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Tissue-specific mutation accumulation in human adult stem cells during life

Gradual accumulation of mutations in human adult stem cells during life is associated with various age-related diseases, including cancer. The number of stem cell divisions throughout life is believed to be a major determinant for mutation accumulation and could explain the extreme variation of cancer incidence across different organs. Yet, mutation patterns and rates of healthy adult stem cells remain unknown. Here, we determined genome-wide mutation patterns in primary adult stem cells of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years. We find that the number of mutations increases linearly with age up to several thousand mutations per cell at 87 years of age, while mutation spectra remain constant throughout life. Small intestine and colon stem cells have a 2-fold higher mutation rate per year compared with liver stem cells. These differences could be exclusively attributed to the mutagenic action of spontaneous deamination of cytosine residues and may reflect the high stem cell division rate in these tissues. The genomic distribution of somatic mutations is non-random and predominantly associated with DNA replication dynamics in the small intestine and colon, and with transcription in the liver. These results indicate that a stable balance between various mutagenic and DNA repair processes is maintained throughout life and that the activity of these processes in adult stem cells varies between tissues.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001001900 HiSeq X Ten Illumina HiSeq 2500 NextSeq 500 61
Publications Citations
Tissue-specific mutation accumulation in human adult stem cells during life.
Nature 538: 2016 260-264
Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer.
Science 358: 2017 234-238
Early divergence of mutational processes in human fetal tissues.
Sci Adv 5: 2019 eaaw1271
The mutational impact of culturing human pluripotent and adult stem cells.
Nat Commun 11: 2020 2493
Human induced pluripotent stem cells display a similar mutation burden as embryonic pluripotent cells <i>in vivo</i>.
iScience 25: 2022 103736
Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue.
Nat Commun 13: 2022 5915
Mutation accumulation in mtDNA of cancers resembles mutagenesis in normal stem cells.
iScience 25: 2022 105610