Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P-falciparum

Persistent and recurrent infections by Plasmodium falciparum malaria parasi tes result from the ability of the parasite to undergo antigenic variation and evade host immune attack(1,2). P. falciparum parasites generate high le vels of variability in gene families that comprise virulence determinants o f cytoadherence and antigenic variation(3-7), such as the var genes. These genes encode the major variable parasite protein (PfEMP-1), and are express ed in a mutually exclusive manner at the surface of the erythrocyte infecte d by P. falciparum(8-12). Here we identify a mechanism by which var gene se quences undergo recombination at frequencies much higher than those expecte d from homologous crossover events alone(13). These recombination events oc cur between sub-telomeric regions of heterologous chromosomes, which associ ate in clusters near the nuclear periphery in asexual blood-stage parasites or in bouquet-like configurations near one pole of the elongated nuclei in sexual parasite forms. We propose that the alignment of var genes in heter ologous chromosomes facilitates gene conversion and promotes the diversity of antigenic and adhesive phenotypes. The association of virulence factors with a specific nuclear subcompartment may also have implications for varia tion during mitotic recombination in asexual blood stages.