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Tissue-specific mutation accumulation in human adult stem cells during life.
- Source :
-
Nature [Nature] 2016 Oct 13; Vol. 538 (7624), pp. 260-264. Date of Electronic Publication: 2016 Oct 03. - Publication Year :
- 2016
-
Abstract
- 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.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Animals
Child
Child, Preschool
Colon metabolism
DNA Mutational Analysis
Female
Genes, Neoplasm genetics
Humans
Incidence
Intestine, Small metabolism
Liver metabolism
Male
Mice
Middle Aged
Multipotent Stem Cells metabolism
Neoplasms epidemiology
Neoplasms genetics
Organoids metabolism
Point Mutation genetics
Young Adult
Adult Stem Cells metabolism
Aging genetics
Mutation Accumulation
Mutation Rate
Organ Specificity
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 538
- Issue :
- 7624
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 27698416
- Full Text :
- https://doi.org/10.1038/nature19768