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Human mutation rate associated with DNA replication timing

Abstract

Eukaryotic DNA replication is highly stratified, with different genomic regions shown to replicate at characteristic times during S phase. Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome. All classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage. This correlation between mutation rate and regionally stratified replication timing may have substantial evolutionary implications.

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Figure 1: Replication time-dependence of evolutionary divergence and human SNP density.

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Acknowledgements

We thank A. Kondrashov, M. Przeworski and J. Cameron for helpful discussions. This work was supported by US National Institutes of Health grants U54HG003042 and R01GM071852 to J.A.S.; R01GM078598, R01MH084676 and U54LM008748 to S.R.S. and R01GM60987 to S.M.M.

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J.A.S., S.R.S. and S.M.M. designed research and wrote the paper. I.A., G.V.K. and R.E.T. analyzed data.

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Correspondence to John A Stamatoyannopoulos or Shamil R Sunyaev.

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Supplementary Figures 1–7 and Supplementary Tables 1 and 2 (PDF 2622 kb)

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Stamatoyannopoulos, J., Adzhubei, I., Thurman, R. et al. Human mutation rate associated with DNA replication timing. Nat Genet 41, 393–395 (2009). https://doi.org/10.1038/ng.363

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