PDF(Pubmed)
Abstract：
Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.
摘要：
体细胞随着年龄的增长积累基因组改变；然而，我们对线粒体DNA（mtDNA）镶嵌的理解仍然有限。在这里，我们调查了来自31个供体的三种细胞类型的2,096个克隆的基因组，鉴定出6,451个mtDNA变异体，其异质性水平约为0.3%。虽然这些变体中的大多数是单个克隆所特有的，暗示随年龄的随机获取，409个变体（6%）在多个胚胎谱系中共享，表明它们来自受精卵中的异质体。突变谱表现出复制链偏倚，暗示mtDNA复制是一个主要的突变过程。我们评估了mtDNA突变率（每个碱基对5.0×10-8）和每年10-20的周转频率，它们是塑造mtDNA镶嵌一生的基本组成部分。基本上抑制了mtDNA截短突变向同质的扩展。我们的发现提供了对起源的全面见解，人体细胞中mtDNA镶嵌的动力学和功能后果。
