Sequence and organization of coelacanth neurohypophysial hormone genes: Evolutionary history of the vertebrate neurohypophysial hormone gene locus
© Gwee et al; licensee BioMed Central Ltd. 2008
Received: 11 January 2008
Accepted: 26 March 2008
Published: 26 March 2008
The mammalian neurohypophysial hormones, vasopressin and oxytocin are involved in osmoregulation and uterine smooth muscle contraction respectively. All jawed vertebrates contain at least one homolog each of vasopressin and oxytocin whereas jawless vertebrates contain a single neurohypophysial hormone called vasotocin. The vasopressin homolog in non-mammalian vertebrates is vasotocin; and the oxytocin homolog is mesotocin in non-eutherian tetrapods, mesotocin and [Phe2]mesotocin in lungfishes, and isotocin in ray-finned fishes. The genes encoding vasopressin and oxytocin genes are closely linked in the human and rodent genomes in a tail-to-tail orientation. In contrast, their pufferfish homologs (vasotocin and isotocin) are located on the same strand of DNA with isotocin gene located upstream of vasotocin gene separated by five genes, suggesting that this locus has experienced rearrangements in either mammalian or ray-finned fish lineage, or in both lineages. The coelacanths occupy a unique phylogenetic position close to the divergence of the mammalian and ray-finned fish lineages.
We have sequenced a coelacanth (Latimeria menadoensis) BAC clone encompassing the neurohypophysial hormone genes and investigated the evolutionary history of the vertebrate neurohypophysial hormone gene locus within a comparative genomics framework. The coelacanth contains vasotocin and mesotocin genes like non-mammalian tetrapods. The coelacanth genes are present on the same strand of DNA with no intervening genes, with the vasotocin gene located upstream of the mesotocin gene. Nucleotide sequences of the second exons of the two genes are under purifying selection implying a regulatory function. We have also analyzed the neurohypophysial hormone gene locus in the genomes of opossum, chicken and Xenopus tropicalis. The opossum contains two tandem copies of vasopressin and mesotocin genes. The vasotocin and mesotocin genes in chicken and Xenopus, and the vasopressin and mesotocin genes in opossum are linked tail-to-head similar to their orthologs in coelacanth and unlike their homologs in human and rodents.
Our results indicate that the neurohypophysial hormone gene locus has experienced independent rearrangements in both placental mammals and teleost fishes. The coelacanth genome appears to be more stable than mammalian and teleost fish genomes. As such, it serves as a valuable outgroup for studying the evolution of mammalian and teleost fish genomes.
Neurohypophysial hormones in vertebrates
Pigs and some marsupials
Mammals, some marsupials, platypus, ratfish (H. colliei)
Some marsupials, non-eutherian tetrapods, some lungfishes
Sharks (Sq. acanthias)
Sharks (Sq. acanthias)
Sharks (Sc. canicula; T. scyllium)
Sharks (T. scyllium)
Sharks (Sc. canicula)
The lobe-finned fishes, lungfish and coelacanth, are the only two surviving lineages that arose between tetrapods and ray-finned fishes. The phylogenetic relationships of tetrapods to lungfish and coelacanth are unclear, although phylogenetic analyses of mitochondrial sequence and nuclear protein coding sequences, and a molecular marker (indel) seem to favor lungfish as the closest relative to tetrapods [22–26], and coelacanth as the most basal lobe-finned fish. It would, therefore, be interesting to determine the neurohypophysial hormones encoded by the coelacanth and the organization of neurohypophysial hormone genes in the coelacanth genome. Coelacanths were long believed to be extinct until a live specimen of the African coelacanth (Latimeria chalumnae) was caught off the coast of South Africa in 1938 . A second species of coelacanth, Latimeria menadoensis, was caught more recently in Indonesia indicating that there are at least two living species of coelacanths [28, 29]. Like cartilaginous fishes and lungfish, coelacanths store urea and trimethylamine oxide to stay hyperosmotic to seawater . In this study, we have characterized the neurohypophysial hormone gene locus in the Indonesian coelacanth by isolating and sequencing a BAC clone. In addition, we have analyzed the neurohypophysial hormone gene loci in Xenopus tropicalis, chicken and gray short-tailed opossum (Monodelphis domestica) and investigated the evolutionary history of the vertebrate neurohypophysial hormone gene locus. Our results show that, in contrast to vasotocin and [Phe2]mesotocin in the Australian lungfish, coelacanth contains vasotocin and mesotocin similar to non-eutherian tetrapods, and that the arrangement of vasotocin and mesotocin genes in coelacanth is different from their homologs in both human and pufferfish.
Results and Discussion
Coelacanth neurohypophysial hormone gene locus
Diverse SINE elements in the coelacanth neurohypophysial hormone gene locus
Approximately 17% of the 166-kb coelacanth neurohypophysial hormone gene locus sequence is represented by repetitive sequences, with LINEs and SINEs accounting for 7.9% and 6.9%, respectively (Fig 2). Altogether, this locus contains 18 LINE elements and 41 SINE elements. Previous studies have identified an ancient family of SINE elements in coelacanth, termed LF-SINE, which is specific to lobe-finned fishes . The coelacanth genome is estimated to contain 105 copies of these SINEs, and some of these elements have been conserved in mammalian genomes as 'ultraconserved elements' (sequences more than 200 bp long and perfectly conserved in human, mouse and rat). Another family of SINE, called LmeSINE1, has also been identified in coelacanth . Using the consensus sequence of the LmeSINEs, Nishihara et al , identified a novel family of SINEs which is widespread in the human and chicken genomes but absent in the coelacanth sequences that were available in the public domain. This family has been designated amniote-specific SINE1 or AmnSINE1 . The SINE elements in the coelacanth neurohypophysial hormone gene locus include not only LF-SINEs and LmeSINE1s, but also two instances of AmnSINE1s (Fig 2, Additional file 1). The presence of AmnSINE1 in the coelacanth indicates that these elements are not specific to amniotes and are more ancient than previously thought.
Coelacanth vasotocin and mesotocin precursors
The coelacanth mesotocin gene encodes a shorter protein of 124 amino acids comprising a signal peptide and mesotocin which is linked to a neurophysin by the tripeptide signal sequence, Gly-Lys-Arg (Fig 3). Like its homolog in the dogfish, Australian lungfish, toad and mammals, the coelacanth mesotocin precursor lacks a copeptin (Fig 4B). Thus, the teleost fish isotocin precursor is the only oxytocin-family precursor that contains a copeptin (Fig 4B). However, it should be noted that the teleost fish isotocin precursor does not contain an arginine residue between the neurophysin and the copeptin (Fig 4B), and consequently the copeptin moiety is not cleaved from the neurophysin molecule .
Second exons of coelacanth vasotocin and mesotocin genes are under purifying selection
GC content of the third codon positions (GC3) in coding exons of neurohypophysial hormone genes
Evolutionary history of vertebrate neurohypophysial hormone gene locus
We also analyzed the neurohypophysial hormone gene locus in the genome of Tetraodon nigroviridis, a freshwater pufferfish. The isotocin and vasotocin genes in this fish are arranged similar to their orthologs in fugu and separated by four genes (Fig 5). Furthermore, the Tetraodon Gnrh2 and Ptpra genes whose orthologs are closely linked to mesotocin or oxytocin genes in tetrapods are located on a different chromosome in Tetraodon and most likely in fugu (Fig 5). Thus, the neurohypophysial hormone gene loci in pufferfishes appear to have experienced multiple rearrangements. As such, the arrangement of isotocin and vasotocin genes in pufferfishes is unlikely to represent the arrangement of their homologs in the last common ancestor of ray-finned fishes and lobe-finned fishes. The two neurohypophysial hormone genes in the common ancestor were more likely to have been linked closely in a tail-to-head orientation similar to their homologs in coelacanth, Xenopus, chicken and opossum. Sequencing of neurohypophysial hormone gene loci in cartilaginous fishes should confirm this hypothesis.
Evolution of vasopressin and oxytocin families of hormones
We have sequenced neurohypophysial hormone genes from coelacanth and shown that coelacanth contains vasotocin and mesotocin like the non-eutherian tetrapods. We also show that the coelacanth vasotocin and mesotocin genes, and their homologs in Xenopus, chicken and opossum are linked in tandem in a tail-to-head orientation unlike the tail-to-tail orientation of their homologs in placental mammals, and tail-to-head orientation of isotocin and vasotocin genes in pufferfishes. These results indicate that the neurohypophysial hormone gene locus has undergone independent rearrangements in placental mammals and teleost fishes. The analysis of the neurohypophysial hormone gene locus has shown that the coelacanth genome is likely to be more stable than that of ray-finned fishes and mammals. This underscores the importance of coelacanth as a valuable outgroup for tracing evolutionary changes in the tetrapod and ray-finned fish lineages.
PCR amplification of coelacanth vasotocin fragment
The amino acid sequences of vasotocin precursors from various vertebrates were aligned using ClustalX and several pairs of degenerate PCR primers were designed to amplify a fragment of vasotocin gene from coelacanth. Genomic DNA of the Indonesian coelacanth extracted from the gill tissue  was used as a template. The primer-pair, 5'-GGN CCN WAY ATH TGY TGY GG-3' and 5'-CAN AYN CCN GGN GCN GCR CA-3', corresponding to the conserved sequences in the neurophysin region (GPN/YICCG and CAAPGV/IC) of the Japanese toad (accession number P08163) and the Australian lungfish (accession number BAA24026) vasotocin precursors, was effective in amplifying a genomic fragment of the expected size (~160 bp). The PCR cycling conditions used consisted of an initial denaturation step at 95°C for 2 min, followed by 35 cycles of 95°C for 30 sec, 50°C for 1 min and 72°C for 30 sec, with a final elongation step at 72°C for 5 min. The PCR product was cloned into a T-vector and sequenced. BLASTX search of the sequence indicated that it is highly similar to neurophysin molecule of the vasotocin precursor cloned from other vertebrates. The sequence of the PCR fragment was extended by inverse PCR using libraries of circularized DNA as described before . The extended sequence, a 2.8 kb XmnI fragment, includes the complete second exon and partial sequences for the flanking introns.
Isolation and sequencing of BAC
A 283-bp PCR product (amplified using the primers 5'-CTG CAG TGT ATC CCA TGT GGT TCT GG-3' and 5'-GTA TCG CCC AAT CAC TAG-3') that includes the complete second exon and 72 bp of the succeeding intron was used to screen an Indonesian coelacanth BAC library , and five positive BAC clones (66G11, 72J19, 117H6, 159M19, and 252B6) were identified. Restriction fragment analysis indicated that the five BACs belong to the same locus. Since the probe used codes for the central portion of the neurophysin which is conserved across species as well as between vasopressin and oxytocin-like precursors, we believe that this is the only neurohypophysial hormone gene locus in coelacanth. One of the positive BAC clones, clone #66G11, was sequenced completely using the shotgun sequencing strategy. In brief, the shotgun sequencing strategy involved shearing of BAC DNA by ultrasonication followed by end-filling by Klenow treatment, and separation of the fragments on a 1% agarose gel. Fragments in the range of 2–3 kb were then extracted from the gel and subcloned into the EcoRV site of pBluescript SK vector. The plasmid inserts were sequenced using standard BigDye Terminator v3.1 chemistry on an ABI 3730xl DNA analyzer. Shotgun reads were assembled with SeqBuilder (Lasergene 6 software package, DNASTAR) and gaps were filled by 'primer-walking' using BAC DNA as a template or by sequencing PCR products.
Protein coding genes were predicted based on homology to known proteins in the National Centre for Biotechnology Information database  and their exon-intron boundaries were refined by manual inspection. Multiple sequence alignments of protein sequences were carried out with ClustalX Version 1.83 . Repetitive sequences were identified using the RepeatMasker (version open-3.1.6). The genomic sequences of the neurohypophysial hormone gene locus for human (March 2006 assembly), Xenopus tropicalis (assembly version 4.1), chicken (assembly version 2.1), gray short-tailed opossum (Jan 2006 assembly), fugu (assembly version 4.0) and Tetraodon nigroviridis (February 2004 assembly) were obtained from the UCSC Genome Browser . The genes in the Xenopus, chicken and opossum neurohypophysial hormone gene locus were annotated based on homology to known protein sequences in NCBI database and the exon-intron boundaries were refined by manual verification.
We thank Diane Tan and Haslinawaty Binte Kassim for technical help. This work was supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore. B.V. is an adjunct staff of the Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore.
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