Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations.
Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations.
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DOI：
10.1038/s41467-018-04797-2
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发表时间：
2018-06-27
影响因子：
16.6
通讯作者：
Johnston IG
中科院分区：
文献类型：
--
作者：
Burgstaller JP;Kolbe T;Havlicek V;Hembach S;Poulton J;Piálek J;Steinborn R;Rülicke T;Brem G;Jones NS;Johnston IG
重要的线粒体DNA（mtDNA）群体存在于细胞中，可能由mtDNA类型的异质混合物组成。这些异质种群通过发育、衰老和世代的进化是遗传疾病的核心，但在哺乳动物中知之甚少。在这里，我们解剖这些人口动态使用前所未有的大小和时间跨度的数据集，包括1947个单细胞卵母细胞和899个体细胞测量的异质性变化在两个遗传不同的小鼠模型的整个生命周期和世代。我们提供了一个新的和详细的定量表征的异质性方差在整个哺乳动物的生命过程中的卵母细胞和幼崽的线性增加。我们发现，平均异质性的差异诱导世代之间，和异质性的种系和体细胞前体分化早期的发展，与单倍型特定方向的分离。我们开发随机理论预测这些动态的影响，衰老和疾病的表现，并讨论其应用于人类mtDNA的动态。细胞中的线粒体群体可能由mtDNA类型的异质性混合物组成，它们通过发育、衰老和世代的进化是遗传疾病的核心。在这里，作者使用一个大型的基于小鼠的数据集来剖析这些种群动态，以描述整个生命和跨代异质性均值和方差的动态。
Vital mitochondrial DNA (mtDNA) populations exist in cells and may consist of heteroplasmic mixtures of mtDNA types. The evolution of these heteroplasmic populations through development, ageing, and generations is central to genetic diseases, but is poorly understood in mammals. Here we dissect these population dynamics using a dataset of unprecedented size and temporal span, comprising 1947 single-cell oocyte and 899 somatic measurements of heteroplasmy change throughout lifetimes and generations in two genetically distinct mouse models. We provide a novel and detailed quantitative characterisation of the linear increase in heteroplasmy variance throughout mammalian life courses in oocytes and pups. We find that differences in mean heteroplasmy are induced between generations, and the heteroplasmy of germline and somatic precursors diverge early in development, with a haplotype-specific direction of segregation. We develop stochastic theory predicting the implications of these dynamics for ageing and disease manifestation and discuss its application to human mtDNA dynamics. Mitochondrial populations in cells may consist of heteroplasmic mixtures of mtDNA types, and their evolution through development, aging and generations is central to genetic diseases. Here the authors dissect these population dynamics using a large mouse-based data set to characterise the dynamics of heteroplasmy mean and variance throughout life and across generations.
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影响因子：
64.5
作者：
Sharpley MS;Marciniak C;Eckel-Mahan K;McManus M;Crimi M;Waymire K;Lin CS;Masubuchi S;Friend N;Koike M;Chalkia D;MacGregor G;Sassone-Corsi P;Wallace DC
通讯作者：
Wallace DC
影响因子：
56.9
作者：
Fan, Weiwei;Waymire, Katrina G.;Wallace, Douglas C.
通讯作者：
Wallace, Douglas C.
影响因子：
8.8
作者：
Burgstaller JP;Johnston IG;Jones NS;Albrechtová J;Kolbe T;Vogl C;Futschik A;Mayrhofer C;Klein D;Sabitzer S;Blattner M;Gülly C;Poulton J;Rülicke T;Piálek J;Steinborn R;Brem G
通讯作者：
Brem G
影响因子：
8.8
作者：
Lee HS;Ma H;Juanes RC;Tachibana M;Sparman M;Woodward J;Ramsey C;Xu J;Kang EJ;Amato P;Mair G;Steinborn R;Mitalipov S
通讯作者：
Mitalipov S
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.