Skip to main content

Thank you for visiting nature.com. 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.

DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes

Abstract

Somatic copy-number alterations (SCNA) are a hallmark of many cancer types, but the mechanistic basis underlying their genome-wide patterns remains incompletely understood. Here we integrate data on DNA replication timing, long-range interactions between genomic material, and 331,724 SCNAs from 2,792 cancer samples classified into 26 cancer types. We report that genomic regions of similar replication timing are clustered spatially in the nucleus, that the two boundaries of SCNAs tend to be found in such regions, and that regions replicated early and late display distinct patterns of frequencies of SCNA boundaries, SCNA size and a preference for deletions over insertions. We show that long-range interaction and replication timing data alone can identify a significant proportion of SCNAs in an independent test data set. We propose a model for the generation of SCNAs in cancer, suggesting that data on spatial proximity of regions replicating at the same time can be used to predict the mutational landscapes of cancer genomes.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Long-range DNA interactions and the distribution of SNCAs with regard to replication timing zones.
Figure 2: SCNA frequencies vary between different replication timing zones.
Figure 3: Genome-wide distributions of long-range interactions and SCNAs.

Similar content being viewed by others

References

  1. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  Google Scholar 

  2. Bell, S.P. & Dutta, A. DNA replication in eukaryotic cells. Annu. Rev. Biochem. 71, 333–374 (2002).

    Article  CAS  Google Scholar 

  3. Gilbert, D.M. Evaluating genome-scale approaches to eukaryotic DNA replication. Nat. Rev. Genet. 11, 673–684 (2010).

    Article  CAS  Google Scholar 

  4. Hansen, R.S. et al. Sequencing newly replicated DNA reveals widespread plasticity in human replication timing. Proc. Natl. Acad. Sci. USA 107, 139–144 (2010).

    Article  CAS  Google Scholar 

  5. Woodfine, K. et al. Replication timing of human chromosome 6. Cell Cycle 4, 172–176 (2005).

    Article  CAS  Google Scholar 

  6. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    Article  CAS  Google Scholar 

  7. Meister, P., Taddei, A. & Gasser, S.M. In and out of the replication factory. Cell 125, 1233–1235 (2006).

    Article  CAS  Google Scholar 

  8. Ryba, T. et al. Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res. 20, 761–770 (2010).

    Article  CAS  Google Scholar 

  9. Saleh-Gohari, N. et al. Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Mol. Cell. Biol. 25, 7158–7169 (2005).

    Article  CAS  Google Scholar 

  10. Lisby, M., Barlow, J.H., Burgess, R.C. & Rothstein, R. Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118, 699–713 (2004).

    Article  CAS  Google Scholar 

  11. Hastings, P.J., Lupski, J.R., Rosenberg, S.M. & Ira, G. Mechanisms of change in gene copy number. Nat. Rev. Genet. 10, 551–564 (2009).

    Article  CAS  Google Scholar 

  12. Hastings, P.J., Ira, G. & Lupski, J.R. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5, e1000327 (2009).

    Article  CAS  Google Scholar 

  13. Lukasova, E. et al. Localisation and distance between ABL and BCR genes in interphase nuclei of bone marrow cells of control donors and patients with chronic myeloid leukaemia. Hum. Genet. 100, 525–535 (1997).

    Article  CAS  Google Scholar 

  14. Wijchers, P.J. & de Laat, W. Genome organization influences partner selection for chromosomal rearrangements. Trends Genet. 27, 63–71 (2011).

    Article  CAS  Google Scholar 

  15. Misteli, T. & Soutoglou, E. The emerging role of nuclear architecture in DNA repair and genome maintenance. Nat. Rev. Mol. Cell Biol. 10, 243–254 (2009).

    Article  CAS  Google Scholar 

  16. Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Article  CAS  Google Scholar 

  17. TCGA. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  18. TCGA. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  19. Kobayashi, T. & Ganley, A.R. Recombination regulation by transcription-induced cohesin dissociation in rDNA repeats. Science 309, 1581–1584 (2005).

    Article  CAS  Google Scholar 

  20. Zhang, F., Gu, W., Hurles, M.E. & Lupski, J.R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 10, 451–481 (2009).

    Article  CAS  Google Scholar 

  21. Stamatoyannopoulos, J.A. et al. Human mutation rate associated with DNA replication timing. Nat. Genet. 41, 393–395 (2009).

    Article  CAS  Google Scholar 

  22. Watanabe, Y. et al. Chromosome-wide assessment of replication timing for human chromosomes 11q and 21q: disease-related genes in timing-switch regions. Hum. Mol. Genet. 11, 13–21 (2002).

    Article  CAS  Google Scholar 

  23. Fisher, R.A. The Design of Experiments, edn. 8 (Hafner, Edinburgh, 1966).

  24. Rheinfurth, M.H. & Howell,, L.W. Probability and Statistics in Aerospace Engineering. NASA, (1998).

  25. Slack, A., Thornton, P.C., Magner, D.B., Rosenberg, S.M. & Hastings, P.J. On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet. 2, e48 (2006).

    Article  Google Scholar 

  26. De, S. & Michor, F. DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat. Struct. Mol. Biol. 18, 950–955 (2011).

    Article  CAS  Google Scholar 

  27. Zhao, J., Bacolla, A., Wang, G. & Vasquez, K.M. Non-B DNA structure-induced genetic instability and evolution. Cell. Mol. Life Sci. 67, 43–62 (2010).

    Article  CAS  Google Scholar 

  28. Snyder, R.D. Consequences of the depletion of cellular deoxynucleoside triphosphate pools on the excision-repair process in cultured human fibroblasts. Mutat. Res. 200, 193–199 (1988).

    Article  CAS  Google Scholar 

  29. Song, S., Wheeler, L.J. & Mathews, C.K. Deoxyribonucleotide pool imbalance stimulates deletions in HeLa cell mitochondrial DNA. J. Biol. Chem. 278, 43893–43896 (2003).

    Article  CAS  Google Scholar 

  30. Kumar, D., Viberg, J., Nilsson, A.K. & Chabes, A. Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Res. 38, 3975–3983 (2010).

    Article  CAS  Google Scholar 

  31. Meyerson, M., Gabriel, S. & Getz, G. Advances in understanding cancer genomes through second-generation sequencing. Nat. Rev. Genet. 11, 685–696 (2010).

    Article  CAS  Google Scholar 

  32. Koboldt, D.C., Ding, L., Mardis, E.R. & Wilson, R.K. Challenges of sequencing human genomes. Brief. Bioinform. 11, 484–498 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank K. Polyak, A. Melnick, K.J. Patel, A. Chakravarti and R. Beroukhim for comments and discussions. S.D. is a recipient of Human Frontier Science Program long-term fellowship and is a Research Fellow at King's College, Cambridge. This work was funded by the National Cancer Institute's initiative to found Physical Science-Oncology Centers (U54CA143798).

Author information

Authors and Affiliations

Authors

Contributions

S.D. and F.M. designed the experiments and wrote the paper. S.D. performed the analysis.

Corresponding authors

Correspondence to Subhajyoti De or Franziska Michor.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Modules 1–10 (PDF 915 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

De, S., Michor, F. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nat Biotechnol 29, 1103–1108 (2011). https://doi.org/10.1038/nbt.2030

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt.2030

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer