Identifying gene function and module connections by the integration of multispecies expression compendia

Area of Science:

• Computational Biology
• Genomics
• Systems Biology

Background:

• The functions of numerous eukaryotic genes remain largely uncharacterized.
• Understanding gene function is crucial for deciphering biological processes and disease mechanisms.

Purpose of the Study:

• To develop and validate a novel computational method, GeneBridge, for imputing gene function and linking genes to biological processes.
• To create a comprehensive resource for exploring gene-module and module-module associations across multiple species.

Main Methods:

• GeneBridge integrates two primary approaches: Gene-Module Association Determination (G-MAD) for gene function annotation and Module-Module Association Determination (M-MAD) for predicting module connectivity.
• The tools were applied to a large-scale, multispecies expression compendium comprising 1700 datasets and over 300,000 samples from human, mouse, rat, fly, worm, and yeast.
• Tissue-specific gene functions were identified by applying G-MAD to relevant tissue datasets.

Main Results:

• G-MAD successfully identified novel gene functions (e.g., DDT in mitochondrial respiration, WDFY4 in T cell activation) and suggested new components for biological modules (e.g., cholesterol biosynthesis).
• Tissue-specific gene functions were elucidated, including roles for EHHADH in liver/kidney and SLC6A1 in brain/liver.
• M-MAD revealed significant module-module associations, such as connections between mitochondria and proteasome, mitochondria and histone demethylation, and ribosomes and lipid biosynthesis.

Conclusions:

• GeneBridge provides a powerful and validated framework for functional genomics and systems biology research.
• The GeneBridge tools and associated expression compendia represent an open resource to accelerate the discovery of links between genes, modules, phenotypes, and diseases.
• This study significantly advances our ability to understand complex gene functions and their roles in biological systems.