title: Multiple genetic backgrounds of the amplified Plasmodium falciparum multidrug resistance (pfmdr1) gene and selective sweep of 184F mutation in Cambodia.
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 alleles in the pfmdr1 gene are associated with AS+MQ resistance. In the present study, we investigated evidence for a selective sweep around pfmdr1 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) pfmdr1 in 93 single-clone P. falciparum infections, of which 31 had multiple copies and 62 had a single copy of the pfmdr1 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 of pfmdr1. 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 allele (0.56+/-0.05), compared with wild-type allele (0.84+/-0.02). Significant linkage disequilibrium was also observed between the loci flanking mutant pfmdr1 allele.
  
  
  CONCLUSIONS
  The 184F mutant allele is under selection, whereas amplification of pfmdr1 gene in this population occurs on multiple genetic backgrounds.
authors.affiliation: Atlanta Research and Education Foundation, Atlanta, Georgia, USA.
authors.forename: Sumiti
authors.initials: S
authors.lastname: Vinayak
authors.forename: Md Tauqeer
authors.initials: MT
authors.lastname: Alam
authors.forename: Rithy
authors.initials: R
authors.lastname: Sem
authors.forename: Naman K
authors.initials: NK
authors.lastname: Shah
authors.forename: Augustina I
authors.initials: AI
authors.lastname: Susanti
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.forename: Sinuon
authors.initials: S
authors.lastname: Muth
authors.forename: Jason D
authors.initials: JD
authors.lastname: Maguire
authors.forename: William O
authors.initials: WO
authors.lastname: Rogers
authors.forename: Thierry
authors.initials: T
authors.lastname: Fandeur
authors.forename: John W
authors.initials: JW
authors.lastname: Barnwell
authors.forename: Ananias A
authors.initials: AA
authors.lastname: Escalante
authors.forename: Chansuda
authors.initials: C
authors.lastname: Wongsrichanalai
authors.forename: Frederick
authors.initials: F
authors.lastname: Ariey
authors.forename: Steven R
authors.initials: SR
authors.lastname: Meshnick
authors.forename: Venkatachalam
authors.initials: V
authors.lastname: Udhayakumar
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D002160:Cambodia / Q000453:epidemiology; D004351:Drug Resistance / Q000235:genetics; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology*; D015767:Mefloquine / Q000494:pharmacology; D018895:Microsatellite Repeats; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum