Abstract
Human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome. Almost all polymorphic residues are located in the peptide-binding groove, resulting in different peptide-binding preferences. Whether a single amino acid change can alter the peptide-binding repertoire of an HLA molecule has never been shown. To experimentally quantify the contribution of a single amino acid change to the peptide repertoire of even a single HLA molecule requires an immense number of HLA peptide-binding measurements. Therefore, we used an in silico method to study the effect of single mutations on the peptide repertoires. We predicted the peptide-binding repertoire of a large set of HLA molecules and used the overlap of the peptide-binding repertoires of each pair of HLA molecules that differ on a single position to measure how much single substitutions change the peptide binding. We found that the effect of a single substitution in the peptide-binding groove depends on the substituted position and the amino acids involved. The positions that alter peptide binding most are the most polymorphic ones, while those that are hardly variable among HLA molecules have the lowest effect on the peptide repertoire. Although expected, the relationship between functional divergence and polymorphism of HLA molecules has never been shown before. Additionally, we show that a single substitution in HLA-B molecules has more effect on the peptide-binding repertoire compared to that in HLA-A molecules. This provides an (alternative) explanation for the larger polymorphism of HLA-B molecules compared to HLA-A molecules.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-015-0849-y) contains supplementary material, which is available to authorized users.
Highlights
Human leukocyte antigen (HLA) molecules play a central role in induction of T cell responses, because a T cell recognizes an infected cell only in the context of peptides presented by HLA molecules
A randomly chosen pair of HLA molecules can be different from each other at several positions. Since it is unclear whether or not the effect of substitutions is additive, we restricted ourselves to the effect of single substitutions
2010) and SYFPEITHI (Rammensee et al 1999) databases, and found data for 26 pairs of HLA molecules that differ in only a single position among these 61 positions
Summary
Human leukocyte antigen (HLA) molecules play a central role in induction of T cell responses, because a T cell recognizes an infected cell only in the context of peptides presented by HLA molecules. HLA molecules present a different set of peptides to T cells and to NK cells, and this property has been, most likely, the main driving force behind the HLA polymorphism. A novel HLA molecule with a (slightly) altered peptide-binding repertoire will be maintained in the population, if the new binding preference provides fitness advantage to its host. Because of the high polymorphism and their role in generating an immune response, it is not surprising that HLA molecules are associated with more diseases than any other region of the genome (Horton et al 2004; de Bakker et al 2006). HLA-B*27:05 is associated with ankylosing spondylitis, in contrast to HLA-B*27:09
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