Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission

被引：107

作者：

Freyer, Christoph ^{[1
,2
]}

Cree, Lynsey M. ^{[3
]}

Mourier, Arnaud ^{[1
]}

Stewart, James B. ^{[1
]}

Koolmeister, Camilla ^{[2
]}

Milenkovic, Dusanka ^{[1
]}

Wai, Timothy ^{[4
]}

Floros, Vasileios I. ^{[3
]}

Hagstrom, Erik ^{[2
]}

Chatzidaki, Emmanouella E. ^{[2
]}

Wiesner, Rudolf J. ^{[5
,6
,7
]}

Samuels, David C. ^{[8
]}

Larsson, Nils-Goeran ^{[1
,2
]}

Chinnery, Patrick F. ^{[3
]}

机构：

[1] Max Planck Inst Biol Ageing, Cologne, Germany

[2] Karolinska Inst, Dept Lab Med, Stockholm, Sweden

[3] Newcastle Univ, Inst Med Genet, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[4] Univ Cologne, Dept Genet, D-50931 Cologne, Germany

[5] Univ Cologne, Ctr Physiol, D-50931 Cologne, Germany

[6] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[7] Univ Cologne, CMMC, D-50931 Cologne, Germany

[8] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 11期

基金：

瑞典研究理事会; 英国医学研究理事会; 欧洲研究理事会;

关键词：

MITOCHONDRIAL-DNA HETEROPLASMY; PURIFYING SELECTION; MUTATION; SEGREGATION; REDUCTION; EVOLUTION; DRIFT; MICE;

D O I：

10.1038/ng.2427

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

A genetic bottleneck explains the marked changes in mitochondria! DNA (mtDNA) heteroplasmy that are observed during the transmission of pathogenic mutations, but the precise timing of these changes remains controversial, and it is not clear whether selection has a role. These issues are important for the genetic counseling of prospective mothers and for the development of treatments aimed at disease prevention. By studying mice transmitting a heteroplasmic single-base-pair deletion in the mitochondrial tRNA(Met) gene, we show that the extent of mammalian mtDNA heteroplasmy is principally determined prenatally within the developing female germline. Although we saw no evidence of mtDNA selection prenatally, skewed heteroplasmy levels were observed in the offspring of the next generation, consistent with purifying selection. High percentages of mtDNA genomes with the tRNAMet mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.

引用

页码：1282 / 1285

页数：4

共 21 条

[1]

BOULET L, 1992, AM J HUM GENET, V51, P1187

[2]

Random genetic drift determines the level of mutant mtDNA in human primary oocytes [J].