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Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum

Abstract

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 debates1,2,3,4 to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America5, 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 map6, 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 pfcrt7 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 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.

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Figure 1: Genome-wide allele sharing analysis of P. falciparum isolates from various geographical regions or CQR/CQS (chloroquine-resistant/chloroquine sensitive) subsets.
Figure 2: Extensive linkage disequilibrium (LD), microsatellite (MS) haplotypes flanking pfcrt, and the rate of LD decline in CQR isolates.
Figure 3: Genome-wide scans for loci of reduced diversity and association of reduced diversity with the CQR phenotype.

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Acknowledgements

We thank various investigators who provided the isolates over the years, S. Davis-Hayman, D. Joy, K. Hayton and B. Marshall for critical reading of the manuscript and editorial assistance, and T. Wellems, L. Miller and D. Lipman for support and encouragement. The opinions of the authors do not necessarily reflect those of the US army or the Department of Defense.

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Correspondence to Xin-zhuan Su.

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Wootton, J., Feng, X., Ferdig, M. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418, 320–323 (2002). https://doi.org/10.1038/nature00813

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