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Abnormal expression of Gli2 can impede the transcription of Hh target genes through disruption of proper balance between Gli2 and Gli3 functions. Therefore, delineation of enhancers that are required for complementary roles of Glis would allow the interrogation of those pathogenic variants that cause gene dysregulation, and a corresponding abnormal phenotype. Previously, we reported tissue\u2010specific enhancers for Gli family including Gli2 through direct tetrapod\u2010teleost comparisons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we employed the sequence alignments of slowly evolving spotted gar and elephant shark and have identified six novel conserved noncoding elements in human <jats:italic>GLI2<\/jats:italic> containing locus. Zebrafish\u2010based transgenic assays revealed that combined action of these autonomous CNEs reflects many aspects of <jats:italic>Gli2<\/jats:italic> specific endogenous transcriptional activity, including CNS and pectoral fins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together with our previous findings, this study suggests that Hh\u2010signaling controlled deployment of Gli2 activity in embryonic patterning arose in the common ancestor of gnathostomes. These <jats:italic>GLI2<\/jats:italic> specific <jats:italic>cis<\/jats:italic>\u2010regulatory modules will help to identify DNA variants that probably reside outside of coding intervals and are associated with congenital anomalies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.291","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T23:53:23Z","timestamp":1609372403000},"page":"669-683","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Comparative genomic analysis of human <i>GLI2<\/i> locus using slowly evolving fish revealed the ancestral gnathostome set of early developmental enhancers"],"prefix":"10.1002","volume":"250","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\u2010 Azam University  Islamabad 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