Molecular evolution of elements controlling HLA-C expression: Adaptation to a role as a killer-cell immunoglobulin-like receptor ligand regulating natural killer cell function

The regulatory elements controlling the transcription of the HLA-A, HLA-B, and HLA-C genes have been extensively studied and compared. However, few studies have considered regulatory differences in the HLA genes from the perspective of their role as ligands for the killer-cell immunoglobulin-like receptor (KIR) family of HLA receptors expressed by natural killer (NK) cells. HLA-C is the most recently evolved gene, and there is considerable evidence pointing to its emergence as a specialized KIR ligand playing a major role in the missing-self recognition system of NK cells. Here I evaluate gene-specific differences in regulatory elements of the HLA genes, showing alterations that are consistent with the adaptation of HLA-C to a role in NK cell regulation.