Single-cell Individual Complete mtDNA Sequencing Uncovers Hidden Mitochondrial Heterogeneity in Human and Mouse Oocytes
Type
PreprintAuthors
Bi, Chongwei
Wang, Lin
Fan, Yong
Ramos Mandujano, Gerardo
Yuan, Baolei

Zhou, Xuan

Wang, Jincheng
Shao, Yanjiao
Zhang, Pu-Yao
Huang, Yanyi
Yu, Yang
Izpisua Belmonte, Juan Carlos
Li, Mo

KAUST Department
Bioscience ProgramBiological and Environmental Sciences and Engineering (BESE) Division
Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia.
KAUST Grant Number
BAS/1/1080-01URF/1/3412-01-01)
Date
2020-12-29Permanent link to this record
http://hdl.handle.net/10754/666791
Metadata
Show full item recordAbstract
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.Citation
Bi, C., Wang, L., Fan, Y., Ramos-Mandujano, G., Yuan, B., Zhou, X., … Li, M. (2020). Single-cell Individual Complete mtDNA Sequencing Uncovers Hidden Mitochondrial Heterogeneity in Human and Mouse Oocytes. doi:10.1101/2020.12.28.424537Sponsors
We thank members of the Li laboratory, Khaled Alsayegh, Samhan Alsolami for helpful discussions; Jinna Xu and Marie Krenz Y. Sicat for administrative support. We thank Chenyang Geng at the BIOPIC core facility at Peking university for technical assistance in PacBio sequencing. We thank Professor Jasmeen Merzaban’s lab and KAUST Animal Research Core Laboratory for sharing mouse strains. The research of the Li laboratory was supported byKAUST Office of Sponsored Research (OSR), under award number BAS/1/1080-01. The work was supported by a KAUST Competitive Research Grant (award number URF/1/3412-01-01) given to ML, YH and JCIB; the National Key R&D Program of China (2016YFC1000601) and the National Natural Science Funds (81571400, 81771580 and 81971381), MMAAP foundation to YY; and the National Key Research and Development Program of China (2019YFA0110804, 2018YFC1003203), and the National Natural Science Foundation of China (81871162) to YFPublisher
Cold Spring Harbor LaboratoryAdditional Links
http://biorxiv.org/lookup/doi/10.1101/2020.12.28.424537ae974a485f413a2113503eed53cd6c53
10.1101/2020.12.28.424537