Journal Article

Mitochondrial DNA mosaicism in normal human somatic cells

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

2024

Overview

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. Analysis of 2,096 single-cell clones from three tissues of 31 healthy donors characterizes mitochondrial DNA mosaicism and highlights the following two origins of mtDNA variants: heteroplasmy in the fertilized egg and postzygotic mutations.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 631/114/2785 / 631/208/212 / 631/80/509 / Age / Agriculture / Animal Genetics and Genomics / Asymmetry / Bioaccumulation / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cells / Cloning / Deoxyribonucleic acid / DNA / DNA Replication - genetics / DNA, Mitochondrial - genetics / Female / Fibroblasts / Gene Function / Genome, Mitochondrial / Genomes / Heteroplasmy / Heteroplasmy - genetics / Human Genetics / Humans / Male / Mitochondria - genetics / Mitochondrial DNA / Mosaicism / Mutation / Mutation Rate / Mutation rates / Replication / Replication origins / Service life assessment / Somatic cells