线粒体突变与衰老:随机漂变不足以解释短寿动物中线粒体缺失突变体的积累。
Mitochondrial mutations and aging: random drift is insufficient to explain the accumulation of mitochondrial deletion mutants in short-lived animals.
机构信息
Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
出版信息
Aging Cell. 2013 Aug;12(4):728-31. doi: 10.1111/acel.12098. Epub 2013 Jun 7.
Mitochondrial DNA deletions accumulate over the life course in post-mitotic cells of many species and may contribute to aging. Often a single mutant expands clonally and finally replaces the wild-type population of a whole cell. One proposal to explain the driving force behind this accumulation states that random drift alone, without any selection advantage, is sufficient to explain the clonal accumulation of a single mutant. Existing mathematical models show that such a process might indeed work for humans. However, to be a general explanation for the clonal accumulation of mtDNA mutants, it is important to know whether random drift could also explain the accumulation process in short-lived species like rodents. To clarify this issue, we modelled this process mathematically and performed extensive computer simulations to study how different mutation rates affect accumulation time and the resulting degree of heteroplasmy. We show that random drift works for lifespans of around 100 years, but for short-lived animals, the resulting degree of heteroplasmy is incompatible with experimental observations.
线粒体 DNA 缺失在许多物种的有丝分裂后细胞中随着生命过程的进行而积累,可能导致衰老。通常,单个突变体呈克隆扩张,最终取代整个细胞的野生型群体。一种解释这种积累驱动力的观点认为,仅随机漂变而没有任何选择优势就足以解释单个突变体的克隆积累。现有的数学模型表明,对于人类来说,这种过程确实可能起作用。然而,要成为 mtDNA 突变体克隆积累的一般解释,重要的是要知道随机漂变是否也可以解释像啮齿动物这样的短寿命物种的积累过程。为了澄清这个问题,我们对这个过程进行了数学建模,并进行了广泛的计算机模拟,以研究不同的突变率如何影响积累时间和由此产生的异质性程度。我们表明,随机漂变适用于大约 100 年的寿命,但对于短寿命的动物,由此产生的异质性程度与实验观察结果不兼容。