Genomic epidemiology of artemisinin resistant malaria

Abstract

The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of 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 variations 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.DOI: http://dx.doi.org/10.7554/eLife.08714.001

Molecular Epidemiology of Plasmodium falciparum kelch13 Mutations in Senegal Determined by Using Targeted Amplicon Deep Sequencing

“…Recent work from the MalariaGEN P. falciparum community project suggests that the same Pfk13 polymorphisms found in Southeast Asia (SEA) are present at low frequencies in Africa and may have evolved independently in that region (19). This is in agreement with the results obtained in our study.…”

“…We compared the Pfk13 alleles identified in our study with the global distribution of previously reported Pfk13 alleles. Our results are in agreement with previous reports (9,10,19) that several Pfk13 alleles are present at low frequencies in the natural parasite populations in different geographic regions. Continued surveillance of the different patterns of Pfk13 polymorphisms will be important for understanding the different factors driving the potential selection, emergence, and spread of polymorphisms associated with artemisinin resistance.…”

“…1). The remaining 10 polymorphisms were previously reported (18,19,24), but we observed different amino acid substitutions at these codon positions. These included codon positions 443, 459, 469, 473, 533, 539, 553, 556, 578, and 692 found in blades 1, 3, and 4 ( Fig.…”

“…The predominant polymorphisms previously reported in Senegal are alleles K189T and K189N, outside the propeller domain (25,26), consistent with our own findings (Table S1). The mutant allele A578S, which is not associated with artemisinin resistance, has been reported in multiple regions in Africa (18,19,24,28) (Table S2). In comparison, we observed a different amino acid substitution at this codon position in a single sample, from alanine (A) to aspartic acid (D) (Table S2).…”

“…Previously, whole-genome and pooled deep sequencing have been used for identification of artemisinin-resistant alleles in Pfk13 (18,19). However, whole-genome sequencing (WGS) can be cost-prohibitive for large-scale surveillance purposes.…”