Individualized VDJ recombination predisposes the available Ig sequence space
- Andrei Slabodkin1,
- Maria Chernigovskaya1,
- Ivana Mikocziova1,
- Rahmad Akbar1,
- Lonneke Scheffer2,
- Milena Pavlović2,
- Habib Bashour3,
- Igor Snapkov1,
- Brij Bhushan Mehta1,
- Cédric R. Weber4,
- Jose Gutierrez-Marcos3,
- Ludvig M. Sollid1,
- Ingrid Hobæk Haff5,
- Geir Kjetil Sandve2,
- Philippe A. Robert1,6 and
- Victor Greiff1,6
- 1Department of Immunology and Oslo University Hospital, University of Oslo, 0372 Oslo, Norway;
- 2Department of Informatics, University of Oslo, 0373 Oslo, Norway;
- 3School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom;
- 4Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland;
- 5Department of Mathematics, University of Oslo, 0371 Oslo, Norway
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↵6 These authors contributed equally to this work.
Abstract
The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire and, consequently, (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also nongenetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor–based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.275373.121.
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Freely available online through the Genome Research Open Access option.
- Received April 19, 2021.
- Accepted October 20, 2021.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
