Open Access Highly Accessed Research article

Hypervariable antigen genes in malaria have ancient roots

Martine M Zilversmit1234*, Ella K Chase3, Donald S Chen2, Philip Awadalla4, Karen P Day2 and Gil McVean35

Author Affiliations

1 National Institute of Allergy of Infectious Disease, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA

2 Department of Microbiology, NYU Langone Medical Center, 341 East 25th Street, New York, NY 10010, USA

3 Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK

4 CHU Sainte-Justine Centre de Recherche, Universit de Montral, 3175 Cote-Ste-Catherine, Montreal, QC, H3T 1C5, Canada

5 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK

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BMC Evolutionary Biology 2013, 13:110  doi:10.1186/1471-2148-13-110

Published: 31 May 2013



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.


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.


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.

Non-allelic homologous recombination; Hidden Markov-model; var genes; Malaria; PfEMP1; Gene family evolution; Balancing selection