title: Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates.
abstract: BACKGROUND
  Var genes encode a family of virulence factors known as PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1) which are responsible for both antigenic variation and cytoadherence of infected erythrocytes. Although these molecules play a central role in malaria pathogenesis, the mechanisms generating variant antigen diversification are poorly understood. To investigate var gene evolution, we compared the variant antigen repertoires from three geographically diverse parasite isolates: the 3D7 genome reference isolate; the recently sequenced HB3 isolate; and the IT4/25/5 (IT4) parasite isolate which retains the capacity to cytoadhere in vitro and in vivo.
  
  
  RESULTS
  These comparisons revealed that only two var genes (var1csa and var2csa) are conserved in all three isolates and one var gene (Type 3 var) has homologs in IT4 and 3D7. While the remaining 50 plus genes in each isolate are highly divergent most can be classified into the three previously defined major groups (A, B, and C) on the basis of 5' flanking sequence and chromosome location. Repertoire-wide sequence comparisons suggest that the conserved homologs are evolving separately from other var genes and that genes in group A have diverged from other groups.
  
  
  CONCLUSIONS
  These findings support the existence of a var gene recombination hierarchy that restricts recombination possibilities and has a central role in the functional and immunological adaptation of var genes.
authors.affiliation: Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109-5219, USA. sue.kraemer@sbri.org
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kraemer
authors.forename: Sue A
authors.initials: SA
authors.lastname: Kyes
authors.forename: Gautam
authors.initials: G
authors.lastname: Aggarwal
authors.forename: Amy L
authors.initials: AL
authors.lastname: Springer
authors.forename: Siri O
authors.initials: SO
authors.lastname: Nelson
authors.forename: Zoe
authors.initials: Z
authors.lastname: Christodoulou
authors.forename: Leia M
authors.initials: LM
authors.lastname: Smith
authors.forename: Wendy
authors.initials: W
authors.lastname: Wang
authors.forename: Emily
authors.initials: E
authors.lastname: Levin
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Newbold
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Myler
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smith
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics*; D002874:Chromosome Mapping; D019143:Evolution, Molecular; D017125:Genes, Protozoan; D014644:Genetic Variation; D018503:Genome, Protozoan; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000145:classification / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum