Fig. 4. Single-cell mtDNA content during oocyte development in the BVSC-tRNA^Ala m.5024C>T mice.

(A) mtDNA content in single growing oocytes. (B) Wild-type and m.5024C>T mutated mtDNA content in single growing oocytes. (C) Schematics of the favored model: fixed subset of replicating molecules R0, selective advantage for mutants λ_m > λ_w, and negative selection above a heteroplasmy threshold that depends on wild-type copy number (see Materials and Methods). (D) Statistical support for the models considered from ABC model selection (see Materials and Methods). As the threshold decreases from left to right, forcing a stricter agreement with experimental data, the support favors a model (green bars, H = 5) where there is a replicative advantage favoring mutant mtDNA and purifying selection acts against levels of mutation that depend on wild-type copy number (H = 0: with positive selection throughout, with negative selection; H = 1: without positive selection, with negative selection; H = 2: negative selection, with positive selection after T; H = 3: with positive selection after T and without negative selection; H = 4: without positive and negative selection). (E) Model prediction of the mean heteroplasmy in antral follicle oocytes after development for different initial heteroplasmy values. The error bars give the standard deviation generated by the top 200 accepted parametrizations. (F to I) Single-cell mtDNA analysis of ovulated oocytes from two 7-week-old BVSC-tRNA^Ala m.5024C>T mothers. (F) mtDNA heteroplasmy levels, (G) single oocyte heteroplasmy levels, (H) heteroplasmy shifts compared to the mothers’ ear biopsy, and (I) transformed heteroplasmy shifts compared to the mothers’ ear biopsy. N = 60. Bars show the mean ± SD.