Figure S2.

The Peptidergic Signaling System Has Been Shaped by Co-evolution of Ligands and Their Receptor Targets, Related to Figure 1

(A) Receptors and their ligands are ubiquitously expressed in human organs and tissues. The data is ordered by mean level of peptide receptor expression. Peptide receptors consistently had lower median expression levels than non-peptide GPCRs. Similar peptide receptor-ligand expression levels were observed for liver and smooth muscle, whereas granulocytes and lung tissue had higher expression of receptors than ligand precursors (Wilcoxon rank sum test; P values: < 1x10⁻⁵ (granulocytes) and 0.02 (lung)).

(B) Evolutionary fingerprints indicated conservation (gray) or absence (white) of receptor and peptide precursor gene orthologs in 313 species (representatives shown). The fingerprint identity (%) reflects the evolutionary relationship of peptide-receptor pairs. Photos from Ensembl genome database project.

(C) The average percentage identity of evolutionary receptor-ligand pairs for all endogenous receptor-ligand pairs is increased when fingerprints of ligands for the same receptor are merged and is greater than for a random protein pair (permutation tests by performing 10,000 randomizations, Wilcoxon rank sum test P value < 1x10⁻⁵).

(D) Jaccard index similarity of human peptide receptor and ligand precursor repertoires (n = 131 and 130, respectively) to selected species ordered by evolutionary distance. Data in Tables S1 and S2.