title: DNA secondary structures are associated with recombination in major Plasmodium falciparum variable surface antigen gene families.
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.
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Øster Farimagsgade 5, Building 22 & 23, PO Box 2099, 1014 Copenhagen K, Denmark, Centre for Medical Parasitology, Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen K, Denmark, Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark, Department of Biology, University of Copenhagen, Ole Maaloees Vej 5, DK-2200 Copenhagen N, Denmark, Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, 1350 Copenhagen, Denmark, Institute of Infection and Immunology Research, School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, Scotland, UK and Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Sander
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rask
authors.forename: Michael
authors.initials: M
authors.lastname: Lisby
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Fordyce
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Jespersen
authors.forename: Richard
authors.initials: R
authors.lastname: Carter
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Deitsch
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.forename: Anders Gorm
authors.initials: AG
authors.lastname: Pedersen
authors.forename: David E
authors.initials: DE
authors.lastname: Arnot
mesh_terms: D000940:Antigenic Variation / Q000235:genetics*; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics*; D016054:DNA, Protozoan / Q000737:chemistry*; D017125:Genes, Protozoan; D005810:Multigene Family; D009690:Nucleic Acid Conformation; D010963:Plasmodium falciparum / Q000235:genetics*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics*; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; D016054:DNA, Protozoan; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum