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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wolfe, K.H., Sharp, P.M. & Li, W.H. Nature 337, 283–285 (1989).
Hellmann, I. et al. Genome Res. 15, 1222–1231 (2005).
Tyekucheva, S. et al. Genome Biol. 9, R76 (2008).
Jeon, Y. et al. Proc. Natl. Acad. Sci. USA 102, 6419–6424 (2005).
Woodfine, K. et al. Hum. Mol. Genet. 13, 191–202 (2004).
Day, N., Hemmaplardh, A., Thurman, R.E., Stamatoyannopoulos, J.A. & Noble, W.S. Bioinformatics 23, 1424–1426 (2007).
Karnani, N., Taylor, C., Malhotra, A. & Dutta, A. Genome Res. 17, 865–876 (2007).
Wheeler, D.A. et al. Nature 452, 872–876 (2008).
Karolchik, D. et al. Nucleic Acids Res. 36, D773–D779 (2008).
Hanawalt, P.C. Science 266, 1957–1958 (1994).
Mirkin, E.V. & Mirkin, S.M. Microbiol. Mol. Biol. Rev. 71, 13–35 (2007).
Yang, Y., Sterling, J., Storici, F., Resnick, M.A. & Gordenin, D.A. PLoS Genet. 4, E1000264 (2008).
Lindahl, T. Nature 362, 709–715 (1993).
Watanabe, Y. et al. Hum. Mol. Genet. 11, 13–21 (2002).
Chuang, J.H. & Li, H. PLoS Biol. 2, E29 (2004).
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding authors
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–7 and Supplementary Tables 1 and 2 (PDF 2622 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.363
This article is cited by
-
Cell cycle gene alterations associate with a redistribution of mutation risk across chromosomal domains in human cancers
Nature Cancer (2024)
-
RIF1 regulates early replication timing in murine B cells
Nature Communications (2023)
-
Evolutionary conservation of the fidelity of transcription
Nature Communications (2023)
-
Convergent evolution of a genomic rearrangement may explain cancer resistance in hystrico- and sciuromorpha rodents
npj Aging and Mechanisms of Disease (2021)
-
ecTMB: a robust method to estimate and classify tumor mutational burden
Scientific Reports (2020)
