Mutation-specific effects in germline transmission of pathogenic mtDNA variants.

Human Reproduction
Auke B C OttenH J M Smeets

Abstract

Does germline selection (besides random genetic drift) play a role during the transmission of heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations in humans? We conclude that inheritance of mtDNA is mutation-specific and governed by a combination of random genetic drift and negative and/or positive selection. mtDNA 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. We 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. Mutation 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. By 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 ran...Continue Reading

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Citations

Mar 15, 2019·Reproduction : the Official Journal of the Society for the Study of Fertility·Alexandra J Harvey
Mar 19, 2020·Journal of Internal Medicine·W Wei, P F Chinnery
Sep 6, 2019·Biochemical Society Transactions·Iain G Johnston, Joerg P Burgstaller
Mar 7, 2020·Genetics and Molecular Biology·Marcos T OliveiraGrzegorz L Ciesielski
Dec 12, 2019·Frontiers in Cell and Developmental Biology·Iain G Johnston
Mar 22, 2019·Human Reproduction Open·B LledoR Bernabeu
Nov 27, 2019·Mitochondrial DNA. Part A. DNA Mapping, Sequencing, and Analysis·Pavitchaya KoolkarnkhaiPassorn Wonnapinij
Dec 12, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Julie SteffannJean-Paul Bonnefont
Feb 28, 2021·Mitochondrion·Kalliopi ChatzovoulouJulie Steffann
Apr 4, 2021·Life·Srikanth Elesela, Nicholas W Lukacs
Jun 26, 2021·Human Molecular Genetics·Tiago M Bernardino GomesAmy E Vincent
May 27, 2021·Annual Review of Genomics and Human Genetics·Swathi P JeediguntaThomas R Hurd

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