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Single-cell Individual Complete mtDNA Sequencing Uncovers Hidden Mitochondrial Heterogeneity in Human and Mouse Oocytes

Chongwei Bi, Lin Wang, Yong Fan, Gerardo Ramos-Mandujano, Baolei Yuan, Xuan Zhou, Jincheng Wang, Yanjiao Shao, Pu-Yao Zhang, Yanyi Huang, Yang Yu, Juan Carlos Izpisua Belmonte, View ORCID ProfileMo Li
doi: https://doi.org/10.1101/2020.12.28.424537
Chongwei Bi
1Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia
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Lin Wang
1Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia
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Yong Fan
2Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, 510150 Guangzhou, China
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Gerardo Ramos-Mandujano
1Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia
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Baolei Yuan
1Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia
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Xuan Zhou
1Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia
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Jincheng Wang
3Beijing Advanced Innovation Center for Genomics (ICG), Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, College of Chemistry, College of Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
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Yanjiao Shao
4Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA
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Pu-Yao Zhang
5Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
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Yanyi Huang
3Beijing Advanced Innovation Center for Genomics (ICG), Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, College of Chemistry, College of Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
6Institute for Cell Analysis, Shenzhen Bay Laboratory, Shenzhen, China
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Yang Yu
5Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
7Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
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  • For correspondence: yuyang5012@hotmail.com Belmonte@salk.edu mo.li@kaust.edu.sa
Juan Carlos Izpisua Belmonte
4Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA
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  • For correspondence: yuyang5012@hotmail.com Belmonte@salk.edu mo.li@kaust.edu.sa
Mo Li
1Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia
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  • ORCID record for Mo Li
  • For correspondence: yuyang5012@hotmail.com Belmonte@salk.edu mo.li@kaust.edu.sa
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Abstract

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 Statement

A 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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 28, 2020.
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Single-cell Individual Complete mtDNA Sequencing Uncovers Hidden Mitochondrial Heterogeneity in Human and Mouse Oocytes
Chongwei Bi, Lin Wang, Yong Fan, Gerardo Ramos-Mandujano, Baolei Yuan, Xuan Zhou, Jincheng Wang, Yanjiao Shao, Pu-Yao Zhang, Yanyi Huang, Yang Yu, Juan Carlos Izpisua Belmonte, Mo Li
bioRxiv 2020.12.28.424537; doi: https://doi.org/10.1101/2020.12.28.424537
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Single-cell Individual Complete mtDNA Sequencing Uncovers Hidden Mitochondrial Heterogeneity in Human and Mouse Oocytes
Chongwei Bi, Lin Wang, Yong Fan, Gerardo Ramos-Mandujano, Baolei Yuan, Xuan Zhou, Jincheng Wang, Yanjiao Shao, Pu-Yao Zhang, Yanyi Huang, Yang Yu, Juan Carlos Izpisua Belmonte, Mo Li
bioRxiv 2020.12.28.424537; doi: https://doi.org/10.1101/2020.12.28.424537

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