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Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes
Replacement of mitochondria through nuclear transfer between oocytes of two different women has emerged recently as a strategy for preventing inheritance of mtDNA diseases. Although experiments in human oocytes have shown effective replacement, the consequences of small amounts of mtDNA carryover ha...
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Published in: | Cell stem cell 2016-06, Vol.18 (6), p.749-754 |
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Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Replacement of mitochondria through nuclear transfer between oocytes of two different women has emerged recently as a strategy for preventing inheritance of mtDNA diseases. Although experiments in human oocytes have shown effective replacement, the consequences of small amounts of mtDNA carryover have not been studied sufficiently. Using human mitochondrial replacement stem cell lines, we show that, even though the low levels of heteroplasmy introduced into human oocytes by mitochondrial carryover during nuclear transfer often vanish, they can sometimes instead result in mtDNA genotypic drift and reversion to the original genotype. Comparison of cells with identical oocyte-derived nuclear DNA but different mtDNA shows that either mtDNA genotype is compatible with the nucleus and that drift is independent of mitochondrial function. Thus, although functional replacement of the mitochondrial genome is possible, even low levels of heteroplasmy can affect the stability of the mtDNA genotype and compromise the efficacy of mitochondrial replacement.
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•Cryopreservation allows coordinated nuclear transfer in human oocytes•Stem cell lines and derivatives show low-level carryover of transferred mtDNA•Recipient mtDNA is functionally compatible with donor nuclear DNA•Genetic drift can lead to restoration of the original donor mitochondrial genotype
Yamada et al. show, using human cells, that even small amounts of mtDNA carried over during nuclear transfer for mitochondrial replacement can lead to mtDNA genotype reversion. This situation would need to be avoided for clinical application and stable prevention of mtDNA diseases. |
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ISSN: | 1934-5909 1875-9777 |
DOI: | 10.1016/j.stem.2016.04.001 |