Human IGH germline gene diversity and allele frequencies in 2486 individuals from 25 global populations delineated by ultra-high throughput genotyping

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 1000 Genomes Project, spanning diverse ancestries, and built KIARVA, an open-access atlas of IG gene variation. Cross-validation with SNP data from over one million genomes confirmed the accuracy and novelty of discovered alleles. Our analysis reveals striking population-specific patterns, including a multigene IGHD segment deletion found in up to 30% of East Asian individuals, and haplotypic differences linked to disease-associated loci. These findings illuminate the evolutionary forces shaping IG diversity and provide a foundational resource for investigating the immunogenetic basis of pathogen susceptibility and vaccine responsiveness worldwide.