Extrachromosomal DNA amplicons in antimalarial‐resistant Plasmodium falciparum
| Autor: | Sabrina A. Carter, Adam C Huckaby, Webster L. Santos, Molly D. Congdon, Jennifer M. McDaniels, Sabrina Lingeman, Pradipsinh K. Rathod, Audrey Francis, Jennifer L. Guler |
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| Přispěvatelé: | Chemistry |
| Rok vydání: | 2020 |
| Předmět: |
Plasmodium
Mitochondrial DNA Plasmodium falciparum malaria Drug Resistance adaptation Microbiology Genome Deep sequencing resistance Antimalarials 03 medical and health sciences Extrachromosomal DNA Humans extrachromosomal DNA Malaria Falciparum genome Molecular Biology Gene Research Articles 030304 developmental biology Genetics 0303 health sciences biology 030306 microbiology Gene Amplification Chromosome DNA Protozoan Amplicon biology.organism_classification Adaptation Physiological Pyrimidines Corrigendum Genome Protozoan Research Article |
| Zdroj: | Mol Microbiol Molecular Microbiology |
| ISSN: | 1365-2958 0950-382X |
| DOI: | 10.1111/mmi.14624 |
| Popis: | Extrachromosomal (ec) DNAs are genetic elements that exist separately from the genome. Since ecDNA can carry beneficial genes, they are a powerful adaptive mechanism in cancers and many pathogens. For the first time, we report ecDNA contributing to antimalarial resistance in Plasmodium falciparum, the most virulent human malaria parasite. Using pulse field gel electrophoresis combined with PCR‐based copy number analysis, we detected two ecDNA elements that differ in migration and structure. Entrapment in the electrophoresis well and low susceptibility to exonucleases revealed that the biologically relevant ecDNA element is large and complex in structure. Using deep sequencing, we show that ecDNA originates from the chromosome and expansion of an ecDNA‐specific sequence may improve its segregation or expression. We speculate that ecDNA is maintained using established mechanisms due to shared characteristics with the mitochondrial genome. Implications of ecDNA discovery in this organism are wide‐reaching due to the potential for new strategies to target resistance development. The most lethal malaria parasite, Plasmodium falciparum, rapidly adapts to acquire drug resistance. For the first time, we report that highly resistant Plasmodium parasites carry additional copies of resistance‐conferring genes separate from the genome, which are known as extra‐chromosomal DNA (ecDNA). This finding provides a new model to study a fundamental mechanism of adaptation that is relevant in many microbes and may lead to a new way to target malaria. |
| Databáze: | OpenAIRE |
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