PATTERNS OF DIVERGENCE DURING EVOLUTION OF ALPHA(1)-PROTEINASE INHIBITORS IN MAMMALS

alpha(1)-Proteinase inhibitor alpha(1)-PI), a member of the serine pro teinase inhibitor superfamily, has a primary role in controlling neutr ophil elastase activity within the mammalian circulation. Several stud ies have indicated that the reactive center region of alpha(1)-PI, the amino acid sequence of which is critical to recognition of and bindin g to target proteinases, is highly divergent within and among species. This appears to be a consequence of accelerated rates of evolution th at may have been driven by positive Darwinian selection. In order to e xamine this and other features of alpha(1)-PI evolution in more detail , we have isolated and sequenced cDNAs representing alpha(1)-PI mRNAs of the mouse species Mus saxicola and Mus minutoides and have compared these with a number of other mammalian alpha(1)-PI mRNAs. Relative to other mammalian mRNAs, the extent of nonsynonymous substitution is ge nerally high throughout the alpha(1)-PI mRNA molecule, indicating grea ter overall rates of amino acid substitution. Within and among mouse s pecies, the 5'-half of the mRNA, but not the 3'-half, has been homogen ized by concerted evolution. Finally, the reactive center is under div ersifying or positive Darwinian selection in murid rodents (rats, mice ) and guinea pigs yet is under purifying selection in primates and art iodactyls. The significance of these findings to alpha(1)-PI function and the possible selective forces driving evolution of serpins in gene ral are discussed.