Structural Changes in Gene Ontology Reveal Modular and Complex Representations of Biological Function

Abstract

[EN] The Gene Ontology is a central resource for representing biological knowledge, yet its internal structure is often treated as static-or as a black box-in computational analyses. Here, we examine 15 years of Gene Ontology evolution using network-based methods, revealing that Gene Ontology changes not only through incremental growth but also through punctuated, curator-driven restructuring. In particular, we document a major reorganization of the Cellular Component branch in 2019, where broad "part" terms were removed and the ontology was modularized into distinct domains for anatomical entities and protein-containing complexes. Semantic modularity aligns Gene Ontology with emerging frameworks such as the Common Anatomy Reference Ontology and Gene Ontology-Causal Activity Modeling, but also disrupts similarity metrics that rely solely on hierarchical proximity. More broadly, the restructuring of the cellular components branch consolidates a shift toward treating Gene Ontology as a multi-layer semantic network-a transformation rooted in a decade-long process of scientific and social consensus across institutions. These findings underscore the need for version-aware, multi-layer models to ensure reproducibility and interpretability-and to better represent biological function across compositional, spatial, and regulatory dimensions as ontologies continue to evolve.