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Accurate delineation of the genomic <jats:italic>cis<\/jats:italic>\u2010regulatory landscape controlling <jats:italic>Gli3<\/jats:italic> transcription during embryonic development is critical for the interpretation of noncoding variants associated with congenital defects. Here, we employed a comparative genomic analysis on fish species with a slow rate of molecular evolution to identify seven previously unknown conserved noncoding elements (CNEs) in <jats:italic>Gli3<\/jats:italic> intronic intervals (CNE15\u201321). Transgenic assays in zebrafish revealed that most of these elements drive activities in <jats:italic>Gli3<\/jats:italic> expressing tissues, predominantly the fins, CNS, and the heart. Intersection of these CNEs with human disease associated SNPs identified CNE15 as a putative mammalian craniofacial enhancer, with conserved activity in vertebrates and potentially affected by mutation associated with human craniofacial morphology. Finally, comparative functional dissection of an appendage\u2010specific CNE conserved in slowly evolving fish (elephant shark), but not in teleost (CNE14\/hs1586) indicates co\u2010option of limb specificity from other tissues prior to the divergence of amniotes and lobe\u2010finned fish. These results uncover a novel subset of intronic <jats:italic>Gli3<\/jats:italic> enhancers that arose in the common ancestor of gnathostomes and whose sequence components were likely gradually modified in other species during the process of evolutionary diversification.<\/jats:p>","DOI":"10.1111\/dgd.12901","type":"journal-article","created":{"date-parts":[[2023,11,5]],"date-time":"2023-11-05T06:35:35Z","timestamp":1699166135000},"page":"75-88","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification of ancestral gnathostome <i>Gli3<\/i> enhancers with activity in mammals"],"prefix":"10.1111","volume":"66","author":[{"given":"Shahid","family":"Ali","sequence":"first","affiliation":[{"name":"National Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid\u2010i\u2010Azam University  Islamabad Pakistan"},{"name":"Department of Organismal Biology and 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Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabail Zehra","family":"Raza","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Faculty of Multidisciplinary Studies, National University of Medical Sciences  Rawalpindi Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hizran","family":"Khatoon","sequence":"additional","affiliation":[{"name":"National Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid\u2010i\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Zoia","sequence":"additional","affiliation":[{"name":"Department for Biomedical Research (DBMR) University of Bern  Bern Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axel","family":"Visel","sequence":"additional","affiliation":[{"name":"Environmental Genomics and System Biology Division 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