Abstract
We have studied the genetic polymorphism at 10 Plasmodium falciparum loci that are considered potential targets for specific antimalarial vaccines. The polymorphism is unevenly distributed among the loci; loci encoding proteins expressed on the surface of the sporozoite or the merozoite (AMA-1, CSP, LSA-1, MSP-1, MSP-2, and MSP-3) are more polymorphic than those expressed during the sexual stages or inside the parasite (EBA-175, Pfs25, PF48/45, and RAP-1). Comparison of synonymous and nonsynonymous substitutions indicates that natural selection may account 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 increasing 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-1, CSP, LSA-1, and PF48/45) because the Gleft and right arrow C transversions are more frequent than expected. Moreover, the Tajima test manifests positive natural selection for the MSP-1 and, less strongly, MSP-3 polymorphisms; the McDonald-Kreitman test manifests natural selection at LSA-1 and PF48/45. We conclude 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.
Highlights
Given that these genes encode antigenic proteins that are recognized by the host’s immune system, the observed high levels of heterozygosity and rates of evolution have been attributed to natural selection, an outcome of the accumulation and frequent switch of suitable mutations, by means of which the parasite escapes the host’s immune defenses (Hughes 1991, 1992; Anders and Saul 1994; Hughes and Hughes 1995)
Life cycle of P. falciparum: P. falciparum belongs to the phylum Apicomplexa, which consists of parasitic taxa characterized by the presence, in at least one stage of their life cycle, of a structure called the “apical complex” that is involved in the penetration of the host cell (Cheng 1986; Collins and Aikawa 1993)
Genetic diversity is greater in the five genes expressed on the surface of either the merozoite ( ϭ 0.016, 0.088, 0.044, and 0.097, respectively, for Apical membrane antigen-1 (AMA-1), Merozoite surface protein-1 (MSP-1), Merozoite surface protein-2 (MSP-2), and Merozoite surface protein-3 (MSP-3)) or the sporozoite ( ϭ 0.006 for circumsporozoite protein (CSP)) than in the four other genes ( ϭ 0.004, 0.004, 0.002, and 0.002, respectively, for Erythrocyte-binding antigen of 175 kD (EBA-175), Pfs25, Pfs48/45, and Rhoptry antigen protein-1 (RAP-1))
Summary
Given that these genes encode antigenic proteins that are recognized by the host’s immune system, the observed high levels of heterozygosity and rates of evolution have been attributed to natural selection, an outcome of the accumulation and frequent switch of suitable mutations, by means of which the parasite escapes the host’s immune defenses (Hughes 1991, 1992; Anders and Saul 1994; Hughes and Hughes 1995) This interpretation is buttressed by the widespread observation that nonsynonymous nucleotide substitutions are more common than synonymous substitutions (Lockyer et al 1989; Thomas et al 1990; Shi et al 1992a). To apply the MK test, we compare P. falciparum with P. reichenowi, its most closely related species (Coatney et al 1971; Collins and Aikawa 1993; Escalante and Ayala 1994; Escalante et al 1995), which is parasitic to chimpanzees
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