Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites
Tim J. Anderson,Shalini Nair,Marina McDew-White,Ian H. Cheeseman,Standwell Nkhoma,Fatma Bilgic,Rose McGready,Rose McGready,Elizabeth A. Ashley,Elizabeth A. Ashley,Aung Pyae Phyo,Aung Pyae Phyo,Nicholas J. White,Nicholas J. White,François Nosten,François Nosten +15 more
TLDR
The central conclusions are that retrospective studies may underestimate the complexity of selective events and the Ne relevant for adaptation for malaria is considerably higher than previously estimated.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 Ne estimated 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 Ne relevant for adaptation for malaria is considerably higher than previously estimated.read more
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Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic.
TL;DR: Recent advances in understanding how antimalarials act and how resistance develops are reviewed, and new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria are discussed.
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Soft sweeps and beyond: understanding the patterns and probabilities of selection footprints under rapid adaptation
TL;DR: The key theoretical concepts and contrast model predictions with observed patterns in Drosophila, humans, and microbes are summarized and called for in‐depth empirical study and further model development.
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Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments : a WWARN individual patient data meta-analysis
Chanaki Amaratunga,Voahangy Andrianaranjaka,Elizabeth A. Ashley,Delia Bethell,Anders Björkman,Craig A. Bonnington,Roland A. Cooper,Mehul Dhorda,Arjen M. Dondorp,Annette Erhart,Rick M. Fairhurst,Abul Faiz,Caterina I. Fanello,Mark M. Fukuda,Philippe J Guerin,Rob Hooft van Huijsduijnen,Tran Tinh Hien,N. V. Hong,Ye Htut,Fang Huang,Georgina S Humphreys,Mallika Imwong,Kalynn Kennon,Pharath Lim,Khin Lin,Chanthap Lon,Andreas Mårtensson,Mayfong Mayxay,Olugbenga A. Mokuolu,Ulrika Morris,Billy Ngasala,Alfred Amambua-Ngwa,Harald Noedl,François Nosten,Marie A. Onyamboko,Aung Pyae Phyo,Christopher V. Plowe,Sasithon Pukrittayakamee,Milijaona Randrianarivelojosia,Philip J. Rosenthal,David L. Saunders,Carol Hopkins Sibley,Frank Smithuis,Michele D. Spring,Paul Sondo,Sokunthea Sreng,Peter Starzengruber,Kasia Stepniewska,Seila Suon,Shannon Takala-Harrison,Kamala Thriemer,Nguyen Thuy-Nhien,Kyaw Myo Tun,Nicholas J. White,Charles J. Woodrow +54 more
TL;DR: An individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa demonstrates that 15 additional pfK13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.
Journal ArticleDOI
Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study
Roberto Amato,Roberto Amato,Richard D. Pearson,Richard D. Pearson,Jacob Almagro-Garcia,Jacob Almagro-Garcia,Chanaki Amaratunga,Pharath Lim,Seila Suon,Sokunthea Sreng,Eleanor Drury,Jim Stalker,Olivo Miotto,Olivo Miotto,Olivo Miotto,Rick M. Fairhurst,Dominic P. Kwiatkowski,Dominic P. Kwiatkowski +17 more
TL;DR: The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013 as mentioned in this paper, but genetic changes in the P falciparum population of western Cambodia were analyzed in the 6 years before those reports.
Journal ArticleDOI
Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance
Gustavo C. Cerqueira,Ian H. Cheeseman,Stephen F. Schaffner,Shalini Nair,Marina McDew-White,Aung Pyae Phyo,Elizabeth A. Ashley,Elizabeth A. Ashley,Alexandre Melnikov,Peter Rogov,Bruce W. Birren,François Nosten,François Nosten,Tim J. Anderson,Daniel E. Neafsey +14 more
TL;DR: Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemis inin resistance in African parasite populations.
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Spread of Artemisinin Resistance in Plasmodium falciparum Malaria
Elizabeth A. Ashley,Mehul Dhorda,Rick M. Fairhurst,Chanaki Amaratunga,Pharath Lim,Seila Suon,Sokunthea Sreng,Jennifer M. Anderson,Mao S,Sam B,Chantha Sopha,Char Meng Chuor,Chea Nguon,Siv Sovannaroth,Sasithon Pukrittayakamee,Podjanee Jittamala,Kesinee Chotivanich,K Chutasmit,C Suchatsoonthorn,R Runcharoen,Tran Tinh Hien,Nguyen Thuy-Nhien,Thanh Nv,Nguyen Hoan Phu,Ye Htut,Han Kt,Kyin Hla Aye,Olugbenga A. Mokuolu,Rasaq Olaosebikan,Olaleke Oluwasegun Folaranmi,Mayfong Mayxay,Maniphone Khanthavong,Bouasy Hongvanthong,Paul N. Newton,M A Onyamboko,Caterina I. Fanello,Antoinette Tshefu,Neelima Mishra,Neena Valecha,Aung Pyae Phyo,François Nosten,Yi P,Rupam Tripura,Steffen Borrmann,Mahfudh Bashraheil,Judy Peshu,M A Faiz,Aniruddha Ghose,M A Hossain,Rasheda Samad,M. R. Rahman,Manal Hasan,Ashraful Islam,Olivo Miotto,Roberto Amato,Bronwyn MacInnis,Jim Stalker,Dominic P. Kwiatkowski,Zbynek Bozdech,Atthanee Jeeyapant,Phaik Yeong Cheah,Tharisara Sakulthaew,Jeremy Chalk,Benjamas Intharabut,Kamolrat Silamut,Lee Sj,Benchawan Vihokhern,Chanon Kunasol,Mallika Imwong,Joel Tarning,Taylor Wj,Shunmay Yeung,Charles J. Woodrow,Jennifer A. Flegg,Debashish Das,Jennifer L. Smith,Meera Venkatesan,Christopher V. Plowe,Kasia Stepniewska,Philippe J Guerin,Arjen M. Dondorp,Nicholas P. J. Day,Nicholas J. White +82 more
TL;DR: Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing, and the incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission.
Journal ArticleDOI
A molecular marker of artemisinin-resistant Plasmodium falciparum malaria
Frédéric Ariey,Benoit Witkowski,Chanaki Amaratunga,Johann Beghain,Anne-Claire Langlois,Nimol Khim,Saorin Kim,Valentine Duru,Christiane Bouchier,Laurence Ma,Pharath Lim,Rithea Leang,Socheat Duong,Sokunthea Sreng,Seila Suon,Char Meng Chuor,Denis Mey Bout,Sandie Menard,William O. Rogers,Blaise Genton,Thierry Fandeur,Olivo Miotto,Pascal Ringwald,Jacques Le Bras,Antoine Berry,Jean Christophe Barale,Rick M. Fairhurst,Françoise Benoit-Vical,Odile Mercereau-Puijalon,Didier Menard +29 more
TL;DR: Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance.
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