ArticleMolecular microbiology2013
Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum.
Article in Molecular microbiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 2 of them syntheses that pooled it.
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Who cites it
43 citing papers in PubMed, 2 syntheses or guidelines pooled it, 63 citations in OpenAlex.
- Evolution of Pfdhps and Pfdhfr mutations before and after adopting seasonal malaria chemoprevention in Nanoro, Burkina Faso.Scientific reports · 2024Pooled it
- Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature.Malaria journal · 2017Pooled it
- Replication stress increases de novo CNVs across the malaria parasite genome.Nucleic acids research · 2026Article
- Replication stress increases de novo CNVs across the malaria parasite genome.bioRxiv : the preprint server for biology · 2025Article
- Direct long-read visualization reveals hidden variation in GCH1 gene copy number and precise expansion steps.BMC genomics · 2025Article
- Assessing fitness costs in malaria parasites: a comprehensive review and implications for drug resistance management.Malaria journal · 2025Review
- Low prevalence of copy number variation in pfmdr1 and pfpm2 in Plasmodium falciparum isolates from southern Angola.Malaria journal · 2025Article
- Genomics reveals heterogeneous Plasmodium falciparum transmission and selection signals in Zambia.Communications medicine · 2024Article
- Genomics reveals heterogeneousmedRxiv : the preprint server for health sciences · 2024Article
- Direct long read visualization reveals metabolic interplay between two antimalarial drug targets.bioRxiv : the preprint server for biology · 2023Article
- Analysis and validation of silica-immobilised BST polymerase in loop-mediated isothermal amplification (LAMP) for malaria diagnosis.Analytical and bioanalytical chemistry · 2022Article
- Decreased Susceptibility to Dihydrofolate Reductase Inhibitors Associated With Genetic Polymorphisms in Ugandan Plasmodium falciparum Isolates.The Journal of infectious diseases · 2022Article
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- Development of Cooperative Primer-Based Real-Time PCR Assays for the Detection of Plasmodium malariae and Plasmodium ovale.The Journal of molecular diagnostics : JMD · 2021Article
- Single-cell sequencing of the small and AT-skewed genome of malaria parasites.Genome medicine · 2021Article
- The contribution of extrachromosomal DNA to genome plasticity in malaria parasites.Molecular microbiology · 2021Article
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- Molecular characterization of Plasmodium falciparum antifolate resistance markers in Thailand between 2008 and 2016.Malaria journal · 2020Article
- Whole-genome re-sequencing reveals the impact of the interaction of copy number variants of the rhg1 and Rhg4 genes on broad-based resistance to soybean cyst nematode.Plant biotechnology journal · 2019Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Resistance to antimalarials targeting the folate pathway is widespread. GTP-cyclohydrolase (gch1), the first enzyme in this pathway, exhibits extensive copy number variation (CN) in parasite isolates from areas with a history of longstanding antifolate use. Increased CN of gch1 is associated with a greater number of point mutations in enzymes targeted by the antifolates, pyrimethamine and sulphadoxine. While these observations suggest that increases in gch1 CN are an adaptation to drug pressure, changes in CN have not been experimentally demonstrated to directly alter drug susceptibility. To determine if changes in gch1 expression alone modify pyrimethamine sensitivity, we manipulated gch1 CN in several parasite lines to test the effect on drug sensitivity. We report that increases in gch1 CN alter pyrimethamine resistance in most parasites lines. However we find evidence of a detrimental effect of very high levels of gch1 overexpression in parasite lines with high endogenous levels of gch1 expression, revealing the importance of maintaining balance in the folate pathway and implicating changes in gch1 expression in preserving proper metabolic flux. This work expands our understanding of parasite adaptation to drug pressure and provides a possible mechanism for how specific mutations become fixed within parasite populations.
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