title: Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites.
abstract: Multiple kelch13 alleles conferring artemisinin resistance (ART-R) are currently spreading through Southeast Asian malaria parasite populations, providing a unique opportunity to observe an ongoing soft selective sweep, investigate why resistance alleles have evolved multiple times and determine fundamental population genetic parameters for Plasmodium We sequenced kelch13 (n = 1,876), genotyped 75 flanking SNPs, and measured clearance rate (n = 3,552) in parasite infections from Western Thailand (2001-2014). We describe 32 independent coding mutations including common mutations outside the kelch13 propeller associated with significant reductions in clearance rate. Mutations were first observed in 2003 and rose to 90% by 2014, consistent with a selection coefficient of ∼0.079. ART-R allele diversity rose until 2012 and then dropped as one allele (C580Y) spread to high frequency. The frequency with which adaptive alleles arise is determined by the rate of mutation and the population size. Two factors drive this soft sweep: (1) multiple kelch13 amino-acid mutations confer resistance providing a large mutational target-we estimate the target is 87-163 bp. (2) The population mutation parameter (Θ = 2Neμ) can be estimated from the frequency distribution of ART-R alleles and is ∼5.69, suggesting that short term effective population size is 88 thousand to 1.2 million. This is 52-705 times greater than Neestimated from fluctuation in allele frequencies, suggesting that we have previously underestimated the capacity for adaptive evolution in Plasmodium Our central conclusions are that retrospective studies may underestimate the complexity of selective events and the Nerelevant for adaptation for malaria is considerably higher than previously estimated.
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX tanderso@txbiomed.org.
authors.forename: Timothy J C
authors.initials: TJ
authors.lastname: Anderson
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
authors.forename: Shalini
authors.initials: S
authors.lastname: Nair
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
authors.forename: Marina
authors.initials: M
authors.lastname: McDew-White
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Cheeseman
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
authors.forename: Standwell
authors.initials: S
authors.lastname: Nkhoma
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
authors.forename: Fatma
authors.initials: F
authors.lastname: Bilgic
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Rose
authors.initials: R
authors.lastname: McGready
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ashley
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Aung
authors.initials: A
authors.lastname: Pyae Phyo
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine, Nuffield Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom.|Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: François
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D004351:Drug Resistance; D005787:Gene Frequency; D005828:Genetics, Population; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000469:parasitology*; D009154:Mutation; D059645:Mutation Rate; D010963:Plasmodium falciparum / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D013785:Thailand
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; C031327:artemisinin
keywords: adaptation; drug resistance; effective population size; plasmodium; rapid evolution; soft selective sweep