Multiple genetic backgrounds of the amplified Plasmodium falciparum multidrug resistance (pfmdr1) gene and selective sweep of 184F mutation in Cambodia.
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.
Vinayak
Sumiti
S
Atlanta Research and Education Foundation, Atlanta, Georgia, USA.
Alam
Md Tauqeer
MT
Sem
Rithy
R
Shah
Naman K
NK
Susanti
Augustina I
AI
Lim
Pharath
P
Muth
Sinuon
S
Maguire
Jason D
JD
Rogers
William O
WO
Fandeur
Thierry
T
Barnwell
John W
JW
Escalante
Ananias A
AA
Wongsrichanalai
Chansuda
C
Ariey
Frederick
F
Meshnick
Steven R
SR
Udhayakumar
Venkatachalam
V
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*
D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum