Presence of retroelements reveal the evolutionary history of the human DR haplotypes.

Comparison of intron sequences has been a successful tool for drawing major conclusions about the evolutionary relationship of DRB genes. This complex family of genes is discussed in this review as well as a proposed model for the evolution of HLA-DR haplotypes. The model is based both on phylogenetic analysis of intron sequences as well as presence of ERV9 LTR elements located at identical position in intron 5 of a number of DRB genes. According to this model, two main evolutionary branches of DR haplotypes exist. The DR53 haplotype represents one branch, and the second branch contains the DR51, DR52, DR1, and DR8 haplotypes. After the divergence of the DR53 haplotype, an ERV9 LTR element was inserted in a primordial gene. Consequently, all DRB1 genes as well as the DRB3 gene within haplotypes of the second branch, contain this LTR element. In addition, conserved regulatory sequence motifs are found present within these LTR elements that might regulate DRB gene expression. Novel haplotypes are generated by recombinations and the maintenance of the DR haplotype variation as well as the frequent genetic rearrangements observed might be evolutionary advantageous.