title: Population genetic analysis of large sequence polymorphisms in Plasmodium falciparum blood-stage antigens.
abstract: Plasmodium falciparum, the causative agent of human malaria, invades host erythrocytes using several proteins on the surface of the invasive merozoite, which have been proposed as potential vaccine candidates. Members of the multi-gene PfRh family are surface antigens that have been shown to play a central role in directing merozoites to alternative erythrocyte receptors for invasion. Recently, we identified a large structural polymorphism, a 0.58Kb deletion, in the C-terminal region of the PfRh2b gene, present at a high frequency in parasite populations from Senegal. We hypothesize that this region is a target of humoral immunity. Here, by analyzing 371 P. falciparum isolates we show that this major allele is present at varying frequencies in different populations within Senegal, Africa, and throughout the world. For allelic dimorphisms in the asexual stage antigens, Msp-2 and EBA-175, we find minimal geographic differentiation among parasite populations from Senegal and other African localities, suggesting extensive gene flow among these populations and/or immune-mediated frequency-dependent balancing selection. In contrast, we observe a higher level of inter-population divergence (as measured by F(st)) for the PfRh2b deletion, similar to that observed for SNPs from the sexual stage Pfs45/48 loci, which is postulated to be under directional selection. We confirm that the region containing the PfRh2b polymorphism is a target of humoral immune responses by demonstrating antibody reactivity of endemic sera. Our analysis of inter-population divergence suggests that in contrast to the large allelic dimorphisms in EBA-175 and Msp-2, the presence or absence of the large PfRh2b deletion may not elicit frequency-dependent immune selection, but may be under positive immune selection, having important implications for the development of these proteins as vaccine candidates.
authors.affiliation: Laboratory of Bacteriology and Virology, Le Dantec Hospital, and Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar BP 7325, Senegal.
authors.forename: Ambroise D
authors.initials: AD
authors.lastname: Ahouidi
authors.forename: Amy K
authors.initials: AK
authors.lastname: Bei
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Neafsey
authors.forename: Ousmane
authors.initials: O
authors.lastname: Sarr
authors.forename: Sarah
authors.initials: S
authors.lastname: Volkman
authors.forename: Dan
authors.initials: D
authors.lastname: Milner
authors.forename: Janet
authors.initials: J
authors.lastname: Cox-Singh
authors.forename: Marcelo U
authors.initials: MU
authors.lastname: Ferreira
authors.forename: Omar
authors.initials: O
authors.lastname: Ndir
authors.forename: Zul
authors.initials: Z
authors.lastname: Premji
authors.forename: Souleymane
authors.initials: S
authors.lastname: Mboup
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005843:Geography; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D016778:Malaria, Falciparum / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology; D012675:Senegal; D018709:Statistics, Nonparametric
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D015800:Protozoan Proteins; C545352:Rh2b protein, Plasmodium falciparum