A role for BCL2L13 and autophagy in germline purifying selection of mtDNA.
A role for BCL2L13 and autophagy in germline purifying selection of mtDNA.
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DOI：
10.1371/journal.pgen.1010573
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发表时间：
2023-01
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
哺乳动物的线粒体DNA（mtDNA）是通过雌性生殖细胞单亲遗传的，不需要重组。这带来了一个主要问题，因为必须消除有害的mtDNA突变，以避免几代人的突变崩溃。至少有两种机制，可以减少突变负荷在母体传播是可操作的：一个随机的瓶颈，从母亲到孩子的mtDNA传输，并针对有害的mtDNA突变的传输定向纯化选择。然而，控制这些过程的分子机制仍然未知。在这项研究中，我们系统地测试了减少自噬是否有助于纯化选择交叉C5024T小鼠模型窝藏一个单一的致病性异质性突变的tRNAAla基因的mtDNA与不同的自噬缺陷的小鼠模型，包括敲除帕金，Bcl 2l13，Ulk 1和Ulk 2。我们的研究揭示了Bcl2l13的敲除对选择过程的统计学稳健影响，以及Ulk 1和潜在Ulk 2的影响的较弱证据，而Parkin的敲除没有观察到统计学显著影响。这指出了这些参与者在生殖系净化选择中的独特作用。总的来说，我们的方法提供了一个框架，调查的作用，其他重要因素参与的神秘过程中的纯化选择和指导进一步调查的作用，BCL2L13在消除蛋白质编码基因的非同义突变。我们通过将不同的自噬缺陷小鼠模型（包括Parkin、Bcl2l13、Ulk 1和Ulk 2基因敲除）与高水平致病性tRNAAla基因突变的雌性小鼠交配，研究了自噬在纯化mtDNA选择中的作用。我们确定了Bcl 2l13对选择过程的强大影响，Ulk 1和Ulk 2的影响较弱，而Parkin没有统计学显著影响。因此，我们的研究提供了强有力的实验证据，自噬的独特作用，生殖细胞纯化选择的mtDNA。此外，我们在手稿中开发的实验策略和统计方法提供了一个新的框架，为未来的研究神秘的净化选择过程中的哺乳动物。
Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNAAla gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2. Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2, while no statistically significant impact is seen for knockout of Parkin. This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes. We have addressed the role of autophagy on purifying selection of mtDNA by mating different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2, to female mice with high levels of the pathogenic tRNAAla gene mutation. We identified a robust effect of Bcl2l13 on the selection process, weaker effects of Ulk1 and Ulk2, whereas Parkin had no statistically significant impact. Our study thus provides strong experimental evidence for distinctive roles of autophagy in germline purifying selection of mtDNA. Furthermore, the experimental strategy and statistical methods we have developed in the manuscript provide a novel framework for future studies of the enigmatic purifying selection process in mammals.
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