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The mutational landscape of human somatic and germline cells

Author

Listed:
  • Luiza Moore

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust)

  • Alex Cagan

    (Wellcome Sanger Institute)

  • Tim H. H. Coorens

    (Wellcome Sanger Institute)

  • Matthew D. C. Neville

    (Wellcome Sanger Institute)

  • Rashesh Sanghvi

    (Wellcome Sanger Institute)

  • Mathijs A. Sanders

    (Wellcome Sanger Institute
    Erasmus University Medical Center)

  • Thomas R. W. Oliver

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust)

  • Daniel Leongamornlert

    (Wellcome Sanger Institute)

  • Peter Ellis

    (Wellcome Sanger Institute
    Inivata)

  • Ayesha Noorani

    (Wellcome Sanger Institute)

  • Thomas J. Mitchell

    (Wellcome Sanger Institute
    University of Cambridge)

  • Timothy M. Butler

    (Wellcome Sanger Institute)

  • Yvette Hooks

    (Wellcome Sanger Institute)

  • Anne Y. Warren

    (Cambridge University Hospitals NHS Foundation Trust)

  • Mette Jorgensen

    (Great Ormond Street Hospital for Children NHS Foundation Trust)

  • Kevin J. Dawson

    (Wellcome Sanger Institute)

  • Andrew Menzies

    (Wellcome Sanger Institute)

  • Laura O’Neill

    (Wellcome Sanger Institute)

  • Calli Latimer

    (Wellcome Sanger Institute)

  • Mabel Teng

    (Wellcome Sanger Institute)

  • Ruben Boxtel

    (Princess Máxima Center for Pediatric Oncology and Oncode Institute)

  • Christine A. Iacobuzio-Donahue

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Inigo Martincorena

    (Wellcome Sanger Institute)

  • Rakesh Heer

    (Newcastle University
    Newcastle Urology, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust)

  • Peter J. Campbell

    (Wellcome Sanger Institute)

  • Rebecca C. Fitzgerald

    (MRC Cancer Unit, University of Cambridge)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

  • Raheleh Rahbari

    (Wellcome Sanger Institute)

Abstract

Over the course of an individual’s lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

Suggested Citation

  • Luiza Moore & Alex Cagan & Tim H. H. Coorens & Matthew D. C. Neville & Rashesh Sanghvi & Mathijs A. Sanders & Thomas R. W. Oliver & Daniel Leongamornlert & Peter Ellis & Ayesha Noorani & Thomas J. Mit, 2021. "The mutational landscape of human somatic and germline cells," Nature, Nature, vol. 597(7876), pages 381-386, September.
    • Handle: RePEc:nat:nature:v:597:y:2021:i:7876:d:10.1038_s41586-021-03822-7
    DOI: 10.1038/s41586-021-03822-7
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    Cited by:

    1. Francesc Muyas & Manuel José Gómez Rodriguez & Rita Cascão & Angela Afonso & Carolin M. Sauer & Claudia C. Faria & Isidro Cortés-Ciriano & Ignacio Flores, 2024. "The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Giulia Schiroli & Vinay Kartha & Fabiana M. Duarte & Trine A. Kristiansen & Christina Mayerhofer & Rojesh Shrestha & Andrew Earl & Yan Hu & Tristan Tay & Catherine Rhee & Jason D. Buenrostro & David T, 2024. "Cell of origin epigenetic priming determines susceptibility to Tet2 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. 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.
    4. 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.
    5. 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.
    6. Marc Jan Bonder & Stephen J. Clark & Felix Krueger & Siyuan Luo & João Agostinho de Sousa & Aida M. Hashtroud & Thomas M. Stubbs & Anne-Katrien Stark & Steffen Rulands & Oliver Stegle & Wolf Reik & Fe, 2024. "scEpiAge: an age predictor highlighting single-cell ageing heterogeneity in mouse blood," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Aaron Wing Cheung Kwok & Chen Qiao & Rongting Huang & Mai-Har Sham & Joshua W. K. Ho & Yuanhua Huang, 2022. "MQuad enables clonal substructure discovery using single cell mitochondrial variants," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Máire Ní Leathlobhair & Anna Frangou & Ben Kinnersley & Alex J. Cornish & Daniel Chubb & Eszter Lakatos & Prabhu Arumugam & Andreas J. Gruber & Philip Law & Avraam Tapinos & G. Maria Jakobsdottir & Il, 2024. "Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    9. Thomas R. W. Oliver & Lia Chappell & Rashesh Sanghvi & Lauren Deighton & Naser Ansari-Pour & Stefan C. Dentro & Matthew D. Young & Tim H. H. Coorens & Hyunchul Jung & Tim Butler & Matthew D. C. Nevill, 2022. "Clonal diversification and histogenesis of malignant germ cell tumours," Nature Communications, Nature, vol. 13(1), pages 1-12, 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.

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