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Msp-2 (and Msp-1) genes, as well as those in other P. falciparum antigenic determinants, are subject to much higher rates of mutation than NR sequences found within the same locus. Indeed, the paucity of silent substitutions within the NR regions indicates that intragenic recombination has generated repeat diversity in relatively short periods of time. Empirical estimates of mutation rates among repetitive DNA sequences, such as satellite DNA, are as high as 10-2 mutations/per generation and therefore several orders of magnitude greater than rates for point mutations (Schug et al., 1998). The high mutation rates, coupled with strong selection for immune evasion, yield an extremely accelerated evolutionary rate for P. falciparum antigens.


Homologous comparisons among allelic variants of antigenic genes manifest that most of the variation is attributable to the rapid mutational processes associated with intragenic recombination. The increased rate of evolution among these genes reconciles the recent origin of extant P. falciparum populations with the abundance of antigenic diversity observed globally and locally. We have noted that nucleotide diversification can result from either intrahelical or interhelical events. An example of intrahelical recombination is that of mitotic, slipped-strand mismatch repair, which is considered to be the principal source of variation in repetitive units such as satellite DNA (Fig. 5). Interhelical recombination derives from the classical process of meiotic crossing over and recombination within or between loci on homologous chromosomes.

Both of these processes occur in P. falciparum. Kerr et al. (1994) have shown that meiotic, interhelical recombination occurs between mixed Msp-2 genotype parasites passaged in laboratory animals. This process constitutes the basis for generating linkage maps of P. falciparum chromosomes (Su and Wellems, 1996). But we have shown that, despite the abundant intragenic recombination within Csp CR, there is an apparent absence of recombination between the 5′ and 3′ NR regions, suggesting that the duplication and deletion of RATs occur by mitotic processes such as the slipped-strand process modeled in Fig. 5 (Rich et al., 1997). This process also has been implicated as the cause of repeat variation in Msp-2 (Fenton et al., 1991).

The debate over the relevance of sexual recombination between P. falciparum types may remain unsettled for some time. It is becoming increasingly clear that the population structure of P. falciparum may not be uniform throughout the species, but depends on local factors related to parasite, vector, and host biology (Paul et al., 1995; Babiker and Walliker,

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