Korotkevich Ekaterina, Conrad Daniel N, Gartner Zev J, O'Farrell Patrick H
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
bioRxiv. 2024 Sep 28:2024.09.27.615276. doi: 10.1101/2024.09.27.615276.
Somatic mutations in mitochondrial genomes (mtDNA) accumulate exponentially during aging. Using single cell sequencing, we characterize the spectrum of age-accumulated mtDNA mutations in mouse and human liver and identify directional forces that accelerate the accumulation of mutations beyond the rate predicted by a neutral model. "Driver" mutations that give genomes a replicative advantage rose to high cellular abundance and carried along "passenger" mutations, some of which are deleterious. In addition, alleles that alter mtDNA-encoded proteins selectively increased in abundance overtime, strongly supporting the idea of a "destructive" selection that favors genomes lacking function. Overall, this combination of selective forces acting in hepatocytes promotes somatic accumulation of mutations in coding regions of mtDNA that are otherwise conserved in evolution. We propose that these selective processes could contribute to the population prevalence of mtDNA mutations, accelerate the course of heteroplasmic mitochondrial diseases and promote age-associated erosion of the mitochondrial genome.
线粒体基因组（mtDNA）中的体细胞突变在衰老过程中呈指数级积累。我们利用单细胞测序技术，对小鼠和人类肝脏中随年龄积累的mtDNA突变谱进行了表征，并确定了加速突变积累的定向力，其积累速度超过了中性模型预测的速率。赋予基因组复制优势的“驱动”突变在细胞中大量富集，并携带了一些“乘客”突变，其中一些是有害的。此外，随着时间的推移，改变线粒体编码蛋白的等位基因丰度选择性增加，这有力地支持了有利于缺乏功能的基因组的“破坏性”选择的观点。总体而言，这些作用于肝细胞的选择力组合促进了mtDNA编码区突变的体细胞积累，而这些编码区在进化过程中原本是保守的。我们认为，这些选择过程可能导致mtDNA突变在人群中的流行，加速异质性线粒体疾病的进程，并促进与年龄相关的线粒体基因组侵蚀。
