ArticlePLoS pathogens2013
Asexual populations of the human malaria parasite, Plasmodium falciparum, use a two-step genomic strategy to acquire accurate, beneficial DNA amplifications.
Article in PLoS pathogens, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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59 citing papers in PubMed, 77 citations in OpenAlex.
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- Direct long-read visualization reveals hidden variation in GCH1 gene copy number and precise expansion steps.BMC genomics · 2025Article
- Low prevalence of copy number variation in pfmdr1 and pfpm2 in Plasmodium falciparum isolates from southern Angola.Malaria journal · 2025Article
- Systematic in vitro evolution inScience (New York, N.Y.) · 2024Article
- Antimalarial resistance risk in Mozambique detected by a novel quadruplex droplet digital PCR assay.Antimicrobial agents and chemotherapy · 2024Article
- Direct long read visualization reveals metabolic interplay between two antimalarial drug targets.bioRxiv : the preprint server for biology · 2023Article
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- Single-cell sequencing of the small and AT-skewed genome of malaria parasites.Genome medicine · 2021Article
- Extrachromosomal DNA amplicons in antimalarial-resistant Plasmodium falciparum.Molecular microbiology · 2021Article
- The contribution of extrachromosomal DNA to genome plasticity in malaria parasites.Molecular microbiology · 2021Article
- Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway inJournal of medicinal chemistry · 2021Article
- Atypical Molecular Basis for Drug Resistance to Mitochondrial Function Inhibitors in Plasmodium falciparum.Antimicrobial agents and chemotherapy · 2021Article
- Selection of CytochromeAntimicrobial agents and chemotherapy · 2021Article
- Isolation of Mutants With Reduced Susceptibility to Piperaquine From a Mutator of the Rodent Malaria ParasiteFrontiers in cellular and infection microbiology · 2021Article
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- In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model.Science translational medicine · 2019Article
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Authors and funding
9 authors at 6 institutions in 1 country.
Funding
Abstract
Malaria drug resistance contributes to up to a million annual deaths. Judicious deployment of new antimalarials and vaccines could benefit from an understanding of early molecular events that promote the evolution of parasites. Continuous in vitro challenge of Plasmodium falciparum parasites with a novel dihydroorotate dehydrogenase (DHODH) inhibitor reproducibly selected for resistant parasites. Genome-wide analysis of independently-derived resistant clones revealed a two-step strategy to evolutionary success. Some haploid blood-stage parasites first survive antimalarial pressure through fortuitous DNA duplications that always included the DHODH gene. Independently-selected parasites had different sized amplification units but they were always flanked by distant A/T tracks. Higher level amplification and resistance was attained using a second, more efficient and more accurate, mechanism for head-to-tail expansion of the founder unit. This second homology-based process could faithfully tune DNA copy numbers in either direction, always retaining the unique DNA amplification sequence from the original A/T-mediated duplication for that parasite line. Pseudo-polyploidy at relevant genomic loci sets the stage for gaining additional mutations at the locus of interest. Overall, we reveal a population-based genomic strategy for mutagenesis that operates in human stages of P. falciparum to efficiently yield resistance-causing genetic changes at the correct locus in a successful parasite. Importantly, these founding events arise with precision; no other new amplifications are seen in the resistant haploid blood stage parasite. This minimizes the need for meiotic genetic cleansing that can only occur in sexual stage development of the parasite in mosquitoes.
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