CladeOScope-GSA: Revealing Evolutionary Associations Across Gene Sets.

Deciphering gene and protein functions and interactions remains a core challenge in biology and medicine. Gene set analysis and multi-omics tools are widely used to interpret gene lists; however, they often overlook shared evolutionary patterns among genes. These conservation and loss patterns, shaped by billions of years of evolutionary pressure, can uncover co-evolutionary signals within gene sets, yet they remain frequently underexplored. In this study, we apply normalized phylogenetic profiling (NPP) across 1905 eukaryotic species and introduce CladeOScope-GSA, a tool for analyzing user-defined gene sets. CladeOScope-GSA uncovers common signatures of conservation, revealing whether a gene set evolves as a cohesive unit or as distinct co-evolving submodules. By tracing gene set origins, diversification, and shared evolutionary histories, the tool identifies the structural organization and key components of gene networks, exposing functional similarities, phenotypic associations, and broader biological relationships. We demonstrate its utility through two well-characterized cases: the porphyria-related pathway and the dynein gene family. In both, CladeOScope-GSA recapitulates known functional substructures and uncovers previously unrecognized evolutionary insights, underscoring its value for advancing our understanding of gene function and pathway evolution on a broad scale.