Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum
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Tyne-2011-Identification and f.pdf
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Author(s)
Tyne, Daria Van
Angelino, Elaine
Barnes, Kayla G.
Rosen, David M.
Lukens, Amanda K.
Daniels, Rachel F.
Milner, Danny A.
Becker, Justin S.
Yamins, Daniel
Ndiaye, Daouda
Date Issued
April 2011
Journal
PLoS Genetics
Publisher
Public Library of Science
Citation
Van Tyne, Daria et al. “Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium Falciparum.” Ed. Nancy A. Moran. PLoS Genetics 7.4 (2011): e1001383. Web. 23 Feb. 2012.
Version
Final published version
Abstract
The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (~1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.
MIT Department
Whitaker College of Health Sciences and Technology
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1371/journal.pgen.1001383
