Extended Data Fig. 4: Mutation accumulation in cells with different division rates.
From: Quantifying cell divisions along evolutionary lineages in cancer
a, From five mice, aged 20-24 months, we obtained clonal cell populations from 20 hematopoietic stem cells (HSCs) and 81 intestinal crypts. b, Distance of HSCs (n = 20) and intestinal crypts (n = 81) from a reference HSC sample (this analysis is done separately for each mouse, but all samples are combined in the plot). c, All pairwise L1 distances among HSCs (n = 54) and intestinal crypts (n = 644). As in b, this analysis is done separately in each mouse. d, Schematic of cell division histories consistent with our results. Two HSCs are separated by a median L1 distance of 0.0312. We think that the vast majority of this L1 burden must be embryonic divisions. Our mice have an average age of 22 months, which translates to approximately 660 days. If HSCs in fact divide every 57 days, the total divisions completed during postnatal life would be less than 12 – a number that is likely small in comparison with the number of embryonic divisions. We therefore suspect that embryonic divisions contribute approximately 0.0312/2 = 0.0156 of L1 burden to each lineage. For intestinal crypts, subtracting the embryonic burden (and the distance to the reference HSC) from the total L1 burden of 0.045 leaves us with a postnatal L1 burden of 0.0138. We can try to convert this burden into a mutation rate by leveraging the relatively well-understood proliferation rate of intestinal stem cells. Lgr5+ intestinal stem cells divide approximately every 2 days. We therefore calculate that stem cells have divided approximately 660/2 = 330 times during the animal’s life. Converting the L1 burden 0.0138 to a mutation rate with this number of divisions, we obtain 4.2 x 10−5 – a rate that is remarkably similar to our in vitro estimates across human cell lines. P-values in b and c were calculated using a two-sided Wilcoxon test. Box plot elements: center line, median; box limits, lower and upper quartiles; whiskers, lowest and highest value within 1.5 IQR. Graphics in a were created with BioRender.com.
