Evolutionary insights into Kelch13 and its relationships with artemisinin resistance in Plasmodium falciparum malaria parasites
Romain Coppée  1@  , Audrey Sabbagh  1, *@  , Jérôme Clain  1, *@  
1 : UMR 216
Institut de recherche pour le développement [IRD] : UMR216, Université Paris V - Paris Descartes
* : Auteur correspondant

Multiple kelch13 mutant alleles conferring artemisinin resistance (ART-R) were identified in Southeast Asian Plasmodium falciparum malaria populations, resulting in amino acid replacements that cluster in the propeller domain. It is suggested that varying fitness costs could be associated with these mutations. Here, we investigated this hypothesis by analyzing the pattern of selection acting on kelch13 along the protein-coding DNA sequence and across the kelch13 phylogenic tree built for 34 Apicomplexa species – including 16 Plasmodium species. Using the Phylogenetic Analysis by Maximum Likelihood (PAML) method, we estimated the non-synonymous (dN) to synonymous (dS) substitution rate ratio ω as a proxy of the long-term fitness cost. First, we found that kelch13 has been exposed to a very high level of purifying selection throughout Apicomplexa and Plasmodium evolution. Second, positions in and around the first β-strand in the propeller domain are predominantly associated with both relaxed purifying selection and ART-R mutations. The position 580 exhibits a relatively low fitness cost, consistent with the hypothesis that pfkelch13 C580Y mutant parasites could be fitter than other pfkelch13 mutants. This would provide a simple explanation for the wide success of the pfkelch13 C580Y mutant lineage in some Asian areas.


Personnes connectées : 1