GENETIC-POLYMORPHISM AND NATURAL-SELECTION IN THE MALARIA PARASITE PLASMODIUM-FALCIPARUM

We have studied the genetic polymorphism at 10 Plasmodium falciparum l oci that are considered potential targets for specific antimalarial va ccines. The polymorphism is unevenly distributed among the loci; loci encoding proteins expressed on the surface of the sporozoite or the me rozoite (AMA-1, CSP, LSA-I, MSP-1, MSP-2, and MSP-3) are more polymorp hic than those expressed during the sexual stages or inside the parasi te (EBA-175, Pfs25, PF48/45, and RAP-1). Comparison of synonymous and nonsynonymous substitutions indicates that natural selection may accou nt for the polymorphism observed at seven of the 10 loci studied. This inference depends on the assumption that synonymous substitutions are neutral,. which we test by analyzing codon bias and G+C content in a set of 92 gene loci. We find evidence for an overall trend towards inc reasing A+T richness, but no evidence for mutation bias. Although the neutrality of synonymous substitutions is not definitely established, this trend towards an A+T rich genome cannot explain the accumulation of substitutions at least in the case of four genes (AMA-I, CSP, LSA-I , and PF48/45) because the G<->C transversions are more frequent than expected. Moreover, the Tajima test manifests positive natural selecti on for the MSP-1 and, less strongly, MSP-3 polymorphisms; the McDonald -Kreitman test manifests natural selection at LSA-1 and PF48/45. We co nclude that there is definite evidence for positive natural selection in the genes encoding AMA-1, CSP, LSA-1, MSP-1, and Pfs48/45. For four other loci, EBA-175, MSP-2, MSP-3, and RAP-1, the evidence is limited . No evidence for natural selection is found for Pfs25.