[Title]
Mitochondrial DNA mosaicism in normal human somatic cells

[Author]

Jisong An 1, Chang Hyun Nam1, Ryul Kim1,2, Yunah Lee 1, Hyein Won1, Seongyeol Park1,2, Won Hee Lee1, Hansol Park 1,2, Christopher J. Yoon 1,3, Yohan An 1, Jie-Hyun Kim4, Jong Kwan Jun5, Jeong Mo Bae6, Eui-Cheol Shin 1, Bun Kim 7, Yong Jun Cha7, Hyun Woo Kwon 8, Ji Won Oh9, Jee Yoon Park10,11, Min Jung Kim12 & Young Seok Ju 1,2*

1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
2Inocras Inc, Daejeon, Republic of Korea.
3Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
4Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
5Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Republic of Korea.
6Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea.
7Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
8Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
9Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea.
10Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
11Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea.
12Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea. 
* e-mail: ysju@kaist.ac.kr

[Journal] 

Nature Genetics (2024)


[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.