Advances in understanding neuronal somatostatin receptors

It has long been considered that somatostatin acts as a neuromodulator in the mammalian central nervous system but its precise physiological roles remain elusive. Early studies to identify somatostatin-binding sites revealed a widespread heterogeneous pattern, especially in the CNS. More recently, a family of somatostatin receptors have been identified, of which five genes (sst_1–5) have been cloned. In this review, we discuss current data describing the localisation of the five receptor types. Recent progress in understanding their function has been made using high-affinity, selective receptor ligands and transgenic animal technology. Finally, the therapeutic potential for somatostatin receptor-selective compounds as analgesics is considered.     

Defining the origins and evolution of the chemokine/chemokine receptor system

The chemokine system has a critical role in mammalian immunity, but the evolutionary history of chemokines and chemokine receptors are ill-defined. We used comparative whole genome analysis of fruit fly, sea urchin, sea squirt, pufferfish, zebrafish, frog, and chicken to identify chemokines and chemokine receptors in each species. We report 127 chemokine and 70 chemokine receptor genes in the 7 species, with zebrafish having the most chemokines, 63, and chemokine receptors, 24. Fruit fly, sea urchin, and sea squirt have no identifiable chemokines or chemokine receptors. This study represents the most comprehensive analysis of the chemokine system to date and the only complete characterization of chemokine systems outside of mouse and human. We establish a clear evolutionary model of the chemokine system and trace the origin of the chemokine system to approximately 650 million years ago, identifying critical steps in their evolution and demonstrating a more extensive chemokine system in fish than previously thought.     

Phylogeny of the insulin-like growth factors (IGFS) and receptors: A molecular approach

The IGFs (IGF-I and IGF-II) are essential for normal mammalian growth and development. Their actions are mediated primarily by their interactions with the type I IGF receptor (IGF-I receptor), a transmembrane tyrosine kinase. The ligands and the IGF-I receptor are structurally related to insulin and to the insulin receptor, respectively. Analysis of evolutionary conservation has often provided insights into essential regions of molecules such as hormones and their receptors. The genes for insulin and IGFs have been partially characterized in a number of vertebrate species extending evolutionarily from humans as far back as fish. The sequences of the exons encoding the mature insulin and IGF peptides are highly conserved among vertebrate species, and IGF-I-Iike molecules are found in species whose origins extend back as much as 550 million years. The insulin receptor is also highly conserved in vertebrate species, and an insulinreceptor-like molecule has been characterized in Drosophila. In contrast, IGF-I receptors have only been characterized in mammalian species and partially studied in Xenopus, in which the tyrosine kinase domain is highly conserved. Studies are presently being undertaken to analyze in more detail the regulation of the genes encoding this important family of growth factors and the structure/function relationships in the gene products themselves. © 1993 Wiley-Liss, Inc.     

The Xenopus FcR family demonstrates continually high diversification of paired receptors in vertebrate evolution

Background  

Recent studies have revealed an unexpected diversity of domain architecture among FcR-like receptors that presumably fulfill regulatory functions in the immune system. Different species of mammals, as well as chicken and catfish have been found to possess strikingly different sets of these receptors. To better understand the evolutionary history of paired receptors, we extended the study of FcR-like genes in amphibian representatives Xenopus tropicalis and Xenopus laevis.     

Evolution and diversity of axon guidance Robo receptor family genes

The diversity of axon guidance (AG) receptors reflects gains in complexity of the animal nervous system during evolution. Members of the Roundabout (Robo) family of receptors interact with Slit proteins and play important roles in many developmental processes, including AG and neural crest cell migration. There are four members of the Robo gene family. However, the evolutionary history of Robo family genes remain obscure. We analyzed the distribution of Robo family members in metazoan species ranging in complexity from hydras to humans. We undertook a phylogenetic analysis in metazoans, synteny analysis, and ancestral chromosome mapping in vertebrates, and detected selection pressure and functional divergence among four mammalian Robo paralogs. Based on our analysis, we proposed that the ancestral Robo gene could have undergone a tandem duplication in the vertebrate ancestor; then one round of whole genome duplication events occurred before the divergence of ancestral lamprey and gnathostome, generating four paralogs in early vertebrates. Robo4 paralog underwent segmental loss in the following evolutionary process. Our results showed that Robo3 paralog is under more powerful purifying selection pressure compared with other three paralogs, which could correlate with its unique expression pattern and function. Furthermore, we found four sites under positive selection pressure on the Ig1‐2 domains of Robo4 that might interfere with its binding to Slits ligand. Diverge analysis at the amino acid level showed that Robo4 paralog have relatively greater functional diversifications than other Robo paralogs. This coincides with the fact that Robo4 predominantly functions in vascular endothelial cells but not the nervous system.     

Genomic organization and characterization of two vomeronasal 1 receptor-like genes (ora1 and ora2) in Atlantic salmon Salmo salar

Olfactory receptors are encoded by three large multigene superfamilies (OR, V1R and V2R) in mammals. Fish do not possess a vomeronasal system; therefore, it has been proposed that their V1R-like genes be classified as olfactory receptors related to class A G protein-coupled receptors (ora). Unlike mammalian genomes, which contain more than a hundred V1R genes, the five species of teleost fish that have been investigated to date appear to have six ora genes (ora1-6) except for pufferfish that have lost ora1. The common ancestor of salmonid fishes is purported to have undergone a whole genome duplication. As salmonids have a life history that requires the use of olfactory cues to navigate back to their natal habitats to spawn, we set out to determine if ora1 or ora2 is duplicated in a representative species, Atlantic salmon (Salmo salar). We used an oligonucleotide probe designed from a conserved sequence of several teleost ora2 genes to screen an Atlantic salmon BAC library (CHORI-214). Hybridization-positive BACs belonged to a single fingerprint contig of the Atlantic salmon physical map. All were also positive for ora2 by PCR. One of these BACs was chosen for further study, and shotgun sequencing of this BAC identified two V1R-like genes, ora1 and ora2, that are in a head-to-head conformation as is seen in some other teleosts. The gene products, ora1 and ora2, are highly conserved among teleosts. We only found evidence for a single ora1-2 locus in the Atlantic salmon genome, which was mapped to linkage group 6. Fluorescent in situ hybridization (FISH) analysis placed ora1-2 on chromosome 12. Conserved synteny was found surrounding the ora1 and ora2 genes in Atlantic salmon, medaka and three-spined stickleback, but not zebrafish.     

The evolution of bat nucleic acid‐sensing Toll‐like receptors

We characterized the nucleic acid‐sensing Toll‐like receptors (TLR) of a New World bat species, the common vampire bat (Desmodus rotundus), and through a comparative molecular evolutionary approach searched for general adaptation patterns among the nucleic acid‐sensing TLRs of eight different bats species belonging to three families (Pteropodidae, Vespertilionidae and Phyllostomidae). We found that the bat TLRs are evolving slowly and mostly under purifying selection and that the divergence pattern of such receptors is overall congruent with the species tree, consistent with the evolution of many other mammalian nuclear genes. However, the chiropteran TLRs exhibited unique mutations fixed in ligand‐binding sites, some of which involved nonconservative amino acid changes and/or targets of positive selection. Such changes could potentially modify protein function and ligand‐binding properties, as some changes were predicted to alter nucleic acid binding motifs in TLR 9. Moreover, evidence for episodic diversifying selection acting specifically upon the bat lineage and sublineages was detected. Thus, the long‐term adaptation of chiropterans to a wide variety of environments and ecological niches with different pathogen profiles is likely to have shaped the evolution of the bat TLRs in an order‐specific manner. The observed evolutionary patterns provide evidence for potential functional differences between bat and other mammalian TLRs in terms of resistance to specific pathogens or recognition of nucleic acids in general.     

Two Frequenins in <Emphasis Type="Italic">Drosophila</Emphasis>: unveiling the evolutionary history of an unusual Neuronal Calcium Sensor (NCS) duplication

Background  

Drosophila Frequenin (Frq), the homolog of the mammalian Neuronal Calcium Sensor-1 (NCS-1), is a high affinity calcium-binding protein with ubiquitous expression in the nervous system. This protein has an important role in the regulation of neurotransmitter release per synapse, axonal growth and bouton formation. In D. melanogaster, Frequenin is encoded by two genes (frq1 and frq2), a very unexpected feature in the Frq/NCS-1 subfamily. These genes are located in tandem in the same genomic region, and their products are 95% identical in their amino acid sequence, clearly indicating their recent origin by gene duplication. Here, we have investigated the factors involved in this unusual feature by examining the molecular evolution of the two frq genes in Drosophila and the evolutionary dynamics of NCS family in a large set of bilaterian species.     

Phylogenetic footprint of the plant clock system in angiosperms: evolutionary processes of <Emphasis Type="Italic">Pseudo-Response Regulator</Emphasis>s

Background  

Plant circadian clocks regulate many photoperiodic and diurnal responses that are conserved among plant species. The plant circadian clock system has been uncovered in the model plant, Arabidopsis thaliana, using genetics and systems biology approaches. However, it is still not clear how the clock system had been organized in the evolutionary history of plants. We recently revealed the molecular phylogeny of LHY/CCA1 genes, one of the essential components of the clock system. The aims of this study are to reconstruct the phylogenetic relationships of angiosperm clock-associated PRR genes, the partner of the LHY/CCA1 genes, and to clarify the evolutionary history of the plant clock system in angiosperm lineages.     

Inhibition of human non-small cell lung cancers with a targeted cytotoxic somatostatin analog, AN-162

Human non-small cell lung cancers (NSCLCs) express receptors for somatostatin. The cytotoxic analog of somatostatin AN-162 (AEZS-124), consisting of doxorubicin linked to a somatostatin analog RC-121 binds to receptors for somatostatin and is targeted to tumors expressing these receptors. The aim of this study was to investigate the effect of targeted cytotoxic somatostatin analog AN-162 on a panel of human NSCLC cell lines (A549, H460, H838, H1299) in vitro (at 0.5–100 μM concentrations) and in vivo on H460 and H1299 NSCLCs xenografted into nude mice (at the dose of 2.5 μmol/kg, i.v., once a week). The expression of mRNA for somatostatin receptor subtypes was investigated by RT-PCR in cell lines and tumor tissues. Somatostatin receptor proteins were also characterized by ligand competition assay and Western blotting. AN-162 significantly decreased cell proliferation in vitro and tumor growth (p < 0.05 vs. all groups) of H460 and H1299 NSCLCs in vivo. Based on real-time PCR array data, AN-162 induced several apoptosis-related genes in vivo in both models. Our results suggest that cytotoxic somatostatin analog AN-162 (AEZS-124) should be considered for the further development of a therapy of patients with NSCLC.     

Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

Voltage-gated sodium channels underlie action potential generation in excitable tissue. To establish the evolutionary mechanisms that shaped the vertebrate sodium channel α-subunit (SCNA) gene family and their encoded Na_v1 proteins, we identified all SCNA genes in several teleost species. Molecular cloning revealed that teleosts have eight SCNA genes, compared to ten in another vertebrate lineage, mammals. Prior phylogenetic analyses have indicated that the genomes of both teleosts and tetrapods contain four monophyletic groups of SCNA genes, and that tandem duplications expanded the number of genes in two of the four mammalian groups. However, the number of genes in each group varies between teleosts and tetrapods, suggesting different evolutionary histories in the two vertebrate lineages. Our findings from phylogenetic analysis and chromosomal mapping of Danio rerio genes indicate that tandem duplications are an unlikely mechanism for generation of the extant teleost SCNA genes. Instead, analyses of other closely mapped genes in D. rerio as well as of SCNA genes from several teleost species all support the hypothesis that a whole-genome duplication was involved in expansion of the SCNA gene family in teleosts. Interestingly, despite their different evolutionary histories, mRNA analyses demonstrated a conservation of expression patterns for SCNA orthologues in teleosts and tetrapods, suggesting functional conservation. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users. [Reviewing Editor: Dr. Axel Meyer]     

The role of plant resistance and tolerance to herbivory in mediating the effects of introduced herbivores

While the generally negative consequences of introduced species are well known, little is appreciated on the role of the evolutionary history of plants with herbivores in mediating the indirect impacts of herbivory. We examined how variation in plant resistance and tolerance traits can mediate the effects of herbivory and can have differential indirect impacts on other species and processes. We used two examples of a native and an introduced herbivore, Castor canadensis (American beaver) and Cervus elaphus (Rocky Mountain elk) with Populus spp. to test a conceptual model regarding possible outcomes of species interactions with native and exotic mammalian herbivores. Using these two herbivore test cases, we make two predictions to create testable hypotheses across systems and taxa: First, adaptive traits of tolerance or resistance to herbivory will be fewer when exotic species feed on plant species with which they have no evolutionary history. Second, historical constraints of species interactions will allow for negative feedbacks to stabilize the effects of herbivory by a native species. Overall, these two case studies illustrate that plant resistance and tolerance traits can mediate the indirect consequences of herbivory on associated interacting species. Specifically, when there is no evolutionary history between the plants and herbivores, which is often the case with species introductions, the effects of herbivory are more likely to reduce genetic variation and habitat mosaics, thus indirectly affecting associated species.     

The Geographic Distribution of Monoamine Oxidase Haplotypes Supports a Bottleneck During the Dispersion of Modern Humans from Africa

Every genetic locus mingles the information about the evolutionary history of the human species with the history of its own evolution. Therefore, to address the question of the origin of humans from a genetic point of view, evolutionary histories from many genetic loci have to be gathered and compared. We have studied two genes residing on the X chromosome encoding monoamine oxidases A and B (MAOA and MAOB). Both genes have been suggested to play a role in psychiatric and/or behavioral traits. To search for DNA variants of the MAO genes, the sequences of exonic and flanking intronic regions of these two genes were determined in a group of Swedish males. The sequence analysis revealed several novel polymorphisms in the MAO genes. Haplotypes containing high-frequency MAOA polymorphisms were constructed, and their frequencies were determined in additional samples from Caucasian, Asian, and African populations. We found two common haplotypes with similar frequencies in Caucasian and Asian populations. However, only one of them was also the most frequent haplotype in Africans, while the other haplotype was present in only one Kenyan male. This profound change in haplotype frequencies from Africans to non-Africans supports a possible bottleneck during the dispersion of modern humans from Africa. Received: 19 April 2000 / Accepted: 9 October 2000     

The molecular phylogeny of eph receptors and ephrin ligands

Background  

The tissue distributions and functions of Eph receptors and their ephrin ligands have been well studied, however less is known about their evolutionary history. We have undertaken a phylogenetic analysis of Eph receptors and ephrins from a number of invertebrate and vertebrate species.     

The role of mitochondrial introgression in illuminating the evolutionary history of Nearctic treefrogs

Inferring the evolutionary history of lineages often becomes difficult when gene histories are in conflict with each other. Introgression, for example, can cause DNA sequences from one species to be more similar to sequences of a different species and lead to incongruence amongst gene trees. However, incorporating congruent and incongruent locus‐specific phylogenetic estimates with the geographical distribution of lineages may provide valuable insight into evolutionary processes important to speciation. In this study, we investigated mitochondrial introgression within the Hyla eximia group to better understand its role in illuminating the evolutionary history and phylogeography of these treefrogs. We reconstructed and compared the matrilineal history of the Hyla eximia group with estimates of evolutionary history inferred from nuclear genes. We tested for introgression within the mitochondrial and nuclear genes using a posterior predictive checking approach. Reconstructions of the species tree based on the mitochondrial DNA (mtDNA) and nuclear DNA data were strongly discordant. Introgression between lineages was widespread in the mtDNA data set (145 occurrences amongst 11 of the 16 lineages), but uncommon in the nuclear genes (12 occurrences amongst four of the 16 lineages). Nonetheless, the geographical structuring of mtDNA within species provides valuable information on biogeographical areas, ancient areas of hybridization, and unique histories of lineages within the H. eximia group. These results suggest that the combination of nuclear, mitochondrial, and spatial information can provide a more complete picture of ‘how evolutionary history played out’, particularly in cases where mitochondrial introgression is known to occur. © 2014 The Linnean Society of London     

Trans-sialidase genes expressed in mammalian forms of Trypanosoma cruzi evolved from ancestor genes expressed in insect forms of the parasite

The trans-sialidase of Trypanosoma cruzi mammalian forms transfers sialic acids from host's cell-surface glycoconjugates to acceptor molecules on parasite cell surface. To investigate the mechanism by which the mammalian stages of Trypanosoma cruzi have acquired their trans-sialidase, we compared the nucleotide and predicted amino acid sequences of trans-sialidase genes expressed in different developmental stages and strains of Trypanosoma cruzi with the sialidase gene of Trypanosoma rangeli and the sialidase genes of the prokaryotic genera Clostridium, Salmonella, and Actinomyces. The trans-sialidase gene products of Trypanosoma cruzi have a significant degree of structural and biochemical similarity to the sialidases found in bacteria and viruses, which would hint that horizontal gene transfer occurred in Trypanosome cruzi trans-sialidase evolutionary history. The comparison of inferred gene trees with species trees suggests that the genes encoding the T. cruzi trans-sialidase of mammalian forms might be derived from genes expressed in the insect forms of the genus Trypanosome. The branching order of trees inferred from T. cruzi trans-sialidase sequences, the sialidase from Trypanosoma rangeli, and bacterial sialidases parallels the expected branching order of the species and suggests that the divergence times of these sequences are remarkably long. Therefore, a vertical inheritance from a hypothetical eukaryotic trans-sialidase gene expressed in insect forms of trypanosomes is more likely to have occurred than the horizontal gene transfer from bacteria, and thus explains the presence of this enzyme in the mammalian infective forms of Trypanosoma cruzi.Correspondence to: M.R.S. Briones     

Phylogeny and expression profiling of CAD and CAD-like genes in hybrid Populus (P. deltoides × P. nigra): evidence from herbivore damage for subfunctionalization and functional divergence

Background  

Cinnamyl Alcohol Dehydrogenase (CAD) proteins function in lignin biosynthesis and play a critical role in wood development and plant defense against stresses. Previous phylogenetic studies did not include genes from seedless plants and did not reflect the deep evolutionary history of this gene family. We reanalyzed the phylogeny of CAD and CAD-like genes using a representative dataset including lycophyte and bryophyte sequences. Many CAD/CAD-like genes do not seem to be associated with wood development under normal growth conditions. To gain insight into the functional evolution of CAD/CAD-like genes, we analyzed their expression in Populus plant tissues in response to feeding damage by gypsy moth larvae (Lymantria dispar L.). Expression of CAD/CAD-like genes in Populus tissues (xylem, leaves, and barks) was analyzed in herbivore-treated and non-treated plants by real time quantitative RT-PCR.     

Evidence that a secondary metabolic biosynthetic gene cluster has grown by gene relocation during evolution of the filamentous fungus Fusarium

Trichothecenes are terpene‐derived secondary metabolites produced by multiple genera of filamentous fungi, including many plant pathogenic species of Fusarium. These metabolites are of interest because they are toxic to animals and plants and can contribute to pathogenesis of Fusarium on some crop species. Fusarium graminearum and F. sporotrichioides have trichothecene biosynthetic genes (TRI) at three loci: a 12‐gene TRI cluster and two smaller TRI loci that consist of one or two genes. Here, comparisons of additional Fusarium species have provided evidence that TRI loci have a complex evolutionary history that has included loss, non‐functionalization and rearrangement of genes as well as trans‐species polymorphism. The results also indicate that the TRI cluster has expanded in some species by relocation of two genes into it from the smaller loci. Thus, evolutionary forces have driven consolidation of TRI genes into fewer loci in some fusaria but have maintained three distinct TRI loci in others.