A re-assessment of gene-tag classification approaches for describing var gene expression patterns during human Plasmodium falciparum malaria parasite infections

<ns4:p>PfEMP1 are variant parasite antigens that are inserted on the surface of <ns4:italic>Plasmodium falciparum</ns4:italic> infected erythrocytes (IE). Through interactions with various host molecules, PfEMP1 mediate IE sequestration in tissues and play a key role in the pathology of severe malaria. PfEMP1 is encoded by a diverse multi-gene family called <ns4:italic>var</ns4:italic>. Previous studies have shown that that expression of specific subsets of <ns4:italic>var</ns4:italic> genes are associated with low levels of host immunity and severe malaria. However, in most clinical studies to date, full-length <ns4:italic>var</ns4:italic> gene sequences were unavailable and various approaches have been used to make comparisons between <ns4:italic>var</ns4:italic> gene expression profiles in different parasite isolates using limited information. Several studies have relied on the classification of a 300 – 500 base-pair “DBLα tag” region in the DBLα domain located at the 5’ end of most <ns4:italic>var</ns4:italic> genes.</ns4:p><ns4:p> We assessed the relationship between various DBLα tag classification methods, and sequence features that are only fully assessable through full-length <ns4:italic>var</ns4:italic> gene sequences. We compared these different sequence features in full-length <ns4:italic>var</ns4:italic> gene from six fully sequenced laboratory isolates.</ns4:p><ns4:p> These comparisons show that despite a long history of recombination,<ns4:bold> </ns4:bold>DBLα sequence tag classification can provide functional information on important features of full-length <ns4:italic>var</ns4:italic> genes. Notably, a specific subset of DBLα tags previously defined as “group A-like” is associated with CIDRα1 domains proposed to bind to endothelial protein C receptor.</ns4:p><ns4:p> This analysis helps to bring together different sources of data that have been used to assess var gene expression in clinical parasite isolates.</ns4:p>