Fig. 3: Specific mutations in the NCR confer a competitive advantage.
From: Selfish mutations promote age-associated erosion of mtDNA integrity in mammals
a An AAA vs C# scatter plot for hepatocytes from 24-month-old WT mice. In this panel, in addition to above key, alleles in the NCR and OriL are colored cyan and purple, respectively. The grey line represents a simulation-based prediction for location of neutral alleles with varying mutation rates. b The spectrum of NCR mutations in hepatocytes from 24-month-old WT mice. Alleles present at over 20% abundance in at least one cell in at least three out of five mice are highlighted. c The exceptional NCR alleles (colored bars as in b) were not detected in four 3-month-old WT mice. d Abundance distribution of highlighted NCR alleles in cells of 24-month-old WT mice. e Simulations testing the influence of the parameters on the cellular distribution of mutation abundance. Adjusting the mutation rate (lower panel) alone cannot mimic the observed patterns (d), while the inclusion of positive selection coefficients improves the match (upper panel). Y-axis scales differ. f–g Simulations show the linear accumulation of a neutral allele in whole tissues with time/Generations (f), while a positively selected mutant allele accumulates at an accelerating rate (g) h, i Measurement of two driver alleles using allele-specific ddPCR shows accelerating accumulation in bulk livers of WT mice. f–i N = 5 simulations or mice per time point. Red lines show linear (f) and power function (g–i) fitting. j Driver mutations localize in the replication initiation region: NCR (blue); the conserved sequence boxes (CSB1-3); the light strand (L) promoter (LSP), which primes DNA synthesis pausing at the termination-associated sequence (TAS); and the heavy strand (H) promoter (HSP). The allele labeled in cyan showed selective amplification in both WT and heterozygous mutator mice, whereas the alleles labeled in green and orange only passed the criteria for drivers in WT or heterozygous mutator mice, respectively. 16286A>G and 16293T>C alleles are likely drivers in WT mice that fell below our thresholds.
