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

Genome Medicine

Corey T Watson¹  Oscar L Rodriguez¹  Aviv Omer²  Gur Yaari²  Ayelet Peres²  Pazit Polak²  William Lees³  Andrew M Collins⁴ 

[1] Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA;Faculty of Engineering, Bar Ilan University, 5290002, Ramat Gan, Israel;Bar Ilan institute of Nanotechnology and Advanced Materials, Bar Ilan University, 5290002, Ramat Gan, Israel;Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, UK;School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, Australia;

关键词: AIRR-seq;    Genotype;    Allele inference;    TRB;    TCR;    Immune repertoires;   

DOI  :  10.1186/s13073-021-01008-4

来源: Springer

【 摘 要 】

BackgroundT 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.MethodsTo 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.ResultsFrom 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.ConclusionsWe 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.

【 授权许可】

CC BY