Extrachromosomal DNA amplicons in antimalarial‐resistant Plasmodium falciparum

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, t...

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Bibliographic Details
Published in:Molecular microbiology 2021-04, Vol.115 (4), p.574-590
Main Authors: McDaniels, Jennifer M., Huckaby, Adam C., Carter, Sabrina A., Lingeman, Sabrina, Francis, Audrey, Congdon, Molly, Santos, Webster, Rathod, Pradipsinh K., Guler, Jennifer L.
Format: Article
Language:English
Subjects:
adaptation
Chromosomes
Copy number
Deoxyribonucleic acid
DNA
Electrophoresis
Entrapment
extrachromosomal DNA
Gel electrophoresis
genome
Genomes
Malaria
Mitochondria
Parasites
Plasmodium
Plasmodium falciparum
resistance
Sequences
Vector-borne diseases
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Summary: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.
ISSN:0950-382X
1365-2958
DOI:10.1111/mmi.14624