The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development.
The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development.
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作者：
Colnaghi M;Pomiankowski A;Lane N
针对有害线粒体突变的选择通过种系过程来促进，从而降低遗传疾病的风险。选择如何工作是有争议的：实验数据是相互矛盾的，以前的建模工作没有澄清的问题;在这里，我们开发的计算和进化模型，比较选择的结果在个人，细胞和线粒体的水平。使用来自小鼠和人类的真实的从头突变率和种系发育参数，进化模型预测了在人类群体中观察到的线粒体突变和疾病的患病率。我们显示了细胞器水平选择的重要性，在线粒体选择性汇集到Balbiani体中，在成熟卵母细胞的极端倍性中实现高质量的线粒体。文献中讨论的替代机制，瓶颈和卵泡闭锁，不太可能解释临床数据，因为在现实条件下，这两个过程都不能有效消除线粒体突变。我们的研究结果解释了女性生殖系结构的主要特征，特别是长期存在的原始生殖细胞过度增殖导致大量损失的悖论。这些过程在动物类群中的几乎普遍性是有意义的，因为在成熟卵母细胞中，在没有性别和重组的情况下，需要在极端倍性下保持线粒体质量。
Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modeling work has not clarified the issues; here, we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.