scholarly journals Identification and functional analysis of long non-coding RNAs in autism spectrum disorders

2020 ◽  
Author(s):  
Zhan Tong ◽  
Yuan Zhou ◽  
Juan Wang
Keyword(s):  
Nervous System ◽  
Transcriptional Regulation ◽  
Copy Number ◽  
System Development ◽  
Copy Number Variant ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Biological Pathways ◽  
Non Coding Rnas

ABSTRACTBackgroundGenetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, our aim was to identify ASD-related lncRNAs and explore their functions and associated biological pathways in autism.MethodsASD-related lncRNAs were identified based on genomic variant data of individuals with ASD from a twin study, and further validated using an independent copy number variant (CNV) dataset. The functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of three different types of functional neighbor genes (i.e. genomic neighbors, competing endogenous RNA (ceRNA) neighbors and gene co-expression neighbors in the cortex). The differential functions of ASD-related lncRNAs in distinct brain regions were demonstrated by using gene co-expression network analysis based on tissue-specific gene expression profiles. Moreover, a functional network analysis were conducted for highly reliable functional neighbor genes of ASD-related lncRNAs. Finally, several potential drugs were predicted based on the enrichment of drug-induced pathway sets in ASD-altered biological pathway list.ResultsIn total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by a copy number variant (CNV) dataset. Most of functional neighbor genes of ASD-related lncRNAs were enriched in several functions and biological pathways, including nervous system development, inflammatory response and transcriptional regulation. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. Moreover, all highly reliable functional neighbor genes were connected in a single functional network. Finally, several potential drugs were predicted and partly supported by the previous reports.ConclusionsWe concluded that ASD-related lncRNAs participate in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. And detailed investigation of ASD-related lncRNAs also provided clues for developing potential ASD diagnosis biomarker and therapy.

scholarly journals Copy number variations in candidate genomic regions confirm genetic heterogeneity and parental bias in Hirschsprung disease

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Francesca Lantieri ◽  
Stefania Gimelli ◽  
Chiara Viaggi ◽  
Elissavet Stathaki ◽  
Michela Malacarne ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Genetic Heterogeneity ◽  
Copy Number ◽  
System Development ◽  
Hirschsprung Disease ◽  
Copy Number Variations ◽  
Nervous System Development ◽  
Comparative Genomic ◽  
Genomic Regions

Abstract Background Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance. Many susceptibility genes including RET, the major HSCR gene, and several linked regions and associated loci have been shown to contribute to disease pathogenesis. Nonetheless, a proportion of patients still remains unexplained. Copy Number Variations (CNVs) have already been involved in HSCR, and for this reason we performed Comparative Genomic Hybridization (CGH), using a custom array with high density probes. Results A total of 20 HSCR candidate regions/genes was tested in 55 sporadic patients and four patients with already known chromosomal aberrations. Among 83 calls, 12 variants were experimentally validated, three of which involving the HSCR crucial genes SEMA3A/3D, NRG1, and PHOX2B. Conversely RET involvement in HSCR does not seem to rely on the presence of CNVs while, interestingly, several gains and losses did co-occur with another RET defect, thus confirming that more than one predisposing event is necessary for HSCR to develop. New loci were also shown to be involved, such as ALDH1A2, already found to play a major role in the enteric nervous system. Finally, all the inherited CNVs were of maternal origin. Conclusions Our results confirm a wide genetic heterogeneity in HSCR occurrence and support a role of candidate genes in expression regulation and cell signaling, thus contributing to depict further the molecular complexity of the genomic regions involved in the Enteric Nervous System development. The observed maternal transmission bias for HSCR associated CNVs supports the hypothesis that in females these variants might be more tolerated, requiring additional alterations to develop HSCR disease.

Postnatal testosterone may be an important mediator of the association between prematurity and male neurodevelopmental disorders: a hypothesis

2017 ◽  
Vol 29 (2) ◽  
Author(s):  
Timothy R. Rice
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodevelopmental Disorders ◽  
System Development ◽  
Explanatory Power ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Special Focus ◽  
Important Mediator ◽  
Androgen Exposure

Abstract Children born premature are at risk for neurodevelopmental disorders, including autism and schizophrenia. This piece advances the hypothesis that altered androgen exposure observed in premature infants is an important mediator of the neurodevelopmental risk in males associated with prematurity. Specifically, the alterations of normative physiologic postnatal activations of the hypothalamic-pituitary-gonadal axis that occur in preterm males are hypothesized to contribute to the risk of neuropsychiatric pathology of prematurity through altered androgen-mediated organizational effects on the developing brain. The physiology of testosterone and male central nervous system development in full-term births is reviewed and compared to the developmental processes of prematurity. The effects of the altered testosterone physiology observed within prematurity outside of the central nervous system are reviewed as a segue into a discussion of the effects within the nervous system, with a special focus on autism spectrum disorders and attention deficit hyperactivity disorder. The explanatory power of this model is reviewed as a supplement to the preexisting models of prematurity and neurodevelopmental risk, including infection and other perinatal central nervous system insults. The emphasis is placed on altered androgen exposure as serving as just one among many mediators of neurodevelopmental risk that may be of interest for further research and evidence-based investigation. Implications for diagnosis, management and preventative treatments conclude the piece.

scholarly journals Spatiotemporal expression of IgLON family members in the developing mouse nervous system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sydney Fearnley ◽  
Reesha Raja ◽  
Jean-François Cloutier
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Developmental Disorders ◽  
System Development ◽  
Expression Patterns ◽  
Family Members ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Spatiotemporal Expression ◽  
Developing Nervous System

AbstractDifferential expression of cell adhesion molecules in neuronal populations is one of the many mechanisms promoting the formation of functional neural circuits in the developing nervous system. The IgLON family consists of five cell surface immunoglobulin proteins that have been associated with various developmental disorders, such as autism spectrum disorder, schizophrenia, and major depressive disorder. However, there is still limited and fragmented information about their patterns of expression in certain regions of the developing nervous system and how their expression contributes to their function. Utilizing an in situ hybridization approach, we have analyzed the spatiotemporal expression of all IgLON family members in the developing mouse brain, spinal cord, eye, olfactory epithelium, and vomeronasal organ. At one prenatal (E16) and two postnatal (P0 and P15) ages, we show that each IgLON displays distinct expression patterns in the olfactory system, cerebral cortex, midbrain, cerebellum, spinal cord, and eye, indicating that they likely contribute to the wiring of specific neuronal circuitry. These analyses will inform future functional studies aimed at identifying additional roles for these proteins in nervous system development.

scholarly journals Spatiotemporal transcriptomic divergence across human and macaque brain development

Science ◽  
2018 ◽  
Vol 362 (6420) ◽  
pp. eaat8077 ◽  
Author(s):  
Ying Zhu ◽  
André M. M. Sousa ◽  
Tianliuyun Gao ◽  
Mario Skarica ◽  
Mingfeng Li ◽  
...  
Keyword(s):  
Brain Development ◽  
System Development ◽  
Brain Regions ◽  
Tissue Level ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Functional Hierarchy ◽  
Topographic Gradients ◽  
Shed Light ◽  
Human Nervous System

Human nervous system development is an intricate and protracted process that requires precise spatiotemporal transcriptional regulation. We generated tissue-level and single-cell transcriptomic data from up to 16 brain regions covering prenatal and postnatal rhesus macaque development. Integrative analysis with complementary human data revealed that global intraspecies (ontogenetic) and interspecies (phylogenetic) regional transcriptomic differences exhibit concerted cup-shaped patterns, with a late fetal-to-infancy (perinatal) convergence. Prenatal neocortical transcriptomic patterns revealed transient topographic gradients, whereas postnatal patterns largely reflected functional hierarchy. Genes exhibiting heterotopic and heterochronic divergence included those transiently enriched in the prenatal prefrontal cortex or linked to autism spectrum disorder and schizophrenia. Our findings shed light on transcriptomic programs underlying the evolution of human brain development and the pathogenesis of neuropsychiatric disorders.

scholarly journals Size matters: Large copy number losses in Hirschsprung disease patients reveal genes involved in enteric nervous system development

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009698
Author(s):  
Laura E. Kuil ◽  
Katherine C. MacKenzie ◽  
Clara S. Tang ◽  
Jonathan D. Windster ◽  
Thuy Linh Le ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Copy Number ◽  
System Development ◽  
Hirschsprung Disease ◽  
Nervous System Development ◽  
Gene Enrichment ◽  
Coding Variants ◽  
Enteric Nervous System Development

Hirschsprung disease (HSCR) is a complex genetic disease characterized by absence of ganglia in the intestine. HSCR etiology can be explained by a unique combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). Pinpointing the responsible culprits within a CNV is challenging as often many genes are affected. Therefore, we selected candidate genes based on gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics. Next, we used a zebrafish model to investigate whether loss of these genes affects enteric neuron development in vivo. This study included three groups of patients, two groups without coding variants in disease associated genes: HSCR-AAM and HSCR patients without associated anomalies (HSCR-isolated). The third group consisted of all HSCR patients in which a confirmed pathogenic rare coding variant was identified. We compared these patient groups to unaffected controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients without RET coding variants. CNV profiling proved that specifically HSCR-AAM patients had larger Copy Number (CN) losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes located within CN losses. Validation in zebrafish using CRISPR/Cas9 targeting confirmed the contribution of UFD1L, TBX2, SLC8A1, and MAPK8 to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expression and between reduced Ret and Tubb5 expression in vivo. Rare large CN losses—often de novo—contribute to HSCR in HSCR-AAM patients. We proved the involvement of six genes in enteric nervous system development and Hirschsprung disease.

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