Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.
Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.
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DOI：
10.1073/pnas.2122073119
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发表时间：
2022-12-06
影响因子：
11.1
通讯作者：
Jones, Nick S.
中科院分区：
文献类型：
--
作者：
Imsalata, Ferdinando;Hoitzing, Hanne;Aryaman, Juvid;Jones, Nick S.
DNA突变的克隆传播是进化和衰老的基本现象。高水平的线粒体DNA突变与衰老中的肌肉无力有关，这对整体健康产生了连锁反应，导致医疗保健系统面临越来越大的压力。几十年来，科学家们一直在研究携带有害突变的线粒体DNA如何在骨骼肌纤维中扩张。我们提供的证据表明，这种扩张可能是由一种不寻常的进化机制驱动的，只需要噪音（随机性），更高密度的突变体和一个具有空间结构的系统。重要的是，突变体不需要复制得更快。这种机制，我们称之为随机生存的denominator，可以产生行波的突变体，在一系列的进化模型的潜在应用。具有缺失的线粒体DNA分子的扩张与衰老有关，特别是在骨骼肌纤维中;其机制三十年来一直不清楚。先前的研究已经将复制优势（RA）分配给含有缺失突变的线粒体DNA，但也有证据表明细胞可以选择性地去除有缺陷的线粒体DNA。在这里，我们提出了一个空间模型，没有RA，而是通过增强突变体和噪声的密度相结合，产生一波扩展突变的速度与实验数据一致。基于RA的标准模型产生太快的波。我们提供了一个公式，预测波速下降的拷贝数，与实验数据相一致。至关重要的是，我们的模型产生行波突变体，即使突变体被优先消除。此外，我们预测，在单细胞实验中观察到的突变负荷可以由从头突变率产生，这大大低于先前认为的中性模型。鉴于空间结构（多个连锁的mtDNA群体），噪音和密度如何影响肌肉细胞衰老的这个例子，我们引入了随机生存的机制的dendritis（SSD），RA的替代品，这可能会支持其他进化现象。
Clonal spread of DNA mutations is a fundamental phenomenon in both evolution and aging. High levels of mitochondrial DNA mutations are linked to muscle weakness in aging, which has a knock-on effect on overall health, contributing to mounting pressures on health care systems. For decades, scientists have asked how mitochondrial DNA harboring deleterious mutations can expand in skeletal muscle fibers. We provide evidence that this expansion could be driven by an unusual evolutionary mechanism, requiring only noise (stochasticity), a higher density of mutants, and a system with spatial structure. Critically, mutants need not replicate faster. This mechanism, that we have termed stochastic survival of the densest, can yield traveling waves of mutants, with potential applications in a range of evolutionary models. The expansion of mitochondrial DNA molecules with deletions has been associated with aging, particularly in skeletal muscle fibers; its mechanism has remained unclear for three decades. Previous accounts have assigned a replicative advantage (RA) to mitochondrial DNA containing deletion mutations, but there is also evidence that cells can selectively remove defective mitochondrial DNA. Here we present a spatial model that, without an RA, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with speeds consistent with experimental data. A standard model based on RA yields waves that are too fast. We provide a formula that predicts that wave speed drops with copy number, consonant with experimental data. Crucially, our model yields traveling waves of mutants even if mutants are preferentially eliminated. Additionally, we predict that mutant loads observed in single-cell experiments can be produced by de novo mutation rates that are drastically lower than previously thought for neutral models. Given this exemplar of how spatial structure (multiple linked mtDNA populations), noise, and density affect muscle cell aging, we introduce the mechanism of stochastic survival of the densest (SSD), an alternative to RA, that may underpin other evolutionary phenomena.
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影响因子：
15.8
作者：
Civitarese AE;Carling S;Heilbronn LK;Hulver MH;Ukropcova B;Deutsch WA;Smith SR;Ravussin E;CALERIE Pennington Team
通讯作者：
CALERIE Pennington Team
DOI：
10.1016/0921-8734(92)90020-p
发表时间：
1992-09-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
ARNHEIM, N;CORTOPASSI, G
通讯作者：
CORTOPASSI, G
DOI：
10.1080/14756366.2019.1687461
发表时间：
2020-01-01
影响因子：
5.6
作者：
Cirigliano, Angela;Amelina, Antonia;Rinaldi, Teresa
通讯作者：
Rinaldi, Teresa
影响因子：
4
作者：
deGrey, ADNJ
通讯作者：
deGrey, ADNJ
影响因子：
4.3
作者：
Hallatschek O
通讯作者：
Hallatschek O