Reduced variatio around drug-resistant dhfr alleles in African plasmodium falciparum
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Date
2005-05-25
Journal Title
Journal ISSN
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Publisher
Oxford University Press
Abstract
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 sulfadoxinepyrimethamine
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.
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Keywords
Plasmodium falciparum, Selective sweeps, Pyrimethamine resistance, African