Expression of the a,-Proteinase Inhibitor Gene Family During Evolution of the Genus Mus

a,-Proteinase inhibitors (a,-PIs) are members of the serpin superfamily of proteinase inhibitors, and are important in the maintenance of homeostasis in a wide variety of animal taxa. Previous studies have shown that in mice (genus Mus), evolution of cx,-PIs is characterized by gene amplification, region-specific concerted evolution, and rapid accumulation of amino acid substitutions. The latter occurs primarily in the reactive center, which is the region of the OL,-PI molecule that determines the inhibitor’s specificity for target proteinases. The Pl residue within the reactive center, which is methionine in so-called orthodox a,-PIs and an amino acid other than methionine in unorthodox cx,-PIs, is a primary determinant of inhibitor specificity. In the present study, we find that the expression of mRNAs encoding unorthodox a,-PIs is polymorphic within Mus species, i.e., among individuals or inbred strains. This is in striking contrast to mRNAs that encode orthodox a,-PIs, whose concentrations are relatively invariant. The intraspecies variations in mRNA expression represent polymorphisms in the structure of the a,-PI gene family. The results, taken together with previously described aspects of al-PI evolution, indicate that the dissimilar levels of polymorphism exhibited by orthodox and unorthodox a,-PIs, which likely have distinct physiological functions, may reflect different levels of selective constraint. The significance of this finding to the evolution of gene families is discussed.