Is a mutator analogous to the Ig hypermutator of the sheep ileal Peyer's patch active on MHC class I genes in the germ line?

Abstract

Polymorphic sequence variation in the peptide-binding domains of MHC class I molecules appears to have been driven largely by the constructive action of natural selection on the specificity of the peptide-binding groove. Similar features are displayed by the variable domains of immunoglobulins generated in the sheep ileal Peyer's patch, but in this case there is evidence that the action of a targeted hypermutator acting on a selected substrate rather than antigen-driven selection is responsible for the pattern of variation in the system. Such a hypermutator acting in the germ line would not only mimic the action of natural selection but also, by convergent mutation, generate similar patterns of variation in unrelated alleles that could be interpreted as evidence for short-tract gene conversion. We analyzed human class I MHC alleles in the light of these data, but failed to find evidence of the action of a similar hypermutator. A search for other mutationally driven patterns of variation also failed, even in hypervariable residues from parsimonious phylogenies. Single-nucleotide variation at these residues is also frequent in recent allelic variants, but the data are as consistent with short-tract gene conversion as with base mutation. We conclude that the patterns of allelic variation in MHC molecules are not driven by mutational pressure, but rather by conventional mutational processes, accompanied by short-tract gene conversion and intense natural selection.