Evolution of the Mhc class I region: the framework hypothesis

A comparison of the major histocompatibility complex (Mhc) region between h uman and mouse highlights both stability and differences. The class II and class III regions are orthologous; they probably existed in the ancestor in a similar organization and were not subjected to major rearrangement. The class I genes, by contrast, are definitely paralogous, having been reorgani zed several times. As long as only class I genes were identified, the class I regions of human and mouse were difficult to compare directly. The ident ification of non-class I genes has allowed a comparative map to be drawn, w hich shows that the class I region is orthologous between human and mouse a s well. The lack of orthology specifically applies to the class I sequences . However, the comparative map shows that the non-orthologous class I seque nces occupy homologous locations with regard to the conserved genes. I prop ose a model to explain this paradox. The conserved genes may represent samp les of a dense "framework" of genes whose alterations are deleterious. The homologous positions occupied by class I genes would thus represent the few permissive places allowing major perturbations. The evolution of the class I sequences, by duplication and deletion, independently in the two species , has taken place within the scope defined by the framework: insertion at t he permissive places, and expansion by creation of class I-related DNA by d uplication, thus pushing back the boundaries of the framework.