Non-Random mtDNA Segregation Patterns Indicate a Metastable Heteroplasmic Segregation Unit in m.3243A>G Cybrid Cells


Journal article


A. Raap, Roshan S Jahangir Tafrechi, F. M. van de Rijke, A. Pyle, Carolina Wählby, K. Szuhai, R. Ravelli, R. de Coo, H. Rajasimha, M. Nilsson, P. Chinnery, D. Samuels, G. Janssen
PLoS ONE, 2012

Semantic Scholar DOI PubMedCentral PubMed
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APA   Click to copy
Raap, A., Tafrechi, R. S. J., van de Rijke, F. M., Pyle, A., Wählby, C., Szuhai, K., … Janssen, G. (2012). Non-Random mtDNA Segregation Patterns Indicate a Metastable Heteroplasmic Segregation Unit in m.3243A>G Cybrid Cells. PLoS ONE.


Chicago/Turabian   Click to copy
Raap, A., Roshan S Jahangir Tafrechi, F. M. van de Rijke, A. Pyle, Carolina Wählby, K. Szuhai, R. Ravelli, et al. “Non-Random MtDNA Segregation Patterns Indicate a Metastable Heteroplasmic Segregation Unit in M.3243A≫G Cybrid Cells.” PLoS ONE (2012).


MLA   Click to copy
Raap, A., et al. “Non-Random MtDNA Segregation Patterns Indicate a Metastable Heteroplasmic Segregation Unit in M.3243A≫G Cybrid Cells.” PLoS ONE, 2012.


BibTeX   Click to copy

@article{a2012a,
  title = {Non-Random mtDNA Segregation Patterns Indicate a Metastable Heteroplasmic Segregation Unit in m.3243A>G Cybrid Cells},
  year = {2012},
  journal = {PLoS ONE},
  author = {Raap, A. and Tafrechi, Roshan S Jahangir and van de Rijke, F. M. and Pyle, A. and Wählby, Carolina and Szuhai, K. and Ravelli, R. and de Coo, R. and Rajasimha, H. and Nilsson, M. and Chinnery, P. and Samuels, D. and Janssen, G.}
}

Abstract

Many pathogenic mitochondrial DNA mutations are heteroplasmic, with a mixture of mutated and wild-type mtDNA present within individual cells. The severity and extent of the clinical phenotype is largely due to the distribution of mutated molecules between cells in different tissues, but mechanisms underpinning segregation are not fully understood. To facilitate mtDNA segregation studies we developed assays that measure m.3243A>G point mutation loads directly in hundreds of individual cells to determine the mechanisms of segregation over time. In the first study of this size, we observed a number of discrete shifts in cellular heteroplasmy between periods of stable heteroplasmy. The observed patterns could not be parsimoniously explained by random mitotic drift of individual mtDNAs. Instead, a genetically metastable, heteroplasmic mtDNA segregation unit provides the likely explanation, where stable heteroplasmy is maintained through the faithful replication of segregating units with a fixed wild-type/m.3243A>G mutant ratio, and shifts occur through the temporary disruption and re-organization of the segregation units. While the nature of the physical equivalent of the segregation unit remains uncertain, the factors regulating its organization are of major importance for the pathogenesis of mtDNA diseases.


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