Accepted_test

Large-scale analysis of haplotype effects in TCR alpha and beta germlines based on Rep-seq data

by Sofiya Vinogradova | Olga Bagrova | Elizaveta Vlasova | Mikhail Shugay | Moscow Institute of Physics and Technology, Dolgoprudny, Russia | Lomonosov Moscow State University, Moscow, Russia | Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; ITMO University, Saint-Petersburg, Russia | Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia

Abstract ID: 604

Event: BGRS-abstracts

Sections: [Sym 4] Section “Human population genomics/genetics”

T cells play a crucial role in the adaptive immune system, with their specificity determined by the diverse repertoire of T cell receptors (TCRs) generated through V(D)J recombination. Recent studies have revealed genomic alterations within the TRA and TRB loci of TCR. However, the coherence of these genomic alterations and their biological implications remain unexplored. This study aims to systematically analyse TCR repertoires in large cohorts from Russian and American populations to identify common and rare haplotypes and interpret the biological implications of observed genomic differences. Here we show significant variations in V and J gene usage across TCR chains, potentially influenced by ethnicity and MHC variation within the population. The analysis of TCRα and TCRβ gene distribution revealed both unimodal and bi-/trimodal patterns, potentially indicating haplotype effects like gene deletion or homo-/hetero- zygote conditions. Statistically significant differences in gene usage were found between Asian and Caucasian populations for TRBV7-4 and Latino and Caucasian populations for TRBV4-3. Hierarchical clustering identified rare haplotypes within populations and distinct subgroups among TRBJ genes. Additionally, CDR3 sequences were classified into functional and non-functional groups, with certain V genes showing a higher prevalence in non-functional sequences, indicating potential thymic selective pressures on specific gene configurations. This research not only deepens our understanding of T cell repertoire diversity across populations but also identifies key drivers of this diversity. This knowledge is crucial for practical applications, as understanding the nuances of adaptive immunity can directly influence the selection of targets for receptor-based therapies.