Genomic epidemiology of the current wave of artemisinin resistant malaria

Abstract

Artemisinin resistant Plasmodium falciparum is advancing across Southeast Asia in a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa.We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of standing variation that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. IntroductionArtemisinin combination therapy (ACT), the frontline treatment for P. falciparum infection, has played a major part in reducing the number of deaths due to malaria over the past decade (World Health Organization 2014). However artemisinin resistant P. falciparum, which has recently spread across large parts of Southeast Asia, now threatens to destabilise malaria control worldwide (Dondorp et al. 2009;Hien et al. 2012;Phyo et al. 2012;Kyaw et al. 2013;Ashley et al. 2014; World Health Organization 2014). One of the main contemporary challenges in global health is to prevent artemisinin resistance from becoming established in Africa, where the consequences for childhood mortality could be disastrous (Dondorp and Ringwald 2013).. CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/019737 doi: bioRxiv preprint first posted online May. 22, 2015; Genomic epidemiology of the current wave of artemisinin resistant malaria Page 2Understanding the epidemiological and evolutionary processes that are driving the current wave of artemisinin resistance is essential to develop effective strategies to stop it spreading. At the molecular level, artemisinin resistance is caused by mutations in a kelch protein encoded by PF3D7_1343700 on P. falciparum chromosome 13, referred to here as kelch13. More specifically, non-synonymous mutations in the kelch13 propeller and BTB-POZ domains (KPBD) result in reduced sensitivity of P. falciparum to artemisinin, as demonstrated by multiple lines of evidence including laboratory studies of artificially acquired resistance, genetic association studies of natural resistance and allelic replacement experiments (Ariey et al. 2014;Ghorbal et al. 2014;Miotto et al. 2015; Straimer et al. 2015; Takala-Harrison et al. 2015). The precise biological function of kelch13 is still not fully understood, but parasites with KBPD mut...

Artemisinin Resistance–Associated K13 Polymorphisms of Plasmodium falciparum in Southern Rwanda, 2010–2015

“…In line with this notion, further analysis of the African isolates suggested neutral evolution of the rare K13 polymorphisms, that is, a large reservoir of "natural" K13-propeller variants in SSA. 12 In the present study from southern Rwanda, we detected the K13 candidate mutations P574L and A675V. Although the A675V variant has been detected only once among more than 4,000 African P. falciparum isolates, [12][13][14] the K13 candidate mutation P574L is reported here for the first time from Africa.…”

“…12 In the present study from southern Rwanda, we detected the K13 candidate mutations P574L and A675V. Although the A675V variant has been detected only once among more than 4,000 African P. falciparum isolates, [12][13][14] the K13 candidate mutation P574L is reported here for the first time from Africa. Both variants are common in southeast Asia, 7,12 and both are associated with delayed parasite clearance.…”

“…So far, more than 20 K13 polymorphisms associated with delayed parasite clearance have been reported with identical mutants arising independently at different locations. 3,7,12,19 In two previous large-scale studies on African isolates, validated K13 mutations had not been observed. In one survey across 14 African sites including 1,184 P. falciparum isolates collected between 2002 and 2011, 23 different mutations (15 coding ones) were observed, of which 18 were restricted to single geographical sites.…”

“…3,12 In SSA, available evidence points to a multitude of rare non-synonymous K13 polymorphisms and almost absence of the validated mutations seen in southeast Asia. 3,[12][13][14] In Rwanda, east Africa, malaria morbidity and mortality declined greatly between 2005 and 2011 following the enforcement of control activities including the adoption of artemetherlumefantrine (AL) as first-line treatment in 2005. In particular, community-level case management programs have contributed greatly to the large-scale deployment of ACTs.…”

Population Genetic Analysis of Plasmodium Falciparum Circumsporozoite Protein in Two Distinct Ecological Regions in Ghana

“…For the VCF le of Cape Coast, all genotypes at each SNP position were mono-allelic (monoclonal); we modeled biallelic genotypes using a custom-made python script. This was based on the approach by the MalariaGEN Pf3k Project, where loci with mixed allele calls were modeled using the read and allelic depth [48]. Brie y, for read depth of two alleles at a SNP position in a sample, at positions with read depth <5, the genotype was undetermined.…”