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Throughout our lifetime, cells accumulate DNA mutations, which contribute to genetic diversity, or “mosaicism”, among cells. These genomic mutations are pivotal for the aging process and the onset of various diseases, including cancer. Mitochondria, essential cellular organelles involved in energy metabolism and apoptosis, possess their own DNA, which are susceptible to mutations. However, studies on mtDNA mutations and mosaicism have been limited due to a variety of technical challenges.
Genomic scientists from KAIST have revealed the genetic mosaicism characterized by variations in mitochondrial DNA (mtDNA) across normal human cells. This study provides fundamental insights into understanding human aging and disease onset mechanisms.
The study, “Mitochondrial DNA mosaicism in normal human somatic cells,” was published in Nature Genetics on July 22. It was led by graduate student Jisong An under the supervision of Professor Young Seok Ju from the Graduate School of Medical Science and Engineering.
Researchers from Seoul National University College of Medicine, Yonsei University College of Medicine, Korea University College of Medicine, Washington University School of Medicine National Cancer Center, Seoul National University Hospital, Gangnam Severance Hospital and KAIST faculty startup company Inocras Inc. also participated in this study.
< Figure 1. a. Flow of experiment. b. Schematic diagram illustrating the origin and dynamics of mtDNA alterations across a lifetime. >
The study involved a bioinformatic analysis of whole-genome sequences from 2,096 single cells obtained from normal human colorectal epithelial tissue, fibroblasts, and blood collected from 31 individuals. The study highlights an average of three significant mtDNA differences between cells, with approximately 6% of these variations confirmed to be inherited as heteroplasmy from the mother.
Moreover, mutations significantly increased during tumorigenesis, with some mutations contributing to instability in mitochondrial RNA. Based on these findings, the study illustrates a computational model that comprehensively elucidates the evolution of mitochondria from embryonic development to aging and tumorigenesis.
This study systematically reveals the mechanisms behind mitochondrial DNA mosaicism in normal human cells, establishing a crucial foundation for understanding the impact of mtDNA on aging and disease onset.
Professor Ju remarked, “By systematically utilizing whole-genome big data, we can illuminate previously unknown phenomena in life sciences.” He emphasized the significance of the study, adding, “For the first time, we have established a method to systematically understand mitochondrial DNA changes occurring during human embryonic development, aging, and cancer development.”
This work was supported by the National Research Foundation of Korea and the Suh Kyungbae Foundation.
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