Emergence and evolution of the glycoprotein hormone and neurotrophin gene families in vertebrates

<p>Abstract</p> <p>Background</p> <p>The three vertebrate pituitary glycoprotein hormones (GPH) are heterodimers of a common α and a specific β subunit. In human, they are located on different chromosomes but in a similar genomic environment. We took advantage of the availability of genomic and EST data from two cartilaginous fish species as well as from two lamprey species to identify their repertoire of neurotrophin, lin7 and KCNA gene family members which are in the close environment of <it>gphβ</it>. <it>Gphα </it>and <it>gphβ </it>are absent outside vertebrates but are related to two genes present in both protostomes and deuterostomes that were named <it>gpa2 </it>and <it>gpb5</it>. Genomic organization and functional characteristics of their protein products suggested that <it>gphα </it>and <it>gphβ </it>might have been generated concomitantly by a duplication of <it>gpa2 </it>and <it>gpb5 </it>just prior to the radiation of vertebrates. To have a better insight into this process we used new genomic resources and tools to characterize the ancestral environment before the duplication occurred.</p> <p>Results</p> <p>An almost similar repertoire of genes was characterized in cartilaginous fishes as in tetrapods. Data in lampreys are either incomplete or the result of specific duplications and/or deletions but a scenario for the evolution of this genomic environment in vertebrates could be proposed. A number of genes were identified in the amphioxus genome that helped in reconstructing the ancestral environment of <it>gpa2 </it>and <it>gpb5 </it>and in describing the evolution of this environment in vertebrates.</p> <p>Conclusion</p> <p>Our model suggests that vertebrate <it>gphα </it>and <it>gphβ </it>were generated by a specific local duplication of the ancestral forms of <it>gpa2 </it>and <it>gpb5</it>, followed by a translocation of <it>gphβ </it>to a new environment whereas <it>gphα </it>was retained in the <it>gpa2</it>-<it>gpb5 </it>locus. The two rounds of whole genome duplication that occurred early in the evolution of vertebrates generated four paralogues of each gene but secondary gene losses or lineage specific duplications together with genomic rearrangements have resulted in the present organization of these genes, which differs between vertebrate lineages.</p

Multiple thyrotropin β-subunit and thyrotropin receptor-related genes arose during vertebrate evolution.

Thyroid-stimulating hormone (TSH) is composed of a specific β subunit and an α subunit that is shared with the two pituitary gonadotropins. The three β subunits derive from a common ancestral gene through two genome duplications (1R and 2R) that took place before the radiation of vertebrates. Analysis of genomic data from phylogenetically relevant species allowed us to identify an additional Tshβ subunit-related gene that was generated through 2R. This gene, named Tshβ2, present in cartilaginous fish, little skate and elephant shark, and in early lobe-finned fish, coelacanth and lungfish, was lost in ray-finned fish and tetrapods. The absence of a second type of TSH receptor (Tshr) gene in these species suggests that both TSHs act through the same receptor. A novel Tshβ sister gene, named Tshβ3, was generated through the third genomic duplication (3R) that occurred early in the teleost lineage. Tshβ3 is present in most teleost groups but was lostin tedraodontiforms. The 3R also generated a second Tshr, named Tshrb. Interestingly, the new Tshrb was translocated from its original chromosomic position after the emergence of eels and was then maintained in its new position. Tshrb was lost in tetraodontiforms and in ostariophysians including zebrafish although the latter species have two TSHs, suggesting that TSHRb may be dispensable. The tissue distribution of duplicated Tshβs and Tshrs was studied in the European eel. The endocrine thyrotropic function in the eel would be essentially mediated by the classical Tshβ and Tshra, which are mainly expressed in the pituitary and thyroid, respectively. Tshβ3 and Tshrb showed a similar distribution pattern in the brain, pituitary, ovary and adipose tissue, suggesting a possible paracrine/autocrine mode of action in these non-thyroidal tissues. Further studies will be needed to determine the binding specificity of the two receptors and how these two TSH systems are interrelated

Mutations on VEEV nsP1 relate RNA capping efficiency to ribavirin susceptibility

International audienceAlphaviruses are arthropod-borne viruses of public health concern. To date no efficient vaccine nor antivirals are available for safe human use. During viral replication the nonstructural protein 1 (nsP1) catalyzes capping of genomic and subgenomic RNAs. The capping reaction is unique to the Alphavirus genus. The whole three-step process follows a particular order: (i) transfer of a methyl group from S-adenosyl methionine (SAM) onto a GTP forming m7GTP; (ii) guanylylation of the enzyme to form a m7GMP-nsP1adduct; (iii) transfer of m7GMP onto 5′-diphosphate RNA to yield capped RNA. Specificities of these reactions designate nsP1 as a promising target for antiviral drug development. In the current study we performed a mutational analysis on two nsP1 positions associated with Sindbis virus (SINV) ribavirin resistance in the Venezuelan equine encephalitis virus (VEEV) context through reverse genetics correlated to enzyme assays using purified recombinant VEEV nsP1 proteins. The results demonstrate that the targeted positions are strongly associated to the regulation of the capping reaction by increasing the affinity between GTP and nsP1. Data also show that in VEEV the S21A substitution, naturally occurring in Chikungunya virus (CHIKV), is a hallmark of ribavirin susceptibility. These findings uncover the specific mechanistic contributions of these residues to nsp1-mediated methyl-transfer and guanylylation reactions

Origin and Evolution of the Neuroendocrine Control of Reproduction in Vertebrates, with Special Focus on Genome and Gene Duplications

International audienceIn human, as in the other mammals, the neuroendocrine control of reproduction is ensured by the brain-pituitary gonadotropic axis. Multiple internal and environmental cues are integrated via brain neuronal networks, ultimately leading to the modulation of the activity of gonadotropin-releasing hormone (GnRH) neurons. The decapeptide GnRH is released into the hypothalamic-hypophyseal portal blood system, and stimulates the production of pituitary glycoprotein hormones, the two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). A novel actor, the neuropeptide Kiss, acting upstream of GnRH, has attracted increasing attention in recent years. Other neuropeptides, such as gonadotropin-inhibiting hormone (GnIH)/ RF-amide related peptide (RFRP), and other members of the RF-amide peptide superfamily, as well as various non-peptidic neuromediators such has dopamine, serotonin also provide a large panel of stimulatory or inhibitory regulators. This paper addresses the origin and evolution of the vertebrate gonadotropic axis. Brain-pituitary neuroendocrine axes are typical of vertebrates, the pituitary gland, mediator and amplifier of brain control on peripheral organs, being a vertebrate innovation. The paper reviews, from molecular and functional perspectives, the evolution across vertebrate radiation of some key-actors of the vertebrate neuroendocrine control of reproduction, and traces back their origin along the vertebrate lineage and in other metazoa before the emergence of vertebrates. A focus is given on how gene duplications, resulting from either local events or from whole genome duplication events (WGD), and followed by paralogous gene loss or conservation, might have shaped the evolutionary scenarios of current families of key-actors of the gonadotropic axis

Looking for the bird Kiss: evolutionary scenario in sauropsids.

International audienceBACKGROUND: The neuropeptide Kiss and its receptor KissR are key-actors in the brain control of reproduction in mammals, where they are responsible for the stimulation of the activity of GnRH neurones. Investigation in other vertebrates revealed up to 3 Kiss and 4 KissR paralogs, originating from the two rounds of whole genome duplication in early vertebrates. In contrast, the absence of Kiss and KissR has been suggested in birds, as no homologs of these genes could be found in current genomic databases. This study aims at addressing the question of the existence, from an evolutionary perspective, of the Kisspeptin system in birds. It provides the first large-scale investigation of the Kisspeptin system in the sauropsid lineage, including ophidian, chelonian, crocodilian, and avian lineages. RESULTS: Sauropsid Kiss and KissR genes were predicted from multiple genome and transcriptome databases by TBLASTN. Phylogenetic and syntenic analyses were performed to classify predicted sauropsid Kiss and KissR genes and to re-construct the evolutionary scenarios of both gene families across the sauropsid radiation.Genome search, phylogenetic and synteny analyses, demonstrated the presence of two Kiss genes (Kiss1 and Kiss2 types) and of two KissR genes (KissR1 and KissR4 types) in the sauropsid lineage. These four genes, also present in the mammalian lineage, would have been inherited from their common amniote ancestor. In contrast, synteny analyses supported that the other Kiss and KissR paralogs are missing in sauropsids as in mammals, indicating their absence in the amniote lineage. Among sauropsids, in the avian lineage, we demonstrated the existence of a Kiss2-like gene in three bird genomes. The divergence of these avian Kiss2-like sequences from those of other vertebrates, as well as their absence in the genomes of some other birds, revealed the processes of Kiss2 gene degeneration and loss in the avian lineage. CONCLUSION: These findings contribute to trace back the evolutionary history of the Kisspeptin system in amniotes and sauropsids, and provide the first molecular evidence of the existence and fate of a Kiss gene in birds

Syntenic analysis of TSHR-related genomic region.

<p>Genomic region flanking <i>Tshr</i>-related genes were analysed in representative species (chromosome number is attached to the species name) by using the region overview on the Ensembl genome browser or by blast analysis on the eel assembled genome (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111361#pone.0111361.s002" target="_blank">Fig. S2B</a> for details). The phylogenetic relationships between the represented species are summarized on the right panel. <i>Tshrb</i> was translocated sometime between the emergence of eel and stickleback lineages. Genes are named according to the Ensembl nomenclature (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111361#pone.0111361.s008" target="_blank">Table S4</a>). Gene positions are given (in Mega base) below the symbolized genes.</p

Thyroid hormones down-regulate thyrotropin beta mRNA level in vivo in the turbot (Psetta maxima)

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Cloning, expression pattern and heterologous expression of recombinant glycoprotein hormone subunits-related molecules GPA2 and GPB5 from rat, bovine and amphioxus

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ERα orchestre les mécanismes épigénétiques qui déclenchent l’expression du gène

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Phylogenetic tree of TSHβ related nucleotide sequences.

<p>Phylogram of maximum likelihood relationships between <i>Tshβ</i> coding sequences of representative species. The bootstrap values over 500 replicates (in %) are given next to each node in red (only the values above 50% are given). Cumulated distance values (from the node marked with a blue asterisk) are given in blue next to the species name for comparison of the estimated relative rate of evolution of teleost TSHβ and TSHβ3 sequences (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111361#pone.0111361.s004" target="_blank">Fig. S4</a> for the regression curve). <i>Tshβ</i> gene references are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111361#pone.0111361.s005" target="_blank">Table S1</a>.</p