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Epidemiology and Surveillance

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

M. Andreína Pacheco, Esha R. Kadakia, Zainab Chaudhary, Douglas J. Perkins, Julia Kelley, Shashidhar Ravishankar, Michael Cranfield, Eldin Talundzic, Venkatachalam Udhayakumar, Ananias A. Escalante
M. Andreína Pacheco
aDepartment of Biology/Institute for Genomics and Evolutionary Medicine (iGEM), Temple University, Philadelphia, Pennsylvania, USA
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Esha R. Kadakia
aDepartment of Biology/Institute for Genomics and Evolutionary Medicine (iGEM), Temple University, Philadelphia, Pennsylvania, USA
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Zainab Chaudhary
aDepartment of Biology/Institute for Genomics and Evolutionary Medicine (iGEM), Temple University, Philadelphia, Pennsylvania, USA
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Douglas J. Perkins
bCenter for Global Health, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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Julia Kelley
cAtlanta Research and Education Foundation, VAMC, Atlanta, Georgia, USA
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Shashidhar Ravishankar
dSchool of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA
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Michael Cranfield
eGorilla Doctors, Wildlife Health Department, University of California, Davis, Davis, California, USA
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Eldin Talundzic
fMalaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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Venkatachalam Udhayakumar
fMalaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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Ananias A. Escalante
aDepartment of Biology/Institute for Genomics and Evolutionary Medicine (iGEM), Temple University, Philadelphia, Pennsylvania, USA
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DOI: 10.1128/AAC.02550-18
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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.

FOOTNOTES

    • Received 5 December 2018.
    • Returned for modification 24 February 2019.
    • Accepted 28 April 2019.
    • Accepted manuscript posted online 13 May 2019.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02550-18.

  • Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

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Evolution and Genetic Diversity of the k13 Gene Associated with Artemisinin Delayed Parasite Clearance in Plasmodium falciparum
M. Andreína Pacheco, Esha R. Kadakia, Zainab Chaudhary, Douglas J. Perkins, Julia Kelley, Shashidhar Ravishankar, Michael Cranfield, Eldin Talundzic, Venkatachalam Udhayakumar, Ananias A. Escalante
Antimicrobial Agents and Chemotherapy Jul 2019, 63 (8) e02550-18; DOI: 10.1128/AAC.02550-18

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Evolution and Genetic Diversity of the k13 Gene Associated with Artemisinin Delayed Parasite Clearance in Plasmodium falciparum
M. Andreína Pacheco, Esha R. Kadakia, Zainab Chaudhary, Douglas J. Perkins, Julia Kelley, Shashidhar Ravishankar, Michael Cranfield, Eldin Talundzic, Venkatachalam Udhayakumar, Ananias A. Escalante
Antimicrobial Agents and Chemotherapy Jul 2019, 63 (8) e02550-18; DOI: 10.1128/AAC.02550-18
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KEYWORDS

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

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