title: Reduced variation around drug-resistant dhfr alleles in African Plasmodium falciparum.
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 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.
authors.affiliation: London School of Hygiene and Tropical Medicine, Pathogen Molecular Biology Unit, Department of Infectious Tropical Diseases, London, United Kingdom. richard.pearce@lshtm.ac.uk
authors.forename: Richard
authors.initials: R
authors.lastname: Pearce
authors.forename: Allen
authors.initials: A
authors.lastname: Malisa
authors.forename: S Patrick
authors.initials: SP
authors.lastname: Kachur
authors.forename: Karen
authors.initials: K
authors.lastname: Barnes
authors.forename: Brian
authors.initials: B
authors.lastname: Sharp
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
mesh_terms: D000349:Africa; D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics*; D005787:Gene Frequency; D017125:Genes, Protozoan; D014644:Genetic Variation; D018503:Genome, Protozoan; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D018895:Microsatellite Repeats; D009154:Mutation; D010963:Plasmodium falciparum / Q000235:genetics*; D011739:Pyrimethamine / Q000627:therapeutic use; D011995:Recombination, Genetic; D012189:Retrospective Studies; D012641:Selection, Genetic; D013413:Sulfadoxine / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine