Somatic mutation landscapes at single-molecule resolution

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 Jing Kwa, Henry Lee-Six, Alex Cagan, Tim H. H. Coorens, Michael Spencer Chapman, Sigurgeir Olafsson, Steven Leonard, David Jones, Heather E. Machado, Megan Davies, Nina F. Øbro, Krishnaa T. Mahubani, Kieren Allinson, Moritz Gerstung, Kourosh Saeb-Parsy, David G. Kent, Elisa Laurenti, Michael R. Stratton, Raheleh Rahbari, Peter J. Campbell, Robert J. Osborne () and Iñigo Martincorena ()
Additional contact information
Federico Abascal: Wellcome Sanger Institute
Luke M. R. Harvey: Wellcome Sanger Institute
Emily Mitchell: Wellcome Sanger Institute
Andrew R. J. Lawson: Wellcome Sanger Institute
Stefanie V. Lensing: Wellcome Sanger Institute
Peter Ellis: Wellcome Sanger Institute
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
Krishnaa T. Mahubani: University of Cambridge
Kieren Allinson: Addenbrooke’s Hospital
Moritz Gerstung: European Bioinformatics Institute (EMBL-EBI)
Kourosh Saeb-Parsy: University of Cambridge
David G. Kent: Cambridge Biomedical Campus
Elisa Laurenti: Cambridge Biomedical Campus
Michael R. Stratton: Wellcome Sanger Institute
Raheleh Rahbari: Wellcome Sanger Institute
Peter J. Campbell: Wellcome Sanger Institute
Robert J. Osborne: Wellcome Sanger Institute
Iñigo Martincorena: Wellcome Sanger Institute

Nature, 2021, vol. 593, issue 7859, 405-410

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03477-4

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