Mutation-specific effects in germline transmission of pathogenic mtDNA variants

AbstractSTUDY QUESTIONDoes germline selection (besides random genetic drift) play a role during the transmission of heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations in humans?SUMMARY ANSWERWe conclude that inheritance of mtDNA is mutation-specific and governed by a combination of random genetic drift and negative and/or positive selection.WHAT IS KNOWN ALREADYmtDNA inherits maternally through a genetic bottleneck, but the underlying mechanisms are largely unknown. Although random genetic drift is recognized as an important mechanism, selection mechanisms are thought to play a role as well.STUDY DESIGN, SIZE, DURATIONWe determined the mtDNA mutation loads in 160 available oocytes, zygotes, and blastomeres of five carriers of the m.3243A>G mutation, one carrier of the m.8993T>G mutation, and one carrier of the m.14487T>C mutation.PARTICIPANTS/MATERIALS, SETTING, METHODSMutation loads were determined in PGD samples using PCR assays and analysed mathematically to test for random sampling effects. In addition, a meta-analysis has been performed on mutation load transmission data in the literature to confirm the results of the PGD samples.MAIN RESULTS AND THE ROLE OF CHANCEBy applying the Kimura distribution, which assumes random mechanisms, we found that mtDNA segregations patterns could be explained by variable bottleneck sizes among all our carriers (moment estimates ranging from 10 to 145). Marked differences in the bottleneck size would determine the proba...
Source: Human Reproduction - Category: Reproduction Medicine Source Type: research