African origin of the malaria parasite Plasmodium vivax

Abstract

Plasmodium vivax is the leading cause of human malaria in Asia and Latin America but is absent from most of central Africa due to the near fixation of a mutation that inhibits the expression of its receptor, the Duffy antigen, on human erythrocytes. The emergence of this protective allele is not understood because P. vivax is believed to have originated in Asia. Here we show, using a non-invasive approach, that wild chimpanzees and gorillas throughout central Africa are endemically infected with parasites that are closely related to human P. vivax. Sequence analyses reveal that ape parasites lack host specificity and are much more diverse than human parasites, which form a monophyletic lineage within the ape parasite radiation. These findings indicate that human P. vivax is of African origin and likely selected for the Duffy-negative mutation. All extant human P. vivax parasites are derived from a single ancestor that escaped out of Africa.

Figure 1. Geographic distribution of P. vivax in wild-living apes

Field sites are shown in relation to the ranges of three subspecies of the common chimpanzee (P. t. ellioti, magenta; P. t. troglodytes, red; and P. t. schweinfurthii, blue), western (Gorilla gorilla, yellow) and eastern (Gorilla beringei, light green) gorillas, as well as bonobos (Pan paniscus, green). Circles, squares and hexagons identify field sites where wild-living chimpanzees, gorillas, or both species were sampled, respectively. Ovals indicate bonobo sampling sites. Triangles denote the location of wildlife rescue centres (see Supplementary Table 1 for a list of all field sites and their two-letter codes). Forested areas are shown in dark green, while arid and semiarid areas are depicted in yellow and brown, respectively. Major lakes and major rivers are shown in blue. Dashed white lines indicate national boundaries. Sites where ape P. vivax was detected are highlighted in yellow, with red lettering indicating that both chimpanzees and gorillas were infected.

Figure 2. Evolutionary relationships of ape and human P. vivax parasites in mitochondrial gene regions

The phylogenetic positions of mitochondrial fragment D (2,524 bp; Supplementary Fig. 1a) sequences from ape and human P. vivax strains are shown in relation to human and macaque parasite reference sequences. All sequences were generated by SGA, except for human (Salvador I, India VII, Mauritania I, North Korean, Brazil I) and simian reference strains from the database (see Supplementary Tables 6-8 for GenBank accession numbers). Ape sequences are color-coded, with capital letters indicating the field site (Fig. 1) and lower case letters denoting species and subspecies origin (ptt: P. t. troglodytes, red; pte: P. t. ellioti, orange; pts: P. t. schweinfurthii, blue; ggg: G. g. gorilla, green). Human sequences are depicted by haplotype (rectangles) and labeled according to their geographic origin in Oceania (light grey), Africa (white), South and Central America (black), South and South East Asia (striped) and the Middle East (dark grey). Haplotypes that include more than one sequence are indicated, with the numbers of sequences listed to the right. A second lineage of related parasite sequences from chimpanzee samples DGptt540 and BQptt392 likely represents a new Plasmodium species. The tree was inferred using maximum likelihood methods. Numbers above and below nodes indicate bootstrap values (≥ 70%) and Bayesian posterior probabilities (≥ 0.95), respectively (the scale bar represents 5 nucleotide substitutions).

Figure 3. Evolutionary relationships of ape and human P. vivax parasites in nuclear and apicoplast gene regions

a,b, The phylogenetic positions of (a) lactate dehydrogenase (ldh) gene (711 bp) and (b) caseinolytic protease C (clpC) gene (574 bp) sequences from ape and human P. vivax strains are shown in relation to human and macaque parasite reference sequences. All sequences were generated by SGA, except for human (Salvador I, India VII, Mauritania I, North Korean, Brazil I) and simian reference strains from the database (asterisks indicate SGA-derived ldh sequences for P. simiovale, P. cynomolgi, and P. fragile; see Supplementary Tables 6-8 for GenBank accession numbers). Newly derived ape P. vivax sequences are labeled and color-coded as in Fig. 2. Human and simian reference sequences are shown in black. Human ldh haplotypes are depicted as described in Fig. 2. Related parasite sequences from chimpanzee samples DGptt540 (ldh) and BQptt392 (clpC) likely represents a new Plasmodium species. Trees were inferred using maximum likelihood methods. Numbers above and below nodes indicate bootstrap values (≥ 70%) and Bayesian posterior probabilities (≥ 0.95), respectively (the scale bars represents 5 and 1 nucleotide (nt) substitutions, respectively).