Ultra-high-throughput IGH genotyping of 25 global populations reveals population-biased allelic diversity and homozygous V and D gene deletions.

The extraordinary diversity of human immunoglobulin (IG) genes underpins effective antibody responses, yet the full scope and functional impact of germline-encoded IG variation across populations is largely unknown. Here, we present ImmuneDiscover, an ultra-high-throughput sequencing platform enabling individualized IG genotyping from nanogram-scale DNA and simultaneous analysis of over 1,000 individuals. Using ImmuneDiscover, we generated high-resolution IG genotypes for 2,486 individuals from the 1,000 Genomes Project, spanning diverse population ancestries, and built Karolinska Institutet Adaptive Immune Receptor Gene Variant Atlas (KIARVA), an open access atlas of IG gene variation. Cross-validation with single-nucleotide polymorphism data from over one million genomes confirmed the accuracy of discovered alleles. Our analysis reveals population-specific patterns, including a multigene IG heavy-chain diversity (IGHD) deletion found homozygously in up to 30% of East Asian individuals, and haplotypic differences linked to disease-associated loci. These findings illuminate the evolutionary forces shaping IG gene diversity and provide a foundational resource for investigating the immunogenetic basis of pathogen susceptibility and vaccine responsiveness worldwide.