An evolutionary timeline of the oxytocin signaling pathway.

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500-1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

A journey from speech to dance through the field of oxytocin.

In this article, I am going through my scientific and personal journey using my work on oxytocin as a compass. I recount how my scientific questions were shaped over the years, and how I studied them through the lens of different fields ranging from linguistics and neuroscience to comparative and population genomics in a wide range of vertebrate species. I explain how my evolutionary findings and proposal for a universal gene nomenclature in the oxytocin-vasotocin ligand and receptor families have impacted relevant fields, and how my studies in the oxytocin and vasotocin system in songbirds, humans and non-human primates have led me to now be testing intranasal oxytocin as a candidate treatment for speech deficits. I also discuss my projects on the neurobiology of dance and where oxytocin fits in the picture of studying speech and dance in parallel. Lastly, I briefly communicate the challenges I have been facing as a woman and an international scholar in science and academia, and my personal ways to overcome them.

How genomics can help biodiversity conservation.

The availability of public genomic resources can greatly assist biodiversity assessment, conservation, and restoration efforts by providing evidence for scientifically informed management decisions. Here we survey the main approaches and applications in biodiversity and conservation genomics, considering practical factors, such as cost, time, prerequisite skills, and current shortcomings of applications. Most approaches perform best in combination with reference genomes from the target species or closely related species. We review case studies to illustrate how reference genomes can facilitate biodiversity research and conservation across the tree of life. We conclude that the time is ripe to view reference genomes as fundamental resources and to integrate their use as a best practice in conservation genomics.

Oxytocin and vasotocin receptor variation and the evolution of human prosociality.

Modern human lifestyle strongly depends on complex social traits like empathy, tolerance and cooperation. These diverse facets of social cognition have been associated with variation in the oxytocin receptor (OTR) and its sister genes, the vasotocin/vasopressin receptors (VTR1A/AVPR1A and AVPR1B/VTR1B). Here, we compared the available genomic sequences of these receptors between modern humans, archaic humans, and 12 non-human primate species, and identified sites that show heterozygous variation in modern humans and archaic humans distinct from variation in other primates, and for which we could find association studies with clinical implications. On these sites, we performed a range of analyses (variant clustering, pathogenicity prediction, regulation, linkage disequilibrium frequency), and reviewed the literature on selection data in different modern-human populations. We found five sites with modern human specific variation, where the modern human allele is the major allele in the global population (OTR: rs1042778, rs237885, rs6770632; VTR1A: rs10877969; VTR1B: rs33985287). Among them, variation in the OTR-rs6770632 site was predicted to be the most functional. Two alleles (OTR: rs59190448 and rs237888) present only in modern humans and archaic humans were putatively under positive selection in modern humans, with rs237888 predicted to be a highly functional site. Three sites showed convergent evolution between modern humans and bonobos (OTR: rs2228485 and rs237897; VTR1A: rs1042615), with OTR-rs2228485 ranking highly in terms of functionality and reported to be under balancing selection in modern humans (Schaschl, 2015) [1]. Our findings have implications for understanding hominid prosociality, as well as the similarities between modern human and bonobo social behavior.

The era of reference genomes in conservation genomics.

Progress in genome sequencing now enables the large-scale generation of reference genomes. Various international initiatives aim to generate reference genomes representing global biodiversity. These genomes provide unique insights into genomic diversity and architecture, thereby enabling comprehensive analyses of population and functional genomics, and are expected to revolutionize conservation genomics.

Oxytocin variation and brain region-specific gene expression in a domesticated avian species.

The Bengalese finch was domesticated more than 250 years ago from the wild white-rumped munia (WRM). Similar to other domesticated species, Bengalese finches show a reduced fear response and have lower corticosterone levels, compared to WRMs. Bengalese finches and munias also have different song types. Since oxytocin (OT) has been found to be involved in stress coping and auditory processing, we tested whether the OT sequence and brain expression pattern and content differ in wild munias and domesticated Bengalese finches. We sequenced the OT from 10 wild munias and 11 Bengalese finches and identified intra-strain variability in both the untranslated and protein-coding regions of the sequence, with all the latter giving rise to synonymous mutations. Several of these changes fall in specific transcription factor-binding sites, and show either a conserved or a relaxed evolutionary trend in the avian lineage, and in vertebrates in general. Although in situ hybridization in several hypothalamic nuclei did not reveal significant differences in the number of cells expressing OT between the two strains, real-time quantitative PCR showed a significantly higher OT mRNA expression in the cerebrum of the Bengalese finches relative to munias, but a significantly lower expression in their diencephalon. Our study thus points to a brain region-specific pattern of neurochemical expression in domesticated and wild avian strains, which could be linked to domestication and the behavioral changes associated with it.

The promiscuity of the oxytocin-vasopressin systems and their involvement in autism spectrum disorder.

Oxytocin and vasopressin systems have been studied separately in autism spectrum disorder (ASD). Here, we provide evidence from an evolutionary and neuroscience perspective about the shared mechanisms and the common roles in regulating social behaviors. We first discuss findings on the evolutionary history of oxytocin and vasopressin ligands and receptors that highlight their common origin and clarify the evolutionary background of the crosstalk between them. Second, we conducted a comprehensive review of the increasing evidence for the role of both neuropeptides in regulating social behaviors. Third, we reviewed the growing evidence on the associations between the oxytocin/vasopressin systems and ASD, which includes oxytocin and vasopressin dysfunction in animal models of autism and in human patients, and the impact of treatments targeting the oxytocin or the vasopressin systems in children and in adults. Here, we highlight the potential of targeting the oxytocin/vasopressin systems to improve social deficits observed in ASD and the need for further investigations on how to transfer these research innovations into clinical applications.

Reconstructing the evolutionary history of the oxytocin and vasotocin receptor gene family: Insights on whole genome duplication scenarios.

Vertebrate genome evolution remains a hotly debated topic, specifically as regards the number and the timing of putative rounds of whole genome duplication events. In this study, I sought to shed light to this conundrum through assessing the evolutionary history of the oxytocin/vasotocin receptor family. I performed ancestral analyses of the genomic segments containing oxytocin and vasotocin receptors (OTR-VTRs) by mapping them back to the reconstructed ancestral vertebrate/chordate karyotypes reported in five independent studies (Nakatani et al., 2007; Putnam et al., 2008; Smith and Keinath, 2015; Smith et al., 2018; Simakov et al., 2020) and found that two alternative scenarios can account for their evolution: one consistent with one round of whole genome duplication in the common ancestor of lampreys and gnathostomes, followed by segmental duplications in both lineages, and another consistent with two rounds of whole genome duplication, with the first occurring in the gnathostome-lamprey ancestor and the second in the jawed vertebrate ancestor. Combining the data reported here with synteny and phylogeny data reported in our previous study (Theofanopoulou et al., 2021), I put forward that a single round of whole genome duplication scenario is more consistent with the synteny and evolution of chromosomes where OTR-VTRs are encountered, without excluding the possibility of a scenario including two rounds of whole genome duplication. Although the analysis of one gene family is not able to capture the full complexity of vertebrate genome evolution, this study can provide solid insight, since the gene family used here has been meticulously analyzed for its genes' orthologous and paralogous relationships across species using high quality genomes.

Universal nomenclature for oxytocin-vasotocin ligand and receptor families.

Oxytocin (OXT; hereafter OT) and arginine vasopressin or vasotocin (AVP or VT; hereafter VT) are neurotransmitter ligands that function through specific receptors to control diverse functions1,2. Here we performed genomic analyses on 35 species that span all major vertebrate lineages, including newly generated high-contiguity assemblies from the Vertebrate Genomes Project3,4. Our findings support the claim5 that OT (also known as OXT) and VT (also known as AVP) are adjacent paralogous genes that have resulted from a local duplication, which we infer was through DNA transposable elements near the origin of vertebrates and in which VT retained more of the parental sequence. We identified six major oxytocin-vasotocin receptors among vertebrates. We propose that all six of these receptors arose from a single receptor that was shared with the common ancestor of invertebrates, through a combination of whole-genome and large segmental duplications. We propose a universal nomenclature based on evolutionary relationships for the genes that encode these receptors, in which the genes are given the same orthologous names across vertebrates and paralogous names relative to each other. This nomenclature avoids confusion due to differential naming in the pre-genomic era and incomplete genome assemblies, furthers our understanding of the evolution of these genes, aids in the translation of findings across species and serves as a model for other gene families.

Correction: Self-domestication in Homo sapiens: Insights from comparative genomics.

[This corrects the article DOI: 10.1371/journal.pone.0185306.].

A large-scale study on the effects of sex on gray matter asymmetry.

Research on sex-related brain asymmetries has not yielded consistent results. Despite its importance to further understanding of normal brain development and mental disorders, the field remains relatively unexplored. Here we employ a recently developed asymmetry measure, based on the Dice coefficient, to detect sex-related gray matter asymmetries in a sample of 457 healthy participants (266 men and 191 women) obtained from 5 independent databases. Results show that women's brains are more globally symmetric than men's (p < 0.001). Although the new measure accounts for asymmetries distributed all over the brain, several specific structures were identified as systematically more symmetric in women, such as the thalamus and the cerebellum, among other structures, some of which are typically involved in language production. These sex-related asymmetry differences may be defined at the neurodevelopmental stage and could be associated with functional and cognitive sex differences, as well as with proneness to develop a mental disorder.

Self-domestication in Homo sapiens: Insights from comparative genomics.

This study identifies and analyzes statistically significant overlaps between selective sweep screens in anatomically modern humans and several domesticated species. The results obtained suggest that (paleo-)genomic data can be exploited to complement the fossil record and support the idea of self-domestication in Homo sapiens, a process that likely intensified as our species populated its niche. Our analysis lends support to attempts to capture the "domestication syndrome" in terms of alterations to certain signaling pathways and cell lineages, such as the neural crest.

A hypothesis on a role of oxytocin in the social mechanisms of speech and vocal learning.

Language acquisition in humans and song learning in songbirds naturally happen as a social learning experience, providing an excellent opportunity to reveal social motivation and reward mechanisms that boost sensorimotor learning. Our knowledge about the molecules and circuits that control these social mechanisms for vocal learning and language is limited. Here we propose a hypothesis of a role for oxytocin (OT) in the social motivation and evolution of vocal learning and language. Building upon existing evidence, we suggest specific neural pathways and mechanisms through which OT might modulate vocal learning circuits in specific developmental stages.

Implications of Oxytocin in Human Linguistic Cognition: From Genome to Phenome.

The neurohormone oxytocin (OXT) has been found to mediate the regulation of complex socioemotional cognition in multiple ways both in humans and other animals. Recent studies have investigated the effects of OXT in different levels of analysis (from genetic to behavioral) chiefly targeting its impact on the social component and only indirectly indicating its implications in other components of our socio-interactive abilities. This article aims at shedding light onto how OXT might be modulating the multimodality that characterizes our higher-order linguistic abilities (vocal-auditory-attentional-memory-social systems). Based on evidence coming from genetic, EEG, fMRI, and behavioral studies, I attempt to establish the promises of this perspective with the goal of stressing the need for neuropeptide treatments to enter clinical practice.

Corrigendum: Brain asymmetry in the white matter making and globularity.

[This corrects the article on p. 1355 in vol. 6, PMID: 26441731.].

Cognitive phylogenies, the Darwinian logic of descent, and the inadequacy of cladistic thinking.

There has been a reappraisal of phylogenetic issues in cognitive science, as reconstructing cognitive phylogenies has been considered a key for unveiling the cognitive novelties that set the stage for what makes humans special. In our opinion, the studies made until now have approached cognitive phylogenies in a non-optimal way, and we wish to both highlight their problems, drawing on recent considerations in philosophy of biology. The inadequacy of current visions on cognitive phylogenies stems from the influence of the traditional "linear cladograms," according to which every seemingly new or more sophisticated feature of a cognitive mechanism, viewed as a novelty, is represented as a node on top of the old and shared elements. We claim that this kind of cladograms does not succeed in depicting the complexity with which traits are distributed across species and, furthermore, that the labels of the nodes of these traditional representational systems fail to capture the "tinkering" nature of evolution. We argue that if we are to conceive of cognitive mechanisms in a multi-dimensional, bottom-up perspective, in accordance with the Darwinian logic of descent, we should rather focus on decomposing these mechanisms into lower-level, generic functions, which have the additional advantage of being implementable in neural matter, which ultimately produces cognition. Doing so renders current constructions of cognitive phylogenies otiose.

Brain asymmetry in the white matter making and globularity.

Recent studies from the field of language genetics and evolutionary anthropology have put forward the hypothesis that the emergence of our species-specific brain is to be understood not in terms of size, but in light of developmental changes that gave rise to a more globular braincase configuration after the split from Neanderthals-Denisovans. On the grounds that (i) white matter myelination is delayed relative to other brain structures and, in humans, is protracted compared with other primates and that (ii) neural connectivity is linked genetically to our brain/skull morphology and language-ready brain, I argue that one significant evolutionary change in Homo sapiens' lineage is the interhemispheric connectivity mediated by the Corpus Callosum. The size, myelination and fiber caliber of the Corpus Callosum present an anterior-to-posterior increase, in a way that inter-hemispheric connectivity is more prominent in the sensory motor areas, whereas "high- order" areas are more intra-hemispherically connected. Building on evidence from language-processing studies that account for this asymmetry ('lateralization') in terms of brain rhythms, I present an evo-devo hypothesis according to which the myelination of the Corpus Callosum, Brain Asymmetry, and Globularity are conjectured to make up the angles of a co-evolutionary triangle that gave rise to our language-ready brain.