Somatic mutation and selection at epidemiological scale

作者：Andrew Lawson, Federico Abascal, Pantelis Nicola, Stefanie V. Lensing, Amy L. Roberts, Georgios Kalantzis, Adrian Baez‐Ortega, Natalia Brzozowska, Julia S. El-Sayed Moustafa, Dovile Vaitkute, Belma Jakupovic, Ayrun Nessa, Samuel Wadge, Anna Paterson, Doris M. Rassl, Raul E. Alcantara, Laura P. O’Neill, Sara Widaa, Siobhan Austin-Guest, Matthew D. C. Neville, Moritz J. Przybilla, Wei Cheng, Maria Morra, Lucy Sykes, Matthew Mayho, Nicole Müller, Nick Williams, Diana Alexander, Luke M. R. Harvey, Thomas C. Clarke, Alexander M. P. Byrne, Jamie R. Blundell, Matthew D. Young, Krishnaa T. Mahbubani, Kourosh Saeb‐Parsy, Hilary C. Martin, Michael R. Stratton, Peter J. Campbell, Raheleh Rahbari, Kerrin S. Small, Iñigo Martincorena · 发表于：medRxiv · 年份：2024 · DOI：10.1101/2024.10.30.24316422 · 被引用次数：12 · 研究领域：Biotechnology and Related Fields

Abstract As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations ( 1–10 . Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq) 11 , a duplex sequencing method with error rates <5 errors per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 49 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression model...