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...
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Public Library of Science
2012
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| Online Access: | http://hdl.handle.net/1721.1/69173 https://orcid.org/0000-0001-5410-7274 |
| _version_ | 1826189982348345344 |
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| author | 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 Sarr, Ousmane Mboup, Soulyemane Happi, Christian Furlotte, Nicholas A. Eskin, Eleazar Kang, Hyun Min Hartl, Daniel L. Neafsey, Daniel E. Cortese, Joseph F. Daniels, Rachel F. Johnson, Charles A. Shlyakhter, Ilya Grossman, Sharon Rachel Birren, Bruce W. Wiegand, Roger C. Wirth, Dyann F. Volkman, Sarah K. Park, Daniel Schaffner, Stephen F Karlsson, Elinor Lander, Eric Steven Sabeti, Pardis |
| author2 | Whitaker College of Health Sciences and Technology |
| author_facet | Whitaker College of Health Sciences and Technology 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 Sarr, Ousmane Mboup, Soulyemane Happi, Christian Furlotte, Nicholas A. Eskin, Eleazar Kang, Hyun Min Hartl, Daniel L. Neafsey, Daniel E. Cortese, Joseph F. Daniels, Rachel F. Johnson, Charles A. Shlyakhter, Ilya Grossman, Sharon Rachel Birren, Bruce W. Wiegand, Roger C. Wirth, Dyann F. Volkman, Sarah K. Park, Daniel Schaffner, Stephen F Karlsson, Elinor Lander, Eric Steven Sabeti, Pardis |
| author_sort | Tyne, Daria Van |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:33:12Z |
| format | Article |
| id | mit-1721.1/69173 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:33:12Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/691732022-09-23T12:51:23Z Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum 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 Sarr, Ousmane Mboup, Soulyemane Happi, Christian Furlotte, Nicholas A. Eskin, Eleazar Kang, Hyun Min Hartl, Daniel L. Neafsey, Daniel E. Cortese, Joseph F. Daniels, Rachel F. Johnson, Charles A. Shlyakhter, Ilya Grossman, Sharon Rachel Birren, Bruce W. Wiegand, Roger C. Wirth, Dyann F. Volkman, Sarah K. Park, Daniel Schaffner, Stephen F Karlsson, Elinor Lander, Eric Steven Sabeti, Pardis Whitaker College of Health Sciences and Technology Broad Institute of MIT and Harvard Massachusetts Institute of Technology. Department of Biology Lander, Eric S. Park, Daniel J. Schaffner, Stephen F. Neafsey, Daniel E. Cortese, Joseph F. Daniels, Rachel F. Johnson, Charles A. Shlyakhter, Ilya Grossman, Sharon Rachel Karlsson, Elinor K. Birren, Bruce W. Wiegand, Roger C. Lander, Eric S. Wirth, Dyann F. Volkman, Sarah K. Sabeti, Pardis C. 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. Bill & Melinda Gates Foundation Ellison Medical Foundation Exxon Mobil Foundation Fogarty International Center National Institute of Allergy and Infectious Diseases (U.S.) Burroughs Wellcome Fund David & Lucile Packard Foundation National Science Foundation (U.S.). Graduate Research Fellowship Program 2012-02-23T18:59:10Z 2012-02-23T18:59:10Z 2011-04 2010-09 Article http://purl.org/eprint/type/JournalArticle 1553-7390 1553-7404 http://hdl.handle.net/1721.1/69173 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. https://orcid.org/0000-0001-5410-7274 en_US http://dx.doi.org/10.1371/journal.pgen.1001383 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | 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 Sarr, Ousmane Mboup, Soulyemane Happi, Christian Furlotte, Nicholas A. Eskin, Eleazar Kang, Hyun Min Hartl, Daniel L. Neafsey, Daniel E. Cortese, Joseph F. Daniels, Rachel F. Johnson, Charles A. Shlyakhter, Ilya Grossman, Sharon Rachel Birren, Bruce W. Wiegand, Roger C. Wirth, Dyann F. Volkman, Sarah K. Park, Daniel Schaffner, Stephen F Karlsson, Elinor Lander, Eric Steven Sabeti, Pardis Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum |
| title | Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum |
| title_full | Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum |
| title_fullStr | Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum |
| title_full_unstemmed | Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum |
| title_short | Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum |
| title_sort | identification and functional validation of the novel antimalarial resistance locus pf10 0355 in plasmodium falciparum |
| url | http://hdl.handle.net/1721.1/69173 https://orcid.org/0000-0001-5410-7274 |
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