Quantifying the Recoverability of V and J Genes from TCR CDR3 Sequences Using Generative Repertoire Models

Abstract

Introduction How much of the variable (V) and joining (J) gene identity of a T-cell receptor is recoverable from its third complementarity-determining region (CDR3) amino-acid sequence alone? Immune repertoire studies often report the CDR3 with V and J annotation that is missing, low-confidence, or inconsistent, so what the CDR3 alone can and cannot fix is both a basic question about the receptor and a practical one for reading those repertoires. Methods For each of 118,096 pooled human rearrangements (37,687 α and 80,409 β) we computed the posterior distribution over candidate genes under a generative model of V(D)J recombination and under its post-selection counterpart, and measured recoverability by conditional entropy, the candidate-list size needed to contain the annotated gene, the fraction of sequences admitting a high-confidence single-gene call, and the structure of gene-by-gene confusion. Results The J gene was nearly determined by the CDR3 in both chains. The V gene was only partially recoverable, and behaved as a group rather than a gene: junctional trimming and non-templated insertion, together with the loss of synonymous codon information in translation, leave sets of mutually confusable V genes whose grouping departs sharply from germline family nomenclature (adjusted Rand index 0.05 for α and 0.21 for β). Selection sharpened the V posterior modestly (usage-controlled entropy shift −0.06 nats for α and −0.28 for β) and redistributed which V gene was most probable, a locus-scale rewrite in β against a mild reweight in α. Both the recoverability measurements and the confusion grouping reproduced in two held-out tumor cohorts. Discussion V identity is an emergent, system-level property of the repertoire, set jointly by recombination and selection and invisible in any single rearrangement, so it should be reported as a calibrated group rather than a single gene. We also release the pipeline with a computational tool which can output a set of candidate genes with confidence values given a CDR3 sequence.