title: Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.
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.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Daria
authors.initials: D
authors.lastname: Van Tyne
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Park
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Schaffner
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Neafsey
authors.forename: Elaine
authors.initials: E
authors.lastname: Angelino
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Kayla G
authors.initials: KG
authors.lastname: Barnes
authors.forename: David M
authors.initials: DM
authors.lastname: Rosen
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Lukens
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Daniels
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.forename: Charles A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Ilya
authors.initials: I
authors.lastname: Shlyakhter
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grossman
authors.forename: Justin S
authors.initials: JS
authors.lastname: Becker
authors.forename: Daniel
authors.initials: D
authors.lastname: Yamins
authors.forename: Elinor K
authors.initials: EK
authors.lastname: Karlsson
authors.forename: Daouda
authors.initials: D
authors.lastname: Ndiaye
authors.forename: Ousmane
authors.initials: O
authors.lastname: Sarr
authors.forename: Souleymane
authors.initials: S
authors.lastname: Mboup
authors.forename: Christian
authors.initials: C
authors.lastname: Happi
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Furlotte
authors.forename: Eleazar
authors.initials: E
authors.lastname: Eskin
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hartl
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Birren
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiegand
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Volkman
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D004983:Ethanolamines / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D018628:Gene Dosage; D015870:Gene Expression; D056726:Genetic Association Studies; D056426:Genetic Loci; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D015810:Linkage Disequilibrium; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000469:parasitology / Q000517:prevention & control; D015767:Mefloquine / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic
chemical_list: D000962:Antimalarials; D004983:Ethanolamines; D005449:Fluorenes; D010616:Phenanthrenes; D000078102:Lumefantrine; C023768:halofantrine; D015767:Mefloquine