Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells.
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 u...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3525564?pdf=render |
| _version_ | 1811259300317757440 |
|---|---|
| author | Anton K Raap Roshan S Jahangir Tafrechi Frans M van de Rijke Angela Pyle Carolina Wählby Karoly Szuhai Raimond B G Ravelli René F M de Coo Harsha K Rajasimha Mats Nilsson Patrick F Chinnery David C Samuels George M C Janssen |
| author_facet | Anton K Raap Roshan S Jahangir Tafrechi Frans M van de Rijke Angela Pyle Carolina Wählby Karoly Szuhai Raimond B G Ravelli René F M de Coo Harsha K Rajasimha Mats Nilsson Patrick F Chinnery David C Samuels George M C Janssen |
| author_sort | Anton K Raap |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T18:28:11Z |
| format | Article |
| id | doaj.art-7159e41e8e794a30ab231bb6bbd37c83 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T18:28:11Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7159e41e8e794a30ab231bb6bbd37c832022-12-22T03:21:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01712e5208010.1371/journal.pone.0052080Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells.Anton K RaapRoshan S Jahangir TafrechiFrans M van de RijkeAngela PyleCarolina WählbyKaroly SzuhaiRaimond B G RavelliRené F M de CooHarsha K RajasimhaMats NilssonPatrick F ChinneryDavid C SamuelsGeorge M C JanssenMany 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.http://europepmc.org/articles/PMC3525564?pdf=render |
| spellingShingle | Anton K Raap Roshan S Jahangir Tafrechi Frans M van de Rijke Angela Pyle Carolina Wählby Karoly Szuhai Raimond B G Ravelli René F M de Coo Harsha K Rajasimha Mats Nilsson Patrick F Chinnery David C Samuels George M C Janssen Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells. PLoS ONE |
| title | Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells. |
| title_full | Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells. |
| title_fullStr | Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells. |
| title_full_unstemmed | Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells. |
| title_short | Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells. |
| title_sort | non random mtdna segregation patterns indicate a metastable heteroplasmic segregation unit in m 3243a g cybrid cells |
| url | http://europepmc.org/articles/PMC3525564?pdf=render |
| work_keys_str_mv | AT antonkraap nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT roshansjahangirtafrechi nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT fransmvanderijke nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT angelapyle nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT carolinawahlby nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT karolyszuhai nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT raimondbgravelli nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT renefmdecoo nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT harshakrajasimha nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT matsnilsson nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT patrickfchinnery nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT davidcsamuels nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells AT georgemcjanssen nonrandommtdnasegregationpatternsindicateametastableheteroplasmicsegregationunitinm3243agcybridcells |