Matching Mitochondrial DNA Haplotypes for Circumventing Tissue-Specific Segregation Bias

Jianxin Pan; Li Wang; Charles Lu; Yanming Zhu; Zhunyuan Min; Xi Dong; Hongying Sha

doi:10.1016/j.isci.2019.03.002

Matching Mitochondrial DNA Haplotypes for Circumventing Tissue-Specific Segregation Bias

iScience. 2019 Mar 29:13:371-379. doi: 10.1016/j.isci.2019.03.002. Epub 2019 Mar 5.

Authors

Jianxin Pan¹, Li Wang², Charles Lu³, Yanming Zhu¹, Zhunyuan Min¹, Xi Dong⁴, Hongying Sha⁵

Affiliations

¹ Reproductive Medicine Center, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² Key Lab of Synthetic Biology of CAS, Shanghai Institute for Biological Sciences, Shanghai Research Center of Biotech., Chinese Academy of Sciences, 500 Caobao Road, Shanghai 200233, China.
³ Reproductive Medicine Center, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China; Washington University in St. Louis, Saint Louis 63110, USA.
⁴ Reproductive Medicine Center, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: dong.xi@zs-hospital.sh.cn.
⁵ Reproductive Medicine Center, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: shahongying@fudan.edu.cn.

Abstract

Mitochondrial DNA (mtDNA) segregation associated with donor-recipient mtDNA mismatch in mitochondria replacement therapy leads to unknown risks. Here, to explore whether matching mtDNA haplotypes contributes to ameliorating segregation, we reproduced various degrees of heteroplasmic mice with three single nucleotide polymorphisms to monitor segregation severity. "Segregation" presented in tissues of heteroplasmic mice containing low-level donor mtDNA heteroplasmy, and disappeared as donor mtDNA heteroplasmy levels ascended. Meanwhile, we found that distribution of donor mtDNA among the blastomeres of preimplantation embryos from the heteroplasmic mice shared the same tendency as that in adult tissues. Statistical analysis showed that no selective replication of donor mtDNA occurred during lifespan. Tracking donor mtDNA distribution showed that uneven distribution of donor mtDNA among embryonic blastomeres gradually became even as donor mtDNA heteroplasmy increased, indicating that the "segregation" in tissues was inherited from the uneven distribution. Our finding suggested that donor-recipient mtDNA matching could circumvent segregation in mitochondria replacement therapy.

Keywords: Biological Sciences; Developmental Genetics; Genetics.