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IPSC culture expansion selects against putatively actionable mutations in the mitochondrial genome.


ABSTRACT: Therapeutic application of induced pluripotent stem cell (iPSC) derivatives requires comprehensive assessment of the integrity of their nuclear and mitochondrial DNA (mtDNA) to exclude oncogenic potential and functional deficits. It is unknown, to which extent mtDNA variants originate from their parental cells or from de novo mutagenesis, and whether dynamics in heteroplasmy levels are caused by inter- and intracellular selection or genetic drift. Sequencing of mtDNA of 26 iPSC clones did not reveal evidence for de novo mutagenesis, or for any selection processes during reprogramming or differentiation. Culture expansion, however, selected against putatively actionable mtDNA mutations. Altogether, our findings point toward a scenario in which intracellular selection of mtDNA variants during culture expansion shapes the mutational landscape of the mitochondrial genome. Our results suggest that intercellular selection and genetic drift exert minor impact and that the bottleneck effect in context of the mtDNA genetic pool might have been overestimated.

SUBMITTER: Kosanke M 

PROVIDER: S-EPMC8514965 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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iPSC culture expansion selects against putatively actionable mutations in the mitochondrial genome.

Kosanke Maike M   Davenport Colin C   Szepes Monika M   Wiehlmann Lutz L   Kohrn Tim T   Dorda Marie M   Gruber Jonas J   Menge Kaja K   Sievert Maike M   Melchert Anna A   Gruh Ina I   Göhring Gudrun G   Martin Ulrich U  

Stem cell reports 20210923 10


Therapeutic application of induced pluripotent stem cell (iPSC) derivatives requires comprehensive assessment of the integrity of their nuclear and mitochondrial DNA (mtDNA) to exclude oncogenic potential and functional deficits. It is unknown, to which extent mtDNA variants originate from their parental cells or from de novo mutagenesis, and whether dynamics in heteroplasmy levels are caused by inter- and intracellular selection or genetic drift. Sequencing of mtDNA of 26 iPSC clones did not re  ...[more]

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