Germline variability in adaptive immune repertoires

B and T cell receptors play a critical role in responding to pathogens and vaccination, and in the pathology of several diseases of the immune system. Gene segments at the T cell receptor and immunoglobulin loci serve as templates for the generation and expression of T and B cell receptors and antibodies. Defining genetic variation within these highly polymorphic loci is critical to furthering our understanding of immunological
diseases and informing the design of vaccines and therapeutics. However, at the genomic level, these loci are difficult to analyze due to their repetitive nature and duplications. To overcome this complexity, several sequencing technologies and algorithms have been developed to more fully define the spectrum of genetic variation in these immune loci in human populations and other species.

To this end, we adapted and developed tools for genotype and haplotype inferences from adaptive immune receptor repertoire sequencing data. Our publicly available tools, RAbHIT, VDJbase, and the reference book allow for user interactivity and data exploration. We applied our methods to several public data sets and revealed a plethora of novel undocumented TRBV, IGHV, IGKV, and IGLV alleles, structural variations, and variations in the untranslated regions including alternative splicing events.

Here, I will cover our recent work and show how the discovered variations affect the expressed repertoires. I will also discuss challenges with these kinds of inferences, such as indistinguishable sequences coming from different genes and/or partial sequencing protocols, and our current thinking on how to overcome these challenges.