RT Journal Article
SR Electronic
T1 Single-cell Individual Complete mtDNA Sequencing Uncovers Hidden Mitochondrial Heterogeneity in Human and Mouse Oocytes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.28.424537
DO 10.1101/2020.12.28.424537
A1 Bi, Chongwei
A1 Wang, Lin
A1 Fan, Yong
A1 Ramos-Mandujano, Gerardo
A1 Yuan, Baolei
A1 Zhou, Xuan
A1 Wang, Jincheng
A1 Shao, Yanjiao
A1 Zhang, Pu-Yao
A1 Huang, Yanyi
A1 Yu, Yang
A1 Izpisua Belmonte, Juan Carlos
A1 Li, Mo
YR 2020
UL http://biorxiv.org/content/early/2020/12/28/2020.12.28.424537.abstract
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.