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Multiple Genetic Backgrounds of the Amplified Plasmodium falciparum Multidrug Resistance ( pfmdr1 ) Gene and Selective Sweep of 184F Mutation in Cambodia

Sumiti Vinayak, Md Tauqeer Alam, Rithy Sem, Naman K. Shah, Augustina I. Susanti, Pharath Lim, Sinuon Muth, Jason D. Maguire, William O. Rogers, Thierry Fandeur, John W. Barnwell, Ananias A. Escalante, Chansuda Wongsrichanalai, Frederick Ariey, Steven R. Meshnick and Venkatachalam Udhayakumar
The Journal of Infectious Diseases
Vol. 201, No. 10 (15 May 2010), pp. 1551-1560
Published by: Oxford University Press
Stable URL: http://www.jstor.org/stable/40599323
Page Count: 10
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Multiple Genetic Backgrounds of the Amplified
              Plasmodium falciparum
              Multidrug Resistance
              (
              pfmdr1
              )
              Gene and Selective Sweep of 184F Mutation in Cambodia
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Abstract

Background, The emergence of artesunate-mefloquine (AS+ MQ)-resistant Plasmodium falciparum in the Thailand-Cambodia region is a major concern for malaria control. Studies indicate that copy number increase and key alíeles in the pfmdrl gene are associated with AS+ MQ resistance. In the present study, we investigated evidence for a selective sweep around pfmdrl because of the spread of adaptive mutation and/or multiple copies of this gene in the P. falciparum population in Cambodia. Methods. We characterized 13 microsatellite loci flanking (± 99 kb) pfmdrl in 93 single-clone P. falciparum infections, of which 31 had multiple copies and 62 had a single copy of the pfmdrl gene. Results. Genetic analysis revealed no difference in the mean (± standard deviation) expected heterozygosity (H e ) at loci around single (0.75 ± 0.03) and multiple (0.76 ± 0.04) copies oí pfmdrl. Evidence of genetic hitchhiking with the selective sweep of certain haplotypes was seen around mutant (184F) pfmdr1 allele, irrespective of the copy number. There was an overall reduction of 28% in mean H e (± SD) around mutant alíele (0.56 ± 0.05), compared with wild-type alíele (0.84 ± 0.02). Significant linkage disequilibrium was also observed between the loci flanking mutant pfmdrl allele. Conclusion. The 184F mutant alíele is under selection, whereas amplification of pfmdr1 gene in this population occurs on multiple genetic backgrounds.

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