Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum

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Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum

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Title: Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum
Author: Van Tyne, Daria Natalie; Park, Daniel John; Schaffner, Stephen; Neafsey, Daniel Edward; Angelino, Elaine Lee; Cortese, Joseph F.; Barnes, Kayla G.; Rosen, David M.; Lukens, Amanda Kathleen; Daniels, Rachel Fath; Milner, Danny Arnold; Johnson, Charles A.; Shlyakhter, Ilya; Grossman, Sharon Rachel; Becker, Justin S.; Yamins, Daniel Louis Kanef; Karlsson, Elinor Kathryn; Ndiaye, Daouda; Sarr, Ousmane; Mboup, Souleymane; Happi, Christian Tientcha; Furlotte, Nicholas A.; Eskin, Eleazar; Kang, Hyun Min; Hartl, Daniel L.; Birren, Bruce W.; Wiegand, Roger C.; Lander, Eric Steven; Wirth, Dyann Fergus; Cooke, Sarah Volkman; Sabeti, Pardis Christine

Note: Order does not necessarily reflect citation order of authors.

Citation: Van Tyne, Daria, Daniel J. Park, Stephen F. Schaffner, Daniel E. Neafsey, Elaine Angelino, Joseph F. Cortese, Kayla G. Barnes et al. 2011. Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum. PLoS Genetics 7(4): e1001383.
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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.
Published Version: doi:10.1371/journal.pgen.1001383
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080868/
Terms of Use: This article is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#OAP
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:5339085

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  • FAS Scholarly Articles [7176]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University
 
 

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