- Open Access
The sociability spectrum: evidence from reciprocal genetic copy number variations
Molecular Autism volume 11, Article number: 50 (2020)
Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; these however, have rarely been put in context with the opposite manifestation featured in hypersociability syndromes. Genetic copy number variations (CNVs) allow to investigate the relationships between gene dosage and its corresponding phenotypes. In particular, CNVs of the 7q11.23 locus, which manifest diametrically opposite social behaviors, offer a privileged window to look into the molecular substrates underlying the developmental trajectories of the social brain. As by definition sociability is studied in humans postnatally, the developmental fluctuations causing social impairments have thus far remained a black box. Here, we review key evidence of molecular players involved at both ends of the sociability spectrum, focusing on genetic and functional associations of neuroendocrine regulators and synaptic transmission pathways. We then proceed to propose the existence of a molecular axis centered around the paradigmatic dosage imbalances at the 7q11.23 locus, regulating networks responsible for the development of social behavior in humans and highlight the key role that neurodevelopmental models from reprogrammed pluripotent cells will play for its understanding.
The evolution of human sociability and its complexity has been the subject of a long-standing debate, leading to a tense tug-of-war between schools of thought that favor either biological or cultural contributions as its main drivers . Nevertheless, despite conflicting views regarding its causes, the importance of social functioning in the overall performance of an individual is unquestionable. Sociability is at the core of most behavioral tasks and arguably, to a large extent, essential to the biological fitness of individuals across species [2, 3].
Sociability has become a promiscuous term in recent years, describing numerous aspects of social interaction and functioning. In its overextended definition, sociability is an umbrella term that covers a wide spectrum of social features (e.g., social cognition, social behavior, social skills, social competence, social functioning) and the study of its aberrations is often associated to individuals with intellectual disability. However, sociability has no direct correlation to intellectual skills. Indeed, while the decreased intellectual ability is often comorbid with sociability aberrations (hypo or hypersociability), increased intellectual ability is not directly linked to sociability changes , indicating that healthy social behavior is dependent of sound intellectual ability, while social performance on itself bears no influence on intellectual skills.
The study of the distribution of sociability in the population shows that its manifestation constitutes a continuous variable fitting a normal (Gaussian) distribution, with most individuals falling in the middle of the range and some individuals exhibiting pathological/abnormal phenotypes, at each tail of the distribution . Within this spectrum, the outlier groups make up two categories: 1) at the lower end, hyposociability, which encompasses psychopathic disorders, anxiety and autism spectrum disorders and 2) at the upper end, hypersociability, which includes the pathological need for social contact, emotional dependence on continuous social company and lack of social inhibition .
The high degree of specification of sociability definitions across different domains has made it difficult to find fitting animal models that reliably reproduce such features, usually requiring multiple extrapolations that are confounded by a myriad of underlying assumptions required for their interpretation [7, 8]. Thus, for the purpose of this review, we will equate sociability to social cognition, which is a more general term dedicated to humans, usually used in the diagnosis and which can be defined as the study of the ability to process, store and apply information about other people and social situations [9, 10].
In this work, we systematically review the neuroendocrine and genetic associations at both ends of the sociability spectrum; then, we proceed to highlight the insights offered by known reciprocal CNVs causing opposite sociability manifestations, with a particular emphasis on the role of dosage imbalances of the 7q11.23 locus.
Neuroendocrine regulators of sociability
Most research regarding the molecular mechanisms regulating sociability has developed around the neuromodulatory functions of the neuroendocrine system, primarily centered on oxytocin (OXT) and arginine vasopressin (AVP) in the central nervous system (CNS). These closely related neuropeptides have been involved in broad areas of sociability such as affiliative behaviors (social bonding between individuals), pair-bonding (preference for contact with a familiar sexual partner), selective aggression towards unfamiliar conspecifics, biparental care, and socially regulated reproduction such as incest avoidance and aggressive behavior [11, 12]. OXT and AVP genes derive from the duplication of the vasocistin gene [13, 14] and encode for two nonapeptides with multiple actions . Besides their systemic action, OXT and AVP acting in the central nervous system are responsible for the regulation of different aspects of social behavior. In the CNS, OXT is produced by the parvocellular neurons of the paraventricular nucleus, while central AVP is synthesized by the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and medial amygdala [3, 15]. Studies in mice revealed that depletion of the AVP receptor 1b (AVPR1B) results in reduced aggressive behavior and social motivation [16, 17], while AVP itself promotes aggression or affiliation, depending on the social situation . OXT is instead related to a general increase of sociability ranging from social memory to affiliating behavior, sexual or parenting, and aggression . Oxytocin signaling is mediated by a G-protein coupled receptor (OXTR) [19, 20], and its knock out (KO) was associated with impairment in discriminating familiar from novel animals [19, 21]. In addition, it has been demonstrated that oxytocin activity in the amygdala diminishes fear behaviors through the activation of GABAergic interneurons [22, 23].
Genetic studies in patients with behavioral disorders have underscored a central role of OXT and AVP signaling pathways in human sociability. In particular, linkage disequilibrium studies have related the AVP receptor gene AVPR1A to autism . Likewise, two microsatellites and two SNPs in the AVPR1A promoter have been associated with ASD [25,26,27]. Moreover, the chromosomic region 12q14, which includes the AVPR1A locus, was associated with autism through chromosome-wide haplotype analysis . Similarly, polymorphisms in the OXT receptor, located in the 3p25.3 locus, have also been associated with autism [29,30,31,32] and deletion of the same chromosomic region causes intellectual disability, although its molecular etiology has been so far attributed only to the methyltransferase SETD5 . Parallel observations showed that SNPs in CD38, a protein that regulates OXT release, have been associated with increased sociability and empathy [5, 34,35,36], suggesting a link between the modulation of OXT-mediated signaling and sociability.
The role of OXT pathway in favoring pro-social behavior and reducing anxiety has led to propose the administration of OXT as a potential treatment for autism, particularly through intranasal delivery [23, 37]. Remarkably, OXT has been used in several clinical trials for the treatment of Prader-Willi syndrome (PWS) [38,39,40,41,42]. However, although children and adults affected by PWS treated with intranasal OXT showed behavioral improvements in some cases, these observations have not been conclusive, mostly due to unfit statistical analyses and reduced patient cohort sizes in the available trials .
Role of synaptic transmission in sociability
One important mechanism by which OXT modulates social interactions is through its crosstalk with the serotoninergic neurotransmission, particularly by the interaction between oxytocin and serotonergic projections from the dorsal raphe to the nucleus accumbens . Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter of complex multifaceted activity, produced in the CNS chiefly in the Raphe nuclei of the brainstem. Interestingly, multiple SNPs in the gene GNAS, encoding a Gαs subunit that couples with serotonin receptors 5HT4 and 5HT7, the AVP receptor 2 and dopamine receptors of the D1-like family, have been identified in a screening of ASD patients [44,45,46,47]. Genetic association studies also linked ASD to the enzyme that catalyzes the conversion of tryptophan into 5-hydroxytryptophan (5-HTP) in the brain, tryptophan-hydroxylase 2 (TPH2) [48,49,50,51,52,53]. In addition, hyperserotonemia in the peripheral blood is a biomarker of ASD , leading to the hypothesis that dysfunction of serotonin synapses caused by the alteration of its neuronal uptake or storage may have a direct behavioral impact . In agreement, researchers found that the chromosomic region 17q11, harboring the gene encoding for the serotonin transporter SLC6A4, was strongly associated with ASD. Importantly, a SNP in this gene was also found to be associated with autism. Finally, serotonin and tryptophan were found at higher concentration in the peripheral blood and in the hippocampus of germ-free animals, which showed reduced anxiety in a sex-dependent manner [56,57,58]. These observations have led to propose the existence of a microbiota-gut-brain axis, defined by the associations between serotoninergic transmission in the central nervous system and gut microbiota, which could represent a therapeutic target for behavioral disorders .
In parallel to the evidence pointing to a pivotal role for serotoninergic signaling in sociability regulation, recent studies increasingly suggest dopamine neurotransmission as an equally relevant component. Increased dopamine in the dorsal striatum causes sociability deficits and repetitive behaviors relevant to ASD, which were reversible by D1 receptor antagonists . Interestingly, KO of the D2 dopaminergic receptors, coupled with Gαι subunit, is linked to the appearance of autistic-like behaviors . Dopamine signaling in the mesocorticolimbic circuit, formed by neurons from the ventral tegmental area project to the prefrontal cortex and to the nucleus accumbens (which is part of the striatum), regulates reward and motivation-related behavior. Alteration of the dopaminergic signaling in the mesolimbic circuit results in reduced dopamine release in the prefrontal cortex and reduced response in the nucleus accumbens [61, 62]. These observations suggest the existence of a dopaminergic mesolimbic circuit that leads to persistent deficits in social interaction and communication in ASD [61, 63].
Endocannabinoids also regulate social behavior through striatum circuits and habitual/compulsive motor routines by feedback loop-inhibition of glutamate release by neurons projecting from brain regions that serve emotional cognitive sensory and motor functions on the medium spiny neurons residing in this brain region [64,65,66,67,68,69]. This function is mediated by the signaling of the cannabinoid-1 receptor activated upon binding of the 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the brain [70,71,72]. Given the evidence pointing to an increased hyper-glutamatergic activation and its link to diacylglycerol metabolism as one of the determinants of ASD [73, 74], researchers have concentrated their work in Dagla, a gene encoding for the diacylglycerol lipase involved in 2-AG biosynthesis. Conditional KO of Dagla in different regions of the striatum affected the sociability (dorsal striatum dependent) and caused repetitive behaviors (ventral striatum dependent). Intriguingly, a paternal-inherited deletion disrupting the DAGLA gene was found in a patient with ASD, although data show that this genetic lesion is not fully penetrant .
Most of the work regarding sociability has focused only on one side of the spectrum, namely the dysfunctions in social behavior leading to autism. Interestingly, a considerable amount of molecular evidence has pointed to the involvement of the glutamatergic synapses in the regulation of “hypersocial” behaviors. Indeed, throughout the years, different single genes have been linked to hypersociability, including important regulators of the pre- and post-synapsis (Fig. 1). A prime example is Dlg4, which encodes for the post-synaptic density protein PSD95, a pivotal protein of the postsynaptic compartment involved in the stabilization of the NMDA receptors by direct biding and anchoring [5, 75]. Dlg4 null mice displayed higher interaction with unfamiliar animals in social recognition and novelty tests. Interestingly, heterozygous mice for Dlg4 had only hypersociability, as opposed to deletions of its homologue Dlg2 (encoding for PSD93), which displayed increased sociality only in the homozygous KO situation [76, 77]. A similar phenotype was observed with Neuregulin-1 (Nrg1) haploinsufficiency, a component of an EGF-like signaling module that interacts with ERBB receptors and is crucial for the regulation of cell-cell communication, neuronal migration, and glutamate signaling [78, 79]. Finally, indirect glutamatergic synapse modulators have shown likewise to have behavioral consequences. One example is the neuronal nitric oxide synthase (nNOS), an enzyme responsible for the synthesis of nitric oxide in the postsynaptic terminal, which acts through retrograde signaling to activate soluble guanylyl cyclase in the presynaptic terminal, thus regulating neurotransmitter release [80, 81]. Disruption of nNOS activity causes improvement or worsening of sociability in the presence of familiar or unfamiliar animals, respectively .
Reciprocal genetic dosage imbalances and its sociability manifestations
Studying neurodevelopmental disorders (NDDs) of defined genetic origin displaying highly penetrant aberrant sociability phenotypes has been instrumental in identifying candidate genes underlying neurodevelopmental mechanisms of sociability. However, one of the biggest challenges when understanding the genetic etiology of behavioral disorders and, in particular, ASD, is the remarkable heterogeneity of their genetic associations and wide range of phenotypic manifestations and comorbidities, which has the historically complicated diagnosis and hindered the development of therapies . Genetic copy number variations (CNVs) account for about 10% of all behavioral disorders and intellectual disability of genetic origin, typically featuring paternal and age biases [84, 85]. The uncovering of the molecular mechanisms underlying the social manifestations in humans has been hampered by the lack of convergence between the genetic lesions and phenotypic manifestations in animal models . Therefore, the onset of cell reprogramming for obtaining induced pluripotent stem cells (iPSCs) introduced a shift of paradigm that is allowing the interrogation of these molecular pathways on a human genetic background in an ever-growing number of NDDs (Table 1). For instance, in a landmark study, researchers derived iPSCs from patients affected by Down Syndrome (DS) and differentiated them into neural progenitors, whose maturation was followed in vivo after transplantation into mice brains. By using single-cell-resolution intravital microscopy they were able to find that dendritic spines and synaptic boutons of DS-derived neurons were aberrantly more stable than in controls, all of which hints to dysfunction of synaptic plasticity that may ultimately reverberate on sociability . More recently, the use of iPSC-derived neurons from Kleefstra Syndrome patients helped to uncover a specific anomalous pattern of excitatory network activity that could be rescued by the administration of NMDARs pharmacological inhibitors, bearing breakthrough potential for therapeutic application .
The application of iPSC-derived models to study reciprocal (or mirrored) CNVs with opposite behavioral impact represents a particularly fertile field to interrogate the effect of gene-dosage imbalances in social behavior . This type of mirrored modifications entailing opposite sociability features is however extremely rare, making up for just a short list of coupled disorders (Table 2). Among these disorders, only 7q11.23 and 15q11.13 represent reciprocal genetic dosages with “truly” opposite hyper and hyposociability manifestations, whereas the psychiatric features of 1q21.1 microdeletion and microduplication exemplify a proposed model in which autism and schizophrenia represent two opposite extremes of a spectrum reflecting the under-development or over-development of the social brain . Moreover, the 15q11.13 phenotypic manifestations derive from changes in gene dosage that are not only exclusively caused by microdeletion or microduplication of the locus but also by uniparental imprinting disomy leading to imbalanced allele silencing, [124,125,126]. Thus, 7q11.23-related syndromes constitute the only known pair of reciprocal CNVs with highly penetrant opposite sociability manifestations, which make them uniquely relevant for the unbiased interrogation of dosage effects.
The recurrent distal 1.35-Mb 1q21.1 microdeletion is an inherited autosomal dominant aberration leading to a series of symptoms with no clear syndromic association . Between 18% and 50% of deletions occur de novo. The microdeletion can be inherited from either parent who can be carriers displaying a less severe phenotype . Its phenotypic manifestations are quite variable, including individuals with no obvious clinical features while others display variable signs including microcephaly (50%), mild intellectual disability (30%), and mildly dysmorphic facial features and eye abnormalities (26%). The most frequent psychiatric and behavioral abnormalities are autistic features, followed by attention deficit hyperactivity disorder and sleep disturbances . The 1q21.1 microduplication is instead associated with developmental delay, congenital anomalies, and macrocephaly in children . Its psychiatric manifestations are likewise variable, including in many cases ASD; however, the high incidence of schizophrenia and psychosis, typically absent in deleted patients, led us to include it as an example of opposite behavioral manifestations (Table 2) .
The 1q21.1 variable CNV typically encompasses 15 genes (PDE4DIP, HYDIN2, PRKAB2, PDIA3P, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, NBPF10, GPR89B, GPR89C, PDZK1P1, and NBPF11) and the molecular mechanisms underlying their pathogenic impact are poorly characterized. A gene expression association study using the peripheric blood of 1q21.1 microduplication patients found a significant dysregulation of language associated genes, including CDH1L and ROBO1, both highly upregulated, whereas, TLE3, a target of FOXP2 was significantly downregulated . These changes could potentially explain language and particularly speech dysfunction. However, in the absence of mechanistic links and confirmation with additional probands, these associations remain speculative. A dedicated mouse model carrying a synthetic 1q21.1 microduplication found schizophrenia-like behaviors as well as increased hyperactivity in response to amphetamine challenge. A battery of inhibitors testing showed a direct dependence of D1/D2 dopaminergic receptors, constituting the first molecular link to the behavioral impact of 1q21.1 CNV .
Variations in gene expression dosage at the 15q11-13 locus cause a group of related syndromes, Prader-Willi syndrome (PWS), Angelman syndrome (AS), and 15q11-13 microduplication syndrome [111, 116, 130]. PWS is caused by a lack of the paternally derived imprinting of the chromosomic region 15q11-13, either through paternal deletion or maternal uniparental disomy and is characterized, among other features, by mild to moderate levels of intellectual disability, compulsive behaviors, ASD and increased risks of morbid obesity [117, 118]. AS, the counterpart of PWS syndrome, is caused by maternal deletion of chromosome 15q11-13 and in particular of the gene coding for E3 ubiquitin ligase 3A (UBE3A). Among its typical features are found microcephaly, severe intellectual deficit, speech impairment, whereas from a behavioral point of view, patients display general happiness and frequent smiling and laughing as well as hyperactivity [119, 131, 132]. These sets of behaviors have been grouped as hypersociability for their proven association to increased motivation to interact with others in social situations .
The molecular mechanisms behind the sociability disruption in 15q11-13-related syndromes have been widely studied and chiefly associated with UBE3A [121, 133], thought to be the main responsible for the increased risk of ASD in PWS patients [134, 135]. Transgenic mice carrying an Ube3a duplication showed a dose-dependency of its gene product to sociability manifestations, in particular fact, mice with maternally-inherited Ube3a deletion displayed a prolonged preference interaction with social stimuli in the three-chamber social approach task . Mechanistic dissection showed that the accumulation of UBE3A in the nucleus downregulates the glutamatergic synapse organizer CBLN1, which is needed for sociability in mice, through the regulation of the activity of VGLUT2-expressing neurons in the ventral tegmental area (VTA) . More recently, the use of AS patient-derived neurons and brain organoids allowed a first demonstration of a direct role of UBE3A in the suppression of neuronal hyperexcitability by inducing the degradation of calcium and voltage-dependent big potassium (BK) channels, thus avoiding heterochronic network synchronization, which is a primary cause of epileptic seizures .
Similar phenotypes to AS have been observed in Koolen-De Vries syndrome (KdeVs), which is caused by haploinsufficiency of the KANSL1 gene [138, 139]. In this case, however, Kansl1 haploinsufficient mice did not recapitulate the increased sociability . Likewise, Down syndrome (DS), caused by trisomy of chromosome 21, displays several traits of hypersociability, including good social skills and affectionate interactions, while showing a lower prevalence of aggression and antisocial behavior, although a defined gene candidate underlying these features is yet to be identified [4, 104, 105, 141].
7q11.23 CNV syndromes as paradigmatic examples
Copy number variations at the 7q11.23 locus cause a pair of paradigmatic syndromes (deletion, Williams-Beuren syndrome, WBS and duplication, 7dupASD) entailing an almost full-penetrance of opposite social manifestations, with 7dupASD receiving an ASD diagnosis in over 90% of the cases and WBS manifesting a wider spectrum of hypersociability-related features compared to other hypersociability syndromes, including an unusual combination of intellectual disability with preservation of language skills [142, 143]. WBS and 7dupASD are autosomal dominant disorders caused by genomic rearrangements due to large region-specific low-copy repeat elements (LCR) and Alu transposable elements that may lead to non-allelic homologous recombination if not correctly aligned during meiosis [112, 113, 144]. Their reported incidence in the population is about 1/10000 for WBS and 1/20000 for 7dupASD.
The deletion/duplication of the Williams-Beuren syndrome critical region (WBSCR) leads to hemizygosity/hemiduplication of 25-28 genes that account for their phenotypic manifestations [145, 146]. Among others, the WBSCR contains genes encoding transcriptional regulators such as GTF2I, GTF2IRD1, BAZ1B, MLXIPL, or signaling molecules FZD9, TBL2, LIMK1 . Following a classification by Golzius and Katsanis , these couple of syndromes belong to the most complex type of CNV or “complex cis-epistatic” model, in which phenotypes are the result of the simultaneous dosage imbalances of numerous genes within the CNV, some of which drive specific endophenotypes and some of which exhibit complex additive and/or multiplicative relationships.
WBS patients present different phenotypes with different degrees of expressivity, including supravalvular aortic stenosis, hypercalcemia, persistent growth failure, facial dysmorphisms, mental retardation, and hypersociability, but often they do not show all these defects together. Indeed, prior to the characterization of a patient showing all phenotypes, WBS was considered two different disorders [114, 147]. To date, FISH and microsatellite marker analysis represent the standard laboratory tests for unequivocal diagnosis [113, 144, 147]. The first gene mapped in the WBSCR that was directly linked to a phenotype was the gene coding for elastin (ELN), which causes the cardiovascular and connective tissue phenotype of the disease (i.e., SVAS) . WBS patients have delays in the acquisition of early motor and language skills and show mild-to-moderate intellectual disability in adulthood (IQ from 50 to 60) . Likewise, WBS patients display defects in visuospatial and visuomotor skills (the ability to spatially relate objects), which has been related to the hypersociability phenotype due to the atypical evaluation of facial trustworthiness [148, 149]. Despite this, they display relative strengths in facial recognition and interpersonal skills, supported by their proficient language [150, 151]. Interestingly, WBS patients usually enjoy music, but very often develop sensitivity to certain noises (selective hyperacusis) . The hypersociability characteristic of patients with WBS is associated with excessive worry and fears; indeed, more than 80% of adults with WBS show anxiety (but not social anxiety), preoccupations or obsessions, irritability, and distractibility .
Opposite to WBS, 7dupASD is characterized by cognitive abnormalities, such as language impairment and deficits of social interaction, epilepsy, anxiety, and mild dimorphisms [150, 152]. 7dupASD patients show both similar and opposite features compared to WBS patients [143, 146]. It is characterized by various symptoms ranging from severe speech impairment to classical autistic disorders and craniofacial dysmorphisms .
The characterization of WBS patients with atypical breakpoints in the WBSCR allowed the study of the specific genes of the region, partially elucidating their contribution to the cognitive, behavioral, and neural phenotype seen in WBS [113, 151]. One conspicuous case emerged from atypical deletions has been the phenotype shown by sparing genes from the TFII-I family present in this region (GTF2I, GTF2IRD1, and GTF2IRD2) [150, 151, 153,154,155,156]. This gene family shares a number of similar intragenic repeats coding for helix-loop-helix structures required for DNA binding and is probably the result of intragenic duplications that occurred during evolution . Phylogenetic reconstruction of GTF2I, GTF2IRD1, and GTF2IRD2 proteins demonstrates that GTF2I and GTF2IRD1 had a common ancestor in early vertebrates. These two genes are found in all land vertebrates and are located close to each other with the same orientation suggesting an ancient duplication. A second duplication, this time with inversion, led to the origin of GTF2IRD2. The final duplicative re-arrangement of the 7q11.23 locus generated GTF2IRD2B during late primate evolution and included a second inversion event which so far has been observed only in the human genome .
In mice, GTF2I regulates the expression of the DLX homeobox gene involved in the differentiation and migration of GABA-expressing neurons in the forebrain, suggesting that the dosage of GTF2I could alter the excitation/inhibition balance , In agreement with multiple evidence suggesting an imbalance excitation/inhibition ratio of cortical neurons as an underlying substrate of sociability network development [115, 158].
Comparative studies addressing the mechanisms that drive the heightened propensity of dogs to initiate social contact, when compared with human socialized gray wolves, explained this behavior as a type of behavioral neoteny, the retention of juvenile features in the adult , which is on itself potentially the result of transcriptional neoteny in the brain . Interestingly, a genome-wide association of SNP in dogs from 85 breeds vs 92 gray wolves identified a top-ranking outlier locus located within the polymorphic WBSCR17 gene, which is typically deleted in WBS. A follow-up study found that a 5 Mb genomic region around the Williams critical region was under positive selection in domestic dog breeds and that hypersociability is a core element of domestication that distinguishes dogs from wolves . Interestingly, this divergence seems to be directly linked to structural variants in GTF2I and GTF2IRD1, placing GTF2I and its surrounding locus at the core of targets with likely direct contribution to the development of brain networks regulating sociability.
In humans, the role of the TFII-I family in determining the hypersociability phenotype has started to be elucidated. Patients carrying atypical deletions sparing only GTF2I do not show hypersociability, but only visuospatial construction deficits and craniofacial features , further emphasizing its role in sociability development. Instead, GTF2IRD1 has been associated with the visuospatial abilities [113, 144, 145, 151]. Moreover, a GTF2I deficit was found in the hippocampus of WBS patients, supporting its contribution to the characteristic spatial cognition deficit of those individuals . Importantly, GTF2I interacts with the serotonin receptor 3A and mutation in GTF2I has been associated with alteration in serotonin currents in the prefrontal cortex . These findings are in line with the hypothesis of GTF2I at the center of the hypersociability phenotype observed in WBS, also in agreement with the role of the serotonin system in regulating social cognition and anxiety.
Use of patient-derived models
While animal models have proven instrumental in uncovering many of the molecular underpinnings of the development of the social brain, some of its human-specific aspects, chiefly those linked to the significantly more complex cortical development, will require models that factor the human genetic background into this mix, such as brain organoids, which have been shown to recapitulate unique aspects of human cortical development https://doi.org/10.1038/nrn.2017.107https://doi.org/10.1038/nature12517https://doi.org/10.1016/j.cell.2019.01.017https://doi.org/10.1016/j.stemcr.2019.09.005https://doi.org/10.1016/j.stem.2016.11.017. An important hurdle is the recurrent failure in recapitulating many phenotypes in a hemizygous condition , unmasking obvious differences in susceptibility and phenotype penetrance due to genetic background.
Work done in our group through transcriptional analysis of human-induced pluripotent stem cell (iPSCs) derived from WSB and 7dupASD patients revealed that many of the biological processes predictive of the disease manifestation (i.e., related to brain development) are found altered already at the pluripotent state in the two conditions . About 10–20% of this transcriptional deregulation was attributed exclusively to GTF2I and this dysregulation was propagated into disease-relevant lineages, including neural crest and neural progenitors . Interestingly, we found that GTF2I not only acts as a transcriptional activator but also is responsible for gene repression through its interaction with LSD1 and HDAC2. These observations provided the first molecular evidence of early transcriptional dysregulation as a potential mechanism explaining the gene dosage imbalances of GTF2I and sociability aberrations .
Another crucial gene of the WBSCR is BAZ1B. We recently demonstrated that BAZ1B is the master regulator of the modern human face, on the basis of a functional molecular dissection of its dosage imbalance in patient-derived neural crest stem cells (NCSCs) . We found that BAZ1B regulates the developing NCSCs derived from patient iPSCs, starting from its earliest migratory stages by downregulating well-established critical regulators of NCSCs migration and maintenance, confirming that its dosage imbalances, characteristic of WBS and 7dupASD, alter NCSCs migration. Interestingly, the gracilization of the cranium has been strongly associated with the “self-domestication hypothesis”, which proposes that social behavior co-evolved with specific craniofacial features through natural selection of traits that favored increased in-group prosociality over aggression in the H. sapiens lineage [165,166,167]. In WBS, the lower-mid face morphology sharply departs from the anatomically modern human one with traits that can be reconducted to a further gracilization of the cranium, which may be related to the hypersociability phenotype characteristic of this syndrome .
Sociability is a phenotypic domain that reaches unparalleled complexity in humans. The study of behavioral disorders and its genetic causes has allowed to define a complex landscape of genes and molecules that play pivotal roles at both ends of the sociability spectrum. Considering that by definition gene dosage/function defects in these disorders are present from early development, an open question is whether their role is exclusively influencing developmental circuits or whether they may be modulating the function of the mature social brain. A particularly relevant subset of genes and proteins involved in several of these syndromes are those whose dosage seems to be directly linked to a sociability outcome (Fig. 2), indicating their potential key role in defining the circuits that regulate social behavior in humans. Since the generation of animal models has proven often disappointing in recapitulating social phenotypes, it becomes salient the importance to maintain a human genetic background. To further unveil the developmental trajectories and specific cell populations affected by specific gene dosages, will require the genetic engineering of human pluripotent cell lines with multiple allelic series of endogenous expression and their differentiation into nerve cells using more comprehensive models such as brain organoids, which will allow to simultaneously address the uniqueness of human brain development within the context of the human-specific genetic background.
Availability of data and materials
Autism spectrum disorder
Copy number variation
Central nervous system
Koolen-De Vries syndrome
Low-copy repeat elements
7q11.23 duplication autism spectrum disorder
Williams-Beuren Critical Region
Neural crest stem cells
Induced pluripotent stem cells
Zeigler-Hill V, Welling LLM, Shackelford TK. Evolutionary perspectives on social psychology. books.google.com; 2015.
Cote J, Dreiss A, Clobert J. Social personality trait and fitness. Proc Biol Sci. 2008 Dec 22;275(1653):2851–8.
Caldwell HK. Neurobiology of sociability. Adv Exp Med Biol. 2012;739:187–205.
Cook F, Oliver C. A review of defining and measuring sociability in children with intellectual disabilities. Res Dev Disabil. 2011 Feb;32(1):11–24.
Toth M. The other side of the coin: hypersociability. Genes Brain Behav. 2019;18(1):e12512.
Trull TJ, Widiger TA. Dimensional models of personality: the five-factor model and the DSM-5. Dialogues Clin Neurosci. 2013;15(2):135–46.
Kondrakiewicz K, Kostecki M, Szadzińska W, Knapska E. Ecological validity of social interaction tests in rats and mice. Genes Brain Behav. 2018;11:e12525.
Kazdoba TM, Leach PT, Crawley JN. Behavioral phenotypes of genetic mouse models of autism. Genes Brain Behav. 2016;15(1):7–26.
Sowden S, Shah P. Self-other control: a candidate mechanism for social cognitive function. Front Hum Neurosci. 2014;8:789.
Billeke P, Aboitiz F. Social cognition in schizophrenia: from social stimuli processing to social engagement. Front Psychiatry. 2013;4:4.
Carter CS, Getz LL. Monogamy and the prairie vole. Sci Am. 1993 Jun;268(6):100–6.
Carter CS, DeVries AC, Getz LL. Physiological substrates of mammalian monogamy: the prairie vole model. Neurosci Biobehav Rev. 1995;19(2):303–14.
Acher R, Chauvet J. The neurohypophysial endocrine regulatory cascade: precursors, mediators, receptors, and effectors. Front Neuroendocrinol. 1995 Jul;16(3):237–89.
Acher R, Chauvet J, Chauvet MT. Man and the chimaera. Selective versus neutral oxytocin evolution. Adv Exp Med Biol. 1995;395:615–27.
Sofroniew MV. Morphology of vasopressin and oxytocin neurones and their central and vascular projections; 1983.
Wersinger SR, Ginns EI, O’Carroll AM, Lolait SJ, Young WS. Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiatry. 2002;7(9):975–84.
Wersinger SR, Kelliher KR, Zufall F, Lolait SJ, O’Carroll A-M, Young WS. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm Behav. 2004;46(5):638–45.
Caldwell HK, Lee H-J, Macbeth AH, Young WS. Vasopressin: behavioral roles of an “original” neuropeptide. Prog Neurobiol. 2008;84(1):1–24.
Lee H-J, Macbeth AH, Pagani JH, Young WS. Oxytocin: the great facilitator of life. Prog Neurobiol. 2009;88(2):127–51.
Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001;81(2):629–83.
Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T, et al. Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci USA. 2005 Nov 1;102(44):16096–101.
Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH, et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron. 2012;73(3):553–66.
Fineberg SK, Ross DA. Oxytocin and the social brain. Biol Psychiatry. 2017 Feb 1;81(3):e19–21.
Kim SJ, Young LJ, Gonen D, Veenstra-VanderWeele J, Courchesne R, Courchesne E, et al. Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism. Mol Psychiatry. 2002 Jan 1;7(5):503–7.
Hammock EAD, Young LJ. Oxytocin, vasopressin and pair bonding: implications for autism. Philos Trans R Soc Lond B, Biol Sci. 2006;361(1476):2187–98.
Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, et al. Examination of AVPR1a as an autism susceptibility gene. Mol Psychiatry. 2004 Oct 1;9(10):968–72.
Yirmiya N, Rosenberg C, Levi S, Salomon S, Shulman C, Nemanov L, et al. Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills. Mol Psychiatry. 2006 May 1;11(5):488–94.
Ma DQ, Cuccaro ML, Jaworski JM, Haynes CS, Stephan DA, Parod J, et al. Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14. Mol Psychiatry. 2007 Apr 1;12(4):376–84.
Liu X, Kawamura Y, Shimada T, Otowa T, Koishi S, Sugiyama T, et al. Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. J Hum Genet. 2010 Mar;55(3):137–41.
Wu S, Jia M, Ruan Y, Liu J, Guo Y, Shuang M, et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry. 2005 Jul 1;58(1):74–7.
Jacob S, Brune CW, Carter CS, Leventhal BL, Lord C, Cook EH. Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neurosci Lett. 2007;417(1):6–9.
Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry. 2008 Oct;13(10):980–8.
Kuechler A, Zink AM, Wieland T, Lüdecke H-J, Cremer K, Salviati L, et al. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur J Hum Genet. 2014;20:23(6).
Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA, Mattay VS, et al. A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proc Natl Acad Sci USA. 2010 Aug 3;107(31):13936–41.
Gong P, Fan H, Liu J, Yang X, Zhang K, Zhou X. Revisiting the impact of OXTR rs53576 on empathy: A population-based study and a meta-analysis. Psychoneuroendocrinology. 2017 Jun;80:131–6.
Chang S-C, Glymour MM, Rewak M, Cornelis MC, Walter S, Koenen KC, et al. Are genetic variations in OXTR, AVPR1A, and CD38 genes important to social integration? Results from two large U.S. cohorts. Psychoneuroendocrinology. 2014;39:257–68.
Alvares GA, Quintana DS, Whitehouse AJO. Beyond the hype and hope: Critical considerations for intranasal oxytocin research in autism spectrum disorder. Autism Res. 2017 Jan;10(1):25–41.
Einfeld SL, Smith E, McGregor IS, Steinbeck K, Taffe J, Rice LJ, et al. A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome. Am J Med Genet A. 2014 Sep;164A(9):2232–9.
Tauber M, Mantoulan C, Copet P, Jauregui J, Demeer G, Diene G, et al. Oxytocin may be useful to increase trust in others and decrease disruptive behaviours in patients with Prader-Willi syndrome: a randomised placebo-controlled trial in 24 patients. Orphanet J Rare Dis. 2011 Jun 24;6:47.
Miller JL, Tamura R, Butler MG, Kimonis V, Sulsona C, Gold J-A, et al. Oxytocin treatment in children with Prader-Willi syndrome: A double-blind, placebo-controlled, crossover study. Am J Med Genet A. 2017 May;173(5):1243–50.
Kuppens RJ, Donze SH, Hokken-Koelega ACS. Promising effects of oxytocin on social and food-related behaviour in young children with Prader-Willi syndrome: a randomized, double-blind, controlled crossover trial. Clin Endocrinol (Oxf). 2016 Dec;85(6):979–87.
Dykens EM, Miller J, Angulo M, Roof E, Reidy M, Hatoum HT, et al. Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome. JCI Insight. 2018;21:3(12).
Rice LJ, Einfeld SL, Hu N, Carter CS. A review of clinical trials of oxytocin in Prader-Willi syndrome. Curr Opin Psychiatry. 2018;31(2):123–7.
Nicholls RD. The impact of genomic imprinting for neurobehavioral and developmental disorders. J Clin Invest. 2000 Feb;105(4):413–8.
Huetter FK, Horn PA, Siffert W. Sex-specific association of a common GNAS polymorphism with self-reported cognitive empathy in healthy volunteers. PLoS One. 2018 Oct 26;13(10):e0206114.
Kim SJ, Gonen D, Hanna GL, Leventhal BL, Cook EH. Deletion polymorphism in the coding region of the human NESP55 alternative transcript of GNAS1. Mol Cell Probes. 2000;14(3):191–4.
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012 Apr 4;485(7397):237–41.
Walther DJ, Peter J-U, Bashammakh S, Hörtnagl H, Voits M, Fink H, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003 Jan 3;299(5603):76.
Lovenberg W, Jequier E, Sjoerdsma A. Tryptophan hydroxylation: measurement in pineal gland, brainstem, and carcinoid tumor. Science. 1967 Jan 13;155(3759):217–9.
Coon H, Dunn D, Lainhart J, Miller J, Hamil C, Battaglia A, et al. Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). Am J Med Genet B, Neuropsychiatr Genet. 2005 May 5;135B(1):42–6.
Egawa J, Watanabe Y, Endo T, Someya T. Association of rs2129575 in the tryptophan hydroxylase 2 gene with clinical phenotypes of autism spectrum disorders. Psychiatry Clin Neurosci. 2013 Sep;67(6):457–8.
Singh AS, Chandra R, Guhathakurta S, Sinha S, Chatterjee A, Ahmed S, et al. Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indian population. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Aug 1;45:131–43.
Yang SY, Yoo HJ, Cho IH, Park M, Kim SA. Association with tryptophan hydroxylase 2 gene polymorphisms and autism spectrum disorders in Korean families. Neurosci Res. 2012 Aug;73(4):333–6.
Folk GE, Long JP. Serotonin as a neurotransmitter: a review. Comp Biochem Physiol C. 1988;91(1):251–7.
Muller CL, Anacker AMJ, Veenstra-VanderWeele J. The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience. 2016 May 3;321:24–41.
Yonan AL, Alarcón M, Cheng R, Magnusson PKE, Spence SJ, Palmer AA, et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet. 2003 Oct;73(4):886–97.
Stone JL, Merriman B, Cantor RM, Yonan AL, Gilliam TC, Geschwind DH, et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet. 2004 Dec;75(6):1117–23.
Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L, et al. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005;77(2):265–79.
Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013 Jun;18(6):666–73.
Lee Y, Kim H, Kim J-E, Park J-Y, Choi J, Lee J-E, et al. Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors. Mol Neurobiol. 2018 Jul;55(7):5658–71.
Pavăl D. A dopamine hypothesis of autism spectrum disorder. Dev Neurosci. 2017 Jul 28;39(5):355–60.
Chevallier C, Kohls G, Troiani V, Brodkin ES, Schultz RT. The social motivation theory of autism. Trends Cogn Sci (Regul Ed). 2012;16(4):231–9.
Scott-Van Zeeland AA, Dapretto M, Ghahremani DG, Poldrack RA, Bookheimer SY. Reward processing in autism. Autism Res. 2010 Apr;3(2):53–67.
Shonesy BC, Parrish WP, Haddad HK, Stephenson JR, Báldi R, Bluett RJ, et al. Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Biol Psychiatry. 2018 Aug 15;84(4):304–15.
Wei D, Lee D, Cox CD, Karsten CA, Peñagarikano O, Geschwind DH, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci USA. 2015 Nov 10;112(45):14084–9.
Karhson DS, Hardan AY, Parker KJ. Endocannabinoid signaling in social functioning: an RDoC perspective. Transl Psychiatry. 2016 Sep 27;6(9):e905.
Manduca A, Servadio M, Damsteegt R, Campolongo P, Vanderschuren LJ, Trezza V. Dopaminergic neurotransmission in the nucleus accumbens modulates social play behavior in rats. Neuropsychopharmacology. 2016;41(9):2215–23.
Chen M, Wan Y, Ade K, Ting J, Feng G, Calakos N. Sapap3 deletion anomalously activates short-term endocannabinoid-mediated synaptic plasticity. J Neurosci. 2011 Jun 29;31(26):9563–73.
Gremel CM, Chancey JH, Atwood BK, Luo G, Neve R, Ramakrishnan C, et al. Endocannabinoid modulation of orbitostriatal circuits gates habit formation. Neuron. 2016;90(6):1312–24.
Shonesy BC, Wang X, Rose KL, Ramikie TS, Cavener VS, Rentz T, et al. CaMKII regulates diacylglycerol lipase-α and striatal endocannabinoid signaling. Nat Neurosci. 2013 Apr;16(4):456–63.
Uchigashima M, Narushima M, Fukaya M, Katona I, Kano M, Watanabe M. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J Neurosci. 2007 Apr 4;27(14):3663–76.
Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009;89(1):309–80.
Ninan I. Oxytocin suppresses basal glutamatergic transmission but facilitates activity-dependent synaptic potentiation in the medial prefrontal cortex. J Neurochem. 2011 Oct;119(2):324–31.
Bejjani A, O’Neill J, Kim JA, Frew AJ, Yee VW, Ly R, et al. Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI. PLoS One. 2012;7(7):e38786.
Coley AA, Gao W-J. PSD95: A synaptic protein implicated in schizophrenia or autism? Prog Neuropsychopharmacol Biol Psychiatry. 2018 Mar 2;82:187–94.
Feyder M, Karlsson R-M, Mathur P, Lyman M, Bock R, Momenan R, et al. Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams’ syndrome. Am J Psychiatry. 2010;167(12):1508–17.
Winkler D, Daher F, Wüstefeld L, Hammerschmidt K, Poggi G, Seelbach A, et al. Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93. Behav Brain Res. 2017;9.
Britsch S. The neuregulin-I/ErbB signaling system in development and disease. Adv Anat Embryol Cell Biol. 2007;190:1–65.
Mei L, Nave K-A. Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014;83(1):27–49.
Roy B, Halvey EJ, Garthwaite J. An enzyme-linked receptor mechanism for nitric oxide-activated guanylyl cyclase. J Biol Chem. 2008 Jul 4;283(27):18841–51.
Neitz A, Mergia E, Eysel UT, Koesling D, Mittmann T. Presynaptic nitric oxide/cGMP facilitates glutamate release via hyperpolarization-activated cyclic nucleotide-gated channels in the hippocampus. Eur J Neurosci. 2011 May;33(9):1611–21.
Tanda K, Nishi A, Matsuo N, Nakanishi K, Yamasaki N, Sugimoto T, et al. Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice. Mol Brain. 2009;2:19.
Quesnel-Vallières M, Weatheritt RJ, Cordes SP, Blencowe BJ. Autism spectrum disorder: insights into convergent mechanisms from transcriptomics. Nat Rev Genet. 2019;20(1):51–63.
Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014 Nov 13;515(7526):216–21.
Hehir-Kwa JY, Rodríguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R, Buitelaar JK, et al. De novo copy number variants associated with intellectual disability have a paternal origin and age bias. J Med Genet. 2011 Nov;48(11):776–8.
Ornoy A, Weinstein-Fudim L, Ergaz Z. Prevention or Amelioration of Autism-Like Symptoms in Animal Models: Will it Bring Us Closer to Treating Human ASD? Int J Mol Sci. 2019;1:20(5).
Bachmann-Gagescu R, Mefford HC, Cowan C, Glew GM, Hing AV, Wallace S, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med. 2010 Oct;12(10):641–7.
Fernandez BA, Roberts W, Chung B, Weksberg R, Meyn S, Szatmari P, et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet. 2010 Mar;47(3):195–203.
Deneault E, Faheem M, White SH, Rodrigues DC, Sun S, Wei W, et al. CNTN5-/+or EHMT2-/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks. Elife. 2019;12:8.
Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CAL, Dijkhuizen T, Bijlsma EK, Gijsbers ACJ, et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet. 2009 Jun;52(2-3):108–15.
Burnside RD, Pasion R, Mikhail FM, Carroll AJ, Robin NH, Youngs EL, et al. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet. 2011 Oct;130(4):517–28.
Das DK, Tapias V, D’Aiuto L, Chowdari KV, Francis L, Zhi Y, et al. Genetic and morphological features of human iPSC-derived neurons with chromosome 15q11.2 (BP1-BP2) deletions. Mol Neuropsychiatry. 2015;1(2):116–23.
Precht KS, Lese CM, Spiro RP, Huttenlocher PR, Johnston KM, Baker JC, et al. Two 22q telomere deletions serendipitously detected by FISH. J Med Genet. 1998 Nov 1;35(11):939–42.
Prasad C, Prasad AN, Chodirker BN, Lee C, Dawson AK, Jocelyn LJ, et al. Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype. Clin Genet. 2000;57(2):103–9.
Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007 Jan;39(1):25–7.
Cocks G, Curran S, Gami P, Uwanogho D, Jeffries AR, Kathuria A, et al. The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders. Psychopharmacology. 2014 Mar;231(6):1079–88.
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008 Feb;82(2):477–88.
Ross PJ, Zhang W-B, Mok RSF, Zaslavsky K, Deneault E, D’Abate L, et al. Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS. Biol Psychiatry. 2019;29.
Dabell MP, Rosenfeld JA, Bader P, Escobar LF, El-Khechen D, Vallee SE, et al. Investigation of NRXN1 deletions: clinical and molecular characterization. Am J Med Genet A. 2013 Apr;161A(4):717–31.
Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008 Mar;40(3):322–8.
Harada N, Visser R, Dawson A, Fukamachi M, Iwakoshi M, Okamoto N, et al. A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome. J Hum Genet. 2004 Jul 16;49(8):440–4.
Stewart DR, Huang A, Faravelli F, Anderlid B-M, Medne L, Ciprero K, et al. Subtelomeric deletions of chromosome 9q: a novel microdeletion syndrome. Am J Med Genet A. 2004 Aug 1;128A(4):340–51.
Neas KR, Smith JM, Chia N, Huseyin S, St Heaps L, Peters G, et al. Three patients with terminal deletions within the subtelomeric region of chromosome 9q. Am J Med Genet A. 2005;132A(4):425–30.
Moore DG, Oates JM, Hobson RP, Goodwin J. Cognitive and social factors in the development of infants with Down syndrome. Downs Syndr Res Pract. 2002 Sep;8(2):43–52.
Laws G, Bishop D. Pragmatic language impairment and social deficits in Williams syndrome: a comparison with Down’s syndrome and specific language impairment. Int J Lang Commun Disord. 2004;39(1):45–64.
Real R, Peter M, Trabalza A, Khan S, Smith MA, Dopp J, et al. In vivo modeling of human neuron dynamics and Down syndrome. Science. 2018;16:362(6416).
Frega M, Linda K, Keller JM, Gümüş-Akay G, Mossink B, van Rhijn J-R, et al. Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling. Nat Commun. 2019;10(1):4928.
Golzio C, Katsanis N. Genetic architecture of reciprocal CNVs. Curr Opin Genet Dev. 2013;23(3):240–8.
Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008 Oct 16;359(16):1685–99.
Haldeman-Englert CR, Jewett T. 1q21.1 Recurrent Microdeletion. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993.
Aman LCS, Manning KE, Whittington JE, Holland AJ. Mechanistic insights into the genetics of affective psychosis from Prader-Willi syndrome. Lancet Psychiatry. 2018 Jan 16;5(4):370–8.
Etokebe GE, Axelsson S, Svaerd NH, Storhaug K, Dembić Z. Detection of Hemizygous Chromosomal Copy Number Variants in Williams-Beuren Syndrome (WBS) by Duplex Quantitative PCR Array: An Unusual Type of WBS Genetic Defect. Int J Biomed Sci. 2008 Sep;4(3):161–70.
Ferrero GB, Howald C, Micale L, Biamino E, Augello B, Fusco C, et al. An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient. Eur J Hum Genet. 2010 Jan;18(1):33–8.
Collette JC, Chen X-N, Mills DL, Galaburda AM, Reiss AL, Bellugi U, et al. William’s syndrome: gene expression is related to parental origin and regional coordinate control. J Hum Genet. 2009 Apr;54(4):193–8.
Sohal VS, Rubenstein JLR. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry. 2019 Sep;24(9):1248–57.
Buiting K, Williams C, Horsthemke B. Angelman syndrome - insights into a rare neurogenetic disorder. Nat Rev Neurol. 2016 Sep 12;12(10):584–93.
Horsthemke B, Wagstaff J. Mechanisms of imprinting of the Prader-Willi/Angelman region. Am J Med Genet A. 2008 Aug 15;146A(16):2041–52.
Dykens EM, Lee E, Roof E. Prader-Willi syndrome and autism spectrum disorders: an evolving story. J Neurodev Disord. 2011 Sep;3(3):225–37.
Richman DM, Gernat E, Teichman H. Effects of social stimuli on laughing and smiling in young children with Angelman syndrome. Am J Ment Retard. 2006;111(6):442–6.
Oliver C, Demetriades L, Hall S. Effects of environmental events on smiling and laughing behavior in Angelman syndrome. Am J Ment Retard. 2002;107(3):194–200.
Stoppel DC, Anderson MP. Hypersociability in the Angelman syndrome mouse model. Exp Neurol. 2017 Apr 11;293:137–43.
Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z, et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature. 2011 Aug 31;478(7367):97–102.
Crespi B, Badcock C. Psychosis and autism as diametrical disorders of the social brain. Behav Brain Sci. 2008 Jun;31(3):241–261; discussion 261.
Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet. 2003 Feb;40(2):87–95.
Vogels A, Fryns JP. The Prader-Willi syndrome and the Angelman syndrome. Genet Couns. 2002;13(4):385–96.
Bennett JA, Germani T, Haqq AM, Zwaigenbaum L. Autism spectrum disorder in Prader-Willi syndrome: A systematic review. Am J Med Genet A. 2015;167A(12):2936–44.
Qiao Y, Badduke C, Tang F, Cowieson D, Martell S, Lewis SME, et al. Whole exome sequencing of families with 1q21.1 microdeletion or microduplication. Am J Med Genet A. 2017.
Dolcetti A, Silversides CK, Marshall CR, Lionel AC, Stavropoulos DJ, Scherer SW, et al. 1q21.1 Microduplication expression in adults. Genet Med. 2013 Apr;15(4):282–9.
Benítez-Burraco A, Barcos-Martínez M, Espejo-Portero I, Fernández-Urquiza M, Torres-Ruiz R, Rodríguez-Perales S, et al. Narrowing the genetic causes of language dysfunction in the 1q21.1 microduplication syndrome. Front Pediatr. 2018;6:163.
Finucane BM, Lusk L, Arkilo D, Chamberlain S, Devinsky O, Dindot S, et al. 15q Duplication Syndrome and Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993.
Bower BD, Jeavons PM. The “happy puppet” syndrome. Arch Dis Child. 1967 Jun;42(223):298–302.
Elian M. Fourteen happy puppets. Clin Pediatr (Phila). 1975;14(10):902–8.
Lopez SJ, Segal DJ, LaSalle JM. UBE3A: An E3 Ubiquitin Ligase With Genome-Wide Impact in Neurodevelopmental Disease. Front Mol Neurosci. 2018;11:476.
Schanen NC. Epigenetics of autism spectrum disorders. Hum Mol Genet. 2006;15 Spec No 2:R138–R150.
Wassink TH, Piven J. The molecular genetics of autism. Curr Psychiatry Rep. 2000 Apr;2(2):170–5.
Krishnan V, Stoppel DC, Nong Y, Johnson MA, Nadler MJS, Ozkaynak E, et al. Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. Nature. 2017 Mar 23;543(7646):507–12.
Sun AX, Yuan Q, Fukuda M, Yu W, Yan H, Lim GGY, et al. Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science. 2019 Dec 20;366(6472):1486–92.
Zollino M, Orteschi D, Murdolo M, Lattante S, Battaglia D, Stefanini C, et al. Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nat Genet. 2012 Apr 29;44(6):636–8.
Koolen DA, Kramer JM. Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012;44(6):639–41.
Arbogast T, Iacono G, Chevalier C, Afinowi NO, Houbaert X, van Eede MC, et al. Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition. PLoS Genet. 2017;13(7):e1006886.
Collacott RA, Cooper SA, Branford D, McGrother C. Behaviour phenotype for Down’s syndrome. Br J Psychiatry. 1998 Jan;172:85–9.
Morris CA. Williams Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993.
Mervis CB, Morris CA, Klein-Tasman BP, Velleman SL, Osborne LR. 7q11.23 Duplication Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993.
Antonell A, Del Campo M, Magano LF, Kaufmann L, de la Iglesia JM, Gallastegui F, et al. Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile. J Med Genet. 2010;47(5):312–20.
Li HH, Roy M, Kuscuoglu U, Spencer CM, Halm B, Harrison KC, et al. Induced chromosome deletions cause hypersociability and other features of Williams-Beuren syndrome in mice. EMBO Mol Med. 2009 Apr;1(1):50–65.
Adamo A, Atashpaz S, Germain P-L, Zanella M, D’Agostino G, Albertin V, et al. 7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages. Nat Genet. 2015;47(2):132–41.
Pober BR. Williams-Beuren syndrome. N Engl J Med. 2010 Jan 21;362(3):239–52.
Lucena J, Pezzi S, Aso E, Valero MC, Carreiro C, Dubus P, et al. Essential role of the N-terminal region of TFII-I in viability and behavior. BMC Med Genet. 2010 Apr 19;11:61.
Shore DM, Ng R, Bellugi U, Mills DL. Abnormalities in early visual processes are linked to hypersociability and atypical evaluation of facial trustworthiness: An ERP study with Williams syndrome. Cogn Affect Behav Neurosci. 2017;6.
Malenfant P, Liu X, Hudson ML, Qiao Y, Hrynchak M, Riendeau N, et al. Association of GTF2i in the Williams-Beuren syndrome critical region with autism spectrum disorders. J Autism Dev Disord. 2012 Jul;42(7):1459–69.
Dai L, Bellugi U, Chen XN, Pulst-Korenberg AM, Järvinen-Pasley A, Tirosh-Wagner T, et al. Is it Williams syndrome? GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays. Am J Med Genet A. 2009 Mar;149A(3):302–14.
Shirai Y, Watanabe M, Sakagami H, Suzuki T. Novel splice variants in the 5’UTR of Gtf2i expressed in the rat brain: alternative 5'UTRs and differential expression in the neuronal dendrites. J Neurochem. 2015 Aug;134(3):578–89.
Makeyev AV, Bayarsaihan D. ChIP-Chip Identifies SEC23A, CFDP1, and NSD1 as TFII-I Target Genes in Human Neural Crest Progenitor Cells. Cleft Palate Craniofac J. 2013 May;50(3):347–50.
Tanikawa M, Wada-Hiraike O, Nakagawa S, Shirane A, Hiraike H, Koyama S, et al. Multifunctional transcription factor TFII-I is an activator of BRCA1 function. Br J Cancer. 2011 Apr 12;104(8):1349–55.
Bayés M, Magano LF, Rivera N, Flores R, Pérez Jurado LA. Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet. 2003;73(1):131–51.
Makeyev AV, Bayarsaihan D. Molecular basis of Williams-Beuren syndrome: TFII-I regulated targets involved in craniofacial development. Cleft Palate Craniofac J. 2011 Jan;48(1):109–16.
Gunbin KV, Ruvinsky A. Evolution of general transcription factors. J Mol Evol. 2013;76(1-2):28–47.
Lopatina OL, Komleva YK, Gorina YV, Olovyannikova RY, Trufanova LV, Hashimoto T, et al. Oxytocin and excitation/inhibition balance in social recognition. Neuropeptides. 2018 Dec;72:1–11.
von Holdt BM, Shuldiner E, Koch IJ, Kartzinel RY, Hogan A, Brubaker L, et al. Structural variants in genes associated with human Williams-Beuren syndrome underlie stereotypical hypersociability in domestic dogs. Sci Adv. 2017;3(7):e1700398.
Somel M, Franz H, Yan Z, Lorenc A, Guo S, Giger T, et al. Transcriptional neoteny in the human brain. Proc Natl Acad Sci USA. 2009;106(14):5743–8.
Edelmann L, Prosnitz A, Pardo S, Bhatt J, Cohen N, Lauriat T, et al. An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism. J Med Genet. 2007 Feb;44(2):136–43.
Segura-Puimedon M, Borralleras C, Pérez-Jurado LA, Campuzano V. TFII-I regulates target genes in the PI-3 K and TGF-β signaling pathways through a novel DNA binding motif. Gene. 2013;527(2):529–36.
Osborne LR. Animal models of Williams syndrome. Am J Med Genet C Semin Med Genet. 2010 May 15;154C(2):209–19.
Zanella M, Vitriolo A, Andirko A, Martins PT, Sturm S, O’Rourke T, et al. Dosage analysis of the 7q11.23 Williams region identifies BAZ1B as a major human gene patterning the modern human face and underlying self-domestication. Sci Adv. 2019;5(12):eaaw7908.
Godinho RM, Spikins P, O’Higgins P. Supraorbital morphology and social dynamics in human evolution. Nat Ecol Evol. 2018;2(6):956–61.
Pesco FD, Fischer J. On the evolution of baboon greeting rituals; 2019.
Hare B. Survival of the Friendliest: Homo sapiens Evolved via Selection for Prosociality. Annu Rev Psychol. 2017;68:155–86.
S.T. is PhD student within the European School of Molecular Medicine (SEMM).
The authors were supported by the following grants: Fondazione Cariplo (2017-0886 to A.L.T.); ENDpoiNTs, European Union’s Horizon 2020 research and innovation programme (Grant No 825759. to G.T.); Fondazione Telethon (GGP19226 to G.T.). S.T. was supported by a FIRC-AIRC fellowship for Italy.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
López-Tobón, A., Trattaro, S. & Testa, G. The sociability spectrum: evidence from reciprocal genetic copy number variations. Molecular Autism 11, 50 (2020). https://doi.org/10.1186/s13229-020-00347-0
- Autism spectrum disorders
- William-Beuren syndrome