Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates.
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Date
2018-06-07Author
Werner, B
Sottoriva, A
Type
Journal Article
Metadata
Show full item recordAbstract
The immortal strand hypothesis poses that stem cells could produce differentiated progeny while conserving the original template strand, thus avoiding accumulating somatic mutations. However, quantitating the extent of non-random DNA strand segregation in human stem cells remains difficult in vivo. Here we show that the change of the mean and variance of the mutational burden with age in healthy human tissues allows estimating strand segregation probabilities and somatic mutation rates. We analysed deep sequencing data from healthy human colon, small intestine, liver, skin and brain. We found highly effective non-random DNA strand segregation in all adult tissues (mean strand segregation probability: 0.98, standard error bounds (0.97,0.99)). In contrast, non-random strand segregation efficiency is reduced to 0.87 (0.78,0.88) in neural tissue during early development, suggesting stem cell pool expansions due to symmetric self-renewal. Healthy somatic mutation rates differed across tissue types, ranging from 3.5 × 10-9/bp/division in small intestine to 1.6 × 10-7/bp/division in skin.
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Subject
Intestine, Small
Skin
Humans
DNA
Computational Biology
Chromosome Segregation
Cell Proliferation
Organ Specificity
DNA Replication
Mutation
High-Throughput Nucleotide Sequencing
Mutation Rate
Research team
Evolutionary Genomics & Modelling
Language
eng
Date accepted
2018-05-25
License start date
2018-06-07
Citation
PLoS computational biology, 2018, 14 (6), pp. e1006233 - ?
Publisher
PUBLIC LIBRARY SCIENCE