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.
Highlights
The immortal DNA strand hypothesis, originally proposed by Cairns in 1975, poses that adult mammalian stem cells do not segregate DNA strands randomly after proliferation [1]
We show that the patterns of mutation accumulation in human tissues with age support highly effective non-random DNA strand segregation after adolescence
We show that measuring the change of the mutational burden and, most crucially, the change of the variance of the mutational burden with age allows determining the probability of DNA strand segregation and the per cell mutation rate in healthy human tissues
Summary
The immortal DNA strand hypothesis, originally proposed by Cairns in 1975, poses that adult mammalian stem cells do not segregate DNA strands randomly after proliferation [1]. Stem cells might preferentially retain the parental ancestral strand, whereas the duplicated strand is passed onto differentiated cells with limited life span (Fig 1). In principle, such hierarchical tissues could produce differentiated progeny indefinitely without accumulating any proliferation-induced mutations in the stem cell compartment [2,3]. Experimental evidence supporting this hypothesis comes from BrdU stain tracing experiments both in vitro and in vivo [4,5,6,7]. Why Cairns hypothesis remains controversial [10]
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