Abstract
The chromosome 22q11.21 copy number variant (CNV) is a vital risk factor that can be a genetic predisposition to neurodevelopmental disorders (NDD). As the 22q11.21 CNV affects multiple genes, causal disease genes and mechanisms affected are still poorly understood. Thus, we aimed to identify the most impactful 22q11.21 CNV genes and the potential impacted human brain regions, developmental stages and signaling pathways. We constructed the spatiotemporal dynamic networks of 22q11.21 CNV genes using the brain developmental transcriptome and physical protein–protein interactions. The affected brain regions, developmental stages, driver genes and pathways were subsequently investigated via integrated bioinformatics analysis. As a result, we first identified that 22q11.21 CNV genes affect the cortical area mainly during late fetal periods. Interestingly, we observed that connections between a driver gene, DGCR8, and its interacting partners, MECP2 and CUL3, also network hubs, only existed in the network of the late fetal period within the cortical region, suggesting their functional specificity during brain development. We also confirmed the physical interaction result between DGCR8 and CUL3 by liquid chromatography-tandem mass spectrometry. In conclusion, our results could suggest that the disruption of DGCR8-dependent microRNA biogenesis plays a vital role in NDD for late fetal cortical development.
Highlights
Our results suggest that the DGCR8-dependent microRNA biogenesis pathway is crucial for the 22q11.21 Copy number variants (CNVs) genes involved in psychiatric disorders
Our spatiotemporal network analysis indicated that mid-fetal and late fetal periods were the critical periods for 22q11.21 CNV proteins to affect human brain development
We identified that one CNV gene, DGCR8, is a driver gene in the parietal, temporal and occipital cortex (R1) during the late fetal period (P4)
Summary
Copy number variants (CNVs) are duplications or deletions of a genomic fragment ranging from one kilobase (Kb) to five megabases (Mb) [1]. They have often been identified as risk factors for genetic disorders [2]. The most commonly 22q11.2 deleted or duplicated region spans LCR-A to LCR-D, located on chromosome 22q11.21 [3]. Deletion of 22q11.21 can cause schizophrenia, intellectual delay or attention deficit hyperactivity disorder [4,5], and duplication of 22q11.21 may lead to learning disability, developmental delay and ASD [3,6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
