Inferring genotype and novel alleles of TCR β-chain from high throughput sequencing of TCR repertoires

Currently, extensive efforts are dedicated to inferring B cell receptor (BCR) germline genotypes from high throughput sequencing of BCR repertoires. Several BCR germline inference tools and approaches have been recently developed. These tools use BCR repertoire sequencing data to infer genotype, haplotype, and chromosome deletions within the BCR loci, as well as discover novel alleles. The T cell receptor (TCR) is generated by an analogous mechanism. However, so far no works have been published on the inference of TCR germline genotypes, novel alleles, and haplotypes. By investigating TCR genotypes, important information about the basic function and dynamics of the adaptive immune system can be revealed. Here, we adapt TIgGER, a BCR tool, to TCR beta chain (TCRβ) germline genotype inference from TCRβ repertoires. TIgGER detects BCR alleles, infers the genotype of a subject and corrects the initial allele assignment. We applied TIgGER to TCRβ repertoire sequences from 28 individuals, inferred their genotypes, and discovered 8 previously unknown alleles. Furthermore, from the inferred genotypes we found that 11 subjects out of 28 were heterozygous to the TRBJ1-6 gene, therefore this gene can be used as an anchor for inferring haplotypes. For this we adapted RAbHIT, a BCR tool, to TCR beta chain (TCRβ) germline haplotype inference. This approach can be utilized to search for TCR-based biomarkers for predispositions of diseases.