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Many genes encoding structural components of corneocytes are clustered in the epidermal differentiation complex (EDC), which has been described in placental and marsupial mammals as well as non-mammalian tetrapods. Here, we analyzed the genomes of the platypus (<jats:italic>Ornithorhynchus anatinus<\/jats:italic>) and the echidna (<jats:italic>Tachyglossus aculeatus<\/jats:italic>) to determine the gene composition of the EDC in the basal clade of mammals, the monotremes. We report that mammal-specific subfamilies of EDC genes encoding small proline-rich proteins (SPRRs) and late cornified envelope proteins as well as single-copy EDC genes such as involucrin are conserved in monotremes, suggesting that they have originated in stem mammals. Monotremes have at least one gene homologous to the group of filaggrin (<jats:italic>FLG<\/jats:italic>), <jats:italic>FLG2<\/jats:italic> and hornerin (<jats:italic>HRNR<\/jats:italic>) in placental mammals, but no clear one-to-one pairwise ortholog of either <jats:italic>FLG<\/jats:italic>, <jats:italic>FLG2<\/jats:italic> or <jats:italic>HRNR<\/jats:italic>. Caspase-14, a keratinocyte differentiation-associated protease implicated in the processing of filaggrin, is encoded by at least 3 gene copies in the echidna. Our results reveal evolutionarily conserved and clade-specific features of the genetic regulation of epidermal differentiation in monotremes.<\/jats:p>","DOI":"10.1038\/s41598-024-51926-7","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T20:02:17Z","timestamp":1705435337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Comparative genomics of monotremes provides insights into the early evolution of mammalian epidermal differentiation genes"],"prefix":"10.1038","volume":"14","author":[{"given":"Julia","family":"Steinbinder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attila Placido","family":"Sachslehner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin Brigit","family":"Holthaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leopold","family":"Eckhart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"51926_CR1","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1002\/ar.24908","volume":"305","author":"E Akat","year":"2022","unstructured":"Akat, E. et al. Comparison of vertebrate skin structure at class level: A review. Anat. Rec. (Hoboken) 305, 3543\u20133608 (2022).","journal-title":"Anat. Rec. (Hoboken)"},{"key":"51926_CR2","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/nature05659","volume":"445","author":"E Fuchs","year":"2007","unstructured":"Fuchs, E. Scratching the surface of skin development. Nature 445, 834\u2013842 (2007).","journal-title":"Nature"},{"key":"51926_CR3","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1111\/exd.13731","volume":"27","author":"L Eckhart","year":"2018","unstructured":"Eckhart, L. & Zeeuwen, P. L. J. M. The skin barrier: Epidermis vs environment. Exp. Dermatol. 27, 805\u2013806 (2018).","journal-title":"Exp. Dermatol."},{"key":"51926_CR4","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1038\/nrm1619","volume":"6","author":"E Candi","year":"2005","unstructured":"Candi, E., Schmidt, R. & Melino, G. The cornified envelope: A model of cell death in the skin. Nat. 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