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Antimicrob Agents Chemother. 2019 Jul 25;63(8). pii: e02550-18. doi: 10.1128/AAC.02550-18. Print 2019 Aug.

Evolution and Genetic Diversity of the k13 Gene Associated with Artemisinin Delayed Parasite Clearance in Plasmodium falciparum.

Author information

1
Department of Biology/Institute for Genomics and Evolutionary Medicine (iGEM), Temple University, Philadelphia, Pennsylvania, USA.
2
Center for Global Health, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
3
Atlanta Research and Education Foundation, VAMC, Atlanta, Georgia, USA.
4
School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA.
5
Gorilla Doctors, Wildlife Health Department, University of California, Davis, Davis, California, USA.
6
Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
7
Department of Biology/Institute for Genomics and Evolutionary Medicine (iGEM), Temple University, Philadelphia, Pennsylvania, USA Ananias.Escalante@temple.edu.

Abstract

Mutations in the Plasmodium falciparum k13 (Pfk13) gene are linked to delayed parasite clearance in response to artemisinin-based combination therapies (ACTs) in Southeast Asia. To explore the evolutionary rate and constraints acting on this gene, k13 orthologs from species sharing a recent common ancestor with P. falciparum and Plasmodium vivax were analyzed. These comparative studies were followed by genetic polymorphism analyses within P. falciparum using 982 complete Pfk13 sequences from public databases and new data obtained by next-generation sequencing from African and Haitian isolates. Although k13 orthologs evolve at heterogeneous rates, the gene was conserved across the genus, with only synonymous substitutions being found at residues where mutations linked to the delayed parasite clearance phenotype have been reported. This suggests that those residues were under constraint from undergoing nonsynonymous changes during evolution of the genus. No fixed nonsynonymous differences were found between Pfk13 and its orthologs in closely related species found in African apes. This indicates that all nonsynonymous substitutions currently found in Pfk13 are younger than the time of divergence between P. falciparum and its closely related species. At the population level, no mutations linked to delayed parasite clearance were found in our samples from Africa and Haiti. However, there is a high number of single Pfk13 mutations segregating in P. falciparum populations, and two predominant alleles are distributed worldwide. This pattern is discussed in terms of how changes in the efficacy of natural selection, affected by population expansion, may have allowed for the emergence of mutations tolerant to ACTs.

KEYWORDS:

Plasmodium falciparum ; Plasmodium vivax ; artemisinin resistance; k13 gene; kelch propeller domain; rates of evolution

PMID:
31085516
PMCID:
PMC6658766
[Available on 2020-01-25]
DOI:
10.1128/AAC.02550-18

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