![]() ![]() Genetic factors are expected to influence the structure and functionality of AIRRs. This V(D)J recombination process creates a diverse repertoire of receptors that together with the innate immune system form the first line of defense against pathogens. B and T cell receptors are assembled within B and T cells, respectively, during differentiation from hematopoietic stem cells, by a complex process involving somatic recombination of a large number of germline-encoded Variable (V), Diversity (D), and Joining (J) gene segments, along with junctional diversity in the form of addition and subtraction of nucleotides at the boundaries where these segments are joined together. It can teach us about fundamental immune processes and reveal dysregulation, with broad implications for biomedicine. Due to the longevity of immunological memory, high-throughput sequencing of adaptive immune receptor repertoires (AIRR-seq) provides detailed insights into the past and present encounters of the human immune system. The immune system’s success in fighting countless evolving pathogens depends on a dynamic and diverse set of B and T cell receptors. Our findings provide a basis for annotation of TCR repertoires for future basic and clinical studies. We reveal a rich picture of germline variability and demonstrate how a single nucleotide polymorphism dramatically affects the composition of the whole repertoire. 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. A subset of these inferences was also observed using independent genomic approaches. Resultsįrom 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. ![]() The pipeline also deals with gene assignment ambiguities, which is especially important in the analysis of data sets of partial sequences. Here, we adapted a B cell pipeline for undocumented alleles, genotype, and haplotype inference for full and partial AIRR-seq TCR data sets. However, this approach relies on complete coverage of the receptors’ variable regions, whereas most T cell studies sequence a small fraction of that region. 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. The chromosomal loci encoding for the variable regions of TCRs and BCRs are challenging to decipher due to repetitive elements and undocumented structural variants. Understanding the genetic factors influencing the composition and dynamics of these repertoires is of major scientific and clinical importance. Adaptive immune receptor repertoire sequencing (AIRR-seq) is a common approach to study immune system dynamics. T and B cell receptor (TCR, BCR) repertoires constitute the foundation of adaptive immunity.
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