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MBE Advance Access published online on August 10, 2005
Molecular Biology and Evolution, doi:10.1093/molbev/msi235
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© The Author 2005. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Accepted July 25, 2005

Research Article

Geographical Distribution of Selected and Putatively Neutral SNPs in SE Asian Malaria Parasites

Tim J. C. Anderson 1*, Shalini Nair 1, Dan Sudimack 1, Jeff T. Williams 1, Mayfong Mayxay 2, Paul N. Newton 3, Jean-Paul Guthmann 4, Frank M. Smithuis 5, Tran Tinh Hien 6, Ingrid V.F. van den Broek 7, Nicholas J. White 8, and François Nosten 9

1 Southwest Foundation for Biomedical Research (SFBR), San Antonio, Tx, USA
2 Faculty of Medical Sciences, National University of Laos, Vientiane, Lao PDR; Wellcome Trust-Mahosot-Oxford Tropical Medicine Research Collaboration, Mahosot Hospital, Vientiane, Lao PDR
3 Centre for Tropical Medicine and Vaccinology, Churchill Hospital, Oxford, UK; Wellcome Trust-Mahosot-Oxford Tropical Medicine Research Collaboration, Mahosot Hospital, Vientiane, Lao PDR
4 Epicentre (Médecins Sans Frontières-France), 8 rue Saint Sabin, 75011 Paris, France
5 Artsen Zonder Grenzen, Médecins Sans Frontières-Holland, Yangon, Myanmar
6 Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
7 Médecins Sans Frontières (UK), 67-74 Saffron Hill, London, UK
8 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Vaccinology, Churchill Hospital, Oxford, UK
9 Shoklo Malaria Research Unit (SMRU), Mae Sot, Tak, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Vaccinology, Churchill Hospital, Oxford, UK

* To whom correspondence should be addressed.
Tim J. C. Anderson, E-mail: tanderso{at}darwin.sfbr.org


  Abstract

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in SE Asia selecting for local adaptation at parasite loci underlying resistance. We compared population structure revealed by 10 non-synonymous mutations (nsSNPs) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (sSNPs) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in 6 SE Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (FST = 0.18-0.66), with the highest frequencies on the Thailand-Burma border, and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (FST = 0-0.14) for 8/10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher FST (p<8 x 10-5) than simulated neutral expectations based on observed FST values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense SNP maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach.

Keywords: Plasmodium falciparum; genetic structure; single nucleotide polymorphism; local adaptation; drug resistance; pfcrt; pfmdr; dhfr; dhps.
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