Integrative Curation of Human and Rhesus Macaque Immunoglobulin Germline Loci for Population-Scale Immunogenomics 2267549

Abstract

Abstract Introduction The immunoglobulin (IG) loci are among the most polymorphic and structurally complex regions of mammalian genomes, yet current germline references remain incomplete and inconsistent across species. We developed unified resources for human and rhesus macaque IG loci by integrating high-fidelity long-read genomic assemblies with matched AIRR-seq data. Our framework curates validated alleles, recombination signal sequences (RSSs), and regulatory elements across 170 human and 300+ macaque samples, establishing a foundation for population-scale and comparative immunogenomics. Methods Targeted long-read assemblies (PacBio HiFi) of IGH, IGK, and IGL loci were analyzed with AIRR-seq repertoires using a unified Nextflow pipeline. Personalized genomic germline sets were inferred and validated by repertoire evidence. Novel alleles were identified through similarity-based clustering and cross-modal validation. RSSs and leader sequences were annotated from flanking regions, and population variation was assessed through allele frequencies, Jaccard similarity, and repertoire concordance. Results For humans, we curated IGH, IGK, and IGL allele sets from 170 individuals, identifying hundreds of novel, population-specific alleles validated by AIRR-seq concordance and annotated with RSSs, leader, and regulatory regions linked to ancestry. In rhesus macaques, we identified 1,643 coding alleles from 300+ animals, including 1,338 novel variants, and cataloged 328 RSS motifs revealing conserved heptamer—nonamer cores but locus-dependent spacer variability. Conclusion The human and macaque unified allele resources establish harmonized, cross-species IG germline references. By integrating genomic and repertoire data, these resources advance immunogenomic annotation, diversity analysis, and modeling of antibody evolution in humans and nonhuman primates. All data and annotations will be available through VDJbase.com, supporting open, standardized immunogenetics research. Funding Source NIAID R24 AI162317 Topic Categories Computational and Systems Immunology (COMP)