T Cell Receptor Beta (TRB) Germline Variability is Revealed by Inference From Repertoire Data

T and B cell repertoires constitute the foundation of adaptive immunity. Adaptive immune receptor repertoire sequencing (AIRR-seq) is a common approach to study immune system dynamics. Understanding the genetic factors influencing the composition and dynamics of these repertoires is of major scientific and clinical importance. The chromosomal loci encoding for the variable regions of T and B cell receptors (TCRs and BCRs, respectively) are challenging to decipher due to repetitive elements and undocumented structural variants. To confront this challenge, AIRR-seq-based methods have been developed recently for B cells, enabling genotype and haplotype inference and discovery of undocumented alleles. Applying these methods to AIRR-seq data reveals a plethora of undocumented genomic variations. However, this approach relies on complete coverage of the receptors9 variable regions, and most T cell studies sequence only a small fraction of the variable region. Here, we adapted BCR inference methods to full and partial TCR sequences, and identified 38 undocumented polymorphisms in TRBV, 15 of them were also observed in genomic data assemblies. Further, we identified 31 undocumented 59 UTR sequences. A subset of these inferences was also observed using independent genomic approaches. We found the two documented TRBD2 alleles to be equally abundant in the population, and show that the single nucleotide that differentiates them is strongly associated with dramatic changes in the expressed repertoire. Our findings expand the knowledge of genomic variation in the TRB (T Cell Receptor Beta) locus and provide a basis for annotation of TCR repertoires for future basic and clinical studies.