Activation, silencing and mutually exclusive expression within the var gene family of Plasmodium falciparum

The var gene family of the human malaria parasite Plasmodium falciparum remains a topic of intense research focus due to the key role these antigen-encoding genes play in the ability of parasites to cause disease and avoid the human immune response. In recent years, as molecular tools for investigating the mechanisms that coordinate var gene expression have become more sophisticated, numerous insights have been acquired into how parasites manage to regulate transcription of this large gene family such that only a single gene is expressed at a time. The results of different experimental approaches have implicated mechanisms of chromatin modification, subnuclear localisation, promoter/promoter interactions and sterile RNAs in the silencing and activation of individual var genes, however, the roles that each of these different aspects play remain ill defined. In addition, some conflicting data regarding silencing and monoallelic expression of recombinant var promoters have recently been published, thus adding to the difficulty of understanding this complex phenomenon. In this review, we hope to present some of the existing data regarding this controversial topic in a way that will be both informative and constructive in our efforts to understand the molecular aspects of antigenic variation by malaria parasites.