A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Individualized VDJ recombination predisposes the available Ig sequence space
Tekijät: Slabodkin Andrei, Chernigovskaya Maria, Mikocziova Ivana, Akbar Rahmad, Scheffer Lonneke, Pavlović Milena, Bashour Habib, Snapkov Igor, Mehta Brij Bhushan, Weber Cédric R., Gutierrez-Marcos Jose, Sollid Ludvig M., Haff Ingrid Hobæk, Sandve Geir Kjetil, Robert Philippe A., Greiff Victor
Julkaisuvuosi: 2021
Journal: Genome Research
Vuosikerta: 31
Numero: 12
DOI: https://doi.org/10.1101/gr.275373.121
Verkko-osoite: https://genome.cshlp.org/content/31/12/2209
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.