T cell receptor beta germline variability is revealed by inference from repertoire data

Aviv Omer, Ayelet Peres, Oscar L. Rodriguez, Corey T. Watson, William Lees, Pazit Polak, Andrew M. Collins, Gur Yaari

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Background: T and B cell receptor (TCR, BCR) 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 TCRs and BCRs are challenging to decipher due to repetitive elements and undocumented structural variants. Methods: To confront this challenge, AIRR-seq-based methods have recently been developed for B cells, enabling genotype and haplotype inference and discovery of undocumented alleles. However, this approach relies on complete coverage of the receptors’ variable regions, whereas most T cell studies sequence a small fraction of that region. Here, we adapted a B cell pipeline for undocumented alleles, genotype, and haplotype inference for full and partial AIRR-seq TCR data sets. The pipeline also deals with gene assignment ambiguities, which is especially important in the analysis of data sets of partial sequences. Results: From the full and partial AIRR-seq TCR data sets, we identified 39 undocumented polymorphisms in T cell receptor Beta V (TRBV) and 31 undocumented 5 UTR sequences. A subset of these inferences was also observed using independent genomic approaches. We found that a single nucleotide polymorphism differentiating between the two documented T cell receptor Beta D2 (TRBD2) alleles is strongly associated with dramatic changes in the expressed repertoire. Conclusions: We reveal a rich picture of germline variability and demonstrate how a single nucleotide polymorphism dramatically affects the composition of the whole repertoire. Our findings provide a basis for annotation of TCR repertoires for future basic and clinical studies.

Original languageEnglish
Article number2
Number of pages19
JournalGenome Medicine
Issue number1
StatePublished - 7 Jan 2022

Bibliographical note

Funding Information:
This study was partially supported by grants from the ISF (832/16 to GY) and the European Union’s Horizon 2020 research and innovation program (825821). The contents of this document are the sole responsibility of the iReceptor Plus Consortium and can under no circumstances be regarded as reflecting the position of the European Union. OLR and CTW were supported in part by funding from the National Institute of Allergy and Infectious Diseases (R24AI138963 to CTW).

Publisher Copyright:
© 2021, The Author(s).


  • AIRR-seq
  • Allele inference
  • Genotype
  • Immune repertoires
  • TCR
  • TRB


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