When pitch adds to volume: coregulation of transcript diversity predicts gene function

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Genes coregulate transcript volume for physiological functions.
• Coregulation of transcript diversity (co-splicing) remains largely unstudied.
• Investigated reliability, consistency, and functional associations of co-splicing correlations.

Purpose of the Study:

• Assess reproducibility of co-splicing correlations for APP, a gene linked to Alzheimer's disease (AD).
• Determine how tissue-specific co-splicing predicts functional gene interactions.
• Compute co-splicing frequency for a large set of genes across numerous human tissues.

Main Methods:

• Analyzed co-splicing correlations across two independent studies and multiple tissues.
• Employed two statistical methods to evaluate co-splicing relationships.
• Investigated enrichment of co-splicing in biological pathways and disease associations.

Main Results:

• Replicated co-splicing correlations between APP and AD-related genes, confirming pathway enrichment.
• Identified novel associations between APP co-splicing, co-expression, epistasis, and tissue vulnerability in AD.
• Confirmed known gene interactions and discovered novel ones, creating a 52-tissue co-splicing map for over 17,000 genes.

Conclusions:

• Transcript diversity coregulation offers novel biological insights and aids GWAS interpretation.
• Co-splicing correlations are reliable, frequent, and valuable for predicting gene function.
• Results support AD interventions targeting the ubiquitin proteasome pathway and highlight the need to consider transcript diversity for treatment and susceptibility.