Erasing the Epigenetic Memory and Beginning to Switch—The Onset of Antigenic Switching of <em>var</em> Genes in <em>Plasmodium falciparum</em>

<div><p>Antigenic variation in <em>Plasmodium falciparum</em> is regulated by transcriptional switches among members of the <em>var</em> gene family, each expressed in a mutually exclusive manner and encoding a different variant of the surface antigens collectively named PfEMP1. Antigenic switching starts when the first merozoites egress from the liver and begin their asexual proliferation within red blood cells. By erasing the epigenetic memory we created parasites with no <em>var</em> background, similar to merozoites that egress from the liver where no <em>var</em> gene is expressed. Creating a null-<em>var</em> background enabled us to investigate the onset of antigenic switches at the early phase of infection. At the onset of switching, <em>var</em> transcription pattern is heterogeneous with numerous genes transcribed at low levels including upsA <em>vars</em>, a subtype that was implicated in severe malaria, which are rarely activated in growing cultures. Analysis of subsequent <em>in vitro</em> switches shows that the probability of a gene to turn on or off is not associated with its chromosomal position or promoter type <em>per se</em> but on intrinsic properties of each gene. We concluded that <em>var</em> switching is determined by gene specific associated switch rates rather than general promoter type or locus associated switch rates. In addition, we show that fine tuned reduction in <em>var</em> transcription increases their switch rate, indicating that transcriptional perturbation can alter antigenic switching.</p>