<i>Plasmodium vivax-like</i> genome sequences shed new insights into <i>Plasmodium vivax</i> biology and evolution

Abstract Although Plasmodium vivax is responsible for the majority of malaria infections outside Africa, little is known about its evolution and pathway to humans. Its closest genetic relative, Plasmodium vivax-like , was discovered in African great apes and is hypothesized to have given rise to P. vivax in humans. To unravel the evolutionary history and adaptation of P. vivax , we generated using long and short read sequence technologies the two first P. vivax-like reference genomes and 9 additional P. vivax-like genotypes. Analyses show that the genomes of P. vivax and P. vivax-like are highly similar and co-linear within the core regions. Phylogenetic analyses clearly show that P. vivax-like parasites form a genetically distinct clade from P. vivax . Concerning the relative divergence dating, we show that the evolution of P. vivax in humans did not occur at the same time as the other human malaria agents, thus suggesting that the transfer of Plasmodium parasites to humans happened several times independently over the history of the Homo genus. We further identify several key genes that exhibit signatures of positive selection exclusively in the human P. vivax parasites. Interestingly, two of these genes have been identified to also be under positive selection in the other main human malaria agent, P. falciparum , thus suggesting their key role in the evolution of the ability of these parasites to infect humans or their anthropophilic vectors. We finally demonstrate that some gene families important for red blood cell (RBC) invasion (a key step of the life cycle of these parasites) have undergone lineage-specific evolution in the human parasite (e.g. Reticulocyte Binding Proteins). Significance statements Among the five species responsible for this malaria in humans, Plasmodium vivax is the most prevalent outside Africa and causes severe and incapacitating clinical symptoms with significant effects on human health. Its closest known relative was recently discovered in African great apes, Plasmodium vivax-like. This study aims to characterize the genome of the closest ape-relative to the human P. vivax parasite in order to get a better understanding of the evolution of this parasite. A total of eleven P. vivax-like samples were obtained from infected chimpanzee blood samples and an infected Anopheles mosquito collected in Gabon. Through technical accomplishment and using short and long read sequence technologies, two newly genomes of P. vivax-like and further nine additional draft sequences were obtained. The genome-wide analyses performed provided new insights into the biology and adaptive evolution of P. vivax to different host species.