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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doaj-2bcae71e6bc0480f90bbcced935ec1062020-11-24T22:05:32ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-04-0174e100138310.1371/journal.pgen.1001383Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.Daria Van TyneDaniel J ParkStephen F SchaffnerDaniel E NeafseyElaine AngelinoJoseph F CorteseKayla G BarnesDavid M RosenAmanda K LukensRachel F DanielsDanny A MilnerCharles A JohnsonIlya ShlyakhterSharon R GrossmanJustin S BeckerDaniel YaminsElinor K KarlssonDaouda NdiayeOusmane SarrSouleymane MboupChristian HappiNicholas A FurlotteEleazar EskinHyun Min KangDaniel L HartlBruce W BirrenRoger C WiegandEric S LanderDyann F WirthSarah K VolkmanPardis C SabetiThe 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.http://europepmc.org/articles/PMC3080868?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum. PLoS Genetics |
author_facet |
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 |
author_sort |
Daria Van Tyne |
title |
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_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_sort |
identification and functional validation of the novel antimalarial resistance locus pf10_0355 in plasmodium falciparum. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2011-04-01 |
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. |
url |
http://europepmc.org/articles/PMC3080868?pdf=render |
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