1 Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet3 Malawi-Liverpool-Wellcome Trust Clinical Research Programme Liverpool School of Tropical Medicine, Pembroke Place, Liverpool.4 Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London.5 Department of Physiology, College of Medicine, University of Malawi, Blantyre.6 Wellcome Trust Sanger Institute, Hinxton, United Kingdom.7 Institut de Recherche en Sciences de la Sant, Bobo-Dioulasso, Burkina Faso.8 Wellcome Trust Sanger Institute, Hinxton Malaria Research and Training Centre, Faculty of Medicine, Pharmacy and Dentistry, University of Bamako, Bamako, Mali.9 Malaria Research and Training Centre, Faculty of Medicine, Pharmacy and Dentistry, University of Bamako, Bamako, Mali.10 Institute of Tropical Medicine, University of Tübingen, Germany.11 Department of Biology, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia.12 KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.13 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.14 Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.15 Texas Biomedical Research Institute, San Antonio, Texas.16 Wellcome Trust Sanger Institute, Hinxton Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.17 Liverpool School of Tropical Medicine, Pembroke Place, Liverpool.18 Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Journal of Infectious Diseases, 2014, Vol 210, Issue 12, p. 1991-2000