Structural variation shapes regulatory and evolutionary diversity at the HLA locus

Abstract

The human leukocyte antigen (HLA) region is among the most polymorphic loci in the human genome and plays a central role in immune function, yet the contribution of structural variation to its genetic and regulatory diversity remains poorly characterised. Using 460 phased, near-complete human genome assemblies from globally diverse populations, we systematically mapped structural variation and gene content across the HLA locus. We show that the HLA region contains substantially more structural variation than any other region of chromosome 6. At the HLA class II locus, all individuals could be assigned to one of 13 distinct HLA-DR-DQ structural haplotypes, whereas the HLA-A region comprised four major haplotypes, which we found to be interspersed among non-human primate lineages. These structural haplotypes exhibit marked differences in population frequency and show increasing allelic diversity over European prehistory. Integration of Iso-Seq and RNA-Seq data revealed that structural haplotypes are associated with differences in HLA gene expression, suggesting that structural variation directly influences immune gene regulation. Together, our results identify structural variation as a key and previously underappreciated contributor to HLA regulatory diversity, with broad functional and evolutionary implications for human immunity. Manuscript summaryStructural variation drives HLA haplotype diversity and gene expression differences across global human populations.