HLA-DR Haplotype Diversity Revealed by Pangenome Sequence Analysis

The HLA-DR region of the MHC, spanning HLA-DRB1 to HLA-DRA, is currently characterised by five unique haplotypes (named DR1, DR51, DR52, DR53 and DR8). All haplotypes have HLA-DRB1, HLA-DRB9 and HLA-DRA. The DR1 haplotype also has HLA-DRB6, the DR52 haplotype, HLA-DRB3 and HLA-DRB2, and DR53 also has HLA-DRB4, HLA-DRB7 and HLA-DRB8. The DR8 haplotype has no additional loci. HLA-DRB3, HLA-DRB4 and HLA-DRB5 are expressed genes, and HLA-DRB2, HLA-DRB6, HLA-DRB7 and HLA-DRB8 are pseudogenes. Whilst the genetic content of each haplotype is known, a detailed genomic comparison of these haplotypes has not been reported. To address this issue, we have performed multi-sequence alignments of the complete HLA-DRA to HLA-DRB1 region on 94 phased genome assemblies from the Pangenome Project. Our analysis reveals extensive structural variation and significant size differences between haplotypes characterised by large insertions and deletions. We also describe two new pseudogenes, locally named HLA-DRBTF1 and HLA-DRBTF2. HLA-DRBTF1 was present on DR1 and DR53 haplotypes, and HLA-DRBTF2 was found on all haplotypes with haplotype-specific short and long variants. Our analysis enables us to propose an updated, simplified map of the HLA-DR region, demonstrating the comparative arrangement of genes and pseudogenes between HLA-DR haplotypes.