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    Origin and evolution of sulfadoxine resistant Plasmodium falciparum

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    Genre
    Journal Article
    Date
    2010-03-01
    Author
    Vinayak, S
    Alam, T
    Mixson-Hayden, T
    McCollum, AM
    Sem, R
    Shah, NK
    Lim, P
    Muth, S
    Rogers, WO
    Fandeur, T
    Barnwell, JW
    Escalante, AA
    Wongsrichanalai, C
    Ariey, F
    Meshnick, SR
    Udhayakumar, V
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    Subject
    Africa
    Antimalarials
    Cambodia
    Codon
    Drug Resistance
    Evolution, Molecular
    Genes, Protozoan
    Genetic Variation
    Haplotypes
    Humans
    Linkage Disequilibrium
    Malaria, Falciparum
    Microsatellite Repeats
    Plasmodium falciparum
    Prevalence
    South America
    Sulfadoxine
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5547
    
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    DOI
    10.1371/journal.ppat.1000830
    Abstract
    The Thailand-Cambodia border is the epicenter for drug-resistant falciparum malaria. Previous studies have shown that chloroquine (CQ) and pyrimethamine resistance originated in this region and eventually spread to other Asian countries and Africa. However, there is a dearth in understanding the origin and evolution of dhps alleles associated with sulfadoxine resistance. The present study was designed to reveal the origin(s) of sulfadoxine resistance in Cambodia and its evolutionary relationship to African and South American dhps alleles. We sequenced 234 Cambodian Plasmodium falciparum isolates for the dhps codons S436A/F, A437G, K540E, A581G and A613S/T implicated in sulfadoxine resistance. We also genotyped 10 microsatellite loci around dhps to determine the genetic backgrounds of various alleles and compared them with the backgrounds of alleles prevalent in Africa and South America. In addition to previously known highly-resistant triple mutant dhps alleles SGEGA and AGEAA (codons 436, 437, 540, 581, 613 are sequentially indicated), a large proportion of the isolates (19.3%) contained a 540N mutation in association with 437G/581G yielding a previously unreported triple mutant allele, SGNGA. Microsatellite data strongly suggest the strength of selection was greater on triple mutant dhps alleles followed by the double and single mutants. We provide evidence for at least three independent origins for the double mutants, one each for the SGKGA, AGKAA and SGEAA alleles. Our data suggest that the triple mutant allele SGEGA and the novel allele SGNGA have common origin on the SGKGA background, whereas the AGEAA triple mutant was derived from AGKAA on multiple, albeit limited, genetic backgrounds. The SGEAA did not share haplotypes with any of the triple mutants. Comparative analysis of the microsatellite haplotypes flanking dhps alleles from Cambodia, Kenya, Cameroon and Venezuela revealed an independent origin of sulfadoxine resistant alleles in each of these regions.
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    PLoS Pathogens
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    http://dx.doi.org/10.34944/dspace/5529
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