Letter | Published:

Differential DNA mismatch repair underlies mutation rate variation across the human genome

Nature volume 521, pages 8184 (07 May 2015) | Download Citation

This article has been updated

Abstract

Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated in heterochromatic late replicating regions and reduced in early replicating euchromatin1,2,3,4,5. Multiple mechanisms have been suggested to underlie this2,6,7,8,9,10, but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing 17 million single-nucleotide variants from the genomes of 652 tumours, we show that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression. However, mutations arising after the inactivation of MMR are no longer enriched in late replicating heterochromatin relative to early replicating euchromatin. Thus, differential DNA repair and not differential mutation supply is the primary cause of the large-scale regional mutation rate variation across the human genome.

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Change history

  • 26 February 2015

    A sentence was edited in the abstract to match the authors’ findings

References

  1. 1.

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

  2. 2.

    & Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488, 504–507 (2012)

  3. 3.

    & DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes. Nature Commun. 3, 1004 (2012)

  4. 4.

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

  5. 5.

    , & DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nature Commun. 4, 1502 (2013)

  6. 6.

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

  7. 7.

    & The critical mutagenic translesion DNA polymerase Rev1 is highly expressed during G2/M phase rather than S phase. Proc. Natl Acad. Sci. USA 103, 8971–8976 (2006)

  8. 8.

    A possible function of constitutive heterochromatin: the bodyguard hypothesis. Genetics 79 (suppl.). 137–150 (1975)

  9. 9.

    & Complex correlations: replication timing and mutational landscapes during cancer and genome evolution. Curr. Opin. Genet. Dev. 25, 93–100 (2014)

  10. 10.

    et al. Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes. Genome Res. 20, 447–457 (2010)

  11. 11.

    et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013)

  12. 12.

    et al. Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 155, 567–581 (2013)

  13. 13.

    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012)

  14. 14.

    The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013)

  15. 15.

    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014)

  16. 16.

    et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013)

  17. 17.

    , & Mechanisms underlying mutational signatures in human cancers. Nature Rev. Genet. 15, 585–598 (2014)

  18. 18.

    , , & Mismatch repair, but not heteroduplex rejection, is temporally coupled to DNA replication. Science 334, 1713–1716 (2011)

  19. 19.

    , & DNA mismatch repair efficiency and fidelity are elevated during DNA synthesis in human cells. Mutat. Res. 662, 59–66 (2009)

  20. 20.

    , , & Oxidative stress triggers the preferential assembly of base excision repair complexes on open chromatin regions. Nucleic Acids Res. 38, 2878–2890 (2010)

  21. 21.

    , & Histone H3 Lys79 methylation is required for efficient nucleotide excision repair in a silenced locus of Saccharomyces cerevisiae. Nucleic Acids Res. 37, 1690–1700 (2009)

  22. 22.

    et al. Global chromatin compaction limits the strength of the DNA damage response. J. Cell Biol. 178, 1101–1108 (2007)

  23. 23.

    et al. Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. Genome Res. 20, 155–169 (2010)

  24. 24.

    et al. DNA replication and transcription programs respond to the same chromatin cues. Genome Res. 24, 1102–1114 (2014)

  25. 25.

    et al. Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol. 6, e245 (2008)

  26. 26.

    et al. Strelka: accurate somatic small-variant calling from sequenced tumor–normal sample pairs. Bioinformatics 28, 1811–1817 (2012)

  27. 27.

    et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nature Biotechnol. 31, 213–219 (2013)

  28. 28.

    et al. A comparative analysis of algorithms for somatic SNV detection in cancer. Bioinformatics 29, 2223–2230 (2013)

  29. 29.

    The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013)

  30. 30.

    et al. Fast computation and applications of genome mappability. PLoS ONE 7, e30377 (2012)

  31. 31.

    et al. Discovery and characterization of artifactual mutations in deep coverage targeted capture sequencing data due to oxidative DNA damage during sample preparation. Nucleic Acids Res. 41, e67 (2013)

  32. 32.

    , & The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155, 858–868 (2013)

  33. 33.

    , & Colorectal carcinogenesis: MSI-H versus MSI-L. Dis. Markers 20, 199–206 (2004)

  34. 34.

    & RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011)

  35. 35.

    , & Measurement of mRNA abundance using RNA-seq data: RPKM measure is inconsistent among samples. Theory Biosci. 131, 281–285 (2012)

  36. 36.

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

  37. 37.

    , , & Identification of higher-order functional domains in the human ENCODE regions. Genome Res. 17, 917–927 (2007)

  38. 38.

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

  39. 39.

    Stopping rules in principal components analysis: a comparison of heuristical and statistical approaches. Ecology 74, 2204–2214 (1993)

  40. 40.

    & Genetic optimization using derivatives: the rgenoud package for R. J. Stat. Softw. 42, 473–487 (2010)

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Acknowledgements

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2011-26206 and ‘Centro de Excelencia Severo Ochoa 2013-2017’ SEV-2012-0208), a European Research Council Consolidator grant IR-DC (616434), Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), the EMBO Young Investigator Program, the EMBL-CRG Systems Biology Program, FP7 project 4DCellFate (277899), FP7 project MAESTRA (ICT-2013-612944) and by Marie Curie Actions.

Author information

Affiliations

  1. EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain

    • Fran Supek
    •  & Ben Lehner
  2. Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain

    • Fran Supek
    •  & Ben Lehner
  3. Division of Electronics, Rudjer Boskovic Institute, 10000 Zagreb, Croatia

    • Fran Supek
  4. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

    • Ben Lehner

Authors

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Contributions

F.S. performed all analyses. F.S. and B.L. designed analyses, interpreted the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ben Lehner.

Extended data

Supplementary information

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    Supplementary Table 1

    This table contains genome data sources.

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DOI

https://doi.org/10.1038/nature14173

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