title: Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes.
abstract: 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.
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Emmanuele
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Sanchez-Quintero
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Sun
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Lallos
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Paull
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zimmer
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Shardonay
authors.initials: S
authors.lastname: Pagett
authors.affiliation: Center for Women's Reproductive Care, College of Physicians and Surgeons, Columbia University, New York, NY 10019, USA; Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Prosser
authors.affiliation: Center for Women's Reproductive Care, College of Physicians and Surgeons, Columbia University, New York, NY 10019, USA; Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Sauer
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: mh29@cumc.columbia.edu.
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Columbia University, Department of Pediatrics, New York, NY 10032, USA. Electronic address: d.egli@nyscf.org.
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D040961:Genetic Drift; D005838:Genotype; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D053652:Nuclear Transfer Techniques; D009865:Oocytes / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial