ArticlePLoS genetics2008
Adaptive copy number evolution in malaria parasites.
Article in PLoS genetics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers, 1 of them a synthesis that pooled it.
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Who cites it
123 citing papers in PubMed, 1 synthesis or guideline pooled it, 202 citations in OpenAlex.
- 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
- CRISPR-activation reveals key resistance genes and vulnerabilities of copy number variants inbioRxiv : the preprint server for biology · 2026Article
- Genomic Plasticity and Molecular Mechanisms of Antimalarial Drug Resistance in Plasmodium falciparum: Implications for Treatment Failure and Genomic Surveillance.BioMed research international · 2026Review
- Target gene mutation discovery and amplicon sequencing for evaluating maduramicin resistance in Eimeria tenella.Communications biology · 2025Article
- Direct long-read visualization reveals hidden variation in GCH1 gene copy number and precise expansion steps.BMC genomics · 2025Article
- Pooled, Long-read Sequencing for Structural Variant Characterization in Schistosome Populations.Genome biology and evolution · 2025Article
- Temporal Patterns of Haplotypic and Allelic Diversity Reflect the Changing Selection Landscape of the Malaria Parasite Plasmodium falciparum.Molecular biology and evolution · 2025Article
- Multilevel Gene Expression Changes in Lineages Containing Adaptive Copy Number Variants.Molecular biology and evolution · 2025Article
- HapCNV: A Comprehensive Framework for CNV Detection in Low-input DNA Sequencing Data.bioRxiv : the preprint server for biology · 2025Article
- Pf8: an open dataset ofWellcome open research · 2025Article
- Recent Advances in the Treatment of Malaria.Pharmaceutics · 2024Review
- Multilevel gene expression changes in lineages containing adaptive copy number variants.bioRxiv : the preprint server for biology · 2024Article
- Defining the next generation of severe malaria treatment: a target product profile.Malaria journal · 2024Review
- 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
- Copy number variation alters local and global mutational tolerance.Genome research · 2023Article
- Nanopore sequencing of PCR products enables multicopy gene family reconstruction.Computational and structural biotechnology journal · 2023Article
- Fitness Costs of pfhrp2 and pfhrp3 Deletions Underlying Diagnostic Evasion in Malaria Parasites.The Journal of infectious diseases · 2022Article
- Nutrient Limitation Magnifies Fitness Costs of Antimalarial Drug Resistance Mutations.Antimicrobial agents and chemotherapy · 2022Article
63 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 6 institutions in 4 countries.
Funding
Abstract
Copy number polymorphism (CNP) is ubiquitous in eukaryotic genomes, but the degree to which this reflects the action of positive selection is poorly understood. The first gene in the Plasmodium folate biosynthesis pathway, GTP-cyclohydrolase I (gch1), shows extensive CNP. We provide compelling evidence that gch1 CNP is an adaptive consequence of selection by antifolate drugs, which target enzymes downstream in this pathway. (1) We compared gch1 CNP in parasites from Thailand (strong historical antifolate selection) with those from neighboring Laos (weak antifolate selection). Two percent of chromosomes had amplified copy number in Laos, while 72% carried multiple (2-11) copies in Thailand, and differentiation exceeded that observed at 73 synonymous SNPs. (2) We found five amplicon types containing one to greater than six genes and spanning 1 to >11 kb, consistent with parallel evolution and strong selection for this gene amplification. gch1 was the only gene occurring in all amplicons suggesting that this locus is the target of selection. (3) We observed reduced microsatellite variation and increased linkage disequilibrium (LD) in a 900-kb region flanking gch1 in parasites from Thailand, consistent with rapid recent spread of chromosomes carrying multiple copies of gch1. (4) We found that parasites bearing dhfr-164L, which causes high-level resistance to antifolate drugs, carry significantly (p = 0.00003) higher copy numbers of gch1 than parasites bearing 164I, indicating functional association between genes located on different chromosomes but linked in the same biochemical pathway. These results demonstrate that CNP at gch1 is adaptive and the associations with dhfr-164L strongly suggest a compensatory function. More generally, these data demonstrate how selection affects multiple enzymes in a single biochemical pathway, and suggest that investigation of structural variation may provide a fast-track to locating genes underlying adaptation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.