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 3.5 × 10−9/bp/division in small intestine to 1.6 × 10−7/bp/division in skin.

On measuring selection in cancer from subclonal mutation frequencies

“…This will be our lower bound for the point mutation rate. Recently, Werner and Sottoriva [41] used the change in the mean and variance of the mutational burden with age in healthy human tissues to estimate the mutation rate in the colon and small intestine; they obtained ∼ 4 * 10 −9 per base pair per cell division. Assuming the value they used for time between stem cell divisions is one week, this leads to a mutation rate of ∼ 6 * 10 −10 per base pair per day.…”

Rate volatility and asymmetric segregation diversify mutation burden in mutator cells

“…John Cairns proposed a far more extreme asymmetric inheritance of mutations in the “Immortal Strand Hypothesis” in which stem cells always segregated away newer DNA duplexes with fixed mutations 27 . In keeping with this hypothesis, a recent computational analysis of human somatic variants argued that the high variance of mutation burden in adult stem cells with age supports a preferential inheritance of ancestral strands 28 . A second study from the field of evolutionary biology examined the potential influence of disparate mutagenesis of leading and lagging strand synthesis to promote variable evolutionary trajectories from the same cell population 29 .…”

Mutation-rate plasticity and the germline of unicellular organisms

“…The variance of the mutational burden σ2 is given by [10]σ2=nfalse(1−pfalse)μL+nfalse(μLfalse)2pfalse(1−pfalse).With these expressions, we can quantify the change of the mutational burden and the change of the variance of the mutational burden per mother cell after a number of normalΔn divisionsnormalΔμfalse~normalΔn=(1−p)μLandnormalΔσ2normalΔn=(1−p)μL+(μL)2p(1−p)…”

“…An asymmetrical cell division results in a senescing ‘mother’ cell and a rejuvenated ‘daughter’ cell, and fecundity of the mother cell decreases with each division as damaged proteins and cell components accumulate. There is increasing evidence that such asymmetries during cell division are not limited to physiological and morphological cell characteristics, but extend to patterns of DNA-strand inheritance, as shown in yeast [6,7] and E. coli [8] and various types of stem cells [9,10].…”