Mitochondrial DNA mosaicism in normal human somatic cells
Authors
Jisong An ; Chang Hyun Nam ; Ryul Kim ; Yunah Lee ; Hyein Won ; Seongyeol Park ; Won Hee Lee ; Hansol Park ; Christopher J Yoon ; Yohan An ; Jie-Hyun Kim ; Jong Kwan Jun ; Jeong Mo Bae ; Eui-Cheol Shin ; Bun Kim ; Yong Jun Cha ; Hyun Woo Kwon ; Ji Won Oh ; Jee Yoon Park ; Min Jung Kim ; Young Seok Ju
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.