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The Evolution of Vertebrate Somatostatin Receptors and Their Ocampo Daza et al. BMC Evolutionary Biology 2012, 12:231 http://www.biomedcentral.com/1471-2148/12/231 RESEARCH ARTICLE Open Access The evolution of vertebrate somatostatin receptors and their gene regions involves extensive chromosomal rearrangements Daniel Ocampo Daza1*, Görel Sundström1,2, Christina A Bergqvist1 and Dan Larhammar1 Abstract Background: Somatostatin and its related neuroendocrine peptides have a wide variety of physiological functions that are mediated by five somatostatin receptors with gene names SSTR1-5 in mammals. To resolve their evolution in vertebrates we have investigated the SSTR genes and a large number of adjacent gene families by phylogeny and conserved synteny analyses in a broad range of vertebrate species. Results: We find that the SSTRs form two families that belong to distinct paralogons. We observe not only chromosomal similarities reflecting the paralogy relationships between the SSTR-bearing chromosome regions, but also extensive rearrangements between these regions in teleost fish genomes, including fusions and translocations followed by reshuffling through intrachromosomal rearrangements. These events obscure the paralogy relationships but are still tractable thanks to the many genomes now available. We have identified a previously unrecognized SSTR subtype, SSTR6, previously misidentified as either SSTR1 or SSTR4. Conclusions: Two ancestral SSTR-bearing chromosome regions were duplicated in the two basal vertebrate tetraploidizations (2R). One of these ancestral SSTR genes generated SSTR2, -3 and -5, the other gave rise to SSTR1, -4 and -6. Subsequently SSTR6 was lost in tetrapods and SSTR4 in teleosts. Our study shows that extensive chromosomal rearrangements have taken place between related chromosome regions in teleosts, but that these events can be resolved by investigating several distantly related species. Keywords: Somatostatin receptors, Whole genome duplications, Chromosome rearrangements Background tetrapods and teleost fishes, respectively. They are es- The availability of a large variety of annotated and pecially important for studies of genomic events that assembled vertebrate genome sequences has made it have taken place in either teleost or tetrapod evolu- possible to address specific evolutionary questions on a tion, as is the case for the chromosomal regions genome-wide scale. This includes both large-scale ana- described in the present study. lyses of genome evolution [1-5] and targeted compara- The basal vertebrate whole genome duplications (2R) tive evolutionary studies of specific gene families. The [1,3,4] and subsequently the teleost-specific genome du- Ensembl genome database (www.ensembl.org) includes plication (3R) [2,7] have expanded numerous endocrine genomes for representatives of most vertebrate classes, and neuronal gene families, see for example references as well as suitable out-groups for the study of verte- [8-15]. Here we have subjected the chromosomal regions brate evolution [6]. The recent addition of the gen- harboring the somatostatin receptor family genes to a omes of the Comoran coelacanth Latimeria chalumnae detailed analysis by collecting sequences from a broad and the spotted gar Lepisosteus oculatus complements range of vertebrate genomes, including several teleost the previous set of species with pivotal out-groups for fishes as well as the spotted gar and the coelacanth. Somatostatin, the short peptide responsible for inhib- * Correspondence: [email protected] ition of growth hormone release, was sequenced from 1Department of Neuroscience, Science for Life Laboratory, Uppsala Universitet, Box 593, SE-75124 Uppsala, Sweden sheep hypothalamus in 1973 [16] and its discovery was Full list of author information is available at the end of the article one of the achievements highlighted by the 1977 Nobel © 2012 Ocampo Daza et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ocampo Daza et al. BMC Evolutionary Biology 2012, 12:231 Page 2 of 19 http://www.biomedcentral.com/1471-2148/12/231 Prize in physiology or medicine. Subsequently this 14- that we have called SSTR6, which is still present in amino-acid peptide was sequenced in numerous other some teleost fishes, the spotted gar and the coelacanth, vertebrate species and was found to be highly conserved but has been lost in tetrapods. Thus, the somatostatin during evolution. Somatostatin is widely distributed and receptor system obtained its present complexity already serves both as a neuroendocrine peptide regulating the in the early stages of vertebrate evolution. By centering pituitary, a neuropeptide acting on other neurons, and our analyses around the SSTR genes we could also as an endocrine peptide. In accordance with this, som- disentangle complex rearrangements in the SSTR- atostatin has been reported to have many physiological bearing chromosome regions in teleost fish genomes. effects [17]. A somatostatin-related peptide was discov- This has implications for analyses of conserved synteny ered in mouse and human and was named cortistatin or and the assignment of orthology for genes located in somatostatin-2 [18]. It is now known to be present these regions. throughout the tetrapods. In teleost fishes additional somatostatin-like peptides exist named somatostatin Results 3–6, each encoded by a separate gene [19]. All of Phylogenetic analysis of the SSTR gene family; these duplicates may have arisen through chromosome identification of a sixth SSTR subtype duplications in 2R and 3R [19,20]. Somatostatin receptor amino acid sequences were col- After the first identification of binding sites for som- lected from genome databases for several species repre- atostatin, evidence began to accumulate for more than senting most of the vertebrate classes: In addition to one receptor subtype. The cloning era of G-protein- tetrapod and teleost fish genomes, the genomes of the coupled receptors led to the discovery of five somato- Comoran coelacanth (Latimeria chalumnae) and the statin receptor subtypes in mammals, named SSTR1 spotted gar (Lepisosteus oculatus) were investigated in through 5 [21]. The conserved structure of somatostatin order to provide relative dating points earlier in the evo- receptor genes consists of a single exon encoding pro- lution of lobe-finned fishes (Sarcopterygii) and ray- tein products of approximately 360 to 420 amino acids. finned fishes (Actinopterygii), respectively. The identified The somatostatin receptors have been classified into two amino acid sequences include predictions from several subfamilies based upon their degree of sequence identity: previously unknown SSTR sequences. These results are The human SSTR1 and SSTR4 amino acid sequences summarized in Table 1, and detailed descriptions of the share 70% sequence identity in the region spanning identified sequences are included as Supplemental note 1 TM1 to TM7 (including the loops), while SSTR2, -3 and (see Additional file 1). -5 share 56-66% amino acid sequence identity to each The SSTR amino acid sequences identified in the gen- other. All five receptor subtypes inhibit adenylyl cyclases ome databases were used to create an alignment for [22] and they can also trigger other second messenger phylogenetic analyses in order to determine the identity pathways to various extents. of previously unknown SSTR sequences and study the Homologs of the mammalian somatostatin receptors evolution of this gene family. Using the human have been described in several teleost fishes, see Nelson kisspeptin-1 receptor as out-group, the resulting phylo- & Sheridan (2005) [23] for review. However, no SSTR4 genetic maximum likelihood (PhyML) tree in Figure 1 subtype has yet been described in a teleost fish. The shows that the vertebrate SSTR family consists of six known SSTR repertoire in chicken is the same as in subtype clusters representing the five known SSTR sub- mammals and several of the receptors have been studied types SSTR1 through SSTR5, as well as a previously functionally [24,25]. It was proposed several years ago unrecognized sixth subtype. We have named these that the SSTR family expanded in 2R [21] although it sequences SSTR6 in our studies. In agreement with pre- was not clear how the appearance of the five members vious analyses of fewer sequences [21,23,27], the tree has correlated with the two genome doublings. A more re- two well-defined ancestral branches; one including cent phylogenetic analysis [26] presented a tree that was SSTR2, -3 and -5, and one containing the SSTR1 and -4 unresolved both with respect to species taxonomy and as well as the SSTR6 subtype. Both branches are somatostatin receptor subtypes. Other investigators have well-supported, and the separate SSTR subtypes form proposed that the SSTRs arose from a series of duplica- well-supported clusters within each branch, using tions throughout vertebrate evolution [27,28]. both bootstrapping and SH-like approximate likelihood Our analyses allow us to conclude that the chromo- ratio statistics (see Additional file 2, Figures S1 and S2). some duplications in early vertebrate evolution (2R), and Some subtypes are missing from some species’ genome in the teleost tetraploidization (3R), can explain the databases (see Additional file 1, Supplemental note 1). known repertoire of
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