Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum

Wootton, John C.
Feng, Xiaorong
Ferdig, Michael T.
Cooper, Roland A.
Mu, Jianbing
Baruch, Dror I.
Magill, Alan J.
Su, Xin-zhuan

*ast; Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894-6075, USA
† Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0425, USA
‡ Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556-016, USA
§ Division of Communicable Disease and Immunology, Walter Reed Army Institute of Research, Washington DC 20307-5100, USA

Received 26 September 2001; accepted 28 March 2002; doi:10.1038/nature00813.

Supplementary Information accompanies the paper on Nature's website (http://www.nature.com/nature).

Correspondence and requests for materials should be addressed to X.-z.S.

Nature 418(6895):p 320-323, July 18, 2002.

Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasitePlasmodium falciparum.Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debatesto 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 genepfcrtand at least four CQR founder events. This disequilibrium and its decay rate in thepfcrt-flanking region are consistent with strong directional selective sweeps occurring over only ∼20-80 sexual generations, especially a single resistantpfcrthaplotype 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 inP. falciparum.