Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A-->G mutation in blood.
The mutation 3243A-->G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mutation decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.
Rajasimha
Harsha Karur
HK
Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Chinnery
Patrick F
PF
Samuels
David C
DC
D000367:Age Factors; D003198:Computer Simulation; D004272:DNA, Mitochondrial / Q000097:blood / Q000235:genetics*; D006412:Hematopoietic Stem Cells; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics; D012357:RNA, Transfer, Lys / Q000235:genetics; D012641:Selection, Genetic
D004272:DNA, Mitochondrial; D012346:RNA, Transfer, Amino Acyl; D012357:RNA, Transfer, Lys