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MBE Advance Access originally published online on May 25, 2005
Molecular Biology and Evolution 2005 22(9):1834-1844; doi:10.1093/molbev/msi177
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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

Research Article

Reduced Variation Around Drug-Resistant dhfr Alleles in African Plasmodium falciparum

Richard Pearce*, Allen Malisa{dagger},{ddagger}, S. Patrick Kachur{ddagger},§, Karen Barnes||, Brian Sharp and Cally Roper*

* London School of Hygiene and Tropical Medicine, Pathogen Molecular Biology Unit, Department of Infectious Tropical Diseases, London, United Kingdom; {dagger} University of Morogoro, Department of Biological Sciences, Faculty of Science, SUA, Morogoro, Tanzania; {ddagger} Ifakara Health Research and Development Centre, Ifakara, Tanzania; § Malaria Branch, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; || University of Cape Town Division of Clinical Pharmacology, Cape Town, South Africa; and Malaria Research Lead Programme, Medical Research Council, Durban, South Africa

E-mail: richard.pearce{at}lshtm.ac.uk.

We have measured microsatellite diversity at 26 markers around the dhfr gene in pyrimethamine-sensitive and -resistant parasites collected in southeast Africa. Through direct comparison with diversity on sensitive chromosomes we have found significant loss of diversity across a region of 70 kb around the most highly resistant allele which is evidence of a selective sweep attributable to selection through widespread use of pyrimethamine (in combination with sulfadoxine) as treatment for malaria. Retrospective analysis through four years of direct and continuous selection from use of sulfadoxine-pyrimethamine as first-line malaria treatment on a Plasmodium falciparum population in KwaZulu Natal, South Africa, has revealed how recombination significantly narrowed the margins of the selective sweep over time. A deterministic model incorporating selection coefficients measured during the same interval indicates that the transition was toward a state of recombination-selection equilibrium. We compared loss of diversity around the same resistance allele in two populations at either extreme of the range of entomological inoculation rates (EIRs), namely, under one infective bite per year in Mpumalanga, South Africa, and more than one per day in southern Tanzania. EIRs determine effective recombination rates and are expected to profoundly influence the dimensions of the selective sweep. Surprisingly, the dimensions were broadly consistent across both populations. We conclude that despite different recombination rates and contrasting drug selection histories in neighboring countries, the region-wide movement of resistant parasites has played a key role in the establishment of resistance in these populations and the dimensions of the selective sweep are dominated by the influence of high initial starting frequencies.

Key Words: Plasmodium falciparum • selective sweeps • pyrimethamine resistance


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