title: Generation of antigenic diversity in Plasmodium falciparum by structured rearrangement of Var genes during mitosis.
abstract: The most polymorphic gene family in P. falciparum is the ∼60 var genes distributed across parasite chromosomes, both in the subtelomeres and in internal regions. They encode hypervariable surface proteins known as P. falciparum erythrocyte membrane protein 1 (PfEMP1) that are critical for pathogenesis and immune evasion in Plasmodium falciparum. How var gene sequence diversity is generated is not currently completely understood. To address this, we constructed large clone trees and performed whole genome sequence analysis to study the generation of novel var gene sequences in asexually replicating parasites. While single nucleotide polymorphisms (SNPs) were scattered across the genome, structural variants (deletions, duplications, translocations) were focused in and around var genes, with considerable variation in frequency between strains. Analysis of more than 100 recombination events involving var exon 1 revealed that the average nucleotide sequence identity of two recombining exons was only 63% (range: 52.7-72.4%) yet the crossovers were error-free and occurred in such a way that the resulting sequence was in frame and domain architecture was preserved. Var exon 1, which encodes the immunologically exposed part of the protein, recombined in up to 0.2% of infected erythrocytes in vitro per life cycle. The high rate of var exon 1 recombination indicates that millions of new antigenic structures could potentially be generated each day in a single infected individual. We propose a model whereby var gene sequence polymorphism is mainly generated during the asexual part of the life cycle.
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Antoine
authors.initials: A
authors.lastname: Claessens
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: William L
authors.initials: WL
authors.lastname: Hamilton
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Mihir
authors.initials: M
authors.lastname: Kekre
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Otto
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Adnan
authors.initials: A
authors.lastname: Faizullabhoy
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Dominic
authors.initials: D
authors.lastname: Kwiatkowski
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000940:Antigenic Variation; D000953:Antigens, Protozoan / Q000235:genetics; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D016054:DNA, Protozoan / Q000235:genetics; D004912:Erythrocytes / Q000166:cytology / Q000469:parasitology; D005091:Exons; D005786:Gene Expression Regulation; D015321:Gene Rearrangement; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D000953:Antigens, Protozoan; D016054:DNA, Protozoan; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum