Evolutionary history of human <i>Plasmodium vivax</i> revealed by genome-wide analyses of related ape parasites

Abstract

Wild-living African apes are endemically infected with parasites that are closely related to human <i>Plasmodium vivax</i>, a leading cause of malaria outside Africa. This finding suggests that the origin of <i>P. vivax</i> was in Africa, even though the parasite is now rare in humans there. To elucidate the emergence of human <i>P. vivax</i> and its relationship to the ape parasites, we analyzed genome sequence data of <i>P. vivax</i> strains infecting six chimpanzees and one gorilla from Cameroon, Gabon, and Côte d'Ivoire. We found that ape and human parasites share nearly identical core genomes, differing by only 2% of coding sequences. However, compared with the ape parasites, human strains of <i>P. vivax</i> exhibit about 10-fold less diversity and have a relative excess of nonsynonymous nucleotide polymorphisms, with site-frequency spectra suggesting they are subject to greatly relaxed purifying selection. These data suggest that human <i>P. vivax</i> has undergone an extreme bottleneck, followed by rapid population expansion. Investigating potential host-specificity determinants, we found that ape <i>P. vivax</i> parasites encode intact orthologs of three reticulocyte-binding protein genes (<i>rbp2d</i>, <i>rbp2e</i>, and <i>rbp3</i>), which are pseudogenes in all human <i>P. vivax</i> strains. However, binding studies of recombinant RBP2e and RBP3 proteins to human, chimpanzee, and gorilla erythrocytes revealed no evidence of host-specific barriers to red blood cell invasion. These data suggest that, from an ancient stock of <i>P. vivax</i> parasites capable of infecting both humans and apes, a severely bottlenecked lineage emerged out of Africa and underwent rapid population growth as it spread globally.