For information about COVID-19, including symptoms and prevention, please read our COVID-19 patient guide. Please also consider supporting Weill Cornell Medicine’s efforts against the pandemic.
Microbiology and Immunology

You are here

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

TitleRapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhang X, Alexander N, Leonardi I, Mason C, Kirkman LA, Deitsch KW
JournalPLoS Biol
Volume17
Issue5
Paginatione3000271
Date Published2019 05
ISSN1545-7885
KeywordsAnimals, Antigenic Variation, Base Sequence, Chromosomes, DNA Breaks, Double-Stranded, Humans, Malaria, Falciparum, Mitosis, Parasites, Plasmodium falciparum, Recombination, Genetic, Telomere
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.

DOI10.1371/journal.pbio.3000271
Alternate JournalPLoS Biol
PubMed ID31083650
PubMed Central IDPMC6532940
Grant ListR01 ES021006 / ES / NIEHS NIH HHS / United States
R21 AI129851 / AI / NIAID NIH HHS / United States
R01 MH117406 / MH / NIMH NIH HHS / United States

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587