Abstract
Malaria parasites possess the remarkable ability to maintain chronic infections that fail to elicit a protective immune response, characteristics that have stymied vaccine development and cause people living in endemic regions to remain at risk of malaria despite previous exposure to the disease. These traits stem from the tremendous antigenic diversity displayed by parasites circulating in the field. For Plasmodium falciparum, the most virulent of the human malaria parasites, this diversity is exemplified by the variant gene family called var, which encodes the major surface antigen displayed on infected red blood cells (RBCs). This gene family exhibits virtually limitless diversity when var gene repertoires from different parasite isolates are compared. Previous studies indicated that this remarkable genome plasticity results from extensive ectopic recombination between var genes during mitotic replication; however, the molecular mechanisms that direct this process to antigen-encoding loci while the rest of the genome remains relatively stable were not determined. Using targeted DNA double-strand breaks (DSBs) and long-read whole-genome sequencing, we show that a single break within an antigen-encoding region of the genome can result in a cascade of recombination events leading to the generation of multiple chimeric var genes, a process that can greatly accelerate the generation of diversity within this family. We also found that recombinations did not occur randomly, but rather high-probability, specific recombination products were observed repeatedly. These results provide a molecular basis for previously described structured rearrangements that drive diversification of this highly polymorphic gene family.
Highlights
Despite recent progress, malaria remains an infectious disease that inflicts a tremendous health and economic burden on many regions of the developing world, in particular sub-Saharan Africa [1]
The data presented here describe how a single double-strand break (DSB) within the subtelomeric regions of P. falciparum chromosomes can stimulate a sequence of recombination events between var genes, accelerating the generation of diversity within this gene family
Two key aspects of Plasmodium DNA repair contribute to this phenomenon: 1) near-complete dependence on homologous recombination (HR) to repair DSBs and 2) a propensity to use telomere healing when breaks occur with subtelomeric regions
Summary
Malaria remains an infectious disease that inflicts a tremendous health and economic burden on many regions of the developing world, in particular sub-Saharan Africa [1]. One unique aspect of P. falciparum biology is the tremendous genome plasticity displayed by parasites that are actively circulating within regions of the world endemic for the disease [2] Much of this diversity is found within the subtelomeric regions of the 14 chromosomes where genes that encode variant surface antigens reside [3]. These chromosomal regions can extend for over 100 kb from the chromosome end and display a unique structure that includes telomere-associated repeat elements (TAREs) and members of several hypervariable gene families, including var, rifin (repetitive interspersed family), stevor (subtelomeric variant open reading frame), and Pfmc-2TM (P. falciparum Maurer’s cleft-2 transmembrane domain protein). The best characterized of these gene families is var, with the total number of var genes within the genome of any given parasite varying between approximately 50 and 90 [3]
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