The Importance of Biologic Knowledge and Gene Expression Context for Genomic Data Interpretation

Area of Science:

• Genomics
• Bioinformatics
• Molecular Biology

Background:

• Whole exome sequencing (WES) advances disease definition and clinical care.
• WES often identifies genomic variants with unclear functional impacts.
• Gene transcript diversity and tissue-specific expression complicate WES data interpretation.

Purpose of the Study:

• To quantify the impact of transcript and tissue expression differences on WES data interpretation.
• To assess how these variations affect gene, pathway, disease, and network analyses.

Main Methods:

• Analysis of multiple large, public genomic datasets.
• Quantification of transcript and tissue expression effects on WES interpretation.
• Examination across gene, pathway, disease, and biologic network levels.

Main Results:

• Transcript selection alters protein-coding effects for 54% of pathways and 40% of disease genes.
• Tissue expression differences impact 33% of pathways and 19% of diseases.
• These variations significantly affect interpretation across most pathways and diseases.

Conclusions:

• Accurate WES data interpretation requires integrating transcript selection and tissue-specific gene expression.
• Genomic variant interpretation varies substantially based on transcript and tissue context.
• Inclusion of these factors is essential for high-resolution WES analysis.