The Evolution of Oxytocin and Vasotocin Receptor Genes in Jawed Vertebrates: A Clear Case for Gene Duplications Through Ancestral Whole-Genome Duplications

Abstract

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.

New Insights Into the Evolution of Corticotropin-Releasing Hormone Family With a Special Focus on Teleosts

“…The crh2 pairing suggests independent gene doubling events for the crh2 paralogs in sterlet and paddlefish lineages. Similar relationships have been recently observed for the oxytocin and vasotocin receptors (67) and is in agreement with the independent lineage specific WGD in the Acipenseridae and Polyondotidae (65,67,68). Surprisingly, crh1 and ucn1 sterlet duplicated paralogs clustered with one of the respective paddlefish paralogs, with well supported nodes, suggesting the duplication events that produced the crh1 and ucn1 doubling in chondrosteans may have preceded the split between paddlefish and acipenser lineages.…”

Reproductive roles of the vasopressin/oxytocin neuropeptide family in teleost fishes

“…Lineage-specific changes in the nonapeptide repertoires have also been reported even within the infraclass of teleost fishes. For example, otocephalans lack an avpr2bb paralogue found in early teleosts as well as euteleosts ( 59 ), as shown in Figure 2B . In our current microsynteny analysis, we found additional otocephalan-specific changes for the oxtrb nonapeptide receptor locus ( Figure 3A ).…”

“…Nonapeptide systems can regulate reproductive physiology via central neuromodulatory and/or peripheral endocrine and/or paracrine pathways via G-protein coupled membrane-bound AVP and OXT peptide family receptors (AVPRs and OXTRs). Since newly available genome sequences have recently allowed for a comprehensive description of the vertebrate nonapeptide receptor repertoires and their evolution resulting in proposed nomenclature changes (55)(56)(57)(58)(59), we here review the repertoire of teleost receptors considering these findings in detail. For the purpose of this review, we once again follow the ZFIN nomenclature, which is largely reflective of these changes.…”

“…These receptors include avpr1a, avpr2, avprl as well as oxtr and their paralogues. A fifth vertebrate nonapeptide receptor family member, avpr1b is present in basal ray-finned fishes as well as tetrapods but is not present in elasmobranchs and teleost fishes ( 55 – 59 ) ( Figures 2A-C ). With regard to intracellular signaling mechanisms, Avprs and Oxtrs use diacylglycerol (DAG), inositol triphosphate (IP 3 ) and calcium (Ca 2+ ) as second-messengers with the exception of Avpr2l, which uses cyclic adenosine monophosphate (cAMP) ( 60 ).…”

“…Teleost-specific changes in the nonapeptide receptor repertoires have been reported, especially regarding possible intracellular AA sequences involved in cell signalling. For example, the teleost Avpr2aa AA sequence harbours extensions of the intracellular loop 3 region, which include relatively well-conserved Tyr, Ser and Thr residues which can be phosphorylated by a variety of intracellular kinases to alter intracellular signaling cascades as well as G-protein coupled receptor attenuation/desensitization, endocytosis, and intracellular trafficking ( 59 ). Lineage-specific changes in the nonapeptide repertoires have also been reported even within the infraclass of teleost fishes.…”