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Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum
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. Th...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532940/ https://www.ncbi.nlm.nih.gov/pubmed/31083650 http://dx.doi.org/10.1371/journal.pbio.3000271 |
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author | Zhang, Xu Alexander, Noah Leonardi, Irina Mason, Christopher Kirkman, Laura A. Deitsch, Kirk W. |
author_facet | Zhang, Xu Alexander, Noah Leonardi, Irina Mason, Christopher Kirkman, Laura A. Deitsch, Kirk W. |
author_sort | Zhang, Xu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6532940 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-65329402019-06-05 Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum Zhang, Xu Alexander, Noah Leonardi, Irina Mason, Christopher Kirkman, Laura A. Deitsch, Kirk W. PLoS Biol Research Article 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. Public Library of Science 2019-05-13 /pmc/articles/PMC6532940/ /pubmed/31083650 http://dx.doi.org/10.1371/journal.pbio.3000271 Text en © 2019 Zhang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Zhang, Xu Alexander, Noah Leonardi, Irina Mason, Christopher Kirkman, Laura A. Deitsch, Kirk W. Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum |
title | Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum |
title_full | Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum |
title_fullStr | Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum |
title_full_unstemmed | Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum |
title_short | Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum |
title_sort | rapid antigen diversification through mitotic recombination in the human malaria parasite plasmodium falciparum |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532940/ https://www.ncbi.nlm.nih.gov/pubmed/31083650 http://dx.doi.org/10.1371/journal.pbio.3000271 |
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