W Messer, Cornell University, United States
Version history
- Preprint posted: June 18, 2022 (view preprint)
- Received: June 18, 2022
- Accepted: February 2, 2023
- Accepted Manuscript published: February 13, 2023 (version 1)
- Accepted Manuscript updated: February 15, 2023 (version 2)
- Version of Record published: March 14, 2023 (version 3)
Copyright
© 2023, Gao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Limited role of generation time changes in driving the evolution of the mutation spectrum in humans
eLife 12:e81188.
https://doi.org/10.7554/eLife.81188
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