Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum
Year: 2011
Type: article
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.
Source: PLoS Genetics
Authors: Daria Van Tyne, Daniel J. Park, Stephen F. Schaffner, Daniel E. Neafsey, Elaine Angelino, Joseph F. Cortese, Kayla G. Barnes, David M. Rosen, Amanda K. Lukens, Rachel F. Daniels, Danny A. Milner, Charles A. Johnson, Ilya Shlyakhter, Sharon R. Grossman, Justin S. Becker, Daniel Yamins, Elinor K. Karlsson, Daouda Ndiaye, Ousmane Sarr, Souleymane Mboup, Christian Happi, Nicholas A. Furlotte, Eleazar Eskin, Hyun Min Kang, Daniel L. Hartl, Bruce W. Birren, Roger C. Wiegand, Eric S. Lander, Dyann F. Wirth, Sarah K. Volkman, Pardis C. Sabeti
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: National Science Foundation, Ellison Medical Foundation, Bill and Melinda Gates Foundation, ExxonMobil Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Fogarty International Center
OpenAlex ID: W1604784023