title: Parallel evolution of adaptive mutations in Plasmodium falciparum mitochondrial DNA during atovaquone-proguanil treatment.
abstract: Here we provide direct evidence that two adaptive nucleotide changes in the same codon (268) of the cytochrome b gene (pfcytb) each occurred repeatedly in independent Plasmodium falciparum lineages exposed to the antimalarial drug atovaquone-proguanil (AP). We analyzed the history of 7 AP resistance alleles from clinical isolates by sequencing the mitochondrial (mt) genome that encodes the pfcytb gene and found that a distinct mt haplotype was associated with each AP resistance allele. By comparing mt sequences and microsatellite genotypes of the isolates both before treatment initiation and at the day of failure for each uncured patient, we observed that the AP resistance alleles occurred and spread within the patients. These data demonstrate that identical AP resistance alleles have multiple independent origins and provide an example of parallel evolution driven by drug treatment selection in P. falciparum.
authors.affiliation: Université Paris Descartes, IFR71 Sciences du Médicament, EA209-Eucaryotes pathogènes: Transports membranaires et Chimiorésistances, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Musset
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Bras
authors.forename: Jérôme
authors.initials: J
authors.lastname: Clain
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D053626:Atovaquone / Q000627:therapeutic use*; D001483:Base Sequence; D005075:Biological Evolution; D045303:Cytochromes b / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D002727:Proguanil / Q000627:therapeutic use*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D000962:Antimalarials; D004272:DNA, Mitochondrial; D045303:Cytochromes b; D002727:Proguanil; D053626:Atovaquone