Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Human mutation rate associated with DNA replication timing


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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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


  1. Wolfe, K.H., Sharp, P.M. & Li, W.H. Nature 337, 283–285 (1989).

    CAS  Article  Google Scholar 

  2. Hellmann, I. et al. Genome Res. 15, 1222–1231 (2005).

    CAS  Article  Google Scholar 

  3. Tyekucheva, S. et al. Genome Biol. 9, R76 (2008).

    Article  Google Scholar 

  4. Jeon, Y. et al. Proc. Natl. Acad. Sci. USA 102, 6419–6424 (2005).

    CAS  Article  Google Scholar 

  5. Woodfine, K. et al. Hum. Mol. Genet. 13, 191–202 (2004).

    CAS  Article  Google Scholar 

  6. Day, N., Hemmaplardh, A., Thurman, R.E., Stamatoyannopoulos, J.A. & Noble, W.S. Bioinformatics 23, 1424–1426 (2007).

    CAS  Article  Google Scholar 

  7. Karnani, N., Taylor, C., Malhotra, A. & Dutta, A. Genome Res. 17, 865–876 (2007).

    CAS  Article  Google Scholar 

  8. Wheeler, D.A. et al. Nature 452, 872–876 (2008).

    CAS  Article  Google Scholar 

  9. Karolchik, D. et al. Nucleic Acids Res. 36, D773–D779 (2008).

    CAS  Article  Google Scholar 

  10. Hanawalt, P.C. Science 266, 1957–1958 (1994).

    CAS  Article  Google Scholar 

  11. Mirkin, E.V. & Mirkin, S.M. Microbiol. Mol. Biol. Rev. 71, 13–35 (2007).

    CAS  Article  Google Scholar 

  12. Yang, Y., Sterling, J., Storici, F., Resnick, M.A. & Gordenin, D.A. PLoS Genet. 4, E1000264 (2008).

    Article  Google Scholar 

  13. Lindahl, T. Nature 362, 709–715 (1993).

    CAS  Article  Google Scholar 

  14. Watanabe, Y. et al. Hum. Mol. Genet. 11, 13–21 (2002).

    CAS  Article  Google Scholar 

  15. Chuang, J.H. & Li, H. PLoS Biol. 2, E29 (2004).

    Article  Google Scholar 

Download references


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



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

Correspondence to John A Stamatoyannopoulos or Shamil R Sunyaev.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints 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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing