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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dc.contributor.author Van Tyne, Daria Natalie
dc.contributor.author Park, Daniel John
dc.contributor.author Schaffner, Stephen
dc.contributor.author Neafsey, Daniel Edward
dc.contributor.author Angelino, Elaine Lee
dc.contributor.author Cortese, Joseph F.
dc.contributor.author Barnes, Kayla G.
dc.contributor.author Rosen, David M.
dc.contributor.author Lukens, Amanda Kathleen
dc.contributor.author Daniels, Rachel Fath
dc.contributor.author Milner, Danny Arnold
dc.contributor.author Johnson, Charles A.
dc.contributor.author Shlyakhter, Ilya
dc.contributor.author Grossman, Sharon Rachel
dc.contributor.author Becker, Justin S.
dc.contributor.author Yamins, Daniel Louis Kanef
dc.contributor.author Karlsson, Elinor Kathryn
dc.contributor.author Ndiaye, Daouda
dc.contributor.author Sarr, Ousmane
dc.contributor.author Mboup, Souleymane
dc.contributor.author Happi, Christian Tientcha
dc.contributor.author Furlotte, Nicholas A.
dc.contributor.author Eskin, Eleazar
dc.contributor.author Kang, Hyun Min
dc.contributor.author Hartl, Daniel L.
dc.contributor.author Birren, Bruce W.
dc.contributor.author Wiegand, Roger C.
dc.contributor.author Lander, Eric Steven
dc.contributor.author Wirth, Dyann Fergus
dc.contributor.author Cooke, Sarah Volkman
dc.contributor.author Sabeti, Pardis Christine
dc.date.accessioned 2011-11-02T17:36:53Z
dc.date.issued 2011
dc.identifier.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. en_US
dc.identifier.issn 1553-7404 en_US
dc.identifier.issn 1553-7390 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5339085
dc.description.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. en_US
dc.description.sponsorship Organismic and Evolutionary Biology en_US
dc.description.sponsorship Other Research Unit en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pgen.1001383 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080868/ en_US
dash.license OAP
dc.subject population structure en_US
dc.subject haplotype structure en_US
dc.subject positive selection en_US
dc.subject malaria parasites en_US
dc.subject drug-resistance en_US
dc.subject genome sequence en_US
dc.subject copy number en_US
dc.subject gene en_US
dc.subject susceptibility en_US
dc.subject association en_US
dc.title Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum en_US
dc.type Journal Article en_US
dc.description.version Accepted Manuscript en_US
dc.relation.journal PLoS Genetics en_US
dash.depositing.author Sabeti, Pardis Christine
dc.date.available 2011-11-02T17:36:53Z
dash.affiliation.other Harvard School of Public Health, Department of Immunology and Infectious Diseases en_US
dash.affiliation.other Broad Institute of MIT and Harvard University en_US
dash.affiliation.other Harvard Medical School en_US

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  • FAS Scholarly Articles [6948]
    Peer reviewed scholarly articles from the Faculty of Arts and Sciences of Harvard University

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