Genomic determinants of antigen expression hierarchy in African trypanosomes

Zhibek Keneskhanova, Kirsty R. McWilliam, Raúl O. Cosentino, Anna Barcons-Simon, Atai Dobrynin, Jaclyn E. Smith, Ines Subota, Monica R. Mugnier, Maria Colomé-Tatché () and T. Nicolai Siegel ()
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Zhibek Keneskhanova: Ludwig-Maximilians-Universität München
Kirsty R. McWilliam: Ludwig-Maximilians-Universität München
Raúl O. Cosentino: Ludwig-Maximilians-Universität München
Anna Barcons-Simon: Ludwig-Maximilians-Universität München
Atai Dobrynin: Ludwig-Maximilians-Universität München
Jaclyn E. Smith: Johns Hopkins Bloomberg School of Public Health
Ines Subota: Ludwig-Maximilians-Universität München
Monica R. Mugnier: Johns Hopkins Bloomberg School of Public Health
Maria Colomé-Tatché: Ludwig-Maximilians-Universität München
T. Nicolai Siegel: Ludwig-Maximilians-Universität München

Nature, 2025, vol. 642, issue 8066, 182-190

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08720-w

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