Evolution of protein inhibitors of serine proteinases: positive Darwinian selection or compositional effects?

In at least two instances involving serine proteinase inhibitors it has been shown that functionally important sites evolve faster and exhibit more interspecific variability than functionally neutral sites. Because these phenomena are difficult to reconcile with the neutral theory of molecular evolution, it has been suggested that the accelerated rate of amino acid substitution at the reactive sites is brought about by positive Darwinian selection. We show that differences in the amino acid composition in the different regions of proteinase inhibitors can account for the differences in the rates of amino acid substitution. By using an index of protein mutability [D. Graur (1985) J Mol Evol 22:53-62], we show that the amino acid composition of the reactive center in the ovomucoids and Spi-2 gene products is such that, regardless of function, they are expected to evolve more rapidly than any other polypeptide for which the rate of substitution is known. In addition, the reactive region in the Spi-2 proteins is shown to be free of compositional constraint. Positive Darwinian selection need not be invoked at the present time in these cases.