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^1,2. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs 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 late 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 shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.

中文翻译：

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通过人类胚胎发育遗传瓶颈分离线粒体 DNA 异质性。

线粒体 DNA (mtDNA) 突变会导致遗传性疾病，并与常见迟发性疾病的发病机制有关，但尚不清楚它们是如何发生的^1,2. 在这里，我们表明 mtDNA 突变存在于健康女性人类胚胎的原始生殖细胞 (PGC) 中。分离的 PGC 的 mtDNA 含量显着降低，离散的线粒体含有约 5 个 mtDNA 分子。体内人类女性 PGC 的单细胞深度 mtDNA 测序显示罕见变异在晚期 PGC 中达到更高的异质性水平，这与观察到的遗传瓶颈一致。我们还看到了针对非同义蛋白质编码、tRNA 基因和 D 环变体的选择特征，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。相关的代谢转变会使有害突变暴露于早期生殖细胞发育过程中的选择，防止穆勒棘轮预测的人群中 mtDNA 突变的不断积累。逃避这一机制的突变将显示人类一代内异质性水平的变化，解释了在具有遗传性 mtDNA 疾病的人类谱系中看到的极端表型变异。