The genome of the zoonotic malaria parasite Plasmodium simium reveals adaptions to host-switching

, a malaria parasite of non-human primates in the Atlantic forest region of Brazil was recently shown to cause zoonotic infection in humans in the region. Phylogenetic analyses based on the whole genome sequences of six isolates infecting humans and two isolates from brown howler monkeys revealed that is monophyletic within the broader diversity of South American , consistent with the hypothesis that first infected non-human primates as a result of a host-switch from humans carrying . We provide molecular evidence that the current zoonotic infections of people have likely resulted from multiple independent host switches, each seeded from a different monkey infection. Very low levels of genetic diversity within genomes and the absence of hybrids suggest that the population emerged recently and has subsequently experienced a period of independent evolution in Platyrrhini monkeys. We further find that Plasmodium Interspersed Repeat (PIR) genes, Plasmodium Helical Interspersed Subtelomeric (PHIST) genes and Tryptophan-Rich Antigens (TRAg) genes in are genetically divergent from and are enriched for non-synonymous single nucleotide polymorphisms, consistent with the rapid evolution of these genes. Analysis of genes involved in erythrocyte invasion revealed several notable differences between and , including large deletions within the coding region of the Duffy Binding Protein 1 (DBP1) and Reticulocyte Binding Protein 2a (RBP2a) genes in . Genotyping of isolates from non-human primates (NHPs) and zoonotic human infections showed that a precise deletion of 38 amino acids in DBP1 is exclusively present in all human infecting isolates, whereas non-human primate infecting isolates were polymorphic for the deletion. We speculate that these deletions in the parasite-encoded key erythrocyte invasion ligands and the additional rapid genetic changes have facilitated zoonotic transfer to humans. Non-human primate malaria parasites can be considered a reservoir of potential infectious human parasites that must be considered in any attempt of malaria elimination. The genome of will thus form an important basis for future functional characterizations on the mechanisms underlying malaria zoonosis.