BMC Evol Biol
February 8, 2008;
Sequence and organization of coelacanth neurohypophysial hormone genes: evolutionary history of the vertebrate neurohypophysial hormone gene locus.
The mammalian neurohypophysial hormones, vasopressin
are involved in osmoregulation and uterine smooth muscle
contraction respectively. All jawed vertebrates contain at least one homolog each of vasopressin
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
genes are closely linked in the human and rodent genomes in a 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
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.
BMC Evol Biol
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Figure 1. The neurohypophysial hormones and genes in human, fugu and coelacanth. (A) Structure of the neurohypophysial preprohormones. VP, vasopressin; VT, vasotocin; OT, oxytocin and IT, isotocin. (B) Organization of neurohypophysial hormone genes in human, fugu and coelacanth. Genes are represented by arrows. Only the neurohypophysial genes are labeled. The coelacanth genes were characterized in this study.
Figure 2. The coelacanth neurohypophysial gene locus. The BAC clone (66G11) sequenced is shown below. Arrows represent genes and indicate the direction of transcription. Vertical bars represent repetitive elements (LINE, LF-SINE, LmeSINE1 and AmnSINE1). VT, vasotocin gene; MT, mesotocin gene; Ubox5, U-box domain containing 5; Gnrh2, gonadotropin-releasing hormone 2.
Figure 3. Comparison of nucleotide and deduced amino acid sequences of coelacanth vasotocin and mesotocin genes. Conserved nucleotides are indicated by an asterisk and identical amino acid residues are shown in bold font. Sequential Arg residues, N-glycosylation sites and Leu-rich core segment in the vasotocin precursor are boxed. The sequential Arg residues serve as a processing signal between the neurophysin and copeptin. Intronic sequences are shown in lower case.
Figure 4. Comparison of amino acid sequences of (A) vasopressin and (B) oxytocin family hormone precursors in vertebrates. ClustalX was used to generate the alignment. Amino acid residues conserved in all vertebrates are marked with an asterisk. B. japonicus, Bufo japonicus; X. tropicalis, Xenopus tropicalis; and T. scyllium, Triakis scyllium. Accession numbers of sequences used in the alignment: NP_000481.2 (human VP), AAA48556.1 (B. japonicus VT), BAA24026.1 (lungfish VT), O42499 (fugu VT), BAA98140.1 (flounder VT), BAD27476.1 (T. scyllium VT) and BAA06669.1 (lamprey VT), NP_000906.1 (human OT), P08162 (B. japonicus MT), BAA24027.1 (lungfish [Phe2]MT), O42493 (fugu IT), BAA98141.1 (flounder IT), BAD27478.1 (T. scyllium phasitocin) and BAD27477.1 (T. scyllium asvatocin). Sequences for Xenopus tropicalis and coelacanth were generated in this study.
Figure 5. Schematic diagram of neurohypophysial hormone gene locus in vertebrates. Arrows represent genes and indicate the orientation of transcription. Genes flanking the Tetraodon Gnrh2 and Ptpra genes and the genes present downstream of fugu CL1 gene are not shown for the sake of clarity. Fugu orthologs for Gnrh2 and Ptpra genes are yet to be sequenced (likely to be present in the gaps of the genome assembly). GFRA4, glial cell line-derived neurotrophic factor family receptor alpha 4 protein gene; ATRN, attractin gene; SLC4A11, solute carrier family 4, sodium bicarbonate transporter-like, member 11; ITPA, Inosine triphosphate protein gene; ProSAPiP1, ProSAP-interacting protein 1 gene; Ubox5, U-box domain containing 5; [Lys8]VP, lysipressin gene; VT, vasotocin gene; MT, mesotocin gene; OT, oxytocin gene; IT, isotocin gene, Gnrh2, gonadotropin-releasing hormone 2; PTPRA, protein tyrosine phosphatase receptor type A gene; FABP1, fatty acid binding protein 1 gene; smyd1, SET and MYND domain containing 1 gene; SPR, sepiapterin reductase protein gene; CCL1 chemokine CL1 gene.
Figure 6. Evolution of vasopressin and oxytocin family of nonapeptides. The letter 'D' within the circle represents a gene duplication event. The numbers within the circles denote the position of the amino acid that has been substituted (shown above the circle). OT, oxytocin; MT, mesotocin; IT, isotocin; VP, vasopressin; [Lys8]VP, lysipressin, VT, vasotocin; ASV, asvatocin; PAI, phasitocin. Protein sequencing has shown that some lungfishes contain mesotocin [9, 10] and some marsupials contain [Phe2]vasopressin . They are not shown for the sake of clarity.
Unique evolution of neurohypophysial hormones in cartilaginous fishes: possible implications for urea-based osmoregulation.