Quantitative haplotype-resolved analysis of mitochondrial DNA heteroplasmy in Human single oocytes, blastoids, and pluripotent stem cells

Author:

Bi Chongwei1,Wang Lin1,Fan Yong2ORCID,Yuan Baolei1,Alsolami Samhan1,Zhang Yingzi1,Zhang Pu-Yao3,Huang Yanyi45ORCID,Yu Yang36,Izpisua Belmonte Juan Carlos17ORCID,Li Mo18ORCID

Affiliation:

1. Bioscience program, Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST) , Thuwal 23955-6900 , Kingdom of Saudi Arabia

2. Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University , 510150 Guangzhou, China

3. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital , Beijing 100191 , China

4. Beijing 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

5. Institute for Cell Analysis, Shenzhen Bay Laboratory , Shenzhen , China

6. Stem Cell Research Center, Peking University Third Hospital , Beijing 100191 , China

7. Altos Labs, Inc. , San Diego , CA 92121 , USA

8. Bioengineering program, Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST) , Thuwal 23955-6900, Kingdom of Guangzhou, Saudi Arabia

Abstract

Abstract Maternal mitochondria are the sole source of mtDNA for every cell of the offspring. Heteroplasmic mtDNA mutations inherited from the oocyte are a common cause of metabolic diseases and associated with late-onset diseases. However, the origin and dynamics of mtDNA heteroplasmy remain unclear. We used our individual Mitochondrial Genome sequencing (iMiGseq) technology to study mtDNA heterogeneity, quantitate single nucleotide variants (SNVs) and large structural variants (SVs), track heteroplasmy dynamics, and analyze genetic linkage between variants at the individual mtDNA molecule level in single oocytes and human blastoids. Our study presented the first single-mtDNA analysis of the comprehensive heteroplasmy landscape in single human oocytes. Unappreciated levels of rare heteroplasmic variants well below the detection limit of conventional methods were identified in healthy human oocytes, of which many are reported to be deleterious and associated with mitochondrial disease and cancer. Quantitative genetic linkage analysis revealed dramatic shifts of variant frequency and clonal expansions of large SVs during oogenesis in single-donor oocytes. iMiGseq of a single human blastoid suggested stable heteroplasmy levels during early lineage differentiation of naïve pluripotent stem cells. Therefore, our data provided new insights of mtDNA genetics and laid a foundation for understanding mtDNA heteroplasmy at early stages of life.

Funder

KAUST Office of Sponsored Research

KAUST

National Natural Science Funds

MMAAP foundation

National Key Research and Development Program of China

National Natural Science Foundation of China

Guangdong Basic and Applied Basic Research Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

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