EVOLUTION OF MURINE ALPHA-(1)-PROTEINASE INHIBITORS - GENE AMPLIFICATION AND REACTIVE CENTER DIVERGENCE

The organization and sequence of genes encoding the alpha(1)-proteinas e inhibitor (alpha(1)PI), a major serine proteinase inhibitor of the m ammalian bloodstream, have been compared in several species, including murine rodents (genus Mus). Analysis of gene copy number indicates th at amplification of alpha(1)PI genes occurred at some time during evol ution of the Mus genus, leading to fixation of a family of about three to five genes in several existing species (e.g., M. domesticus and M. saxicola), and only a single gene in others (e.g., M. caroli). A phyl ogeny for the various mammalian alpha(1)PI mRNAs was constructed based upon synonymous substitutions within coding regions. The mRNAs in dif ferent murine species diverged from a common ancestor before the forma tion of the first species lineages of the Mus genus, i.e., about 10-13 million years ago. Thus, alpha(1)PI gene amplification must have occu rred prior to Mus speciation; gene families were retained in some, but not all, murine species. The reactive center region of the alpha(1)PI polypeptide, which determines target protease specificity, has diverg ed rapidly during evolution of the Mus species, but not during evoluti on of other mammalian species included in the analysis. It is likely t hat this accelerated evolution of the reactive center, which has been noted previously for serine proteinase inhibitors, was driven by some sort of a positive Darwinian selection that was exerted in a taxon-spe cific manner. We suggest that evolution of alpha(1)PI genes of murine rodents has been characterized by both modification of gene copy numbe r and rapid reactive center divergence. These processes may have resul ted in a broadened repertoire of proteinase inhibitors that was evolut ionarily advantageous during Mus speciation.