title: Plasmodium falciparum field isolates from areas of repeated emergence of drug resistant malaria show no evidence of hypermutator phenotype.
abstract: Multiple transcontinental waves of drug resistance in Plasmodium falciparum have originated in Southeast Asia before spreading westward, first into the rest of Asia and then to sub-Saharan Africa. In vitro studies have suggested that hypermutator P. falciparum parasites may exist in Southeast Asia and that an increased rate of acquisition of new mutations in these parasites may explain the repeated emergence of drug resistance in Southeast Asia. This study is the first to test the hypermutator hypothesis using field isolates. Using genome-wide SNP data from human P. falciparum infections in Southeast Asia and West Africa and a test for relative rate differences we found no evidence of increased relative substitution rates in P. falciparum isolates from Southeast Asia. Instead, we found significantly increased substitution rates in Mali and Bangladesh populations relative to those in populations from Southeast Asia. Additionally we found no association between increased relative substitution rates and parasite clearance following treatment with artemisinin derivatives.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, USA; Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Brown
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Jacob
authors.affiliation: Institute for Genome Sciences and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Joana C
authors.initials: JC
authors.lastname: Silva
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Takala-Harrison
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine and Pharmacy, University of Science, Techniques and Technology of Bamako, Bamako, Mali.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Djimdé
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Center for Tropical Medicine, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Mark
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria and Malaria Research Initiative Bandarban, Bandarban, Bangladesh.
authors.forename: Harald
authors.initials: H
authors.lastname: Noedl
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Myaing Myaing
authors.initials: MM
authors.lastname: Nyunt
authors.affiliation: Department of Medical Research (Lower Myanmar), Yangon, Myanmar.
authors.forename: Myat Phone
authors.initials: MP
authors.lastname: Kyaw
authors.affiliation: Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao Democratic People's Republic; Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Lao Democratic People's Republic.
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.affiliation: Centre for Tropical Medicine Oxford University Clinical Research Unit Vietnam (OUCRU), Ho Chi Minh City, Viet Nam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.affiliation: Laboratory of Molecular Evolution, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, USA. Electronic address: mike@umiacs.umd.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cummings
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D001210:Asia, Southeastern / Q000453:epidemiology; D016054:DNA, Protozoan / Q000032:analysis / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology*; D059645:Mutation Rate; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D016054:DNA, Protozoan; C031327:artemisinin
keywords: Artemisinin; Drug resistance; Molecular evolution; Mutation rate; Plasmodium falciparum