<p>Box 2: Hypotheses to explain the occurrence of dimorphic allele lineages in Plasmodium falciparum (in chronological order)</p><p>Local adaptation (Tanabe et al., 1987): “Suppose the two alleles produce proteins with equivalent function in the parasite but different mechanisms of action. For example, both could participate in red cell recognition or invasion but bind different groups on the red cell surface. This would account for localized diversity in their structure (the recognition domains) and allow for constant regions (the structural domains controlling processing and membrane association). Such proteins could have evolved separately in biologically isolated populations of the parasite, perhaps when P. falciparum was becoming infectious to man. During subsequent evolution, when the populations fused and interbred, functional constraints would perpetuate the dimorphism of the two alleles, but allow some intragenic recombination.”</p><p>Gene duplication and recent population admixture (Miller et al, 1993): “One might imagine a gene duplication event that allowed one gene to drift in the absence of selective pressure and then the loss of one or the other gene in each of the dominant ancestral lines. We find it simpler to think that the dimorphism itself arose from two geographically isolated sources of P. falciparum and that as man became peripatetic and malaria spread, the geographic barriers that allowed dimorphic forms to evolve dissolved.” </p><p>Proliferation and deletion of repeat motifs (Rich and Ayala, 2000): “The distinctive dimorphism of the two P. falciparum alleles results from proliferation of repeats in two different regions of the molecule [MSP-2]. Presumably because the overall MSP-2 molecule is constrained in size, the proliferation of repeats leads consequently to loss of nucleotides along the gene regions; i.e., the 3D7 repeat precursors were lost in FC27 alleles, and the FC27 repeat precursors were lost in 3D7 alleles.”</p><p>Gene duplication (Hartl et al., 2002): “Variation as extreme, and apparently as ancient, as found in the Msp-1 alleles could arise by gene duplication and divergence. Especially if the MAD20-like and K1-like antigens are mutually antagonistic, chromosomes with paralogous copies of MAD20-like and K1-type alleles would be strongly favoured under conditions of low transmission. Under conditions of high transmission with many multiple infections, the selection would be less intense and, through either deletion or unequal crossing-over, the different lineages could lose one or the other paralog. This would create a situation in which the Msp-1 alleles in the contemporary population are highly divergent and extremely ancient, even though they derived from a single haploid genome when they were still paralogs.” </p><p>Introgression (Polley et al., 2005): “An introgression event could reconcile conflicting evidence from the genome for the age of P. falciparum alleles (...). Fertilisation between two different species of malaria parasite during the sexual stage of the malaria life cycle could rapidly introduce novel polymorphisms into many loci. Although many of these would subsequently be lost due to the effects of purifying selection and random genetic drift, a recent introgression event might still leave some polymorphisms intact through purely neutral processes.”</p>