Work

An integrated human immunoglobulin germline resource linking allele diversity to expressed repertoire structure

Year: 2026

Type: preprint

Abstract: Human immunoglobulin (IG) loci are highly polymorphic, yet existing germline resources remain noisy and incomplete, limiting our ability to link inherited variation to antibody repertoires. Here, we integrate high-fidelity long-read genomic sequencing with matched adaptive immune receptor repertoire sequencing (AIRR-seq) to construct HUSA, a population-scale, evidence-resolved germline resource. Using a conservative allele inference framework, HUSA expands current references more than three-fold, identifying over 1300 alleles while preserving allele-level evidence provenance across genomic and repertoire data. By linking genotype and expressed repertoires within individuals, we show that coding-region similarity predicts the structure of adjacent recombination signal sequences and leader regions, revealing that IG alleles are organized as linked cis-regulatory units associated with differences in recombination context and allele usage. These results define key germline constraints shaping repertoire formation and establish a robust, genotype-aware foundation for the analysis of immune receptor repertoires.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.06.05.730236