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Front Endocrinol (Lausanne)
2022 Feb 03;12:792644. doi: 10.3389/fendo.2021.792644.
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The Evolution of Oxytocin and Vasotocin Receptor Genes in Jawed Vertebrates: A Clear Case for Gene Duplications Through Ancestral Whole-Genome Duplications.
Ocampo Daza D
,
Bergqvist CA
,
Larhammar D
.
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The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins, have six cognate receptors encoded by six receptor subtype genes in jawed vertebrates. The peptides elicit a broad range of responses that are specifically mediated by the receptor subtypes including neuronal functions regulating behavior and hormonal actions on reproduction and water/electrolyte balance. Previously, we have demonstrated that these six receptor subtype genes, which we designated VTR1A, VTR1B, OTR, VTR2A, VTR2B and VTR2C, arose from a syntenic ancestral gene pair, one VTR1/OTR ancestor and one VTR2 ancestor, through the early vertebrate whole-genome duplications (WGD) called 1R and 2R. This was supported by both phylogenetic and chromosomal conserved synteny data. More recently, other studies have focused on confounding factors, such as the OTR/VTR orthologs in cyclostomes, to question this scenario for the origin of the OTR/VTR gene family; proposing instead less parsimonious interpretations involving only one WGD followed by complex series of chromosomal or segmental duplications. Here, we have updated the phylogeny of the OTR/VTR gene family, including a larger number of vertebrate species, and revisited seven representative neighboring gene families from our previous conserved synteny analyses, adding chromosomal information from newer high-coverage genome assemblies from species that occupy key phylogenetic positions: the polypteriform fish reedfish (Erpetoichthys calabaricus), the cartilaginous fish thorny skate (Amblyraja radiata) and a more recent high-quality assembly of the Western clawed frog (Xenopus tropicalis) genome. Our analyses once again add strong support for four-fold symmetry, i.e., chromosome quadruplication in the same time window as the WGD events early in vertebrate evolution, prior to the jawed vertebrate radiation. Thus, the evolution of the OTR/VTR gene family can be most parsimoniously explained by two WGD events giving rise to the six ancestral genes, followed by differential gene losses of VTR2 genes in different lineages. We also argue for more coherence and clarity in the nomenclature of OT/VT receptors, based on the most parsimonious scenario.
FIGURE 1 Maximum likelihood phylogeny of VTR2A, VTR2B and VTR2C genes. Inset: Placement of data shown in and within the OTR/VTR phylogeny. Phylogeny constructed with IQ-TREE supported by 100 iterations of ultrafast bootstrapping (UFBoot). Weakly supported nodes are indicated by yellow (<75 %) and red (<50 %) arrowheads. Some node support values for shallow nodes have been omitted for visual clarity. Sequence names include species abbreviations followed by chromosome/linkage group designations (where available) and gene symbols. Species abbreviations are listed in Table 1. Asterisks indicate partial sequences. The phylogeny was rooted with the common octopus (Octopus vulgaris) cephalotocin (CTR1, CTR2) and octopressin (OPR) receptor sequences.
FIGURE 2 Maximum likelihood phylogeny of VTR1A, VTR1B and OTR genes. Inset: Placements of the VTR2A, VTR2B and VTR2C branches within the full OTR/VTR phylogeny. See caption for more details.
FIGURE 3 Exon/intron structures of human, thorny skate, reedfish, spotted gar and zebrafish VTR1A (A), VTR1B (B) and OTR (C) genes. Additional representative genes are marked with an asterisk. Only coding exons are shown. Exons are drawn to scale and exon lengths are given in base-pairs. Roman numerals designate the approximate locations of the transmembrane (TM) region-encoding sequences. The third intracellular loop (IL3)-encoding sequences are indicated in dark gray. The conserved DRY/DRC motifs are indicated by yellow arrows.
FIGURE 4 Exon/intron structures of human, thorny skate, reedfish, spotted gar and zebrafish VTR2A (A), VTR2B (B) and VTR2C (C) genes. Additional representative genes are marked with an asterisk. See caption for details. Within the OTR/VTR gene family, only VTR2A genes (A) diverge from the conserved exon/intron structure due to intron insertions in several lineages. The blue arrowhead marks the first intron of the human VTR2A (AVPR2) gene (in blue), which is shared with all mammalian VTR2A genes. Pink arrowheads indicate introns inserted in ray-finned fish evolution between conserved Gln-Val (Q-V)-encoding codons. The green arrowhead indicates a predicted intron inserted into the IL3-encoding region in VTR2Ab genes from spiny-rayed fishes (Acanthomorpha). The purple arrowhead indicates a predicted N-terminal intron seen only in the three-spined and nine-spined stickleback VTR2Ab genes.
FIGURE 5 Conserved synteny in OTR/VTR gene-bearing chromosome regions in the human, chicken, Xenopus and thorny skate genomes. Xenopus tropicalis gene symbols are in lower case, following the gene nomenclature convention for this species.
FIGURE 6 Conserved synteny in OTR/VTR gene-bearing chromosome regions in the reedfish, spotted gar and zebrafish genomes. We suggest the nomenclature OTRa and OTRb for the teleost isotocin receptor gene duplicates, and VTR2a and VTR2b for the vasotocin receptor VTR2B gene duplicates. Zebrafish gene symbols are in lower case, following the gene nomenclature convention for this species.
FIGURE 7 Conserved synteny in OTR/VTR gene-bearing chromosome regions in the Asian arowana genome shows evidence of duplications in the teleost whole genome duplication (3R). All identified gene pairs, apart from the BRK1, RBM5 and HUWE1 gene pairs (in gray), showed divergence early in teleost evolution, rooted by a single spotted gar and/or reedfish ortholog in the corresponding Ensembl gene trees. Where the orthology relationships to the zebrafish genes was clear in the Ensembl gene trees, gene names with “a” and “b”-designations have been suggested. Where there was only one zebrafish ortholog, this was designated the “a”-duplicate.
FIGURE 8 Proposed evolution of OTR/VTR genes and gene repertoires in the analyzed vertebrate lineages. The red seven-pointed star indicates the local gene duplication that gave rise to ancestral vertebrate V1R and V2R genes. Red arrows indicate the vertebrate WGDs: 1R and 2R at the base of vertebrates, the teleost 3R at 320 million years ago (MYA) (39), the American paddlefish 3R at 50 MYA (18) and the sterlet 3R which has been estimated at both 180 MYA (17) and 21.3 MYA (19). Bars by red arrows indicate the estimated time windows for these WGD events in the cited literature. Time estimates of 1R and 2R vary wildly and are often overestimated, reaching back beyond the protostome-deuterostome split just over 600 MYA (40). Nonetheless, a time window of 600−450 MYA is reasonable based on estimates of the vertebrate-tunicate split, at the earliest, and the split between bony fishes and cartilaginous fishes, at the latest (40). The uncertain divergence of cyclostomes relative to 1R and 2R is indicated by a dashed branch. Light gray genes indicate the cyclostome OTR/VTR genes, which could not be unambiguously assigned to a subtype. The chordate phylogeny is based on divergence time estimations from 40, and TimeTree.org (http://timetree.org). Footnotes: 1) “Lizards” is a paraphyletic group including Schlegel’s Japanese gecko (Gekko japonicus), common wall lizard (Podarcis muralis) and Carolina anole lizard. 2) Some teleost species lack duplicate VTR2B genes (see ), and no VTR2B could be found in the Northern pike (Esox lucius). 3) Some teleost species lack VTR2C genes. 4) Teleost VTR2C genes cluster with the cartilaginous fish VTR2C2 local duplicate (see Figure 1), possibly due to a combination of truncated C-terminals in both lineages and phylogenetic artifacts.
FIGURE 9 Duplication scheme of OTR/VTR genes through the 1R/2R and 3R whole-genome duplications. Gene losses following WGDs are indicated by ⦸ symbols. D0-D3 designations refer to paralogous chromosome blocks in jawed vertebrate genomes that originated in 1R/2R, as per (9).
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