Abstract
ABSTRACTPlasmodium falciparum, the major cause of malaria morbidity and mortality in humans, has been shown to have emerged after cross-species transmission of one of six host-specific parasites (subgenus Laverania) infecting wild chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla). Binding of the parasite-encoded ligand RH5 to the host protein basigin is essential for erythrocyte invasion and has been implicated in host specificity. A recent study claimed to have found two amino acid changes in RH5 that “drove the host shift leading to the emergence of P. falciparum as a human pathogen.” However, the ape Laverania data available at that time, which included only a single distantly related chimpanzee parasite sequence, were inadequate to justify any such conclusion. Here, we have investigated Laverania Rh5 gene evolution using sequences from all six ape parasite species. Searching for gene-wide episodic selection across the entire Laverania phylogeny, we found eight codons to be under positive selection, including three that correspond to contact residues known to form hydrogen bonds between P. falciparum RH5 and human basigin. One of these sites (residue 197) has changed subsequent to the transmission from apes to humans that gave rise to P. falciparum, suggesting a possible role in the adaptation of the gorilla parasite to the human host. We also found evidence that the patterns of nucleotide polymorphisms in P. falciparum are not typical of Laverania species and likely reflect the recent demographic history of the human parasite.
Highlights
Plasmodium falciparum, the major cause of malaria morbidity and mortality in humans, has been shown to have emerged after cross-species transmission of one of six host-specific parasites infecting wild chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla)
The malaria parasite P. falciparum became widespread among humans following a cross-species jump of a gorilla parasite, perhaps within the last few thousand years [23]; understanding the host-parasite interactions that allowed that event is of obvious interest
A recent analysis of the evolution of the reticulocytebinding protein homologue 5 (RH5)-BSG ligand-receptor pair concluded that the data “support the hypothesis that positive selection at these genes drove the host shift leading to the emergence of P. falciparum as a human pathogen” [19]
Summary
Plasmodium falciparum, the major cause of malaria morbidity and mortality in humans, has been shown to have emerged after cross-species transmission of one of six host-specific parasites (subgenus Laverania) infecting wild chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla). Searching for gene-wide episodic selection across the entire Laverania phylogeny, we found eight codons to be under positive selection, including three that correspond to contact residues known to form hydrogen bonds between P. falciparum RH5 and human basigin One of these sites (residue 197) has changed subsequent to the transmission from apes to humans that gave rise to P. falciparum, suggesting a possible role in the adaptation of the gorilla parasite to the human host. The relative dearth of genetic diversity in P. falciparum compared with that of chimpanzee Laverania species [11] and the apparent absence of other ape Laverania parasites infecting humans living in close proximity to African apes [12, 13] suggest that the human parasite arose from a single gorilla-to-human transmission in the recent past These observations raise questions of what determines host specificity and why ape-to-human transmissions are not more common. The host tropism of P. falciparum seemed to correlate with the strength of RH5-BSG interactions, raising the possibility that adaptation at the Rh5 locus might have been an important step in the origin of the human parasite [15]
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