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Chromatin organization is a major influence on regional mutation rates in human cancer cells

Nature volume 488, pages 504507 (23 August 2012) | Download Citation


Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells1,2,3,4,5,6,7. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

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  1. 1.

    et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456, 66–72 (2008)

  2. 2.

    et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184–190 (2010)

  3. 3.

    et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010)

  4. 4.

    et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011)

  5. 5.

    et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011)

  6. 6.

    et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465, 473–477 (2010)

  7. 7.

    , & The large-scale distribution of somatic mutations in cancer genomes. Hum. Mutat. 33, 136–143 (2012)

  8. 8.

    , & Mutation rates differ among regions of the mammalian genome. Nature 337, 283–285 (1989)

  9. 9.

    , & Mutation rate variation in the mammalian genome. Curr. Opin. Genet. Dev. 13, 562–568 (2003)

  10. 10.

    & Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes. Hum. Genet. 83, 181–188 (1989)

  11. 11.

    et al. Human mutation rate associated with DNA replication timing. Nature Genet. 41, 393–395 (2009)

  12. 12.

    et al. Chromatin structure and evolution in the human genome. BMC Evol. Biol. 7, 72 (2007)

  13. 13.

    & Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 18, 337–340 (2002)

  14. 14.

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

  15. 15.

    et al. Dynamic regulation of nucleosome positioning in the human genome. Cell 132, 887–898 (2008)

  16. 16.

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

  17. 17.

    et al. A high-resolution recombination map of the human genome. Nature Genet. 31, 241–247 (2002)

  18. 18.

    et al. The UCSC Genome Browser database: extensions and updates 2011. Nucleic Acids Res. 40, D918–D923 (2012)

  19. 19.

    et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nature Genet. 40, 897–903 (2008)

  20. 20.

    et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007)

  21. 21.

    , & Quantifying the variation in the effective population size within a genome. Genetics 189, 1389–1402 (2011)

  22. 22.

    & Chromatin organization in sperm may be the major functional consequence of base composition variation in the human genome. PLoS Genet. 7, e1002036 (2011)

  23. 23.

    & Cellular machineries for chromosomal DNA repair. Genes Dev. 18, 602–616 (2004)

  24. 24.

    et al. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell 31, 167–177 (2008)

  25. 25.

    Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 (2007)

  26. 26.

    et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 35, D5–D12 (2007)

  27. 27.

    A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)

  28. 28.

    , , , & Enredo and Pecan: genome-wide mammalian consistency-based multiple alignment with paralogs. Genome Res. 18, 1814–1828 (2008)

  29. 29.

    , , , & Identifying positioned nucleosomes with epigenetic marks in human from ChIP-Seq. BMC Genomics 9, 537 (2008)

  30. 30.

    Broad Institute Sequencing Platform and Whole Genome Assembly Team et al. A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478, 476–481 (2011)

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This work was funded by an European Research Council (ERC) Starting Grant, European Union Framework 7 project 277899 4DCellFate, ERASysBioPLUS, Ministerio de Ciencia e Innovación (MICINN) grants BFU2008-00365 and BFU2011-26206, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), the European Molecular Biology Organization (EMBO) Young Investigator Program, the EMBL-CRG Systems Biology Program and a Juan de la Cierva postdoctoral fellowship to B.S-B. We thank T. Vavouri and T. Warnecke for comments on the manuscript, and R.S. Hansen for assistance with analysing replication timing data.

Author information


  1. EMBL-CRG Systems Biology Unit, CRG and UPF, Barcelona 08003, Spain

    • Benjamin Schuster-Böckler
    •  & Ben Lehner
  2. Pear Computer LLP, London W5 1SH, UK

    • Benjamin Schuster-Böckler
  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys, 23, Barcelona 08010, Spain

    • Ben Lehner


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B.S.-B. performed all analyses. B.S.-B. and B.L. designed analyses and wrote the manuscript. B.L. conceived the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ben Lehner.

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