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Diversification and coevolution of the ghrelin/growth hormone secretagogue receptor system in vertebrates.
Ecol. Evol. 6, 2516-2535 (2016)
The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O-acyltransferase (GOAT) or membrane-bound O-acyltransferase domain-containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS-R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS-R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single-gene locus in all vertebrate species, and accordingly, a single GHS-R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS-R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS-R isoforms were identified in teleost genomes. This diversification of GHS-R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS-R but not the ghrelin gene. The identification of the GHS-R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure-function relationships of the ghrelin/GHS-R system.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Coevolution ; Divergence ; Function ; Ghrelin ; Growth Hormone Secretagogue Receptor ; Vertebrates; Growth-hormone; Solvent Accessibility; Genome Duplication; Protein Evolution; Functional-characterization; Nonsynonymous Substitution; Structural Determinants; Genes; Identification; Selection
e-ISSN
2045-7758
Journal
Ecology and Evolution
Quellenangaben
Volume: 6,
Issue: 8,
Pages: 2516-2535
Publisher
Wiley
Publishing Place
[S.l.]
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Obesity (IDO)