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interhelical exchange of DNA (Levinson and Gutman, 1987). Intragenic recombination often is associated with the evolution of minisatellite or microsatellite DNA loci, such as those recently described in P. falciparum (Su and Wellems, 1996; Anderson et al., 1999). However, intragenic recombination also has been implicated in generating variability within coding regions in a variety of eukaryotes; including the Drosophila yolk protein gene and the human α2-globin gene, to cite just two examples (Ho et al., 1996; Oron-Karni et al., 1997).

New RATs can arise by one of two processes: (i) replacement or silent substitutions in a codon, and (ii) the slippage mechanism that leads to RAT proliferation. The two amino acid motifs and the different RAT types have arisen by the first process. The variation in the number of RATs arises by the second process. The second process occurs with a frequency several orders of magnitude greater than the first process (Schug et al., 1998).

How much of the variation now present in the Csp CR region of falciparum may have arisen by the second process? Notice that only two amino acid motifs are present in the whole set of 25 Csp sequences and that both motifs are present in every one of the sequences (Table 4 and Table 5). Thus, there is no evidence that any replacement substitution has occurred in the recent evolution of P. falciparum.

CRYPTIC REPEATS IN THE MSP-1 POLYMORPHISM

The Msp-1 gene codes for MSP-1 (also referred to as MSA-1, P195, and otherwise), which is a large 185- to 215-kDa protein precursor that is proteolytically cleaved into several membrane protein constituents. The known alleles of Msp-1 belong to one or the other of two allelic classes (group I and group II). There is considerable nucleotide substitution and length variation between the two classes but much less variation within each class (Tanabe et al., 1987; Hughes, 1992). The two classes are commonly designated by the strains in which they were originally identified: K1 (group I) and MAD20 (group II).

Tanabe et al. (1987) partitioned MSP-1 into 17 blocks, based on the degree of amino acid polymorphism (Table 7). They classified seven blocks (blocks 2, 4, 6, 8, 10, 14, and 16) as highly variable; five blocks (blocks 7, 9, 11, 13, and 15) as semiconserved, and five blocks (blocks 1, 3, 5, 12, and 17, which include the two terminal segments) as conserved. The “highly variable ” (as well as the “semiconserved”) amino acid polymorphisms occur only when comparisons are made between the two allele groups, whereas amino acid, as well as synonymous, nucleotide polymorphisms are very low within each allele group. An exception is block 2, which encodes a set of repetitive tripeptides and thus is subject to the same intragenic recombination described above for Csp, as a mechanism



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