The mutational landscape of human somatic and germline cells
Open accessAbstract
Over the course of an individual's lifetime, normal human cells accumulate mutations 1. 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 damage 2, 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.
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Selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.
“Interestingly, these selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [23]
Clonal structures in normal tissues (p. 3) reports cancer-driver mutations in normal tissues and describes such mutations as conferring a selective advantage. Identification of Cancer Driver Mutations (p. 23) includes missense mutations at validated cancer hotspots, supporting the nonsynonymous-mutation example. The copy does not establish that these events were initially thought to be restricted to cancer. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAcross most, if not all, tissues, after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time.
“A consistent pattern has been observed across most, if not all, tissues: after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time (Figure 1).17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [23]
The Clonal structures in normal tissues section (p. 3) describes how clonal architecture differs among adult tissues, and the Discussion (p. 6) emphasizes variation in clonal dynamics. Neither passage establishes an early-life expansion of the stem-cell pool followed by declining clonal heterogeneity across most tissues; searches for age-related loss of clonal diversity found no such account in our copy. (LLM, conf=0.72)
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Cites
Mutational signatures associated with tobacco smoking in human cancer
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Self-citationTissue-specific mutation accumulation in human adult stem cells during life
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Self-citationDetecting ultralow-frequency mutations by Duplex Sequencing
Kennedy, S. R., Schmitt, M. W., Fox, E. J., Kohrn, B. F., Salk, J. J., Ahn, E. H., Prindle, M. J., Kuong, K. J., Shen, J.-C., Risques, R.-A., et al. (2014) · Nature Protocols · doi:10.1038/nprot.2014.170 · Cited by 503 · see citing works
The mutational landscape of normal human endometrial epithelium
Moore, L., Leongamornlert, D., Coorens, T. H. H., Sanders, M. A., Ellis, P., Dentro, S. C., Dawson, K. J., Butler, T., Rahbari, R., Mitchell, T. J., et al. (2020) · Nature · doi:10.1038/s41586-020-2214-z · Cited by 499 · cited 1× · see citing works
“(1) Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, CB10 1SA, 13 UK 14 (2) Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, 15 Cambridge, CB2 0QQ, UK 16 (3) Department of Hematology, Erasmus University Medical Center, 3015 CN Rotterdam, The 17 Ne…”
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Self-citationTissue-specific designs of stem cell hierarchies
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Flagged first, then by citations
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Genome-wide mapping of somatic mutation rates uncovers drivers of cancer
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Temporal genomic dynamics shape clinical trajectory in multiple myeloma
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Evolution of Multiple Myeloma from a Genomic Perspective
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- Authors
- Moore, L., Cagan, A., Coorens, T. H. H., Neville, M. D. C., Sanghvi, R., Sanders, M. A., Oliver, T. R. W., Leongamornlert, D., Ellis, P., Noorani, A., Mitchell, T. J., Butler, T. M., Hooks, Y., Warren, A. Y., Jorgensen, M., Dawson, K. J., Menzies, A., O’Neill, L., Latimer, C., Teng, M., van Boxtel, R., Iacobuzio-Donahue, C. A., Martincorena, I., Heer, R., Campbell, P. J., Fitzgerald, R. C., Stratton, M. R., & Rahbari, R.
- Affiliations
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Erasmus MC (NL)
- University of Cambridge (GB)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Corresponding author
- Stratton, Michael R.
- Rahbari, Raheleh
- ORCID
- Moore, Luiza
- Cagan, Alex
- Coorens, Tim H. H.
- Neville, Matthew D. C.
- Sanghvi, Rashesh
- Sanders, Mathijs A.
- Oliver, Thomas R. W.
- Leongamornlert, Daniel
- Mitchell, Thomas J.
- Butler, Timothy M.
- Warren, Anne Y.
- Menzies, Andrew
- Latimer, Calli
- van Boxtel, Ruben
- Iacobuzio-Donahue, Christine A.
- Martincorena, Inigo
- Heer, Rakesh
- Campbell, Peter J.
- Fitzgerald, Rebecca C.
- Stratton, Michael R.
- Rahbari, Raheleh
- Venue
- Nature
- Published
- 2021-08-25
- Volume
- 597
- Issue
- 7876
- Pages
- 381-386
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3194049481
- Cited by
- 379
- References
- 6
- Citations by year
- 2026: 62 · 2025: 79 · 2024: 79 · 2023: 81 · 2022: 56 · 2021: 22
- FWCI
- 23.90
- Type
- journal article
- Language
- en
- Open access
- green
- pure.eur.nl
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by-nc-nd)
- Funders
- European Hematology Association (TRTH182)
- Wellcome Trust
- Cancer Research UK (27176, 21777, 27114)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- mutational signatures, somatic mutations, germline mutations, mutation rate, oxidative damage, spermatogonia, human cell types, mutational landscape
- MeSH terms
- Aged, Clone Cells, Female, Germ Cells, Health, Humans, Male, Middle Aged, Organ Specificity, Spermatogonia, Germ-Line Mutation, Oxidative Stress, Microdissection, Mutation Rate
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