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MBE Advance Access originally published online on May 7, 2007
Molecular Biology and Evolution 2007 24(8):1582-1585; doi:10.1093/molbev/msm087
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© The Author 2007. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Letters

Parallel Evolution of Adaptive Mutations in Plasmodium falciparum Mitochondrial DNA During Atovaquone-Proguanil Treatment

Lise Musset*,{dagger}, Jacques Le Bras*,{dagger} and Jérôme Clain*

* Université Paris Descartes, IFR71 Sciences du Médicament, EA209-Eucaryotes pathogènes: Transports membranaires et Chimiorésistances, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
{dagger} Centre National de Référence du Paludisme, APHP, Hôpital Bichat-Claude Bernard, Paris, France

E-mail: jerome.clain{at}univ-paris5.fr

Accepted for publication April 19, 2007.

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.

Key Words: Plasmodium falciparum • atovaquone-proguanil resistance • cytochrome b • parallel evolution

Geoffrey Mc Fadden, Associate Editor


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