1. T Cell Receptor Beta Germline Variability is Revealed by Inference From Repertoire Data
- Author
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Pazit Polak, William D. Lees, Omer A, Andrew M. Collins, Ayelet Peres, Oscar L. Rodriguez, Gur Yaari, and Corey T. Watson
- Subjects
Genotype ,T cell ,Receptors, Antigen, T-Cell, alpha-beta ,B-cell receptor ,Receptors, Antigen, T-Cell ,AIRR-seq ,Single-nucleotide polymorphism ,Immune receptor ,Biology ,QH426-470 ,03 medical and health sciences ,0302 clinical medicine ,Allele inference ,medicine ,Genetics ,Humans ,Molecular Biology ,Genetics (clinical) ,Alleles ,030304 developmental biology ,0303 health sciences ,Repertoire ,Research ,T-cell receptor ,High-Throughput Nucleotide Sequencing ,Acquired immune system ,medicine.anatomical_structure ,Germ Cells ,Immune repertoires ,Molecular Medicine ,Medicine ,TCR ,030215 immunology ,TRB - Abstract
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.
- Published
- 2021
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