Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos.
Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos.
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DOI：
10.1038/s41556-017-0017-8
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发表时间：
2018-03
影响因子：
21.3
通讯作者：
Chinnery PF
中科院分区：
文献类型：
--
作者：
Floros VI;Pyle A;Dietmann S;Wei W;Tang WCW;Irie N;Payne B;Capalbo A;Noli L;Coxhead J;Hudson G;Crosier M;Strahl H;Khalaf Y;Saitou M;Ilic D;Surani MA;Chinnery PF
线粒体DNA（mtDNA）突变引起遗传性疾病，并与常见迟发性疾病的发病机制有关，但它们是如何产生的尚不清楚。在这里，我们发现mtDNA突变存在于健康女性人类胚胎的原始生殖细胞（PGCs）中。线粒体DNA含量显著减少的分离PGC，离散线粒体含有约5个线粒体DNA分子。体内人类女性PGC的单细胞深度mtDNA测序显示，在后期PGC中达到更高异质性水平的罕见变体与观察到的遗传瓶颈一致。我们还看到了针对非同义蛋白编码、tRNA基因和D环变体的选择的特征，伴随着涉及mtDNA复制和转录的基因的逐步上调，并与从糖酵解到氧化代谢的转变有关。相关的代谢转变将使有害突变在早期生殖细胞发育期间暴露于选择，从而防止穆勒棘轮预测的人类群体中mtDNA突变的无情积累。逃避这一机制的突变将在人类一代人中显示异质性水平的巨大变化，解释了在遗传性mtDNA疾病的人类谱系中观察到的极端表型变异。
Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear. Here we show mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs which have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in later PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller’s ratchet. Mutations escaping this mechanism will show massive shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
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影响因子：
64.8
作者：
Kobayashi T;Zhang H;Tang WWC;Irie N;Withey S;Klisch D;Sybirna A;Dietmann S;Contreras DA;Webb R;Allegrucci C;Alberio R;Surani MA
通讯作者：
Surani MA
影响因子：
30.8
作者：
Freyer, Christoph;Cree, Lynsey M.;Mourier, Arnaud;Stewart, James B.;Koolmeister, Camilla;Milenkovic, Dusanka;Wai, Timothy;Floros, Vasileios I.;Hagstrom, Erik;Chatzidaki, Emmanouella E.;Wiesner, Rudolf J.;Samuels, David C.;Larsson, Nils-Goeran;Chinnery, Patrick F.
通讯作者：
Chinnery, Patrick F.
影响因子：
30.8
作者：
Hill, Jahda H.;Chen, Zhe;Xu, Hong
通讯作者：
Xu, Hong
影响因子：
9.9
作者：
Fukuoh A;Cannino G;Gerards M;Buckley S;Kazancioglu S;Scialo F;Lihavainen E;Ribeiro A;Dufour E;Jacobs HT
通讯作者：
Jacobs HT
影响因子：
30.8
作者：
Cao, Liqin;Shitara, Hiroshi;Yonekawa, Hiromichi
通讯作者：
Yonekawa, Hiromichi