Rapid antigen diversification through mitotic recombination in the human malaria parasite < i > Plasmodium falciparum < /i >

by Xu Zhang, Noah Alexander, Irina Leonardi, Christopher Mason, Laura A. Kirkman, Kirk W. Deitsch 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. ForPlasmodium falciparum, the most virulent of the human malaria parasites, this diversity is exemplified by the variant gene family calledvar, which encodes the major surface antigen displayed on infected red blood cells (RBCs). This gene family exhibits virtually limitless diversity whenvar gene repertoires from different parasite isolates are compared. Previous studies indicated that this remarkable genome plasticity results from extensive ectopic recombination betweenvar 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 chimericvar genes, a process that can greatly accelerate the generation of...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research