Evolution of human genes encoding cell surface receptors involved in the regulation of appetite: an analysis based on the phylostratigraphic age and divergence indexes

Abstract

Genes encoding cell surface receptors make up a significant portion of the human genome (more than a thousand genes) and play an important role in gene networks. Cell surface receptors are transmembrane proteins that interact with molecules (ligands) located outside the cell. This interaction activates signal transduction pathways in the cell. A large number of exogenous ligands of various origins, including drugs, are known for cell surface receptors, which accounts for interest in them from biomedical researchers. Appetite (the desire of the animal organism to consume food) is one of the most primitive instincts that contribute to survival. However, when the supply of nutrients is stable, the mechanism of adaptation to adverse factors acquired in the course of evolution turned out to be excessive, and therefore obesity has become one of the most serious public health problems of the twenty-first century. Pathological human conditions characterized by appetite violations include both hyperphagia, which inevitably leads to obesity, and anorexia nervosa induced by psychosocial stimuli, as well as decreased appetite caused by neurodegeneration, inflammation or cancer. Understanding the evolutionary mechanisms of human diseases, especially those related to lifestyle changes that have occurred over the past 100–200 years, is of fundamental and applied importance. It is also very important to identify relationships between the evolutionary characteristics of genes in gene networks and the resistance of these networks to changes caused by mutations. The aim of the current study is to identify the distinctive features of human genes encoding cell surface receptors involved in appetite regulation using the phylostratigraphic age index (PAI) and divergence index (DI). The values of PAI and DI were analyzed for 64 human genes encoding cell surface receptors, the orthologs of which were involved in the regulation of appetite in model animal species. It turned out that the set of genes under consideration contains an increased number of genes with the same phylostratigraphic age (PAI = 5, the stage of vertebrate divergence), and almost all of these genes (28 out  of 31) belong to the superfamily of G-protein coupled receptors. Apparently, the synchronized evolution of such a large group of genes (31 genes out of 64) is associated with the development of the brain as a separate organ in the first vertebrates. When studying the distribution of genes from the same set by DI values, a significant enrichment with genes having a low DIs was revealed: eight genes (GPR26, NPY1R, GHSR, ADIPOR1, DRD1, NPY2R, GPR171, NPBWR1) had extremely low DIs (less than 0.05). Such low DI values indicate that most likely these genes are subjected to stabili zing selection. It was also found that the group of genes with low DIs was enriched with genes that had brain-specific patterns of expression. In particular, GPR26, which had the lowest DI, is in the group of brain-specific genes. Because the endogenous ligand for the GPR26 receptor has not yet been identified, this gene seems to be an extremely interesting object for further theoretical and experimental research. We believe that the features of the genes encoding cell surface receptors we have identified using the evolutionary metrics PAI and DI can be a starting point for further evolutionary analysis of the gene network regulating appetite.