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nants, where amino acid polymorphisms (nonsynonymous nucleotide polymorphisms) are common and likely to be affected by natural selection. Numerous studies have indicated that Csp, Msp-1, Msp-2, and other antigenic genes are polymorphic and that their multiple allelic forms differ in their ability to abrogate recognition by the host's immune response (Tanabe et al., 1987; Smythe et al., 1991; Ukhayakumar et al., 1994; Zevering et al., 1994; Babiker and Walliker, 1997). These observations have been interpreted as instantiation of widespread polymorphism throughout the genome. Yet, we have investigated allelic variation in a diverse set of gene loci and found a complete absence of silent site polymorphism (Rich et al., 1998) and have proposed a recent derivation (within thousands of years) of the extant P. falciparum world populations from a single propagule.

It seems paradoxical that P. falciparum antigenic genes would be so highly polymorphic, because these genes must have shared the recent allelic homogenization caused by the population bottleneck we have inferred. Indeed, some authors have hypothesized that the polymorphisms of genes encoding P. falciparum surface proteins are very old, even older than the species itself.

We shall argue herein that the antigenic gene polymorphisms of P. falciparum are consistent with the conclusion drawn from the analysis of synonymous DNA sites, that the current world populations of the parasite are of recent origin, derived from a single strain within the last several thousand years. We will review our previous analysis of Csp (Rich et al., 1998) and then we will examine the Msp-1 and Msp-2 polymorphisms.

EVOLUTIONARY ASSOCIATION OF P. FALCIPARUM WITH THE HOMINID LINEAGE

Fig. 1 is a phylogenetic tree of Plasmodium species derived from Csp gene sequences (Escalante et al., 1995; for very similar trees based on other genes see Escalante and Ayala, 1994; Ayala et al., 1998, 1999). Estimates of divergence times are shown in Table 1.

It is apparent that the three human parasites, P. falciparum, Plasmodium malariae, and Plasmodium vivax are very remotely related to each other, so that the evolutionary divergence of these three human parasites greatly predates the origin of the hominids. Plasmodium ovale, a fourth human parasite, is also remotely related to the other three (Qari et al., 1996). These results are consistent with the diversity of physiological and epidemiological characteristics of these four Plasmodium species (Coatney et al., 1971; López-Antuñano and Schumunis, 1993).

P. falciparum is more closely related to Plasmodium reichenowi, the chimpanzee parasite, than to any other Plasmodium species. The time of divergence between these two Plasmodium species is estimated at 8–12 million



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