title: Positive selection underlies the species-specific binding of Plasmodium falciparum RH5 to human basigin.
abstract: Plasmodium falciparum, the causative agent of the deadliest form of malaria, is a member of the Laverania subgenus, which includes ape-infecting parasites. P. falciparum is thought to have originated in gorillas, although infection is now restricted to humans. Laverania parasites display remarkable host-specificity, which is partially mediated by the interaction between parasite ligands and host receptors. We analyse the evolution of BSG (basigin) and GYPA (glycophorin A) in primates/hominins, as well as of their Plasmodium-encoded ligands, PfRH5 and PfEBA175. We show that, in primates, positive selection targeted two sites in BSG (F27 and H102), both involved in PfRH5 binding. A population genetics-phylogenetics approach detected the strongest selection for the gorilla lineage: one of the positively selected sites (K191) is a major determinant of PfRH5 binding affinity. Analysis of RH5 genes indicated episodic selection on the P. falciparum branch; the positively selected W447 site is known to stabilize the interaction with human basigin. Conversely, we detect no selection in the receptor-binding region of EBA175 in the P. falciparum lineage. Its host receptor, GYPA, shows evidence of positive selection in all hominid lineages; selected codons include glycosylation sites that modulate PfEBA175 binding affinity. Data herein provide an evolutionary explanation for species-specific binding of the PfRH5-BSG ligand-receptor pair and support the hypothesis that positive selection at these genes drove the host shift leading to the emergence of P. falciparum as a human pathogen.
authors: Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842, Bosisio Parini, Italy.
authors: Diego
authors: D
authors: Forni
authors: Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842, Bosisio Parini, Italy.
authors: Chiara
authors: C
authors: Pontremoli
authors: Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842, Bosisio Parini, Italy.
authors: Rachele
authors: R
authors: Cagliani
authors: Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842, Bosisio Parini, Italy.
authors: Uberto
authors: U
authors: Pozzoli
authors: Department of Physiopathology and Transplantation, University of Milan, 20090, Milan, Italy.|Don C. Gnocchi Foundation ONLUS, IRCCS, 20148, Milan, Italy.
authors: Mario
authors: M
authors: Clerici
authors: Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842, Bosisio Parini, Italy.
authors: Manuela
authors: M
authors: Sironi
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics*; D051926:Basigin / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D019143:Evolution, Molecular; D005828:Genetics, Population; D006021:Glycophorins / Q000235:genetics; D006071:Gorilla gorilla / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D002679:Pan troglodytes / Q000235:genetics; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000235:genetics* / Q000502:physiology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics*; D012641:Selection, Genetic; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013045:Species Specificity
chemical_list: D000953:Antigens, Protozoan; C497886:BSG protein, human; D002352:Carrier Proteins; C409972:GYPA protein, human; D006021:Glycophorins; D015800:Protozoan Proteins; C531020:RH5 protein, Plasmodium falciparum; C065668:erythrocyte-binding antigen 175, Plasmodium; D051926:Basigin
keywords: Plasmodium falciparum; RH5; basigin; positive selection