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PMID: 34433962 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The mutational landscape of human somatic and germline cells.

Nature ·Vol. 597 ·No. 7876 ·2021-00-00 ·Pages 381-386

Moore L, Cagan A, Coorens THH, Neville MDC, Sanghvi R, Sanders MA, Oliver TRW, Leongamornlert D, Ellis P, Noorani A, Mitchell TJ, Butler TM, Hooks Y, Warren AY, Jorgensen M, Dawson KJ, Menzies A, O'Neill L, Latimer C, Teng M, van Boxtel R, Iacobuzio-Donahue CA, Martincorena I, Heer R, Campbell PJ, Fitzgerald RC, Stratton MR, Rahbari R

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.

MeSH Terms
Aged Clone Cells/metabolism Female Germ Cells/metabolism Germ-Line Mutation Health Humans Male Microdissection Middle Aged Mutation Rate Organ Specificity/genetics Oxidative Stress Spermatogonia/metabolism
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Moore Luiza ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. | Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Cagan Alex ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Coorens Tim H H ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Neville Matthew D C ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Sanghvi Rashesh ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Sanders Mathijs A
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. | Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
Oliver Thomas R W ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. | Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Leongamornlert Daniel ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Ellis Peter
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. | Inivata, Cambridge, UK.
Noorani Ayesha
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Mitchell Thomas J ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. | Department of Surgery, University of Cambridge, Cambridge, UK.
Butler Timothy M ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Hooks Yvette
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Warren Anne Y
Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Jorgensen Mette
Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Dawson Kevin J
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Menzies Andrew
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
O'Neill Laura
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Latimer Calli
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Teng Mabel
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
van Boxtel Ruben ORCID
Princess Máxima Center for Pediatric Oncology and Oncode Institute, Utrecht, Netherlands.
Iacobuzio-Donahue Christine A ORCID
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. | Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Martincorena Inigo ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Heer Rakesh
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. | Newcastle Urology, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Campbell Peter J ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
Fitzgerald Rebecca C ORCID
MRC Cancer Unit, University of Cambridge, Cambridge, UK.
Stratton Michael R ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. [email protected].
Rahbari Raheleh ORCID
Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. [email protected].
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/s41586-021-03822-7
Email
[email protected]
[email protected]
Published
2021-00-00
Epub
2021-00-25
Pages
381-386
Language
English
Region
England
NLM ID
0410462
Subset
IM
Grants
Wellcome Trust · United Kingdom
Medical Research Council · United Kingdom
Corrections
CommentIn
PMID: 34433973
CommentIn
PMID: 34522034
External Links
PubMed source DOI: 10.1038/s41586-021-03822-7 View journal details
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