Gene duplication plays a major role in gene co-option: Studies into the evolution of the motilin/ghrelin family and their receptors

Abstract

Extant genes can be modified, or 'tinkered with', to provide new roles or new characteristics of these genes. At the genetic level, this often involves gene duplication and specialization of the resulting genes into particular functions. We investigate how ligand-receptor partnerships evolve after gene duplication. While significant work has been conducted in this area, the examination of additional models should help us better understand the proposed models and potentially reveal novel evolutionary patterns and dynamics. We use bioinformatics, comparative genomics and phylogenetic analyses to show that preproghrelin and prepromotilin descended from a common ancestor and that a gene duplication generated these two genes shortly after the divergence of amphibians and amniotes. The evolutionary history of the receptor family differs from that of their cognate ligands. GPR39 diverges first, and an ancestral receptor gives rise to receptors classified as fish-specific clade A, GHSR and MLNR by successive gene duplications occurring before the divergence of tetrapods and ray-finned fish. The ghrelin/GHSR system is maintained and functionally conserved from fish to mammals. Motilin-MLNR specificity must have arisen by ligand-receptor coevolution after the MLN hormone gene diverged from the GHRL gene in the amniote lineage. Conserved molecular machinery can give rise to new neuroendocrine response mechanisms by the co-option of duplicated genes. Gene duplication is both parsimonious and creative in producing elements for evolutionary tinkering and plays a major role in gene co-option, thus aiding the evolution of greater biological complexity.ghrelin, motilin, gene family, ligand, receptor, coevolution, gene interaction Citation:He J, David I M, Zhang Y P. Gene duplication plays a major role in gene co-option: Studies into the evolution of the motilin/ghrelin family and their receptors.

The Power of an Evolutionary Perspective in Studies of Endocrinology

“…In combination with phylogenetic reconstruction, the monophyly of each receptor type was established, and no more than one copy of each type of receptor was identified in any of the studied species. GHSR and MLNR are more closely related to each other than they are to any other characterized receptor, and the gene duplication that generated them happened more than 450 million years ago, before the divergence of rayfinned fish and tetrapods (He et al 2011). Through comparative and evolutionary analyses, we found a new type of receptor in fish, which does not have an ortholog in any non-fish vertebrate.…”

“…The function of this new receptor is unknown. The sequence of this new receptor has some peculiarities, such as possessing long extracellular loops 2 and 3, which are about 100 residues longer than the analogous loops in GHSR and MLNR (He et al 2011). Residues at both ends of these loops have been shown to be functionally important for hormone binding and action in homologous receptors; however, the function of these residues in the loops of these novel receptors is not clear (Matsuura, Dong and Miller 2002).…”

“…2). Based on the distribution of GHRL and MLN genes in the species studied, comparative genomics analysis between human and other vertebrates, and endoproteinase cleavage sites distribution in GHRL/MLN genes, we surmise that MLN was generated by a gene duplication on the early amniote lineage as illustrated in figure 2 (He et al 2011). Other potential evolutionary scenarios (e.g., duplication prior to the fish-tetrapod divergence) require a larger number of gene deletion events along with parallel gain or loss of endopeptidease cleavage sites, and thus are less parsimonious.…”

“…This time period of rapid evolution coincides with the date of the GHRL/ MLN gene duplication event, thus it is reasonable to speculate, that the burst of rapid evolution in MLNR was a consequence of coevolution with its new ligand, and that motilin binding specificity of MLNR only evolved as a result of ligandreceptor coevolution after the motilin gene diverged from the ghrelin gene on the amniote lineage. In contrast, GHSR has evolved under a constant selective constraint throughout vertebrates, with the ghrelin/GHSR system being maintained and functionally conserved from fish to mammals (He et al 2011). …”

“…Divergence of function in different species is accomplished by hormone/receptor coevolution to improve binding affinity and/or specificity. A major role for gene co-option, involving gene duplication and divergence, should be recognized that creates potential elements which selection can act upon within a biological network to evolve new functions (He et al 2011;True and Carroll 2002). The growth of gene families allows for more flexible gene expression and/or the evolution of new biochemical specificities (Rubenstein 1990;Sharman and Holland 1996), thus facilitating the evolution of greater biological complexity (Duboule and Wilkins1998).…”