Keneskhanova, Z.* ; McWilliam, K.R.* ; Cosentino, R.O.* ; Barcons-Simon, A.* ; Dobrynin, A. ; Smith, J.E.* ; Subota, I.* ; Mugnier, M.R.* ; Colomé-Tatché, M. ; Siegel, T.N.*
Genomic determinants of antigen expression hierarchy in African trypanosomes.
Nature, DOI: 10.1038/s41586-025-08720-w (2025)
Antigenic variation is an immune evasion strategy used by many different pathogens. It involves the periodic, non-random switch in the expression of different antigens throughout an infection. How the observed hierarchy in antigen expression is achieved has remained a mystery1,2. A key challenge in uncovering this process has been the inability to track transcriptome changes and potential genomic rearrangements in individual cells during a switch event. Here we report the establishment of a highly sensitive single-cell RNA sequencing approach for the model protozoan parasite Trypanosoma brucei. This approach has revealed genomic rearrangements that occur in individual cells during a switch event. Our data show that following a double-strand break in the transcribed antigen-coding gene-an important trigger for antigen switching-the type of repair mechanism and the resultant antigen expression depend on the availability of a homologous repair template in the genome. When such a template was available, repair proceeded through segmental gene conversion, creating new, mosaic antigen-coding genes. Conversely, in the absence of a suitable template, a telomere-adjacent antigen-coding gene from a different part of the genome was activated by break-induced replication. Our results show the critical role of repair sequence availability in the antigen selection mechanism. Furthermore, our study demonstrates the power of highly sensitive single-cell RNA sequencing methods in detecting genomic rearrangements that drive transcriptional changes at the single-cell level.
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Publication type
Article: Journal article
Document type
Scientific Article
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Keywords
Blood-stream Forms; Gene-expression
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Language
english
Publication Year
2025
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0
HGF-reported in Year
2025
ISSN (print) / ISBN
0028-0836
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1476-4687
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Nature Publishing Group
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London
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Peer reviewed
POF-Topic(s)
30205 - Bioengineering and Digital Health
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-554200-001
Grants
European Research Council (ERC) Starting
ERC Consolidator
MSCA ITN Cell2Cell
European Union
LMUexcellent - Federal Ministry of Education and Research (BMBF)
Free State of Bavaria under the Excellence Strategy of the German Federal Government
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Wellcome Trust
German Research Foundation
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Erfassungsdatum
2025-03-31