Kuiper Lieke M, Shi Wen, Verlouw Joost A M, Hong Yun Soo, Arp Pascal, Puiu Daniela, Broer Linda, Xie Jiaqi, Newcomb Charles, Rich Stephen S, Taylor Kent D, Rotter Jerome I, Bader Joel S, Guallar Eliseo, van Meurs Joyce B J, Arking Dan E
Genetic Laboratory, Department of Internal Medicine, Erasmus MC, 3015 GD Rotterdam, the Netherlands.
Center for Prevention, Lifestyle and Health, National Institute for Public Health and Environment (RIVM), 3721 MA Bilthoven, the Netherlands.
iScience. 2025 May 6;28(6):112590. doi: 10.1016/j.isci.2025.112590. eCollection 2025 Jun 20.
A common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation, leading to a state of mitochondrial DNA heteroplasmy. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age, a phenomenon that has been attributed to genetic drift. In this large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined = 1404) at two time points (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead suggesting a role for positive selection for a subset of predicted deleterious mutations at the cellular level, despite a negative impact of these mutations on overall mortality.
人类衰老的一个共同特征是获得体细胞突变，而线粒体尤其容易发生突变，从而导致线粒体DNA异质性状态。横断面研究表明，异质性的检测率随参与者年龄的增长而增加，这一现象被归因于遗传漂变。在这项大规模纵向研究中，我们在两个时间点（两次访视之间的平均时间为8.6年）对两个前瞻性队列（共1404人）进行了异质性测量，结果表明有害异质性更有可能在变异等位基因频率（VAF）上增加。我们进一步证明，VAF的增加与全因死亡率风险的增加有关。这些结果对体细胞mtDNA突变主要是由于遗传漂变而产生的说法提出了挑战，相反，这表明尽管这些突变对总体死亡率有负面影响，但在细胞水平上，对一部分预测的有害突变进行正向选择发挥了作用。
