Deep meta-analysis of human pangenome data reveals triplication of the IGH constant gene locus

Variability in immunogenetics is essential for immune system diversity, enhancing disease resistance and adaptation to pathogens. A key evolutionary mechanism that enhances immunoglobulin (IG) diversity involves the duplication of genes. Here, we describe a genomic variant of the human Immunoglobulin heavy chain (IGH) constant gene locus, characterized by a triplication affecting both the chromosomal segment encoding the α (IGHA), ε (IGHE), and γ (IGHG) isotypes, and the 3’ Regulatory Region (3’RR), i.e. a cluster of enhancers that modulate class switch recombination and gene expression in B-lineage cells. While most mammal genomes contain a single copy of the 3’RR, the Hominoidea species harbour two copies due to a lineage specific segmental duplication that also involves the IGHA, IGHE, and IGHG genes. The presence of a triplication at this locus further increases the number of IGH subclasses, suggesting expanded variability and modulation of immunoglobulin class switching and production in B lymphocytes, with potential consequences for plasma cell maturation. The triplication was detected in samples from unrelated individuals across geographically distant populations (including China, South America, Africa), suggesting that it represents a common haplotype of the human IGH constant region. Moreover, the triplicated region includes the hs1.2 enhancer, whose *2 allele has been associated with both autoimmune diseases and heightened immunological response to viral infection. These observations point out the relevance of this haplotype variant for future studies on autoimmunity and host–pathogen interactions.