The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, lower expression on the cell surface, and more extensive ligand-receptor interactions with killer cell immunoglobulin-like receptors (KIR). These characteristics have led to the notion that HLA-C has a relatively limited role in antigen presentation to T cells during the acquired immune response, but rather has evolved to serve a primary role in the innate immune response as a ligand for KIR. A single nucleotide polymorphism (SNP) 35Kb upstream of HLA-C - (termed -35) was shown to associate with levels of HLA-C mRNA transcripts and cell surface expression, which was suggested to be the basis for its association with control of HIV viral load and disease progression. More recently, variation in the 3'UTR of HLA-C, which is in strong linkage disequilibrium (LD) with -35, was shown to affect HLA-C cell surface expression due to differential regulation of HLA-C alleles by a miRNA, miR-148a. HLA-C alleles that escape miR-148a recognition have a single base pair deletion at position 263 downstream of the stop codon of HLA-C (263del) along with other closely linked variants in the miR-148a binding site. Allotypes encoded by these 263del alleles are expressed at a relatively high level on the cell surface. The 3'UTR of the alternative set of HLA-C alleles has an insertion at position 263 (263ins) and have an intact miR-148a binding site and expression of both mRNA and protein encoded by these alleles are downregulated by the miRNA. The miRNA regulation of HLA-C indicates the potential for control of immune responses through expression. It is therefore of interest to examine the evolutionary history of this process in HLA-C alleles, to determine how escape from miRNA initially occurred, and to investigate whether selection might have influenced the spread of the escape variant. We have shown that the target site through which miR-148a exerts control of HLA-C existed in the most recent ancestor of all extant HLA-C alleles, but this sequence differed extensively in the ancestor of extant HLA-B alleles, all of which escape miR-148a regulation. Our data indicate that some 3-5 MYA, a genetic exchange occurred between an HLA-C allele and an HLA-B allele belonging to a B*07-like lineage, resulting in the conversion of a short 3'UTR tract of an HLA-C allele by the paralogous HLA-B region. The conversion event encompassed the miRNA binding site and rendered the escape of this novel HLA-C allele from miR-148a downregulation. The conversion event did not encompass the coding region, so functionally this novel HLA-C allele differed from its parental HLA-C allele only by having higher expression levels. The chromosome carrying this variant successfully spread through human or proto-human populations, giving rise to multiple HLA-C lineages of different binding and functional propensities, suggesting some benefit of high HLA-C expression. Further, many key variants of the antigen binding and KIR receptor binding regions of the escape HLA-C alleles resemble those found in miR-148a inhibited alleles, suggesting that selective convergence occurred to generate an array of escape alleles that resemble the inhibited counterparts in critical regions. A greater understanding of the nature of the diversity at the HLA class I loci and the mechanisms by which the diversity occurs, may provide clues to its involvement in health and disease.

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