title: Changes in malaria parasite drug resistance in an endemic population over a 25-year period with resulting genomic evidence of selection.
abstract: BACKGROUND
  Analysis of genome-wide polymorphism in many organisms has potential to identify genes under recent selection. However, data on historical allele frequency changes are rarely available for direct confirmation.
  
  
  METHODS
  We genotyped single nucleotide polymorphisms (SNPs) in 4 Plasmodium falciparum drug resistance genes in 668 archived parasite-positive blood samples of a Gambian population between 1984 and 2008. This covered a period before antimalarial resistance was detected locally, through subsequent failure of multiple drugs until introduction of artemisinin combination therapy. We separately performed genome-wide sequence analysis of 52 clinical isolates from 2008 to prospect for loci under recent directional selection.
  
  
  RESULTS
  Resistance alleles increased from very low frequencies, peaking in 2000 for chloroquine resistance-associated crt and mdr1 genes and at the end of the survey period for dhfr and dhps genes respectively associated with pyrimethamine and sulfadoxine resistance. Temporal changes fit a model incorporating likely selection coefficients over the period. Three of the drug resistance loci were in the top 4 regions under strong selection implicated by the genome-wide analysis.
  
  
  CONCLUSIONS
  Genome-wide polymorphism analysis of an endemic population sample robustly identifies loci with detailed documentation of recent selection, demonstrating power to prospectively detect emerging drug resistance genes.
authors.affiliation: Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Davis C
authors.initials: DC
authors.lastname: Nwakanma
authors.forename: Craig W
authors.initials: CW
authors.lastname: Duffy
authors.forename: Alfred
authors.initials: A
authors.lastname: Amambua-Ngwa
authors.forename: Eniyou C
authors.initials: EC
authors.lastname: Oriero
authors.forename: Kalifa A
authors.initials: KA
authors.lastname: Bojang
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Drakeley
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Sutherland
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Milligan
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Macinnis
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Brian M
authors.initials: BM
authors.lastname: Greenwood
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
mesh_terms: D000483:Alleles; D000962:Antimalarials / Q000627:therapeutic use; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004351:Drug Resistance; D005714:Gambia / Q000453:epidemiology; D018503:Genome, Protozoan; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology* / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan
keywords: archival analysis; genomic surveillance; policy and practice; population genetics; resistance monitoring