Longitudinal genomic surveillance of<i>Plasmodium falciparum</i>malaria parasites reveals complex genomic architecture of emerging artemisinin resistance in western Thailand

Gc, Cerqueira; Cheeseman, Ian H.; Schaffner, Stephen F.; Nair, Shalini; McDew-White, Marina; Ap, Phyo; Ashley, Elizabeth A.; Melnikov, Alexandre; Rogov, Peter; Bw, Birren; Nosten, François; Tj, Anderson; De, Neafsey

doi:10.1101/084897

Cited by 5 publications

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“…We emphasize that this does not rule out involvement of other loci in other aspects of resistance such as fitness costs. A longitudinal genome sequencing study on a subset of the parasites examined here identified several regions of the genome that show rapid changes in SNP frequency, identifying several putative genome regions that may be selected by ART (Cerqueira et al 2015). Similarly, previous analyses have identified genome regions distant from kelch13 associated with ART-R (Cheeseman et al 2012; Miotto et al 2013; Takala-Harrison et al 2013; Cheeseman et al 2015; Miotto et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites

et al. 2016

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“…Furthermore, the lower levels of disease endemicity and acquired immunity in SEA strongly increase the likelihood that infected individuals will become symptomatic and thus will be treated with drugs. In Africa most infections are asymptomatic, hence the proportion of the parasite population exposed to ART selection is lower (Cerqueira et al, 2017, Nair et al, 2018.…”

Section: Detection Of Candidate Mutations In K13-propeller Domain Associated With Art Resistance In Huye Southern Rwanda In 2015mentioning

confidence: 99%

Prevalence of the Pfdhfr and Pfdhps mutations among asymptomatic pregnant women in Southeast Nigeria

et al. 2018

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Sulfadoxine-pyrimethamine (SP) is the recommended drug for intermittent preventive treatment of malaria in pregnancy in most of sub-Saharan Africa. Resistance to SP is related to mutations in the dhfr and dhps gene of Plasmodium falciparum. This study determined the prevalence of Pfdhfr and Pfdhps polymorphisms found in asymptomatic pregnant women attending antenatal care in Calabar, Nigeria. From October 2013 to November 2014, asymptomatic pregnant women attending antenatal care clinics were enrolled after obtaining informed consent. Malaria diagnosis testing was done using thick and thin smears. Dried blood spot filter papers were collected. Parasite DNA was extracted from the filter papers using a chelex extraction. Extraction was followed by nested PCR and restriction enzyme digestion. P. falciparum infection was detected by microscopy in 7% (32/459) participants. Twenty-eight P. falciparum isolates were successfully genotyped. In the Pfdhfr gene, the triple mutation was almost fixed; S108N mutation was (100%), N51I (93%) and C59R mutations (93%), whereas the I164L mutation was absent. The prevalence of Pfdhps S436A, A437G, A581G and A613S mutations was 82.1% (23/28), 96.4% (27/28), 71.4% (20/28) and 71.4% (20/28) respectively. The K540E mutation was absent. The prevalence of the Pfdhfr triple mutation IRNI was 92.9% (26/28). The efficacy of SP as IPTp in Southeast Nigeria may be severely threatened. The continuous monitoring of SP molecular markers of resistance is required to assess thresholds. The evaluation of alternative preventive treatment strategies and drug options for preventing malaria in pregnancy may be necessary.

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“…We emphasize that this does not rule out involvement of other loci in other aspects of resistance phenotype such as parasite fitness. A longitudinal genome sequencing study on a subset of the parasites examined in this paper identified several regions of the genome that show rapid changes in SNP frequency, identifying several other potential genome regions that may be selected by ART selection (42). Similarly, previous association analyses have identified other genome regions associated with ART-R other than the chr.…”

Section: Mutations Outside the Propeller Domain Are Associated With Smentioning

confidence: 63%

Why are there so many independent origins of artemisinin resistance in malaria parasites?

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McDew-White

et al. 2016

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SummaryMultiple alleles at the kelch13 locus conferring artemisinin resistance (ART-R) are currently spreading through malaria parasite populations in Southeast Asia, providing a unique opportunity to directly observe an ongoing soft selective sweep, to investigate why resistance alleles have evolved multiple times and to determine fundamental population genetic parameters for Plasmodium. We sequenced the kelch13 gene (n=1,876), genotyped 75 flanking SNPs, and measured clearance rate (n=3,552) in parasite infections from Western Thailand (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014). We describe 32 independent coding mutations: these included common mutations outside the kelch13 propeller region 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. There was no change in diversity in flanking markers, but resistance allele diversity rose until 2012 and then dropped as one allele (C580Y) spread to high frequency. The rapid spread of C580Y suggests that the genomic signature may be considerably harder in the near future, and that retrospective studies may underestimate the complexity of selective sweeps. The frequency with which adaptive alleles arise is determined by the rate of mutation to generate beneficial alleles and the population size. Two factors drive this soft sweep: (1) multiple amino-acid mutations in kelch13 can confer resistance providing a large mutational target -we estimate the target size is between 87 and 163bp. (2) The population mutation parameter (Θ=2N e μ) can be estimated from the frequency distribution of resistant alleles and is ~ 5.69, suggesting that short term effective population size is between 88 thousand and 1.2 million. This is 52 to 705-fold greater than N e estimates based on fluctuation in allele frequencies, suggesting that . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/056291 doi: bioRxiv preprint first posted online May. 31, 2016; 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, ART-R evolution is not limited by availability of mutations, and the N e relevant for adaptation for malaria is considerably higher than previously estimated.Significance Statement: Previous work has identified surprisingly few origins of resistance to antimalarial drugs such as chloroquine and pyrimethamine. This has lead to optimism about prospects for minimizing resistance evolution through combination therapy. We studied a longitudinal collection of malaria parasites from the Thai-Myanmar border to examine an ongoing selective event in which ≥32 independent alleles associated with ART-R evolved. Three factors appear to explain the large number of origins obs...

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Longitudinal genomic surveillance ofPlasmodium falciparummalaria parasites reveals complex genomic architecture of emerging artemisinin resistance in western Thailand

Cited by 5 publications

References 68 publications

Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites

Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites

Prevalence of the Pfdhfr and Pfdhps mutations among asymptomatic pregnant women in Southeast Nigeria

Why are there so many independent origins of artemisinin resistance in malaria parasites?

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