The orthology of HLA-E and H2-Qa1 is hidden by their concerted evolution with other MHC class I molecules.

Background: Whether MHC molecules undergo concerted evolution or not has been the subject of a long-standing debate.

Results: By comparing sequences of eight functional homologues of HLA-E from primates and rodents with those of MHC class Ia molecules from the same eight species, we find that different portions of MHC class I molecules undergo different patterns of evolution. By focusing our analyses sequentially on these various portions, we have obtained clear evidence for concerted evolution of MHC class I molecules, suggesting the occurrence of extensive interallelic and intergenic exchanges. Intra-species homogenisation of sequences is particularly noticeable at the level of exon 4, which codes for the alpha3 domain, but our results suggest that homogenisation also concerns certain residues of the alpha1-alpha2 codomain that lie outside the antigen recognition site.

Conclusion: A model is presented in which Darwinian selective pressures due to pathogens could, at the same time, favour diversification of MHC class Ia molecules and promote concerted evolution of separate loci by spreading advantageous motifs arising by mutations in individual MHC molecules to other alleles and to other loci of the MHC region. This would also allow MHC molecules to co-evolve with the proteins with which they interact to fulfil their functions of antigen presentation and regulation of NK cell activity. One of the raisons d'être of the MHC may therefore be to favour at the same time both diversification of MHC class Ia molecules and homogenisation of the whole pool of MHC class I molecules (Ia and Ib) involved in antigen presentation.

Reviewers: This article was reviewed by Stephan Beck, Lutz Walter and Pierre Pontarotti.