Discovery of polypeptide ligand-receptor pairs based on their co-evolution.

Sequencing diverse genomes allowed the tracing of orthologous and paralogous genes to understand the co-evolution of polypeptide ligands and receptors. This review documents the discovery of several polypeptide ligands and their cognate receptors mainly expressed in the reproductive tissue using evolutionary genomics. We discussed the sub-functionization of paralogs and co-evolution of ligand-receptor families. Based on the conserved signaling among paralogous receptors and common knock-out phenotypes of ligand-receptor pairs, relationships between relaxin family peptides and leucine-rich repeat-containing, G protein-coupled receptors (LGR) were revealed. We also described the identification of a novel paralogous glycoprotein hormone thyrostimulin and design of a long-acting FSH. Human stresscopin and stresscopin-related peptide, paralogous to CRH, were also identified based on the conserved signaling pathways. Recently, a novel ligand placensin expressed in human placenta was found based on the paralogous relationship with a metabolic hormone asprosin. Placensin likely contributes to stage-dependent increases in insulin resistance during human pregnancy and its elevated secretion was associated with gestational diabetes mellitus. Although many ligands were predicted based on sequence signatures, ligands of shorter sequences have not been identified, together with many "orphan" receptors without known ligands. Future development of tools for predicting ligands and high throughput assays to identify ligand-receptor pairs based on ligand binding and/or signal transduction could advance hormone-based physiology and pathophysiology.