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Somatic mutation landscapes at single-molecule resolution

Author

Listed:
  • Federico Abascal

    (Wellcome Sanger Institute)

  • Luke M. R. Harvey

    (Wellcome Sanger Institute)

  • Emily Mitchell

    (Wellcome Sanger Institute
    Cambridge Biomedical Campus)

  • Andrew R. J. Lawson

    (Wellcome Sanger Institute)

  • Stefanie V. Lensing

    (Wellcome Sanger Institute)

  • Peter Ellis

    (Wellcome Sanger Institute
    Inivata, Babraham Research Campus)

  • Andrew J. C. Russell

    (Wellcome Sanger Institute)

  • Raul E. Alcantara

    (Wellcome Sanger Institute)

  • Adrian Baez-Ortega

    (Wellcome Sanger Institute)

  • Yichen Wang

    (Wellcome Sanger Institute)

  • Eugene Jing Kwa

    (Wellcome Sanger Institute)

  • Henry Lee-Six

    (Wellcome Sanger Institute)

  • Alex Cagan

    (Wellcome Sanger Institute)

  • Tim H. H. Coorens

    (Wellcome Sanger Institute)

  • Michael Spencer Chapman

    (Wellcome Sanger Institute)

  • Sigurgeir Olafsson

    (Wellcome Sanger Institute)

  • Steven Leonard

    (Wellcome Sanger Institute)

  • David Jones

    (Wellcome Sanger Institute)

  • Heather E. Machado

    (Wellcome Sanger Institute)

  • Megan Davies

    (Cambridge Biomedical Campus)

  • Nina F. Øbro

    (Cambridge Biomedical Campus
    University of Cambridge)

  • Krishnaa T. Mahubani

    (University of Cambridge
    University of Cambridge
    Cambridge Biomedical Campus)

  • Kieren Allinson

    (Addenbrooke’s Hospital)

  • Moritz Gerstung

    (European Bioinformatics Institute (EMBL-EBI))

  • Kourosh Saeb-Parsy

    (University of Cambridge
    Cambridge Biomedical Campus)

  • David G. Kent

    (Cambridge Biomedical Campus
    University of York)

  • Elisa Laurenti

    (Cambridge Biomedical Campus
    University of Cambridge)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

  • Raheleh Rahbari

    (Wellcome Sanger Institute)

  • Peter J. Campbell

    (Wellcome Sanger Institute
    University of Cambridge)

  • Robert J. Osborne

    (Wellcome Sanger Institute
    Biofidelity, Cambridge Science Park)

  • Iñigo Martincorena

    (Wellcome Sanger Institute)

Abstract

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

Suggested Citation

  • Federico Abascal & Luke M. R. Harvey & Emily Mitchell & Andrew R. J. Lawson & Stefanie V. Lensing & Peter Ellis & Andrew J. C. Russell & Raul E. Alcantara & Adrian Baez-Ortega & Yichen Wang & Eugene J, 2021. "Somatic mutation landscapes at single-molecule resolution," Nature, Nature, vol. 593(7859), pages 405-410, May.
  • Handle: RePEc:nat:nature:v:593:y:2021:i:7859:d:10.1038_s41586-021-03477-4
    DOI: 10.1038/s41586-021-03477-4
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    Citations

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    Cited by:

    1. Ewart Kuijk & Onno Kranenburg & Edwin Cuppen & Arne Van Hoeck, 2022. "Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Kitty Sherwood & Joseph C. Ward & Ignacio Soriano & Lynn Martin & Archie Campbell & Raheleh Rahbari & Ioannis Kafetzopoulos & Duncan Sproul & Andrew Green & Julian R. Sampson & Alan Donaldson & Kai-Re, 2023. "Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Sophie Pénisson & Amaury Lambert & Cristian Tomasetti, 2022. "Evaluating cancer etiology and risk with a mathematical model of tumor evolution," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Sujath Abbas & Oriol Pich & Ginny Devonshire & Shahriar A. Zamani & Annalise Katz-Summercorn & Sarah Killcoyne & Calvin Cheah & Barbara Nutzinger & Nicola Grehan & Nuria Lopez-Bigas & Rebecca C. Fitzg, 2023. "Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Philip S. Robinson & Laura E. Thomas & Federico Abascal & Hyunchul Jung & Luke M. R. Harvey & Hannah D. West & Sigurgeir Olafsson & Bernard C. H. Lee & Tim H. H. Coorens & Henry Lee-Six & Laura Butlin, 2022. "Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Jonathan C. M. Wan & Dennis Stephens & Lingqi Luo & James R. White & Caitlin M. Stewart & Benoît Rousseau & Dana W. Y. Tsui & Luis A. Diaz, 2022. "Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Tianyu Zhu & Huige Tong & Zhaozhen Du & Stephan Beck & Andrew E. Teschendorff, 2024. "An improved epigenetic counter to track mitotic age in normal and precancerous tissues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    8. Peng Dai & Lucia Ruojia Wu & Sherry Xi Chen & Michael Xiangjiang Wang & Lauren Yuxuan Cheng & Jinny Xuemeng Zhang & Pengying Hao & Weijie Yao & Jabra Zarka & Ghayas C. Issa & Lawrence Kwong & David Yu, 2021. "Calibration-free NGS quantitation of mutations below 0.01% VAF," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    9. Heather E. Machado & Nina F. Øbro & Nicholas Williams & Shengjiang Tan & Ahmed Z. Boukerrou & Megan Davies & Miriam Belmonte & Emily Mitchell & E. Joanna Baxter & Nicole Mende & Anna Clay & Philip Anc, 2023. "Convergent somatic evolution commences in utero in a germline ribosomopathy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    10. Chen Sun & Kunal Kathuria & Sarah B. Emery & ByungJun Kim & Ian E. Burbulis & Joo Heon Shin & Daniel R. Weinberger & John V. Moran & Jeffrey M. Kidd & Ryan E. Mills & Michael J. McConnell, 2024. "Mapping recurrent mosaic copy number variation in human neurons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    11. Shamir Montazid & Sheila Bandyopadhyay & Daniel W. Hart & Nan Gao & Brian Johnson & Sri G. Thrumurthy & Dustin J. Penn & Bettina Wernisch & Mukesh Bansal & Philipp M. Altrock & Fabian Rost & Patrycja , 2023. "Adult stem cell activity in naked mole rats for long-term tissue maintenance," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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