Extrachromosomal DNA amplicons in antimalarial‐resistant Plasmodium falciparum,Molecular Microbiology

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Extrachromosomal DNA amplicons in antimalarial‐resistant Plasmodium falciparum
Molecular Microbiology ( IF 2.6 ) Pub Date : 2020-10-14 , DOI: 10.1111/mmi.14624
Jennifer M McDaniels ₁ , Adam C Huckaby ₁ , Sabrina A Carter ₁ , Sabrina Lingeman ₁ , Audrey Francis ₁ , Molly Congdon ₂ , Webster Santos ₂ , Pradipsinh K Rathod ₃ , Jennifer L Guler _{1,

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Affiliation

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.

中文翻译：

抗疟疾恶性疟原虫中的染色体外 DNA 扩增子

染色体外 (ec) DNA 是独立于基因组而存在的遗传元件。由于 ecDNA 可以携带有益基因，因此它们是癌症和许多病原体中强大的适应机制。我们首次报道了导致恶性疟原虫（人类毒性最强的疟原虫）抗疟耐药性的 ecDNA。使用脉冲场凝胶电泳结合基于 PCR 的拷贝数分析，我们检测到两个在迁移和结构上不同的 ecDNA 元件。电泳孔中的包埋和对核酸外切酶的低敏感性表明，生物学相关的 ecDNA 元件较大且结构复杂。通过深度测序，我们表明 ecDNA 起源于染色体，并且 ecDNA 特异性序列的扩展可能会改善其分离或表达。我们推测，由于与线粒体基因组具有共同的特征，ecDNA 是使用既定机制来维持的。由于针对抗性发展的新策略的潜力，ecDNA 的发现对该生物体的影响是广泛的。

更新日期：2020-10-14

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