Plasmodium falciparum antigenic variation. Mapping mosaic var gene sequences onto a network of shared, highly polymorphic sequence blocks

Abstract

SummaryPlasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a potentially important family of immune targets, encoded by an extremely diverse gene family called var. Understanding of the genetic organization of var genes is hampered by sequence mosaicism that results from a long history of nonhomologous recombination. Here we have used software designed to analyse social networks to visualize the relationships between large collections of short var sequences tags sampled from clinical parasite isolates. In this approach, two sequences are connected if they share one or more highly polymorphic sequence blocks. The results show that the majority of analysed sequences including several var-like sequences from the chimpanzee parasite Plasmodium reichenowi can be either directly or indirectly linked together in a single unbroken network. However, the network is highly structured and contains putative subgroups of recombining sequences. The major subgroup contains the previously described group A var genes, previously proposed to be genetically distinct. Another subgroup contains sequences found to be associated with rosetting, a parasite virulence phenotype. The mosaic structure of the sequences and their division into subgroups may reflect the conflicting problems of maximizing antigenic diversity and minimizing epitope sharing between variants while maintaining their host cell binding functions.

Plasmodium falciparum var gene expression is modified by host immunity

“…Therefore, cys2 var gene sequences were classified according to whether they carried REY, MFK, or neither motif. The second method was based on the observation that DBL␣ tag sequences fall into groups that tend not to share polymorphic regions (25). One of these groups corresponds well with the group A var genes.…”

“…Base calling was performed on the sequencing reads using Phred software and low-quality ends of the reads were subsequently clipped using a Perl script we developed (Method S1). A second script was written to: (a) check that duplicate reads were correctly assembled into the same contig; (b) exclude sequences that, when translated, encoded a peptide of fewer than 100 aa long; (c) removed the constitutively expressed var1 sequences from the analysis (Method S1); (d) classified the sequences into previously described groups (16,25); and (e) counted the number of individual bacterial colonies that carried each sequence type.…”

“…To examine the relationship between cys2 var gene expression and host immunity we have extended our previous sampling, sequencing, and classification approach (16,22,25) to 217 parasites obtained from Kenyan children with clinical malaria. We relate these expression patterns to each child's clinical manifestation of disease, age, and level of antibodies to the surface of infected erythrocytes at the time of disease.…”

Linking the antigen archive structure to pathogen fitness in African trypanosomes

“…Recent empirical findings from antigen repertoires of different pathogens point towards a clustered genetic architecture composed of blocks of highly intra-connected variants and low between-block switch rates [11,23]. Based on this view, we propose a simplified description of the antigen archive using only three parameters: the number of genes in a single block (block size, h), the number of such blocks N blocks and e(,1), the average between-/within-block switching ratio (see the electronic supplementary material, S1 for details).…”

“…The recent availability of parasite genome data is revealing the structure and fine-scale architecture of antigen gene archives [10,23,24], thus calling for an evolutionary perspective to understand such complexity. In this article, we start this process, laying down a blue print for how these ideas might be linked together.…”