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Here, we assembled a large\u2010scale, tissue\u2010matched transcriptomic resource comprising more than 16\u00a0000 RNA\u2010seq samples from 15 corresponding human, pig, and mouse tissues, and established a unified framework integrating global co\u2010expression conservation, co\u2010expression network architecture, tissue\u2010specific programs, 3D genome architecture, and human complex\u2010trait genetics. Using 14\u00a0910 one\u2010to\u2010one orthologous genes, we found that human\u2010pig pairs showed higher global co\u2010expression similarity than human\u2010mouse pairs in most tissues, with exceptions including skin, pancreas, and kidney. Integration with 176 human complex traits further revealed distinct phenotypic associations of species\u2010preferred patterns: human\u2010pig\u2010preferred genes showed preferential associations with cardiometabolic, biochemical, and blood\u2010related traits, whereas both\u2010conserved genes showed stronger associations with neuropsychiatric, cognitive, and behavioral phenotypes. Together, our results demonstrate that cross\u2010species similarity is hierarchical and context\u2010dependent, 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\u2010centered exploration across humans, pigs, and mice.<\/jats:p>","DOI":"10.1002\/advs.77881","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Layer Transcriptomic Comparison Across Human, Pig, and Mouse Informs Tissue\u2010 and Trait\u2010Specific Animal Model Selection"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2458-2861","authenticated-orcid":false,"given":"Jingwen","family":"Dou","sequence":"first","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics Breeding and Reproduction Ministry of Education Huazhong Agricultural 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