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Silent (i.e., synonymous) nucleotide polymorphisms are appropriate for estimating the age of genes, because silent nucleotide polymorphisms are often adaptively neutral (or very nearly so). Thus, silent nucleotide polymorphisms reflect the mutation rate and the time elapsed since their divergence from a common ancestor. Table 2 summarizes data for 10 genes (Rich et al., 1998). The gene sequences analyzed derive from isolates of P. falciparum geographically representative of the global malaria endemic regions (see table 1 in Rich et al., 1998; and, for the Csp gene, Rich et al., 1997). A scarcity of synonymous polymorphisms also has been observed in a separate study of 10 P. falciparum genes, most of them antigenic (Escalante et al., 1998).

As we have expounded elsewhere (Rich et al., 1998; Ayala et al., 1998, 1999), five possible hypotheses may account for the absence of silent polymorphisms in P. falciparum: (i) persistent low effective population size, (ii) low rates of spontaneous mutation, (iii) strong selective constraints on silent variation, (iv) one or more recent selective sweeps affecting the genome as a whole, and (v) a demographic sweep, i.e., a recent population bottleneck, so that extant world populations of P. falciparum would have recently derived from a single ancestral strain. We have concluded that only the fifth hypothesis is consistent with the observations and have used coalescent theory to estimate the age of the ancestral strain or “cenancestor” (Table 3).

The issue arises of how to account for a recent demographic sweep in P. falciparum. One possible hypothesis is that P. falciparum has become a human parasite in recent times, by lateral transfer from some other host species (Waters et al., 1991). This hypothesis is contrary to available evidence (Escalante and Ayala, 1994; Escalante et al., 1995). An alternative explanation is that human parasitism by P. falciparum has long been highly restricted geographically and has dispersed throughout the Old World continents only within the last several thousand years, perhaps within the last 10,000 years, after the Neolithic revolution (Coluzzi, 1994, 1997, 1999). Three possible scenarios may have led to this historically recent dispersion: (i) changes in human societies, (ii) genetic changes in the host-parasite-vector association that have altered their compatibility, and (iii) climatic changes that entailed demographic changes (migration, density, etc.) in the human host, the mosquito vectors, and/or the parasite.

One factor that may have impacted the widespread distribution of P. falciparum in human populations from a limited original focus, probably in tropical Africa, may have been changes in human living patterns, particularly the development of agricultural societies and urban centers that increased human population density (Livingstone, 1958; Wiesenfeld, 1967;

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