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Individualized VDJ recombination predisposes the available Ig sequence space

View ORCID ProfileAndrei Slabodkin, View ORCID ProfileMaria Chernigovskaya, View ORCID ProfileIvana Mikocziova, View ORCID ProfileRahmad Akbar, View ORCID ProfileLonneke Scheffer, View ORCID ProfileMilena Pavlović, View ORCID ProfileHabib Bashour, View ORCID ProfileIgor Snapkov, View ORCID ProfileBrij Bhushan Mehta, View ORCID ProfileCédric R. Weber, View ORCID ProfileJose Gutierrez-Marcos, View ORCID ProfileLudvig M. Sollid, Ingrid Hobæk Haff, View ORCID ProfileGeir Kjetil Sandve, View ORCID ProfilePhilippe A. Robert, View ORCID ProfileVictor Greiff
doi: https://doi.org/10.1101/2021.04.19.440409
Andrei Slabodkin
1Department of Immunology, University of Oslo, Oslo, Norway
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Maria Chernigovskaya
1Department of Immunology, University of Oslo, Oslo, Norway
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  • ORCID record for Maria Chernigovskaya
Ivana Mikocziova
1Department of Immunology, University of Oslo, Oslo, Norway
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Rahmad Akbar
1Department of Immunology, University of Oslo, Oslo, Norway
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Lonneke Scheffer
2Department of Informatics, University of Oslo, Oslo, Norway
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Milena Pavlović
2Department of Informatics, University of Oslo, Oslo, Norway
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Habib Bashour
3School of Life Sciences, University of Warwick, Coventry, United Kingdom
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Igor Snapkov
1Department of Immunology, University of Oslo, Oslo, Norway
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Brij Bhushan Mehta
1Department of Immunology, University of Oslo, Oslo, Norway
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Cédric R. Weber
4Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
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Jose Gutierrez-Marcos
3School of Life Sciences, University of Warwick, Coventry, United Kingdom
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Ludvig M. Sollid
1Department of Immunology, University of Oslo, Oslo, Norway
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Ingrid Hobæk Haff
5Department of Mathematics, University of Oslo, Oslo, Norway
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Geir Kjetil Sandve
2Department of Informatics, University of Oslo, Oslo, Norway
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Philippe A. Robert
1Department of Immunology, University of Oslo, Oslo, Norway
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  • For correspondence: victor.greiff@medisin.uio.no p.p.a.robert@medisin.uio.no
Victor Greiff
1Department of Immunology, University of Oslo, Oslo, Norway
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  • For correspondence: victor.greiff@medisin.uio.no p.p.a.robert@medisin.uio.no
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Abstract

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual’s naïve 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 non-genetic 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.

Competing Interest Statement

VG declares advisory board positions in aiNET GmbH and Enpicom B.V.

Footnotes

  • ↵☯ These authors jointly supervised this work.

  • https://github.com/csi-greifflab/desygnator

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 19, 2021.
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Individualized VDJ recombination predisposes the available Ig sequence space
Andrei Slabodkin, Maria Chernigovskaya, Ivana Mikocziova, Rahmad Akbar, Lonneke Scheffer, Milena Pavlović, Habib Bashour, Igor Snapkov, Brij Bhushan Mehta, Cédric R. Weber, Jose Gutierrez-Marcos, Ludvig M. Sollid, Ingrid Hobæk Haff, Geir Kjetil Sandve, Philippe A. Robert, Victor Greiff
bioRxiv 2021.04.19.440409; doi: https://doi.org/10.1101/2021.04.19.440409
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Individualized VDJ recombination predisposes the available Ig sequence space
Andrei Slabodkin, Maria Chernigovskaya, Ivana Mikocziova, Rahmad Akbar, Lonneke Scheffer, Milena Pavlović, Habib Bashour, Igor Snapkov, Brij Bhushan Mehta, Cédric R. Weber, Jose Gutierrez-Marcos, Ludvig M. Sollid, Ingrid Hobæk Haff, Geir Kjetil Sandve, Philippe A. Robert, Victor Greiff
bioRxiv 2021.04.19.440409; doi: https://doi.org/10.1101/2021.04.19.440409

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