Multi-Layer Transcriptomic Comparison Across Human, Pig, and Mouse Informs Tissue- and Trait-Specific Animal Model...

Animal models are fundamental to biomedical research, yet the relative suitability of pigs and mice remains unclear across tissues, regulatory layers, and phenotype domains. Here, we assembled a large-scale, tissue-matched transcriptomic resource comprising more than 16 000 RNA-seq samples from 15 corresponding human, pig, and mouse tissues, and established a unified framework integrating global co-expression conservation, co-expression network architecture, tissue-specific programs, 3D genome architecture, and human complex-trait genetics. Using 14 910 one-to-one orthologous genes, we found that human-pig pairs showed higher global co-expression similarity than human-mouse pairs in most tissues, with exceptions including skin, pancreas, and kidney. Integration with 176 human complex traits further revealed distinct phenotypic associations of species-preferred patterns: human-pig-preferred genes showed preferential associations with cardiometabolic, biochemical, and blood-related traits, whereas both-conserved genes showed stronger associations with neuropsychiatric, cognitive, and behavioral phenotypes. Together, our results demonstrate that cross-species similarity is hierarchical and context-dependent, varying across tissues, regulatory layers, and trait domains. Rather than supporting a universally optimal model organism, our study provides a comparative framework for prioritizing animal models based on regulatory conservation, together with an interactive portal for gene-centered exploration across humans, pigs, and mice.