title: Genome-wide SNP genotyping highlights the role of natural selection in Plasmodium falciparum population divergence.
abstract: BACKGROUND
  The malaria parasite Plasmodium falciparum exhibits abundant genetic diversity, and this diversity is key to its success as a pathogen. Previous efforts to study genetic diversity in P. falciparum have begun to elucidate the demographic history of the species, as well as patterns of population structure and patterns of linkage disequilibrium within its genome. Such studies will be greatly enhanced by new genomic tools and recent large-scale efforts to map genomic variation. To that end, we have developed a high throughput single nucleotide polymorphism (SNP) genotyping platform for P. falciparum.
  
  
  RESULTS
  Using an Affymetrix 3,000 SNP assay array, we found roughly half the assays (1,638) yielded high quality, 100% accurate genotyping calls for both major and minor SNP alleles. Genotype data from 76 global isolates confirm significant genetic differentiation among continental populations and varying levels of SNP diversity and linkage disequilibrium according to geographic location and local epidemiological factors. We further discovered that nonsynonymous and silent (synonymous or noncoding) SNPs differ with respect to within-population diversity, inter-population differentiation, and the degree to which allele frequencies are correlated between populations.
  
  
  CONCLUSIONS
  The distinct population profile of nonsynonymous variants indicates that natural selection has a significant influence on genomic diversity in P. falciparum, and that many of these changes may reflect functional variants deserving of follow-up study. Our analysis demonstrates the potential for new high-throughput genotyping technologies to enhance studies of population structure, natural selection, and ultimately enable genome-wide association studies in P. falciparum to find genes underlying key phenotypic traits.
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. neafsey@broad.mit.edu
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Neafsey
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Schaffner
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Volkman
authors.forename: Daniel
authors.initials: D
authors.lastname: Park
authors.forename: Philip
authors.initials: P
authors.lastname: Montgomery
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.forename: Amanda
authors.initials: A
authors.lastname: Lukens
authors.forename: David
authors.initials: D
authors.lastname: Rosen
authors.forename: Rachel
authors.initials: R
authors.lastname: Daniels
authors.forename: Nathan
authors.initials: N
authors.lastname: Houde
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Erin
authors.initials: E
authors.lastname: Tyndall
authors.forename: Casey
authors.initials: C
authors.lastname: Gates
authors.forename: Nicole
authors.initials: N
authors.lastname: Stange-Thomann
authors.forename: Ousmane
authors.initials: O
authors.lastname: Sarr
authors.forename: Daouda
authors.initials: D
authors.lastname: Ndiaye
authors.forename: Omar
authors.initials: O
authors.lastname: Ndir
authors.forename: Soulyemane
authors.initials: S
authors.lastname: Mboup
authors.forename: Marcelo U
authors.initials: MU
authors.lastname: Ferreira
authors.forename: Sandra do Lago
authors.initials: Sdo L
authors.lastname: Moraes
authors.forename: Aditya P
authors.initials: AP
authors.lastname: Dash
authors.forename: Chetan E
authors.initials: CE
authors.lastname: Chitnis
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiegand
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hartl
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Birren
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
mesh_terms: D000818:Animals; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000145:classification / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic