| Summary: | Abstract Background Interactions between proteins are key components in the chemical and physical processes of living organisms. Among these interactions, membrane receptors and their ligands are particularly important because they are at the interface between extracellular and intracellular environments. Many studies have investigated how binding partners have co-evolved in genomes during the evolution. However, little is known about the establishment of the interaction on a phylogenetic scale. In this study, we systematically studied the time of birth of genes encoding human membrane receptors and their ligands in the animal tree of life. We examined a total of 553 pairs of ligands/receptors, representing non-redundant interactions. Results We found that 41% of the receptors and their respective first ligands appeared in the same branch, representing 2.5-fold more than expected by chance, thus suggesting an evolutionary dynamic of interdependence and conservation between these partners. In contrast, 21% of the receptors appeared after their ligand, i.e. three-fold less often than expected by chance. Most surprisingly, 38% of the receptors appeared before their first ligand, as much as expected by chance. Conclusions According to these results, we propose that a selective pressure is exerted on ligands and receptors once they appear, that would remove molecules whose partner does not appear quickly.
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