Natural selection maintains a stable polymorphism at the circumsporozoite protein locus of Plasmodium falciparum in a low endemic area

Circumsporozoite protein gene sequences of Plasmodium falciparum were collected in 1996–1997 and in 2006–2007 from a single endemic area in Thailand. Repeat units were more similar within the same haplotype than between haplotypes, supporting the hypothesis that repeat arrays evolve by a process of concerted evolution. There was evidence that natural selection has favored amino acid changes in the Th2R and Th3R T-cell epitope regions. One haplotype in these epitopes, designated *5/*1, occurred in approximately 70% of sequences in both collection periods. The most common other haplotypes differed from *5/*1 by at least two amino acid replacements; and divergence in the epitopes was correlated with divergence in the repeats. These patterns are most consistent with balancing selection driven by interactions with the immune system of the vertebrate host, probably involving both T-cell recognition of the Th2R and Th3R epitopes and antibody responses to the repeats.