Loy, Dorothy E.Plenderleith, Lindsey J.Sundararaman, Sesh A.Liu, WeiminGruszczyk, JakubChen, Yi JunTrimboli, StephanieLearn, Gerald H.MacLean, Oscar A.Morgan, Alex L.K.Li, YingyingAvitto, Alexa N.Giles, JasminCalvignac-Spencer, SébastienSachse, AndreasLeendertz, Fabian H.Speede, SheriAyouba, AhidjoPeeters, MartineRayner, Julian C.Tham, Wai HongSharp, Paul M.Hahn, Beatrice H.2025-06-302025-06-300027-8424PubMed:30127015ORCID:/0000-0001-7950-8699/work/218987910http://www.scopus.com/inward/record.url?scp=85052746591&partnerID=8YFLogxKhttps://hdl.handle.net/1885/733765976Wild-living African apes are endemically infected with parasites that are closely related to human Plasmodium vivax, a leading cause of malaria outside Africa. This finding suggests that the origin of P. vivax was in Africa, even though the parasite is now rare in humans there. To elucidate the emergence of human P. vivax and its relationship to the ape parasites, we analyzed genome sequence data of P. vivax 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 P. vivax 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 P. vivax has undergone an extreme bottleneck, followed by rapid population expansion. Investigating potential host-specificity determinants, we found that ape P. vivax parasites encode intact orthologs of three reticulocyte-binding protein genes (rbp2d, rbp2e, and rbp3), which are pseudogenes in all human P. vivax 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 P. vivax 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.permission to perform studies in C\u00F4te d\u2019Ivoire. This work was supported in part by NIH Grants R01 AI097137, R01 AI091595, R37 AI050529, and P30 AI045008 (to B.H.H.); a grant from the Agence Nationale de Recherche (Programme Blanc, Sciences de la Vie, de la Sant\u00E9 et des Ecosyst\u00E9mes, ANR 11 BSV3 021 01, Projet PRIMAL) (to M.P.); and an Australian Research Council Future Fellowship and Howard Hughes Medical Institute\u2013Wellcome Trust International Research Scholar Award 208693/Z/17/Z (to W.-H.T.). D.E.L. was supported by an NIH Training Grant T32 AI 007532; O.A.M. was supported by Biotechnology and Biological Sciences Research Council Grant BB/ M010996/1 (EASTBIO); and A.L.K.M. was supported by Wellcome Trust PhD Programme Grant 108905/Z/15/Z.enPublisher Copyright: © 2018 National Academy of Sciences. All Rights Reserved.GenomicsGreat apesMalariaPlasmodium vivaxZoonotic transmission2018-09-0410.1073/pnas.181005311585052746591