Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.
Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only approximately 20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.
Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894-6075, USA.
John C
JC
Wootton
Xiaorong
X
Feng
Michael T
MT
Ferdig
Roland A
RA
Cooper
Jianbing
J
Mu
Dror I
DI
Baruch
Alan J
AJ
Magill
Xin-Zhuan
XZ
Su
D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D019143:Evolution, Molecular; D018703:Founder Effect; D014644:Genetic Variation / Q000235:genetics*; D018503:Genome, Protozoan; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D018895:Microsatellite Repeats / Q000235:genetics; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012641:Selection, Genetic
D000962:Antimalarials; D002738:Chloroquine