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De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes [RNA-Seq]

ABSTRACT: Three-dimensional genome organization plays a critical role in gene regulation, and disruption of chromatin structure has been shown to lead to developmental disorders through the changed contact between key genes and their distal regulatory elements. Structural variants (SVs) have the ability to disrupt local genome organization, such as the joining of topologically associated domains upon deletion of a boundary. Unfortunately, testing large numbers of SVs for their effects on chromatin structure and gene expression is time and cost prohibitive. To overcome these experimental limitations, we previously developed SuPreMo, a convolutional neural network based method that accurately predicts how sequence variants change genome structure. Here, we extended the tool to specifically measure changed contact at regions of interest, such as cell type specific regulatory elements. Using this updated SuPreMo, we tested hundreds of de novo SVs (dnSVs) from autism spectrum disorder (ASD) individuals and their unaffected siblings and predicted how nearby genes’ regulatory interactions were affected in neurons. We found that putative cis-regulatory element interactions (CREints) are more disrupted by dnSVs from ASD probands versus unaffected siblings, allowing us to prioritize proband CREints of genes involved in neuronal development. We experimentally validated our top locus using induced pluripotent stem cell-derived excitatory neurons with and without the dnSV and found that the variant resulted in mis-regulation of 1102 genes. This in vitro characterization of a candidate causal variant is important, because most ASD patients do not carry a damaging protein-coding variant that alters neurodevelopment or neuronal function. This study establishes disrupted genome folding as a new genetic mechanism for ASD and provides a general strategy for prioritizing variants predicted to disrupt regulatory interactions in any tissue.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281327 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder, which is characterized by disturbances of brain function and behavioral deficits in core areas of impaired reciprocal socialization, impairment in communication skills, and repetitive or restrictive interests and behaviors. ASD is known to have a significant genetic risk, but the underlying genetic variation can be attributed to hundreds of genes. The molecular and pathophysiologic basis of ASD remains elusive because of its genetic heterogeneity and complexity, its high comorbidity with other diseases, and the paucity of brain tissue for study. The invasive nature of collecting primary neuronal tissue from patients might be circumvented through reprogramming peripheral cells to induced pluripotent stem cells (iPSCs), which are able to generate live neurons carrying the genetic variants of disease. This breakthrough allows us to access the cellular and molecular phenotypes of patients with âintrinsic autismâ, that is patients without known genetic disorders or identifiable syndromes or malformations. To do this, we studied a relatively homogeneous patient population of boys with intrinsic autism by excluding patients with known genetic disease or recognizable phenotypes or syndromes, as well as those with profound mental retardation or primary seizure disorders. We generated iPSCs from patients with intrinsic autism, their unaffected male siblings and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons. The expression profile for autistic and their unaffected siblings' iPSC-derived neurons were compared. A distinct expression profile was found between autism and sib control. The significantly differentially expressed genes (> 2-fold, FDR < 0.05) in autistic iPSC-derived neurons were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions (FDR < 0.05), and were significantly enriched for genes previously associated with ASD (p < 0.05). Our findings suggest approaches such as iPSC-derived neurons will be an important method to obtain tissue for study that appropriately recapitulates the complex dynamics of an autistic neural cell. We generated induced pluripotent stem cells (iPSCs) from male patients with intrinsic autism, their unaffected male siblings, and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons following 80 days of post-mitotic neural differentiation. These samples, including fibroblast, iPSC, iPSC-derived neural progenitors (NPC) and iPSC-derived neurons, were analyzed for the change of gene expression profile by whole genome microarray.

Project description:Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder, which is characterized by disturbances of brain function and behavioral deficits in core areas of impaired reciprocal socialization, impairment in communication skills, and repetitive or restrictive interests and behaviors. ASD is known to have a significant genetic risk, but the underlying genetic variation can be attributed to hundreds of genes. The molecular and pathophysiologic basis of ASD remains elusive because of its genetic heterogeneity and complexity, its high comorbidity with other diseases, and the paucity of brain tissue for study. The invasive nature of collecting primary neuronal tissue from patients might be circumvented through reprogramming peripheral cells to induced pluripotent stem cells (iPSCs), which are able to generate live neurons carrying the genetic variants of disease. This breakthrough allows us to access the cellular and molecular phenotypes of patients with ‘intrinsic autism’, that is patients without known genetic disorders or identifiable syndromes or malformations. To do this, we studied a relatively homogeneous patient population of boys with intrinsic autism by excluding patients with known genetic disease or recognizable phenotypes or syndromes, as well as those with profound mental retardation or primary seizure disorders. We generated iPSCs from patients with intrinsic autism, their unaffected male siblings and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons. The expression profile for autistic and their unaffected siblings' iPSC-derived neurons were compared. A distinct expression profile was found between autism and sib control. The significantly differentially expressed genes (> 2-fold, FDR < 0.05) in autistic iPSC-derived neurons were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions (FDR < 0.05), and were significantly enriched for genes previously associated with ASD (p < 0.05). Our findings suggest approaches such as iPSC-derived neurons will be an important method to obtain tissue for study that appropriately recapitulates the complex dynamics of an autistic neural cell.

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De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes [RNA-Seq]

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