Insights into the polymorphism in HLA‐DRA and its evolutionary relationship with HLA haplotypes

HLA‐DRA encodes the alpha chain of the HLA‐DR protein, one of the classical HLA class II molecules. Reported polymorphism within HLA‐DRA is currently limited compared with other HLA genes, as only a single polymorphism encodes an amino acid difference in the translated protein. Since this SNP (rs7192, HLA00662.1:g.4276G>T p.Val217Leu) lies within exon 4, in the region encoding the cytoplasmic tail, the resulting protein is effectively monomorphic. For this reason, in‐depth studies on HLA‐DRA and its function have been limited. However, analysis of sequences from the 1000 Genomes Project and preliminary data from our lab reveals unrepresented polymorphism within HLA‐DRA, suggesting a more complex role within the MHC than previously assumed. This study focuses on elucidating the extent of HLA‐DRA polymorphism, and extending our understanding of the gene's role in HLA‐DR~HLA‐DQ haplotypes. Ninety‐eight samples were sequenced for full‐length HLA‐DRA, and from this analysis, we identified 20 novel SNP positions in the intronic sequences within the 5711 bp region represented in IPD‐IMGT/HLA. This polymorphism gives rise to at least 22 novel HLA‐DRA alleles, and the patterns of intronic and 3′ UTR polymorphism correspond to HLA‐DRA~HLA‐DRB345~HLA‐DRB1~HLA‐DQB1 haplotypes. The current understanding of the organization of the genes within the HLA‐DR region assumes a single lineage for the HLA‐DRA gene, as opposed to multiple gene lineages, such as in HLA‐DRB. This study suggests that the intron and 3′ UTR polymorphism of HLA‐DRA indicates different lineages, and represents the HLA‐DRA~HLA‐DRB345~HLA‐DRB1~HLA‐DQB1 haplotypes.