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Matching Mitochondria DNA Haplotypes Circumvent Tissue-Specific Segregation Bias

30 Pages Posted: 7 Nov 2018 Publication Status: Review Complete

See all articles by Jianxin Pan

Jianxin Pan

Fudan University - State Key Laboratory of Medical Neurobiology

Charles Lu

Fudan University - State Key Laboratory of Medical Neurobiology

Zhunyuan Min

Fudan University - State Key Laboratory of Medical Neurobiology

Xi Dong

Fudan University - State Key Laboratory of Medical Neurobiology

Hongying Sha

Fudan University - State Key Laboratory of Medical Neurobiology

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Abstract

Segregation of different mtDNA genotypes is common in tissues of mitochondrial disease patients, tissues of heteroplasmic mice and human cells of treated with mitochondrial replacement, allowing for the expression of pathogenic phenotypes, suggesting that functional compatibility between “donor” and “recipient” mtDNA, as well as between the mtDNA and nuclear genome is of the utmost importance to future potential clinical applications, such as mitochondria replacement. Here, we hypothesis that shortened genetic distance (matching mtDNA haplotypes) between donor and recipient mtDNA has the potential to circumvent the segregation bias towards mutant mtDNA in tissues of mitochondria replacement offspring. Based on heteroplasmic mice with only three single nucleotide polymorphisms difference, we found that tissues within each adult and daughter blastomeres within each embryo of the 2-cell, 4-cell and 8-cell groups shared the same dispersion of mtDNA heteroplasmy: diverse heteroplasmy levels in each blastomere across the 2-cell to 8-cell embryos and tissues in each adult with low mean levels of heteroplasmy. However, a more uniform distribution was witnessed in the blastomeres of embryos at 2 to 8-cell stage and tissues in adults with high mean levels of heteroplasmy. CV values present negative correlation with the mean heteroplasmy of embryos at 2-cell to 8-cell stage and adults, respectively. There is no difference for both the heteroplasmy distribution (p > 0.05) and CV (p > 0.05) values among blastomeres of embryos at 2-, 4- to 8-cell stages and adult tissues, suggesting no selective replication of mtDNA is taking place during the progressive cleavage across developmental stages. The deviations of individual tissue in adult with low mean levels of heteroplasmy were caused by uneven inheritance of donor mitochondria in each blastomere of early embryos, rather than tissue segregation. Our finding indicated that by matching the haplotypes of the donor and recipient mtDNA, we could “fool” the nucleus into treating the donated mtDNA and the native pathogenic mtDNA the same, thereby eliminating any proliferative advantage and circumventing any segregation bias and preventing the occurrence of mitochondrial diseases.

Keywords: mitochondrial disease, mtDNA, tissue segregation, haplotype, heteroplasmy, mitochondrial replacement, genetic distance, mice, embryo, blastomere

Suggested Citation

Pan, Jianxin and Lu, Charles and Min, Zhunyuan and Dong, Xi and Sha, Hongying, Matching Mitochondria DNA Haplotypes Circumvent Tissue-Specific Segregation Bias (November 6, 2018). Available at SSRN: https://ssrn.com/abstract=3279419 or http://dx.doi.org/10.2139/ssrn.3279419
This version of the paper has not been formally peer reviewed.

Jianxin Pan

Fudan University - State Key Laboratory of Medical Neurobiology

Shanghai, 200032
China

Charles Lu

Fudan University - State Key Laboratory of Medical Neurobiology

Shanghai, 200032
China

Zhunyuan Min

Fudan University - State Key Laboratory of Medical Neurobiology

Shanghai, 200032
China

Xi Dong

Fudan University - State Key Laboratory of Medical Neurobiology

Shanghai, 200032
China

Hongying Sha (Contact Author)

Fudan University - State Key Laboratory of Medical Neurobiology ( email )

Shanghai, 200032
China

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