Complex DNA structures trigger copy number variation across the Plasmodium falciparum genome

Area of Science:

• Genetics
• Molecular Biology
• Parasitology

Background:

• Antimalarial drug resistance in Plasmodium falciparum is a significant global health challenge.
• Genome amplifications, a type of DNA copy number variation (CNV), contribute to parasite survival by overexpressing drug targets.
• Long A/T-rich sequences are associated with resistance-conferring CNVs in Plasmodium.

Purpose of the Study:

• To investigate the role of DNA hairpins and A/T tracks in driving CNV formation in Plasmodium falciparum.
• To identify specific sequence features and repair mechanisms involved in antimalarial resistance.
• To explore potential therapeutic targets for blocking parasite adaptation.

Main Methods:

• Adapted a sequence analysis pipeline to pinpoint CNV breakpoints with near single base-pair resolution in 35 parasite clones.
• Predicted the formation of stable DNA hairpins near identified CNV breakpoints using parental genome sequences.
• Analyzed genomic features at 'trigger sites' and detected signatures of error-prone repair pathways.

Main Results:

• Identified stable DNA hairpins proximal to all analyzed CNV breakpoints, with particularly stable hairpins near five shared breakpoints.
• Characterized specific genomic features at these 'trigger sites' across the Plasmodium genome.
• Detected evidence of error-prone repair pathways at the breakpoints, suggesting a role in CNV formation.

Conclusions:

• Propose a model where DNA hairpins initiate lesions and A/T tracks facilitate microhomology-mediated repair, leading to CNV formation in Plasmodium.
• Suggest that targeting these specific DNA repair pathways could be a strategy to inhibit Plasmodium falciparum adaptation to antimalarial drugs.