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These proteins, exemplified by keratin-associated proteins (KRTAPs) in mammals and epidermal differentiation complex (EDC) proteins in all tetrapods, have low amino acid sequence complexity and interact with other proteins to form stable supramolecular structures. No KRTAPs and only few EDC proteins exist in amphibians, suggesting an alternative mechanism of epithelial cornification. Here, we used comparative genomics and proteomics to identify a previously uncharacterized group of epidermal differentiation-associated proteins that are specific for amphibians. These proteins are encoded by genes of the amphibian epidermal differentiation cluster (AEDC), which has evolved by tandem duplications and sequence modifications of an ancestral gene at a locus syntenic with that of adipogenesis regulatory factor in other vertebrates. AEDC genes are specifically expressed in the epithelium of the skin and its appendages, such as the cornified spines within nuptial pads of frogs. Internal sequence duplications within AEDC proteins have led to amino acid sequence repeats similar to those of EDC proteins and KRTAPs. We conclude that epidermal differentiation-associated proteins have originated multiple times and evolved similar sequence features in amphibians and other clades of vertebrates.<\/jats:p>","DOI":"10.1093\/molbev\/msag196","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:53:14Z","timestamp":1785930794000},"source":"Crossref","is-referenced-by-count":1,"title":["Evolution of an amphibian-specific family of epidermal differentiation-associated genes"],"prefix":"10.1093","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1447-9254","authenticated-orcid":false,"given":"Attila Placido","family":"Sachslehner","sequence":"first","affiliation":[{"name":"Department of Dermatology, Medical University of Vienna , Waehringer Guertel 18-20, Vienna 1090 ,","place":["Austria"]},{"name":"Department of Evolutionary Biology, University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4208-9455","authenticated-orcid":false,"given":"Julia","family":"Steinbinder","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical University of Vienna , Waehringer Guertel 18-20, Vienna 1090 ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7853-1780","authenticated-orcid":false,"given":"Anja","family":"Wagner","sequence":"additional","affiliation":[{"name":"Core Facility Proteomics, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0803-614X","authenticated-orcid":false,"given":"Klaus","family":"Kratochwill","sequence":"additional","affiliation":[{"name":"Core Facility Proteomics, Medical University of Vienna , Vienna ,","place":["Austria"]},{"name":"Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5645-2036","authenticated-orcid":false,"given":"Leopold","family":"Eckhart","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical University of Vienna , Waehringer Guertel 18-20, Vienna 1090 ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"2026081907311890200_msag196-B1","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1002\/ar.24908","article-title":"Comparison of vertebrate skin structure at class level: a review","volume":"305","author":"Akat","year":"2022","journal-title":"Anat Rec 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