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Tissue-specific mutation accumulation in human adult stem cells during life
Open accessAbstract
The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.
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“We included all variants in each clone at autosomal or X chromosomes, not present in the bulk control sample that passed VariantFiltration, with a GATK phred-scaled quality score ≥60; minimum base coverage of 5X, a mapping quality ≥30, and a variant allele frequency of at least 0.1558,74.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [58]
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“Low-quality and subclonal mutations accumulated during clonal expansion of the organoid lines were excluded by annotating using SMuRF release 2.1.5 as described previously58”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [58]
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“To assess the genome-wide off-target effects of base editor activity in intestinal organoids, we compared culture-related (SBS1, SBS5, SBS18), as well as APOBEC-related (SBS2, SBS13) mutational signatures to the overall mutational profile using the Bioconductor R package MutationalPatterns v.3.2.056,58,59.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [58]
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“This is especially relevant when DNA damage impacts on stem cells, hampering their role in tissue renewal or leading to their exhaustion, which in turn promotes aging and increases susceptibility to age-related pathologies 6,7 .”
From Hallmarks of aging: An expanding universe (2023) · cites this paper as [6]
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“The study of somatic mutations with standard whole-genome sequencing requires isolating clonal groups of cells recently derived from a single cell8,13,14.”
From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [14]
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“studies in humans have shown that cell division rates are not a major determinant of somatic mutation rates across human tissues14,18.”
From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [14]
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“They also appear to differ in their association with the rate of cell division in humans, with SBS1 being more common in fast-proliferating tissues, such as colon and embryonic or foetal tissues, and SBS5 dominating in post-mitotic cells in the absence of cell division14,18,20.”
From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [14]
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“This sample was included because results in humans have shown that the mutation rates of colorectal and small intestine epithelial stem cells are similar14,20 (Extended Data Fig. 1).”
From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [14]
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“Intestinal stem cells do, as expected, accumulate random DNA damage, 99”
From Aging of hematopoietic stem cells (2018) · cites this paper as [99]
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“In humans, several stem cell types, including those of the colon and liver, have been shown to acquire somatic mutations at a steady rate during ageing60; this feature is likely universal.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [60]
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“Aging is associated with a steady increase in the number of somatic mutations in virtually all tissues 1–5.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [1]
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Analysis of Cell and Nucleus Genome by Next-Generation Sequencing
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Somatic mutation accumulation seen through a single-molecule lens
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Metadata
- Authors
- Blokzijl, F., de Ligt, J., Jager, M., Sasselli, V., Roerink, S., Sasaki, N., Huch, M., Boymans, S., Kuijk, E., Prins, P., Nijman, I. J., Martincorena, I., Mokry, M., Wiegerinck, C. L., Middendorp, S., Sato, T., Schwank, G., Nieuwenhuis, E. E. S., Verstegen, M. M. A., van der Laan, L. J. W., de Jonge, J., IJzermans, J. N. M., Vries, R. G., van de Wetering, M., Stratton, M. R., Clevers, H., Cuppen, E., & van Boxtel, R.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Wellcome Sanger Institute (GB)
- University Medical Center Utrecht (NL)
- Erasmus MC (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- Corresponding author
- Cuppen, Edwin
- ORCID
- Blokzijl, Francis
- Jager, Myrthe
- Sasselli, Valentina
- Roerink, Sophie
- Sasaki, Nobuo
- Huch, Meritxell
- Boymans, Sander
- Kuijk, Ewart
- Prins, Pjotr
- Middendorp, Sabine
- Sato, Toshiro
- Schwank, Gerald
- Nieuwenhuis, Edward E. S.
- Verstegen, Monique M. A.
- IJzermans, Jan N. M.
- Vries, Robert G.
- Stratton, Michael R.
- Clevers, Hans
- Cuppen, Edwin
- Venue
- Nature
- Published
- 2016-10-03
- Volume
- 538
- Issue
- 7624
- Pages
- 260-264
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5536223
- OpenAlex
- W2524881570
- Cited by
- 935
- References
- 42
- Citations by year
- 2026: 52 · 2025: 73 · 2024: 74 · 2023: 91 · 2022: 104 · 2021: 136 · 2020: 136 · 2019: 100 · 2018: 96 · 2017: 66 · 2016: 5
- FWCI
- 37.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Cancer Research UK (21777)
- Japan Society for the Promotion of Science (26293177, 15K08974, 15K15297, 16H07176)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- adult stem cells, somatic mutation accumulation, mutation rate, mutation spectrum, liver stem cells, colon stem cells, mutational signatures, driver genes, carcinogenesis, aging, cancer risk, interindividual variability
- MeSH terms
- Mutation Accumulation, Adolescent, Adult, Aged, Aged, 80 and over, Aging, Animals, Child, Child, Preschool, Colon, DNA Mutational Analysis, Female, Humans, Intestine, Small, Liver, Male, Middle Aged, Neoplasms, Organ Specificity, Organoids, Incidence, Point Mutation, Multipotent Stem Cells, Mice, Genes, Neoplasm, Adult Stem Cells, Young Adult, Mutation Rate
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