Somatic mutation rates scale with lifespan across mammals
Open accessPublished version of a preprint
Abstract
The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans 1–7 . Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans 8 , although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined—including variation of around 30-fold in lifespan and around 40,000-fold in body mass—the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437 · see citing works
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660 · see citing works
Self-citationNowell, P. C. (1976) · Science · doi:10.1126/science.959840 · Cited by 6,471 · see citing works
Age-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841 · see citing works
The origin and evolution of mutations in acute myeloid leukemia
Welch, J. S., Ley, T. J., Link, D. C., Miller, C. A., Larson, D. E., Koboldt, D. C., Wartman, L. D., Lamprecht, T. L., Liu, F., Xia, J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.023 · Cited by 1,575 · see citing works
Clonal hematopoiesis in human aging and disease
Jaiswal, S., & Ebert, B. L. (2019) · Science · doi:10.1126/science.aan4673 · Cited by 1,156 · see citing works
Tissue-specific mutation accumulation in human adult stem cells during life
Blokzijl, F., de Ligt, J., Jager, M., Sasselli, V., Roerink, S., Sasaki, N., Huch, M., Boymans, S., Kuijk, E., Prins, P., et al. (2016) · Nature · doi:10.1038/nature19768 · Cited by 935 · see citing works
Self-citationBody size, energy metabolism and lifespan
Speakman, J. R. (2005) · Journal of Experimental Biology · doi:10.1242/jeb.01556 · Cited by 914 · see citing works
The central role of DNA damage in the ageing process
Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. J. (2021) · Nature · doi:10.1038/s41586-021-03307-7 · Cited by 907 · see citing works
On the nature of the aging process
Szilard, L. (1959) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.45.1.30 · Cited by 651 · see citing works
The Human Gut Bacterial Genotoxin Colibactin Alkylates DNA
Wilson, M. R., Jiang, Y., Villalta, P. W., Stornetta, A., Boudreau, P. D., Carrá, A., Brennan, C. A., Chun, E., Ngo, L., Samson, L. D., et al. (2019) · Science · doi:10.1126/science.aar7785 · Cited by 635 · see citing works
Age-related remodelling of oesophageal epithelia by mutated cancer drivers
Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., et al. (2019) · Nature · doi:10.1038/s41586-018-0811-x · Cited by 628 · 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 · see citing works
Self-citationSIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species
Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., Tan, R., Simon, M., Henderson, S., Steffan, J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.043 · Cited by 353 · see citing works
The role of mitochondrial dysfunction in age-related diseases
Lane, R. K., Hilsabeck, T., & Rea, S. L. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.05.021 · Cited by 205 · see citing works
Convergent somatic mutations in metabolism genes in chronic liver disease
Ng, S. W. K., Rouhani, F. J., Brunner, S. F., Brzozowska, N., Aitken, S. J., Yang, M., Abascal, F., Moore, L., Nikitopoulou, E., Chappell, L., et al. (2021) · Nature · doi:10.1038/s41586-021-03974-6 · Cited by 190 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Hallmarks of aging: An expanding universe
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023) · Cell · doi:10.1016/j.cell.2022.11.001 · Cited by 6,549 · see citing works
The Information Theory of Aging
Lu, Y. R., Tian, X., & Sinclair, D. A. (2023) · Nature Aging · doi:10.1038/s43587-023-00527-6 · Cited by 141 · see citing works
Rosendahl Huber, A., Pleguezuelos-Manzano, C., Puschhof, J., Ubels, J., Boot, C., Saftien, A., Verheul, M., Trabut, L. T., Groenen, N., van Roosmalen, M., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.02.009 · Cited by 106 · see citing works
Clonal hematopoiesis and inflammation – the perpetual cycle
Avagyan, S., & Zon, L. I. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.12.001 · Cited by 79 · see citing works
Contribution of pks+ E. coli mutations to colorectal carcinogenesis
Chen, B., Ramazzotti, D., Heide, T., Spiteri, I., Fernandez-Mateos, J., James, C., Magnani, L., Graham, T. A., & Sottoriva, A. (2023) · Nature Communications · doi:10.1038/s41467-023-43329-5 · Cited by 74 · see citing works
“Furthermore, exposure to pks + E. coli generates a characteristic short indel signature (COSMIC ID18) which manifests as short T deletions at T homopolymers 10 .”
Carcinogenesis resistance in the longest‐lived rodent, the naked mole‐rat
Yamamura, Y., Kawamura, Y., Oka, K., & Miura, K. (2022) · Cancer Science · doi:10.1111/cas.15570 · Cited by 20 · see citing works
Temporal genomic dynamics shape clinical trajectory in multiple myeloma
Maura, F., Kaddoura, M., Poos, A. M., Baughn, L. B., Ziccheddu, B., Bärtsch, M.-A., Cirrincione, A., Maclachlan, K., Chojnacka, M., Diamond, B., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02292-1 · Cited by 14 · see citing works
<i>Tet2</i> and <i>Jak2</i> clonal hematopoiesis do not modify murine tauopathy
Gaebel, L., Gerhardt, T., Khamhoung, A., Huynh, P., Heiser, M., Brisnovali, N. F., Jacob, W., Yates, A. G., Douglas, A., Fidler, T., et al. (2026) · Journal of Alzheimer’s Disease · doi:10.1177/13872877261458734 · Cited by 1 · see citing works
- Authors
- Cagan, A., Baez-Ortega, A., Brzozowska, N., Abascal, F., Coorens, T. H. H., Sanders, M. A., Lawson, A. R. J., Harvey, L. M. R., Bhosle, S., Jones, D., Alcantara, R. E., Butler, T. M., Hooks, Y., Roberts, K., Anderson, E., Lunn, S., Flach, E., Spiro, S., Januszczak, I., Wrigglesworth, E., Jenkins, H., Dallas, T., Masters, N., Perkins, M. W., Deaville, R., Druce, M., Bogeska, R., Milsom, M. D., Neumann, B., Gorman, F., Constantino-Casas, F., Peachey, L., Bochynska, D., Smith, E. S. J., Gerstung, M., Campbell, P. J., Murchison, E. P., Stratton, M. R., & Martincorena, I.
- Affiliations
- Wellcome Sanger Institute (GB)
- Zoological Society of London (GB)
- German Cancer Research Center (DE)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca (RO)
- European Bioinformatics Institute (GB)
- Corresponding author
- Cagan, Alex
- Martincorena, Iñigo
- ORCID
- Cagan, Alex
- Brzozowska, Natalia
- Abascal, Federico
- Coorens, Tim H. H.
- Sanders, Mathijs A.
- Lawson, Andrew R. J.
- Harvey, Luke M. R.
- Bhosle, Shriram
- Jones, David
- Butler, Timothy M.
- Lunn, Sharna
- Flach, Edmund
- Spiro, Simon
- Januszczak, Inez
- Wrigglesworth, Ethan
- Jenkins, Hannah
- Perkins, Matthew W.
- Bogeska, Ruzhica
- Milsom, Michael D.
- Neumann, Björn
- Peachey, Laura
- Bochynska, Diana
- Smith, Ewan St. John
- Gerstung, Moritz
- Campbell, Peter J.
- Murchison, Elizabeth P.
- Stratton, Michael R.
- Martincorena, Iñigo
- Venue
- Nature
- Published
- 2022-04-13
- Volume
- 604
- Issue
- 7906
- Pages
- 517-524
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9021023
- OpenAlex
- W4225246272
- Cited by
- 481
- References
- 17
- Citations by year
- 2026: 83 · 2025: 104 · 2024: 98 · 2023: 113 · 2022: 79 · 2021: 4
- FWCI
- 33.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- Explore Bristol Research (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo
- Apollo (cc-by)
- Funders
- European Hematology Association (TRTH182)
- Wellcome Trust (206194)
- Cancer Research UK (21777, C57387/A21777)
- Dunhill Medical Trust (RPGF2002188)
- José Carreras Leukämie-Stiftung
- Natural Environment Research Council (NE/S000127/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- somatic mutation rate, lifespan, mutational signatures, intestinal crypts, 5-methylcytosine deamination, oxidative DNA damage, endogenous mutagenesis, cross-species comparison, mammals, aging, cancer, evolutionary constraints, life-history traits
- MeSH terms
- Animals, Humans, Longevity, Mammals, Mutation, Mutagenesis, Mutation Rate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
