title: Whole-genome scans provide evidence of adaptive evolution in Malawian Plasmodium falciparum isolates.
abstract: BACKGROUND
  Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation.
  
  
  METHODS
  We performed whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure and identify loci under selection.
  
  
  RESULTS
  High genetic diversity (π = 2.4 × 10(-4)), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission. Allele frequency-based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens. Comparison of the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between Africa and Asia, within Southeast Asia, and within Africa. Haplotype-based tests of selection to sequence data from all 6 populations identified signals of directional selection at known drug-resistance loci, including pfcrt, pfdhps, pfmdr1, and pfgch1.
  
  
  CONCLUSIONS
  The sequence variations observed at drug-resistance loci reflect differences in each country's historical use of antimalarial drugs and may be useful in formulating local malaria treatment guidelines.
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme Liverpool School of Tropical Medicine, Pembroke Place, Liverpool.
authors.forename: Harold
authors.initials: H
authors.lastname: Ocholla
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Preston
authors.affiliation: Department of Physiology, College of Medicine, University of Malawi, Blantyre.
authors.forename: Mwapatsa
authors.initials: M
authors.lastname: Mipando
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, University of Copenhagen Department of Infectious Diseases, Copenhagen University Hospital, Denmark.
authors.forename: Anja T R
authors.initials: AT
authors.lastname: Jensen
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton.
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: MacInnis
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcock
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme Liverpool School of Tropical Medicine, Pembroke Place, Liverpool.
authors.forename: Anja
authors.initials: A
authors.lastname: Terlouw
authors.affiliation: Institut de Recherche en Sciences de la Sant, Bobo-Dioulasso, Burkina Faso.
authors.forename: Issaka
authors.initials: I
authors.lastname: Zongo
authors.affiliation: Institut de Recherche en Sciences de la Sant, Bobo-Dioulasso, Burkina Faso.
authors.forename: Jean-Bosco
authors.initials: JB
authors.lastname: Oudraogo
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton Malaria Research and Training Centre, Faculty of Medicine, Pharmacy and Dentistry, University of Bamako, Mali.
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimde
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Samuel
authors.initials: S
authors.lastname: Assefa
authors.affiliation: Malaria Research and Training Centre, Faculty of Medicine, Pharmacy and Dentistry, University of Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Institute of Tropical Medicine, University of Tübingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.affiliation: Department of Biology, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, United Kingdom Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Tim J C
authors.initials: TJ
authors.lastname: Anderson
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Liverpool School of Tropical Medicine, Pembroke Place, Liverpool.
authors.forename: Alister
authors.initials: A
authors.lastname: Craig
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme Liverpool School of Tropical Medicine, Pembroke Place, Liverpool.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Montgomery
mesh_terms: D000220:Adaptation, Biological; D000962:Antimalarials / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D018503:Genome, Protozoan; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology*; D008295:Malawi; D008297:Male; D017720:Molecular Epidemiology; D010963:Plasmodium falciparum / Q000235:genetics* / Q000302:isolation & purification; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D000962:Antimalarials
keywords: Malawi; Plasmodium falciparum; genetic epidemiology; genomes