Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates

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 3.5x10-9 /bp/division in small intestine to 1.6x10-7/bp/division in skin.\n\nAuthor SummaryCairn proposed in 1975 that upon proliferation, cells might not segregate DNA strands randomly into daughter cells, but preferentially keep the ancestral (blue print) template strand in stem cells. This mechanism would allow to drastically reduce the rate of mutation accumulation in human tissues. Testing the hypothesis in human stem cells within their natural tissue environment remains challenging. Here we show that the patterns of mutation accumulation in human tissues with age support highly effective non-random DNA strand segregation after adolescence. In contrast, during early development in infants, DNA strand segregation is less effective, likely because stem cell populations are continuing to grow.