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We investigated the evolution of this complex gene family across metazoans. The characteristic aminoterminal melastatin domain and the carboxyterminal NUDT9 homology domain with similarity to ADP-ribose pyrophosphatase were added to the common ancestor of TRPM and its sister channel TRPS. Gene duplications before the origin of bilaterians resulted in four TRPM genes: \u03b1, \u03b2, \u03b2like, and \u03b3. The two latter were discovered in this study. All four and TRPS are present in extant mollusks, while differential losses occurred in the other animal lineages. TRPS, TRPM\u03b2like, and TRPM\u03b3 were lost in early chordates, meaning that the vertebrate ancestor started with TRPM\u03b1 and \u03b2, both of which were duplicated before the first vertebrate tetraploidization 1R. The ancestor of the micro-RNA genes mir-211 and mir-204 was inserted in an intron of the ancestor of TRPM1\/TRPM3. The TRPM6\/TRPM7 ancestor acquired a kinase domain, probably a copy of the syntenic alpha protein kinase ALPK2\/3 ancestor gene. Vertebrate 1R and gnathostome 2R together with local gene duplication and losses resulted in eight TRPM (TRPM1 to 8) in the gnathostome ancestor. In cyclostomes, extensive gene losses after the hexaploidization led to four TRPM. The teleost-specific tetraploidization 3R generated further TRPM ohnologs. The NUDT9 homology domain is retained in TRPM2 and TRPS but was lost repeatedly during TRPM evolution. Thus, the TRPM family displays considerable evolutionary variation with regard to gene and domain gains and losses.<\/jats:p>","DOI":"10.1093\/molbev\/msag098","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T11:46:37Z","timestamp":1775821597000},"source":"Crossref","is-referenced-by-count":0,"title":["Evolution in metazoans of the TRPM channel family involves multiple gains and losses of genes and domains"],"prefix":"10.1093","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-3419","authenticated-orcid":false,"given":"Marina","family":"Morini","sequence":"first","affiliation":[{"name":"Laboratory Biology of Aquatic Organisms and Ecosystems (BOREA), National Museum of Natural History (MNHN), National Center for Scientific Research (CNRS), Institute of Research for Development (IRD), Sorbonne University , Paris ,","place":["France"]},{"name":"Grupo de Acuicultura y Biodiversidad, Instituto de Ciencia y Tecnologia Animal, Universitat Polit\u00e8cnica de Val\u00e8ncia , Valencia ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3983-9340","authenticated-orcid":false,"given":"Christina","family":"Bergqvist","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Science for Life Laboratory, Uppsala University , Uppsala ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6441-5294","authenticated-orcid":false,"given":"Juan F","family":"Asturiano","sequence":"additional","affiliation":[{"name":"Grupo de Acuicultura y Biodiversidad, Instituto de Ciencia y Tecnologia Animal, Universitat Polit\u00e8cnica de Val\u00e8ncia , Valencia ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8646-4935","authenticated-orcid":false,"given":"Sylvie","family":"Dufour","sequence":"additional","affiliation":[{"name":"Laboratory Biology of Aquatic Organisms and Ecosystems (BOREA), National Museum of Natural History (MNHN), National Center for Scientific Research (CNRS), Institute of Research for Development (IRD), Sorbonne University , Paris ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6736-0663","authenticated-orcid":false,"given":"Dan","family":"Larhammar","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Science for Life Laboratory, Uppsala University , Uppsala ,","place":["Sweden"]},{"name":"Guangdong Institute of Intelligence Science and Technology , Hengqin, Zhuhai 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