DNA secondary structures are associated with recombination in major Plasmodium falciparum variable surface antigen gene families

Adam F. Sander, Thomas Lavstsen, Thomas Salhøj Rask, Michael Lisby, Ali Salanti, Sarah L. Fordyce, Jakob S. Jespersen, Richard Carter, Kirk W. Deitsch, Thor G. Theander, Anders Gorm Pedersen, David E. Arnot

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    Abstract

    Many bacterial, viral and parasitic pathogens undergo antigenic variation to counter host immune defense mechanisms. In Plasmodium falciparum, the most lethal of human malaria parasites, switching of var gene expression results in alternating expression of the adhesion proteins of the Plasmodium falciparum-erythrocyte membrane protein 1 class on the infected erythrocyte surface. Recombination clearly generates var diversity, but the nature and control of the genetic exchanges involved remain unclear. By experimental and bioinformatic identification of recombination events and genome-wide recombination hotspots in var genes, we show that during the parasite’s sexual stages, ectopic recombination between isogenous var paralogs occurs near low folding free energy DNA 50-mers and that these sequences are heavily concentrated at the boundaries of regions encoding individual Plasmodium falciparum-erythrocyte membrane protein 1 structural domains. The recombinogenic potential of these 50-mers is not parasite-specific because these sequences also induce recombination when transferred to the yeast Saccharomyces cerevisiae. Genetic cross data suggest that DNA secondary structures (DSS) act as inducers of recombination during DNA replication in P. falciparum sexual stages, and that these DSS-regulated genetic exchanges generate functional and diverse P. falciparum adhesion antigens. DSS-induced recombination may represent a common mechanism for optimizing the evolvability of virulence gene families in pathogens.
    Original languageEnglish
    JournalNucleic acids research
    Volume42
    Issue number4
    Pages (from-to)2270-2281
    ISSN0305-1048
    DOIs
    Publication statusPublished - 2014

    Keywords

    • Antigenic variation
    • Antigens
    • Protozoan
    • DNA
    • Genes
    • Multigene family
    • Nucleic acid conformation
    • Plasmodium falciparum
    • Protein structure
    • Tertiary
    • Protozoan Proteins
    • Recombination
    • Genetic
    • Saccharomyces cerevisiae

    Cite this

    Sander, A. F., Lavstsen, T., Rask, T. S., Lisby, M., Salanti, A., Fordyce, S. L., Jespersen, J. S., Carter, R., Deitsch, K. W., Theander, T. G., Pedersen, A. G., & Arnot, D. E. (2014). DNA secondary structures are associated with recombination in major Plasmodium falciparum variable surface antigen gene families. Nucleic acids research, 42(4), 2270-2281. https://doi.org/10.1093/nar/gkt1174