An evolutionary switch in tissue-specific gene expression. Abundant expression of alpha 1-antitrypsin in the kidney of a wild mouse species.

alpha 1-Antitrypsin (AT), one of the major proteinase inhibitors in mammalian serum, is generally considered to be synthesized exclusively in the liver. We have found that a wild-derived Mus species, Mus caroli, expresses AT mRNA in kidney at levels approaching that in liver; no other mouse, inbred or wild-derived, exhibits this striking property. Liver and kidney mRNAs from M. caroli encode very similar AT polypeptides that are distinct from that encoded by Mus musculus liver mRNA. In vivo, liver AT is secreted into the bloodstream, while kidney AT, which is processed differently from the liver protein, is excreted into the urine. Analysis of RNA from a hybrid between M. musculus and M. caroli indicates that a cis-acting genetic element may be responsible for the difference in AT expression. Restriction enzyme digestion patterns of AT genomic sequences in M. caroli DNA are considerably different from those in M. musculus; in addition, these sequences are undermethylated in liver DNA from M. musculus and in liver and kidney DNA from M. caroli, reflecting the respective patterns of expression. Further studies of the altered tissue specificity of AT expression that is apparent in these two related species should lead to new insights into the nature and evolution of genetic determinants of tissue-specific phenotypes.