Durham S E, Samuels D C, Chinnery P F
Mitochondrial Research Group M4014, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Neuromuscul Disord. 2006 Jun;16(6):381-6. doi: 10.1016/j.nmd.2006.03.012. Epub 2006 May 8.
Mitochondrial DNA (mtDNA) mutations accumulate in the skeletal muscle of patients with mtDNA disease, and also as part of healthy ageing. Simulations of human muscle fibres suggest that, over many decades, the continuous destruction and copying of mtDNA (relaxed replication) can lead to dramatic changes in the percentage level of mutant mtDNA in non-dividing cells through random genetic drift. This process should apply to both pathogenic and neutral mutations. To test this hypothesis we sequenced the entire mitochondrial genome for 20 muscle fibres from a healthy elderly 85-year-old individual, chosen because of the low frequency of cytochrome c oxidase negative fibres. Phenotypically neutral single base substitutions were detected in 15% of the healthy fibres, supporting the hypothesis that positive selection is not essential for the clonal expansion of mtDNA point mutations during human life. Treatments that enhance mtDNA replication, such as vigorous excercise, could amplify this process, with potentially detrimental long-term consequences.
线粒体DNA（mtDNA）突变会在患有线粒体DNA疾病患者的骨骼肌中累积，同时也是健康衰老过程的一部分。对人类肌纤维的模拟研究表明，在数十年间，mtDNA的持续破坏和复制（松弛复制）会通过随机遗传漂变导致非分裂细胞中突变mtDNA百分比水平发生显著变化。这一过程应适用于致病性突变和中性突变。为验证这一假设，我们对一名85岁健康老年人的20条肌纤维的整个线粒体基因组进行了测序，选择该个体是因为其细胞色素c氧化酶阴性纤维的频率较低。在15%的健康纤维中检测到了表型中性的单碱基替换，这支持了以下假设：在人类生命过程中，正向选择对于mtDNA点突变的克隆扩增并非必不可少。增强mtDNA复制的治疗方法，如剧烈运动，可能会放大这一过程，并可能产生有害的长期后果。
