Non-coding Regulatory Variants in ASD (Autism Spectrum Disorders) Disrupt CTCF Domains and Shape Cell-Type-Specific...

Area of Science:

• Genetics
• Neuroscience
• Genomics

Background:

• Autism Spectrum Disorder (ASD) has significant genetic heterogeneity, with non-coding regulatory variants being largely unexplored.
• Understanding the functional impact of these variants at the single-cell level and in organoid models is crucial for ASD pathogenesis research.

Purpose of the Study:

• To investigate the role of non-coding regulatory variants in ASD pathogenesis.
• To characterize the impact of these variants on gene expression in specific cell types and developmental stages.

Main Methods:

• Targeted sequencing of active cis-regulatory elements (cCREs) in individuals with ASD.
• Utilizing the Sei deep learning framework to predict regulatory impact scores for variants.
• Integrating single-nucleus RNA-seq data from ASD brains and human cortical organoid data for gene expression analysis.

Main Results:

• Identified and prioritized de novo and ultra-rare inherited variants with significant regulatory impact.
• Found enrichment of de novo variants in promoter-like sequences and CTCF-mediated chromatin boundaries.
• Observed distinct cellular and temporal gene expression patterns for genes affected by de novo versus inherited variants.

Conclusions:

• Non-coding mutations significantly contribute to ASD risk by disrupting gene regulation, particularly CTCF domains.
• De novo regulatory mutations primarily affect dynamically expressed genes, while inherited variants impact constitutively expressed genes.
• The study validates dosage sensitivity mechanisms and highlights the overlap between regulatory and coding mutations in ASD.