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MSP-2 POLYMORPHISM

The Msp-2 gene codes for MSP-2 (or MSA-2), a glycoprotein anchored, like MSP-1, in the merozoite membrane, but 45 kDa in size, and thus much smaller than MSP-1. The Msp-2 of P. falciparum shows much greater variability in length, amino acid content, and number of repeats than Csp, but the pattern of allele polymorphism in Msp-2 is consistent with the hypothesis that it has rapidly arisen by intragenic recombination.

Similar to CSP, MSP-2 is characterized by conserved N and C termini, with 43 and 74 residues, respectively (Smythe et al., 1991). Bracketed within these segments, is the highly variable repeat region. Two allelic families have been identified and named after the isolates in which they were first identified. The FC27 family is characterized by at least one copy of a 32-aa sequence and a variable number of repeats, 12 aa in length. The 3D7/Camp family contains tandem amino acid repeats measuring 4–10 aa in length (Felger et al., 1994).

The 3D7/Camp alleles are more variable in length and sequence of repeat types than those of the FC27 family (Felger et al., 1997). Fenton et al. (1991) have proposed a model to explain the origin of repeat diversity within the 3D7/Camp family of alleles. They divided the 3D7/Camp family into distinct allelic subclasses, which included types A1 and A3, distinguished by amino acid repeats of different length. For example, A1 alleles possess 4-aa motifs, whereas a repeating 8-aa motif occurs in A3. Fenton et al. (1991) have shown that the allelic subclasses within the 3D7/ Camp family are derived from a common ancestral nucleotide sequence and that the diversity arises from duplication and deletion of repeat subunits.

Recently, Dubbeld et al. (1998) have cloned and sequenced the Msp-2 gene of P. reichenowi, which is a “unique mosaic of P. falciparum allelic forms and species-specific elements.” We have used the methods described by Fenton et al. (1991) to determine whether the Msp-2 of P. reichenowi provides insight into the ancestry of the FC27 and 3D7/Camp families. Fig. 5 shows the amino acid sequence alignment of two P. falciparum MSP-2s with the P. reichenowi MSP-2. The P. falciparum alleles from the 3D7 and OKS isolates are representative of the 3D7/Camp and FC27 families, respectively. The two P. falciparum alleles are identical at nucleotide sites encoding the N and C termini, but exhibit little similarity, even at the amino acid level, in the intervening repeat region.

A closer look at the nucleotides within the central portion of the gene manifests the homology of three distinct regions, which we define as repeat homology regions (RHRs). RHR1 shows common ancestry between the P. reichenowi Msp-2 and the 3D7 Msp-2 alleles (Fig. 6, black shading). Diversity within this region results from proliferation of a ggtgct hexamer (Fenton et al., 1991). This hexamer is ancestral to both the 3D7/Camp and



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