title: Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite.
abstract: Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite--the deadliest of those that cause malaria--is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites' in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.
authors: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. dpark@broadinstitute.org
authors: Daniel J
authors: DJ
authors: Park
authors: Amanda K
authors: AK
authors: Lukens
authors: Daniel E
authors: DE
authors: Neafsey
authors: Stephen F
authors: SF
authors: Schaffner
authors: Hsiao-Han
authors: HH
authors: Chang
authors: Clarissa
authors: C
authors: Valim
authors: Ulf
authors: U
authors: Ribacke
authors: Daria
authors: D
authors: Van Tyne
authors: Kevin
authors: K
authors: Galinsky
authors: Meghan
authors: M
authors: Galligan
authors: Justin S
authors: JS
authors: Becker
authors: Daouda
authors: D
authors: Ndiaye
authors: Souleymane
authors: S
authors: Mboup
authors: Roger C
authors: RC
authors: Wiegand
authors: Daniel L
authors: DL
authors: Hartl
authors: Pardis C
authors: PC
authors: Sabeti
authors: Dyann F
authors: DF
authors: Wirth
authors: Sarah K
authors: SK
authors: Volkman
mesh_terms: D001483:Base Sequence; D004351:Drug Resistance / Q000235:genetics*; D005787:Gene Frequency; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000235:genetics*; D025341:Principal Component Analysis; D012641:Selection, Genetic; D012675:Senegal; D017422:Sequence Analysis, DNA / Q000379:methods