Evolution of the interleukin-1 gene family in mammals.

The phylogeny of interleukin-1 family genes shows that human interleukin-1 alpha (IL-1 alpha) is more closely related to IL-1 alpha of the bovine than to IL-1 alpha of the mouse, whereas human interleukin-1 beta (IL-1 beta) is more closely related to IL-1 beta of the mouse than to IL-1 beta of the bovine. The IL-1 receptor antagonist (IL-1ra) shows homology to the C-terminal region of both IL-1 alpha and IL-1 beta. In the C-terminal region, the IL-1 alpha genes of human and mouse have diverged more from each other at nonsynonymous sites than have either IL-1 beta or IL-1ra; because the same pattern is not seen at synonymous sites, it must be due not to a difference in mutation rate but rather to a greater degree of functional constraint on this region in the IL-1 beta and IL-1ra proteins than in the IL-1 alpha protein. But synonymous sites in IL-1 beta of mouse have evolved more rapidly than in IL-1 beta of human, indicating a higher rate of mutation in the former gene. In the N-terminal region of the protein, nonsynonymous sites have evolved at similar rates in IL-1 alpha and IL-1 beta. The first exon of the IL-1ra gene, which encodes the leader peptide, shows evidence of homology with the first exon of IL-1 beta, which is not translated. Thus, it seems likely that IL-1ra evolved by duplication of an IL-1 beta gene and loss of expression of exons 2-4.