PT  - JOURNAL ARTICLE
AU  - Bi, Chongwei
AU  - Wang, Lin
AU  - Fan, Yong
AU  - Ramos-Mandujano, Gerardo
AU  - Yuan, Baolei
AU  - Zhou, Xuan
AU  - Wang, Jincheng
AU  - Shao, Yanjiao
AU  - Zhang, Pu-Yao
AU  - Huang, Yanyi
AU  - Yu, Yang
AU  - Izpisua Belmonte, Juan Carlos
AU  - Li, Mo
TI  - Single-cell Individual Complete mtDNA Sequencing Uncovers Hidden Mitochondrial Heterogeneity in Human and Mouse Oocytes
AID  - 10.1101/2020.12.28.424537
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.28.424537
4099  - http://biorxiv.org/content/early/2020/12/28/2020.12.28.424537.short
4100  - http://biorxiv.org/content/early/2020/12/28/2020.12.28.424537.full
AB  - The ontogeny and dynamics of mtDNA heteroplasmy remain unclear due to limitations of current mtDNA sequencing methods. We developed individual Mitochondrial Genome sequencing (iMiGseq) of full-length mtDNA for ultra-sensitive variant detection, complete haplotyping, and unbiased evaluation of heteroplasmy levels, all at the individual mtDNA molecule level. iMiGseq uncovers unappreciated levels of heteroplasmic variants in single healthy human oocytes well below the current 1% detection limit, of which numerous variants are detrimental and could contribute to late-onset mitochondrial disease and cancer. Extreme mtDNA heterogeneity among oocytes of the same mouse female, and a strong selection against deleterious mutations in human oocytes are observed. iMiGseq could comprehensively characterize and haplotype single-nucleotide and structural variants of mtDNA and their genetic linkage in NARP/Leigh syndrome patient-derived cells. Therefore, iMiGseq could not only elucidate the mitochondrial etiology of diseases, but also help diagnose and prevent mitochondrial diseases with unprecedented precision.Competing Interest StatementA patent application based on methods described in this paper has been filed by King Abdullah University of Science and Technology, in which CB, LW, and ML are listed as inventors. The authors declare no other competing interest.