Rapid evolution of the ribonuclease A superfamily: Adaptive expansion of independent gene clusters in rats and mice

The two eosinophil ribonucleases, eosinophil-derived neurotoxin (EDN/RNase 2) and eosinophil cationic protein (ECP/RNase 3), are among the most rapidl y evolving coding sequences known among primates. The eight mouse genes ide ntified as orthologs of EDN and ECP form a highly divergent, species-limite d cluster. We present here the rat ribonuclease cluster, a group of eight d istinct ribonuclease A superfamily genes that are more closely related to o ne another than they are to their murine counterparts. The existence of ind ependent gene clusters suggests that numerous duplications and diversificat ion events have occurred at these loci recently, sometime after the diverge nce of these two rodent species (similar to 10-15 million years ago). Nonsy nonymous substitutions per site (d(N)) calculated for the 64 mouse/rat gene pairs indicate that these ribonucleases are incorporating nonsilent mutati ons at accelerated rates, and comparisons of nonsynonymous to synonymous su bstitution (d(N)/d(S)) suggest that diversity in the mouse ribonuclease clu ster is promoted by positive (Darwinian) selection. Although the pressures promoting similar but clearly independent styles of rapid diversification a mong these primate and rodent genes remain uncertain, our recent findings r egarding the function of human EDN suggest a role for these ribonucleases i n antiviral host defense.