MBE Advance Access published online on June 27, 2003
Molecular Biology and Evolution, doi:10.1093/molbev/msg162
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2003; all rights reserved
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1 Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio TX 78245, USA
* To whom correspondence should be addressed. E-mail: tanderso{at}darwin.sfbr.org.
Malaria parasites (Plasmodium falciparum) provide an excellent system to study the genomic effects of strong selection in a recombining eukaryote, since the rapid spread of resistance to multiple drugs during the last the past 50 years has been well documented, the full genome sequence and a microsatellite map are now available, and haplotype data can be easily generated. We examined microsatellite variation around the dihydrofolate reductase (dhfr) gene on Chromosome 4 of P. falciparum. Point mutations in dhfr are known to be responsible for resistance to the antimalarial drug Pyrimethamine, and resistance to this drug has spread rapidly in SE Asia following its introduction in 1970s. We genotyped 33 microsatellite markers distributed across Chr 4 in 61 parasites from a location on the Thailand/Myanmar border. We observed minimal microsatellite length variation in a 12 kb (0.7 cM) region flanking the dihydrofolate reductase (dhfr) gene and diminished variation for Key Words:
Expected heterozygosity, dihydrofolate reductase, Pyrimethamine, microsatellite, Plasmodium falciparum
© 2003 Society for Molecular Biology and Evolution
Original Articles
A Selective Sweep Driven by Pyrimethamine Treatment in SE Asian Malaria Parasites
2 Shoklo Malaria Research Unit (SMRU), Mae Sot, Tak, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
3 Shoklo Malaria Research Unit (SMRU), Mae Sot, Tak, Thailand
4 Faculty of Medicine, National University of Laos, Vientiane, Lao PDR
5 Nuffield Dept. of Medicine, John Radcliffe Hospital, Oxford, UK; Wellcome Trust-Mahosot-Oxford Tropical Medicine Research Collaboration, Mahosot Hospital, Vientiane, Lao PDR
6 Epicentre (Médecins Sans Frontières-France), 8 rue Saint Sabin, 75011 Paris, France
7 Artsen Zonder Grenzen, Médecins Sans Frontières-Holland, Yangon, Myanmar
8 Hospital for Tropical Diseases, Cho Quan Hospital, Ho Chimin, Vietnam
9 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Dept. of Medicine, John Radcliffe Hospital, Oxford, UK
10 Shoklo Malaria Research Unit (SMRU), Mae Sot, Tak, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Dept. of Medicine, John Radcliffe Hospital, Oxford, UK
Abstract 
100 kb (6 cM), indicative of a single origin of resistant alleles. Furthermore, we found the same or similar microsatellite haplotypes flanked resistant dhfr alleles sampled from 11 parasite populations in five SE Asian countries indicating recent invasion of a single lineage of resistant dhfr alleles in locations 2000 km apart. Three features of these data are of especial interest: 1) Pyrimethamine resistance is generally assumed to have evolved multiple times, since the genetic basis is simple and resistance can be selected easily in the laboratory. Yet our data clearly indicate a single origin of resistant dhfr alleles sampled over a large region of SE Asia. 2) The wide valley (6 cM) of reduced variation around dhfr provides "proof-of-principle" that genome-wide association may be an effective way to locate genes under strong recent selection 3) The width of the selective valley is consistent with predictions based on independent measures of recombination, mutation and selection intensity, suggesting that we have a reasonable estimates of these parameters. We conclude that scanning the malaria genome for evidence of recent selection may prove an extremely effective way to locate genes underlying recently evolved traits such as drug resistance, as well as providing an opportunity to study the dynamics of selective events that have occurred recently or are currently in progress.
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