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Background  The  var  genes of the human malaria parasite  Plasmodium falciparum  are highly polymorphic loci coding for the erythrocyte membrane proteins 1 (PfEMP1), which are responsible for the cytoaherence of  P. falciparum  infected red blood cells to the human vasculature. Cytoadhesion, coupled with differential expression of  var  genes, contributes to virulence and allows the parasite to establish chronic infections by evading detection from the host’s immune system. Although studying genetic diversity is a major focus of recent work on the  var  genes, little is known about the gene family's origin and evolutionary history.    Results  Using a novel hidden Markov model-based approach and  var  sequences assembled from additional isolates and species, we are able to reveal elements of both the early evolution of the  var  genes as well as recent diversifying events. We compare sequences of the  var  gene DBLα domains from divergent isolates of  P. falciparum  (3D7 and HB3), and a closely-related species,  Plasmodium reichenowi . We find that the gene family is equally large in  P. reichenowi  and  P. falciparum  -- with a minimum of 51  var  genes in the  P. reichenowi  genome (compared to 61 in 3D7 and a minimum of 48 in HB3). In addition, we are able to define large, continuous blocks of homologous sequence among  P. falciparum  and  P. reichenowi var  gene DBLα domains. These results reveal that the contemporary structure of the  var  gene family was present before the divergence of  P. falciparum  and  P. reichenowi , estimated to be between 2.5 to 6 million years ago. We also reveal that recombination has played an important and traceable role in both the establishment, and the maintenance, of diversity in the sequences.    Conclusions  Despite the remarkable diversity and rapid evolution found in these loci within and among  P. falciparum  populations, the basic structure of these domains and the gene family is surprisingly old and stable. Revealing a common structure as well as conserved sequence among two species also has implications for developing new primate-parasite models for studying the pathology and immunology of falciparum malaria, and for studying the population genetics of  var  genes and associated virulence phenotypes.

Hypervariable antigen genes in malaria have ancient roots