Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for <i>HLA</i> Class I Genes

Abstract

Polymorphisms located within the <i>MHC</i> have been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions of <i>HLA</i> genes are involved in allele-specific expression and may therefore underlie some of these disease associations. We determined sequences extending nearly 2 kb upstream of the transcription start site for 68 alleles from 57 major lineages of classical <i>HLA</i> class I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, with <i>HLA-B</i> showing the highest (∼1.9%), followed by <i>HLA-A</i> (∼1.8%), and <i>HLA-C</i> showing the lowest diversity (∼0.9%). Despite its greater diversity, <i>HLA-B</i> mRNA expression levels determined in 178 European Americans do not vary in an allele- or lineage-specific manner, unlike the differential expression levels of <i>HLA-A</i> or <i>HLA-C</i> reported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for most <i>HLA-A</i> and <i>-C</i> loci. Although promoter sequence divergence might impact promoter activity, we observed no clear link between the phylogenetic structures as represented by pairwise nucleotide differences in the promoter regions with estimated differences in mRNA expression levels for the classical class I loci. Further, no pair of class I loci showed coordinated expression levels, suggesting that distinct mechanisms across loci determine their expression level under nonstimulated conditions. These data serve as a foundation for more in-depth analysis of the functional consequences of promoter region variation within the classical <i>HLA</i> class I loci.