Genes‐to‐Pathways Species Conservation Analysis: Enabling the Exploration of Conservation of Biological Pathways and Processes Across Species

Abstract

AbstractThe last two decades have witnessed a strong momentum toward integration of cell‐based and computational approaches in safety assessments. This is fueling a global regulatory paradigm shift toward reduction and replacement of the use of animals in toxicity tests while promoting the use of new approach methodologies. The understanding of conservation of molecular targets and pathways provides an opportunity to extrapolate effects across species and ultimately to determine the taxonomic applicability domain of assays and biological effects. Despite the wealth of genome‐linked data available, there is a compelling need for improved accessibility, while ensuring that it reflects the underpinning biology. We present the novel pipeline Genes‐to‐Pathways Species Conservation Analysis (G2P‐SCAN) to further support understanding on cross‐species extrapolation of biological processes. This R package extracts, synthetizes, and structures the data available from different databases, that is, gene orthologs, protein families, entities, and reactions, linked to human genes and respective pathways across six relevant model species. The use of G2P‐SCAN enables the overall analysis of orthology and functional families to substantiate the identification of conservation and susceptibility at the pathway level. In the present study we discuss five case studies, demonstrating the validity of the developed pipeline and its potential use as species extrapolation support. We foresee this pipeline will provide valuable biological insights and create space for the use of mechanistically based data to inform potential species susceptibility for research and safety decision purposes. Environ Toxicol Chem 2023;42:1152–1166. © 2023 UNILEVER GLOBAL IP LTD. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.