Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum.

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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Zhang X,Alexander N,Leonardi I,Mason C,Kirkman LA,Deitsch KW

doi

10.1371/journal.pbio.3000271

subject

Has Abstract

pub_date

2019-05-13 00:00:00

pages

e3000271

issue

5

eissn

1544-9173

issn

1545-7885

pii

PBIOLOGY-D-19-00090

journal_volume

17

pub_type

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