Silence, activate, poise and switch! Mechanisms of antigenic variation in Plasmodium falciparum

Phenotypic variation in genetically identical malaria parasites is an emerging topic. Although antigenic variation is only part of a more global parasite strategy to create adaptation through epigenetically controlled transcriptional variability, it is the central mechanism enabling immune evasion and promoting pathogenesis. The var gene family is the best-studied example in a wide range of clonally variant gene families in Plasmodium falciparum. It is unique in its strict selection of a single member for activation, a process termed monoallelic expression. The conceptual advances that have emerged from studying var genes show striking common epigenetic features with many other clonally variant gene families or even single-copy genes that show a variegated expression in parasite populations. However, major mechanistic questions, such as the existence of a potential expression site and the identity of transcription factors or genetic elements driving singular gene choice, are still unanswered. In this review we discuss the recent findings in the molecular processes essential for clonal variation, namely silencing, activation, poising and switching. Integrating findings about all clonally variant gene families and other mutually exclusive expression systems will hopefully drive mechanistic understanding of antigenic variation.