Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates.
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ICR Authors
Authors
Werner, B
Sottoriva, A
Sottoriva, A
Document Type
Journal Article
Date
2018-06-07
Date Accepted
2018-05-25
Abstract
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.
Citation
PLoS computational biology, 2018, 14 (6), pp. e1006233 - ?
Source Title
Publisher
PUBLIC LIBRARY SCIENCE
ISSN
1553-734X
eISSN
1553-7358
Collections
Research Team
Evolutionary Genomics & Modelling