Systematically developing a registry of splice-site creating variants utilizing massive publicly available...

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Genomic variants affecting splicing are crucial in genetic disorders and cancer.
• Novel splice-site creating variants (SSCVs) are difficult to detect and often missed in genomic studies.
• SSCVs are promising targets for splice-switching antisense oligonucleotide (ASO) therapies.

Purpose of the Study:

• To develop a novel computational framework for identifying SSCVs using only transcriptome data.
• To create a comprehensive registry of SSCVs from large-scale transcriptome datasets.
• To investigate the characteristics and implications of SSCVs, including their role in Alu exonization and disease.

Main Methods:

• Development of a novel framework to screen for SSCVs using transcriptome sequence data.
• Application of the framework to 322,072 publicly available transcriptomes.
• Analysis of identified SSCVs for disease relevance, Alu exonization patterns, and evolutionary relationships.

Main Results:

• Identification of 30,130 SSCVs, with 5121 impacting disease-causing variants.
• Characterization of Alu exonization via SSCVs, including hotspots and evolutionary insights.
• Discovery of novel gain-of-function SSCVs in the NOTCH1 gene, suppressible by ASOs.

Conclusions:

• A systematic approach for automated SSCV discovery facilitates the study of splicing mechanisms.
• The identified SSCV catalog serves as a valuable resource for drug discovery and therapeutic development.
• The findings highlight the potential of ASOs in targeting and correcting splicing defects caused by SSCVs.