Plasmodium falciparum, the most important causative agent of human malaria, 
undergoes antigenic variation as a means of prolonging infection and ensuring 
transmission between hosts. Clonal variation is observed in the surface adhesins 
expressed on infected erythrocytes: primarily in the PfEMP1 adhesin encoded by 
the large var gene family. The sirtuin PfSIR2A was the first protein discovered 
to have a major influence on antigenic variation in P. falciparum. In the 
absence of PfSIR2A, normal silencing of the variantly-expressed var gene family 
is partially deregulated. To thoroughly investigate the role of PfSIR2A in 
controlling antigenic variation, multiple independent clones of wildtype and 
PfSIR2A-knockout (DeltaSir2a) parasites were generated. var gene expression was 
then measured qualitatively, quantitatively and longitudinally over extended 
periods in culture. DeltaSir2a parasites were found to activate about 10 
specific var genes in every independent clone analyzed. The activated genes were 
biased towards the upsA, upsBA and upsEvar gene subclasses. The total var 
transcript level was two to three-fold higher in DeltaSir2a parasites than in 
wildtype parasites and at least one transcript - encoding the pregnancy malaria 
adhesin VAR2CSA - was successfully translated and expressed on the infected cell 
surface. In the absence of PfSIR2A, antigenic switching over time was also 
diminished, although not abolished. This work expands our understanding of 
clonal antigenic variation in this important human pathogen and demonstrates a 
central role for PfSIR2A in regulating both the variant expression of specific 
var gene subsets and the overall quantity of var gene expression.