Fig. 2.

Evolutionary history of the IL-1 ligand family. a Chromosomal gene location as evidence of ancestral relationship of IL-1 family members. The highly conserved nature of surrounding genes suggests three separate evolutionary families, as follows: IL-1β, IL-18, and IL-33. b A simplified evolutionary tree with time scale of cartilaginous and bony fish, birds, reptiles, mammals and the approximate time line of the evolutionary occurrence of IL-1 family members^54,55. IL-1β and IL-18 are expressed exclusively in all vertebrate species, including cartilaginous fish, suggesting that they evolved prior to the divergence of bony and cartilaginous fish ~425 million years ago (ii); IL-1α, IL-33 and IL-36 α, β & γ are expressed exclusively in mammals therefore likely formed in the common ancestor of all mammals (Synapsid lineage) (iv). This event must have occurred after divergence of the Synapsid lineage (iv) 320 million years ago but prior to the divergence of mammals 160 million years ago (v). c An ancestral and superfamily scheme of the IL-1 ligands. d Composite evolutionary history of the IL-1 family of cytokines constructed by overlaying the evidence from chromosomal location and clade IL-1 family gene profile on to the maximum likelihood tree from Supplementary Data 2. The percentage of trees in which the associated group clustered together is shown next to the branches from 1000 bootstrap replications. Primary branches that occur in <50% of trees were collapsed. The tree is drawn to scale, with branch lengths measured in the number of amino acid replacements per site. The analysis involved 155 amino acid sequences with a final alignment length of 64 positions. All positions containing gaps and missing data were eliminated. Scale bar is 0.5 replacements per site