Mitochondrial DNA mutations in human colonic crypt stem cells
J. Clin. Invest. Robert W. Taylor, et al. 112:1351 doi:10.1172/JCI19435 [Go to this article.]

Figure 4
Mathematical modeling of mitochondrial DNA mutation and replication in colonic crypt stem cells. Simulated cells contained approximately 10,000 mtDNA and divided every 24 hours. Each symbol is the result of 300 (at high mutation rates) to 3,000 (at low mutation rates) independent simulations. (a) The percentage of simulated crypt stem cells containing detectable (>30%) mutant mtDNA during a human lifespan. Each curve corresponds to a different mutation rate indicated on the figure. The model predicts that the random partitioning of mitochondrial genomes during crypt cell division will cause random genetic drift and lead to the clonal expansion of somatic mtDNA mutations during human life. (b) The percentage of simulated crypt stem cells containing a detectable amount of mtDNA mutations as a function of the mtDNA mutation rate (circles, no mutations, > 30%; triangles, one mutation, >30%; inverted triangles, two mutations, >30%; asterisk, three or more mutations. The curves represent the theoretical simple probability functions). The model predicts that the mutation rate must be approximately 5 × 10^–5 per genome per day in order to simultaneously generate crypt stem cells that contain no mutations, and some that have two or more detectable mutations, at age 80 years. Previous simulations demonstrate that the random partitioning of individual genomes during stem cell division will cause random genetic drift and clonal expansion of somatic mtDNA mutations, and the speed of the random drift is dependent upon the frequency of the crypt stem cell divisions. Changing the rate of stem cell division to once per 48 hours did not alter the simulation results.