title: Diversification and coevolution of the ghrelin/growth hormone secretagogue receptor system in vertebrates.
abstract: 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.
authors.affiliation: Genome Centre at Max Planck Institute for Plant Breeding Research Carl-von-Linné-Weg 10D-50829 Köln Germany; Molecular Zoology Laboratory Department of Zoology University of Johannesburg Kingsway Campus Auckland Park 2006 South Africa.
authors.forename: Mbaye
authors.initials: M
authors.lastname: Tine
authors.affiliation: Max Planck Institute for Molecular Genetics Ihnestrasse 63-73 14195 Berlin Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Kuhl
authors.affiliation: Molecular Zoology Laboratory Department of Zoology University of Johannesburg Kingsway Campus Auckland Park 2006 South Africa.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Teske
authors.affiliation: Helmholtz Diabetes Center & German Diabetes Center (DZD) Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases Technische Universität München 80333 Munich Germany.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: Helmholtz Diabetes Center & German Diabetes Center (DZD) Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases Technische Universität München 80333 Munich Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
keywords: Coevolution; divergence; function; ghrelin; growth hormone secretagogue receptor; vertebrates