Search Results (9)

Williams–Beuren Syndrome (WBS) is a rare neurodevelopmental disease caused by a microdeletion on chromosome 7 (7q11.23) and associated with behavioral disorders such as hypersociability, impaired visuospatial memory, anxiety, and motor disorders. The precise underlying neurobiological bases remain unknown. The CD mouse is a genetic model that reproduces the deletion found in WBS patients on the equivalent mouse locus. Taking into account that monoaminergic systems are known to modulate behaviors that are altered in WBS, we hypothesized that CD mice could present quantitative and qualitative changes in brain noradrenaline, dopamine, and serotonin systems compared to wild-type (WT) littermates. We sampled 10 brain regions in female mice for quantifying monoamines and related compounds by high-performance liquid chromatography coupled to electrochemical detection. We found a decrease in dopamine in the nucleus accumbens and serotonin and its metabolites in the hypothalamus. Using correlative approaches of tissue content across the brain, we found that the relationships between neurotransmitters or their metabolic ratios (metabolite/neurotransmitter) changed in CD compared to WT. Notably, compared to WT, the ratios in CD mice showed striatal correlations for the serotonin/dopamine systems interaction, and cortical, thalamic, and hypothalamic correlations for the noradrenaline/dopamine systems interaction. The data suggest specific alterations of monoaminergic systems across the brain that could sustain the abnormal behavioral responses displayed by CD mice. Full article

Social interaction between the domesticated animal and the domesticator is one of the key features of the “domestication syndrome”. Recent research has identified genes in the WBSCR (Williams–Beuren syndrome control region) locus as significant contributors to social behavior in dogs. Large chromosomal deletions and duplications in the human WBSCR locus lead to the development of WBS (Williams–Beuren syndrome) and WBSCR duplication syndrome, respectively. Hypersociability is one of the key symptoms of WBS, while the duplication syndrome is manifested as an autism spectrum disorder (ASD). The data from both humans and dogs highlight the WBSCR locus as one of the key genetic determinants of social behavior in mammals. Several genes in the WBSCR are candidates for the regulation of social behavior in mammals including GTF2I, GTF2IRD, AUTS2 and GALNT17. Here, we discuss the role of WBSCR locus in the regulation of social behavior in mammals including the recent data that highlight the importance of 3D genome alterations in this genomic region for both domestication of animals and development of neurobehavioral disorders in humans. In addition, we bring attention to the role of the poorly characterized GALNT17 gene as a putative player in the development of ASD symptoms and in the regulation of social behavior in animals. We provide a brief summary of its known functions and propose the future research directions aimed at the elucidation of Galnt17 involvement in the regulation of central nervous system (CNS) functions. Full article

Williams syndrome (WS) is a neurodevelopmental disorder characterized by distinctive cognitive and personality profiles which also impacts various physiological systems. The syndrome arises from the deletion of about 25 genes located on chromosome 7q11.23, including Gtf2i. Prior research indicated a strong association between pre-natal Gtf2i deletion, and the hyper-social phenotypes observed in WS, as well as myelination deficits. As most studies addressed pre-natal Gtf2i deletion in mouse models, post-natal neuronal roles of Gtf2i were unknown. To investigate the impact of post-natal deletion of neuronal Gtf2i on hyper-sociability, we intravenously injected an AAV-PHP.eB virus expressing Cre-recombinase under the control of αCaMKII, a promoter in a mouse model with floxed Gtf2i. This targeted deletion was performed in young mice, allowing for precise and efficient brain-wide infection leading to the exclusive removal of Gtf2i from excitatory neurons. As a result of such gene deletion, the mice displayed hyper-sociability, increased anxiety, impaired cognition, and hyper-mobility, relative to controls. These findings highlight the potential of systemic viral manipulation as a gene-editing technique to modulate behavior-regulating genes during the post-natal stage, thus presenting novel therapeutic approaches for addressing neurodevelopmental dysfunction. Full article

Coyotes are ubiquitous on the North American landscape as a result of their recent expansion across the continent. They have been documented in the heart of some of the most urbanized cities, such as Chicago, Los Angeles, and New York City. Here, we explored the genomic composition of 16 coyotes in the New York metropolitan area to investigate genomic demography and admixture for urban-dwelling canids in Queens County, New York. We identified moderate-to-high estimates of relatedness among coyotes living in Queens (r = 0.0–0.5) and adjacent neighborhoods, suggestive of a relatively small population. Although we found low background levels of domestic-dog ancestry across most coyotes in our sample (5%), we identified a male suspected to be a first-generation coyote–dog hybrid with 46% dog ancestry, as well as his two putative backcrossed offspring that carried approximately 25% dog ancestry. The male coyote–dog hybrid and one backcrossed offspring each carried two transposable element insertions that are associated with human-directed hypersociability in dogs and gray wolves. An additional, unrelated coyote with little dog ancestry also carried two of these insertions. These genetic patterns suggest that gene flow from domestic dogs may become an increasingly important consideration as coyotes continue to inhabit metropolitan regions. Full article

Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a de novo hemizygous deletion of ~26 genes from chromosome 7q11.23, among them the general transcription factor II-I (GTF2I). By studying a novel murine model for the hypersociability phenotype associated with WS, we previously revealed surprising aberrations in myelination and cell differentiation properties in the cortices of mutant mice compared to controls. These mutant mice had selective deletion of Gtf2i in the excitatory neurons of the forebrain. Here, we applied diffusion magnetic resonance imaging and fiber tracking, which showed a reduction in the number of streamlines in limbic outputs such as the fimbria/fornix fibers and the stria terminalis, as well as the corpus callosum of these mutant mice compared to controls. Furthermore, we utilized next-generation sequencing (NGS) analysis of cortical small RNAs’ expression (RNA-Seq) levels to identify altered expression of microRNAs (miRNAs), including two from the miR-34 cluster, known to be involved in prominent processes in the developing nervous system. Luciferase reporter assay confirmed the direct binding of miR-34c-5p to the 3’UTR of PTPRU—a gene involved in neural development that was elevated in the cortices of mutant mice relative to controls. Moreover, we found an age-dependent variation in the expression levels of doublecortin (Dcx)—a verified miR-34 target. Thus, we demonstrate the substantial effect a single gene deletion can exert on miRNA regulation and brain structure, and advance our understanding and, hopefully, treatment of WS. Full article

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders, characterized by a deficit in social interaction and communication. Many genetic variants are associated with ASD, including duplication of 7q11.23 encompassing 26–28 genes. Symmetrically, the hemizygous deletion of 7q11.23 causes Williams–Beuren syndrome (WBS), a multisystem disorder characterized by “hyper-sociability” and communication skills. Interestingly, deletion of four non-exonic mobile elements (MEs) in the “canine WBS locus” were associated with the behavioral divergence between the wolf and the dog and dog sociability and domestication. We hypothesized that indel of these MEs could be involved in ASD, associated with its different phenotypes and useful as biomarkers for patient stratification and therapeutic design. Since these MEs are non-exonic they have never been discovered before. We searched the corresponding MEs and loci in humans by comparative genomics. Interestingly, they mapped on different but ASD related genes. The loci in individuals with phenotypically different autism and neurotypical controls were amplified by PCR. A sub-set of each amplicon was sequenced by Sanger. No variant resulted associated with ASD and neither specific phenotypes were found but novel small-scale insertions and SNPs were discovered. Since MEs are hyper-methylated and epigenetically modulate gene expression, further investigation in ASD is necessary. Full article

There is arguably no other North American species that better illustrates the complexities of the human-wildlife interface than the coyote. In this study, a melanistic coyote in metropolitan Atlanta, Georgia was exhibiting unusually bold behaviors that included encounters with humans, domestic dogs, and attempts to enter homes. After tracking this coyote (nicknamed Carmine) across a highly urbanized landscape with participatory science, including at least 80 publicly reported sightings, he was captured and relocated to a wildlife sanctuary. Genome-wide analyses revealed 92.8% coyote ancestry, 1.7% gray wolf ancestry, and 5.5% domestic dog ancestry. The dog alleles in Carmine’s genome were estimated to have been acquired by his ancestors 14–29 years ago. Despite his bold behavior, Carmine did not carry any mutations known to shape hypersociability in canines. He did, however, carry a single copy of the dominant mutation responsible for his melanistic coat color. This detailed study of Carmine dispels common assumptions about the reticent coyote personality and the origins of behavior. His unusual bold behavior created a higher level of human-coyote interaction. He now serves as a public ambassador for human-wildlife coexistence, urging the global community to reconsider mythologies about wildlife and promote coexistence with them in landscapes significantly altered by human activity in our rapidly changing world. Full article

Assistance dog training programs can see as many as 60% of their trainees dismissed. Many training programs utilize behavioral assays prior to admittance to identify likely successful candidates, yet such assays can be insconsistent. Recently, four canine retrotransposon mobile element insertions (MEIs) in or near genes WBSCR17 (Cfa6.6 and Cfa6.7), GTF2I (Cfa6.66) and POM121 (Cfa6.83) were identified in domestic dogs and gray wolves. Variations in these MEIs were significantly associated with a heightened propensity to initiate prolonged social contact or hypersociability. Using our dataset of 837 dogs, 228 of which had paired survey-based behavioral data, we discovered that one of the insertions in WBSCR17 is the most important predictor of dog sociable behaviors related to human proximity, measured by the Canine Behavioral Assessment Research Questionnaire (C-BARQ©). We found a positive correlation between insertions at Cfa6.6 and dog separation distress in the form of restlessness when about to be left alone by the owner. Lastly, assistance dogs showed significant heterozygosity deficiency at locus Cfa6.6 and higher frequency of insertions at Cfa6.6 and Cfa6.7. We suggest that training programs could utilize this genetic survey to screen for MEIs at WBSCR17 to identify dogs with sociable traits compatible with successful assistance dog performance. Full article

Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25–28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS. Full article