Functional annotation of rare structural variation in the human brain.

Area of Science:

• Genomics
• Molecular Biology
• Neuroscience

Background:

• Structural variants (SVs) are significant contributors to human disorders.
• Functional annotation of SVs, especially their regulatory impact, remains a challenge.

Purpose of the Study:

• To quantify the dosage and regulatory effects of SVs by integrating them with RNA sequencing data from human post-mortem brains.
• To develop a predictive model for the expression effects of copy number variants (CNVs).
• To functionally annotate the regulatory consequences of CNVs in a large cohort.

Main Methods:

• Integration of SVs with RNA sequencing data.
• Analysis of genic and regulatory content altered by CNVs.
• Training a linear model to predict expression effects of rare CNVs.
• Annotation of regulatory disruption in 14,891 individuals.

Main Results:

• Genic and regulatory SVs occur at lower frequencies than intergenic SVs.
• The functional impact of CNVs depends on the proportion of altered genic/regulatory content and gene loss-of-function intolerance.
• Pathogenic deletions in neurodevelopmental disorders exhibit extreme regulatory disruption scores, outperforming frequency or length for prioritization.
• Regulatory SVs, especially those affecting CTCF sites, are deleterious.

Conclusions:

• The study provides a method for functionally annotating the regulatory consequences of CNVs.
• Prioritizing SVs based on regulatory disruption offers a valuable approach for identifying disease-associated variants.
• This work highlights the deleteriousness of regulatory SVs and their role in human disorders.