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 0.15.
“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]
The Methods (‘Point mutation filtering’) support using variants that passed VariantFiltration and excluding variants with evidence of the alternative allele in the reference sample. But the paper specifies autosomes only, a GATK quality score ≥100, coverage ≥20× in both samples, and VAF ≥0.3—not X chromosomes or the claimed thresholds of ≥60, 5×, and 0.15. The cited passages do not establish a mapping-quality threshold of ≥30. (LLM, conf=0.94)
Experimental — accuracy not yet measuredLow-quality and subclonal mutations accumulated during clonal expansion of the organoid lines were excluded by annotating using SMuRF release 2.1.5.
“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]
The Methods (‘Point mutation filtering’; page not available) describe quality filtering and exclusion of mutations with variant allele frequency below 0.3 to remove mutations potentially acquired after clonal expansion. The Methods (‘Point mutation calling’) name GATK tools, but our copy does not identify SMuRF release 2.1.5 as the annotation method. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTo 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.3.2.0.
“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]
The paper identifies signatures corresponding to SBS1, SBS5 and SBS18, and reports in its Abstract (page unavailable) that mutations induced during culture were predominantly characterized by the signature corresponding to SBS18. It describes the signatures corresponding to SBS1 and SBS5 in relation to mutations accumulating during life, not as culture-related signatures. The cited passages do not address APOBEC-related SBS2 or SBS13. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIntestinal stem cells accumulate random DNA damage.
“Intestinal stem cells do, as expected, accumulate random DNA damage, 99”
From Aging of hematopoietic stem cells (2018) · cites this paper as [99]
In humans, several stem cell types, including those of the colon and liver, acquire somatic mutations at a steady rate during ageing; this feature is likely universal.
“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]
Aging is associated with a steady increase in the number of somatic mutations in virtually all tissues.
“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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- 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 · 2015: 1
- 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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