Loading…

Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum

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 malar...

Full description

Saved in:
Bibliographic Details
Published in:PLoS genetics 2011-04, Vol.7 (4), p.e1001383
Main Authors: Van Tyne, Daria, Park, Daniel J, Schaffner, Stephen F, Neafsey, Daniel E, Angelino, Elaine, Cortese, Joseph F, Barnes, Kayla G, Rosen, David M, Lukens, Amanda K, Daniels, Rachel F, Milner, Jr, Danny A, Johnson, Charles A, Shlyakhter, Ilya, Grossman, Sharon R, Becker, Justin S, Yamins, Daniel, Karlsson, Elinor K, Ndiaye, Daouda, Sarr, Ousmane, Mboup, Souleymane, Happi, Christian, Furlotte, Nicholas A, Eskin, Eleazar, Kang, Hyun Min, Hartl, Daniel L, Birren, Bruce W, Wiegand, Roger C, Lander, Eric S, Wirth, Dyann F, Volkman, Sarah K, Sabeti, Pardis C
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1001383