{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:32:51Z","timestamp":1793381571258,"version":"4.5.0"},"update-to":[{"DOI":"10.12688\/openreseurope.13795.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000}}],"reference-count":112,"publisher":"CERN","license":[{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Commission","award":["683257"],"award-info":[{"award-number":["683257"]}],"id":[{"id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","asserted-by":"publisher"}]},{"name":"European Commission","award":["PCOFUND-GA-2013-609102"],"award-info":[{"award-number":["PCOFUND-GA-2013-609102"]}],"id":[{"id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Science Foundation","award":["1523943"],"award-info":[{"award-number":["1523943"]}]},{"name":"U.S. National Science Foundation","award":["1457735"],"award-info":[{"award-number":["1457735"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Open Res Europe"],"abstract":"<jats:p>Background: The study of regressive evolution has yielded a wealth of examples where the underlying genes bear molecular signatures of trait degradation, such as pseudogenization or deletion. Typically, it appears that such disrupted genes are limited to the function of the regressed trait, whereas pleiotropic genes tend to be maintained by natural selection to support their myriad purposes. One such set of pleiotropic genes is involved in the synthesis (\n                    AANAT, \n                    ASMT) and signaling (\n                    MTNR1A, \n                    MTNR1B) of melatonin, a hormone secreted by the vertebrate pineal gland. Melatonin provides a signal of environmental darkness, thereby influencing the circadian and circannual rhythmicity of numerous physiological traits. Therefore, the complete loss of a pineal gland and the underlying melatonin pathway genes seems likely to be maladaptive, unless compensated by extra-pineal sources of melatonin.\n                \n                    Methods: We examined \n                    AANAT, \n                    ASMT, \n                    MTNR1A and \n                    MTNR1B in 123 vertebrate species, including pineal-less placental mammals and crocodylians. We searched for inactivating mutations and modelled selective pressures (dN\/dS) to test whether the genes remain functionally intact.\n                \n                    Results: We report that crocodylians retain intact melatonin genes and express \n                    AANAT and \n                    ASMT in their eyes, whereas all four genes have been repeatedly inactivated in the pineal-less xenarthrans, pangolins, sirenians, and whales. Furthermore, colugos have lost these genes, and several lineages of subterranean mammals have partial melatonin pathway dysfunction. These results are supported by the presence of shared inactivating mutations across clades and analyses of selection pressure based on the ratio of non-synonymous to synonymous substitutions (dN\/dS), suggesting extended periods of relaxed selection on these genes.\n                \n                    Conclusions: The losses of melatonin synthesis and signaling date to tens of millions of years ago in several lineages of placental mammals, raising questions about the evolutionary resilience of pleiotropic genes, and the causes and consequences of losing melatonin pathways in these species.<\/jats:p>","DOI":"10.12688\/openreseurope.13795.2","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T05:00:24Z","timestamp":1639371624000},"update-policy":"https:\/\/doi.org\/10.68336\/openreseurope.updatepolicy","source":"Crossref","is-referenced-by-count":11,"title":["Genomic evidence for the parallel regression of melatonin synthesis and signaling pathways in placental mammals"],"prefix":"10.68336","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7722-7305","authenticated-orcid":true,"given":"Christopher A.","family":"Emerling","sequence":"first","affiliation":[{"name":"Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, CA, 94720, USA"},{"name":"Institut des Sciences de l\u2019Evolution de Montpellier (ISEM), CNRS, IRD, EPHE, Universit\u00e9 de Montpellier, Montpellier, France"},{"name":"Biology Department, Reedley College, Reedley, CA, 93654, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Springer","sequence":"additional","affiliation":[{"name":"Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, Riverside, CA, 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Gatesy","sequence":"additional","affiliation":[{"name":"Division of Vertebrate Zoology, American Museum of Natural History, New York, NY, 10024, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Jones","sequence":"additional","affiliation":[{"name":"Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, CA, 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deana","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, CA, 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8336-857X","authenticated-orcid":true,"given":"David","family":"Xia-Zhu","sequence":"additional","affiliation":[{"name":"Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, CA, 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Collin","sequence":"additional","affiliation":[{"name":"Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, Riverside, CA, 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6501-6287","authenticated-orcid":true,"given":"Fr\u00e9d\u00e9ric","family":"Delsuc","sequence":"additional","affiliation":[{"name":"Institut des Sciences de l\u2019Evolution de Montpellier (ISEM), CNRS, IRD, EPHE, Universit\u00e9 de Montpellier, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"13904","published-online":{"date-parts":[[2021,12,13]]},"reference":[{"key":"7151","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-014-1579-2"},{"key":"7152","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.39"},{"key":"7153","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.63167"},{"key":"7154","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2015.05.039"},{"key":"7155","doi-asserted-by":"publisher","DOI":"10.1007\/BF01252129"},{"key":"7156","unstructured":"Behrmann G: The pineal organ (Epiphysis cerebri) of the harbour porpoise Phocoena phocoena. (Linn\u00e9, 1758). Aquat Mamm. 1990; 16(3): 96\u2013100. Reference Source (https:\/\/www.aquaticmammalsjournal.org\/share\/AquaticMammalsIssueArchives\/1990\/Aquatic_Mammals_16_3\/16.3Behrmann.pdf)"},{"key":"7157","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky741"},{"key":"7158","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.1070210203"},{"key":"7159","doi-asserted-by":"publisher","DOI":"10.1093\/icb\/33.2.200"},{"key":"7160","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-2999(01)01230-4"},{"key":"7161","unstructured":"Chapman HC: Observations on the structure of the manatee. Proc Acad Nat Sci Philadelphia. 1875; 27(3): 452\u2013462. Reference Source (https:\/\/www.jstor.org\/stable\/4624519?seq=1#metadata_info_tab_contents)"},{"key":"7162","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0196-1"},{"key":"7163","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12137"},{"key":"7164","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00084"},{"key":"7165","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12234"},{"key":"7166","doi-asserted-by":"publisher","DOI":"10.1016\/0016-6480(87)90073-6"},{"key":"7167","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2002.02161.x"},{"key":"7168","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12211"},{"key":"7169","doi-asserted-by":"publisher","DOI":"10.1016\/0192-0561(89)90187-2"},{"key":"7170","doi-asserted-by":"publisher","DOI":"10.1080\/10635150701884632"},{"key":"7171","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh340"},{"key":"7172","doi-asserted-by":"publisher","DOI":"10.1093\/icb\/icy004"},{"key":"7173","doi-asserted-by":"publisher","DOI":"10.1016\/j.ympev.2017.07.014"},{"key":"7174","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msw265"},{"key":"7175","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2015.1817"},{"key":"7176","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2014.2192"},{"key":"7177","doi-asserted-by":"publisher","DOI":"10.1016\/j.ympev.2014.05.016"},{"key":"7178","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.4894211"},{"key":"7179","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4966"},{"key":"7180","doi-asserted-by":"publisher","DOI":"10.1007\/s00360-009-0387-8"},{"key":"7181","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.85.1.311"},{"key":"7182","doi-asserted-by":"publisher","DOI":"10.1046\/j.1600-079x.2003.00109.x"},{"key":"7183","doi-asserted-by":"publisher","DOI":"10.1007\/BF00612714"},{"key":"7184","doi-asserted-by":"publisher","DOI":"10.1578\/AM.37.4.2011.433"},{"key":"7185","doi-asserted-by":"publisher","DOI":"10.13140\/RG.2.2.28346.49604"},{"key":"7186","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1602878"},{"key":"7187","doi-asserted-by":"publisher","DOI":"10.1016\/0016-6480(79)90147-3"},{"key":"7188","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1402060217"},{"key":"7189","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1402050305"},{"key":"7190","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msv250"},{"key":"7191","doi-asserted-by":"publisher","DOI":"10.1126\/science.1237930"},{"key":"7192","doi-asserted-by":"publisher","DOI":"10.1016\/0016-6480(90)90216-9"},{"key":"7193","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-079x.2003.00040.x"},{"key":"7194","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9384(82)90020-8"},{"key":"7195","doi-asserted-by":"publisher","DOI":"10.1016\/0016-6480(81)90106-4"},{"key":"7196","unstructured":"Hattori A, Migitaka H, Iigo M, et al.: Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int. 1995; 35(3): 627\u201334. https:\/\/pubmed.ncbi.nlm.nih.gov\/7773197"},{"key":"7197","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msw221"},{"key":"7198","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02017-0"},{"key":"7199","doi-asserted-by":"publisher","DOI":"10.1038\/247224a0"},{"key":"7200","doi-asserted-by":"publisher","DOI":"10.1126\/science.7233183"},{"key":"7201","unstructured":"Holm S: A simple sequential rejective method procedure. Scand J Stat. 1979; 6(2): 65\u201370. Reference Source (https:\/\/www.jstor.org\/stable\/4615733)"},{"key":"7202","unstructured":"Holzmann T: Morphologie und mikroskopische Anatomie des Gehirns beim fetalen Narwal, Monodon monoceros. University of Frankfurt am Main,1991."},{"key":"7203","doi-asserted-by":"publisher","DOI":"10.1101\/521617"},{"key":"7204","doi-asserted-by":"publisher","DOI":"10.1007\/BF00345581"},{"key":"7205","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24619"},{"key":"7206","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts199"},{"key":"7207","doi-asserted-by":"publisher","DOI":"10.1210\/endo-101-1-119"},{"key":"7208","doi-asserted-by":"publisher","DOI":"10.1159\/000048238"},{"key":"7209","doi-asserted-by":"publisher","DOI":"10.1038\/nature10533"},{"key":"7210","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msx116"},{"key":"7211","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.028"},{"key":"7212","doi-asserted-by":"publisher","DOI":"10.1515\/mamm.1976.40.2.327"},{"key":"7213","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1998.275.6.E934"},{"key":"7214","doi-asserted-by":"publisher","DOI":"10.3390\/genes10020121"},{"key":"7215","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2008.05.023"},{"key":"7216","doi-asserted-by":"publisher","DOI":"10.1007\/BF01451037"},{"key":"7217","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600633"},{"key":"7218","doi-asserted-by":"publisher","DOI":"10.1002\/cne.901350304"},{"key":"7219","doi-asserted-by":"publisher","DOI":"10.1093\/sysbio\/syz068"},{"key":"7220","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000634"},{"key":"7221","doi-asserted-by":"publisher","DOI":"10.1126\/science.1211028"},{"key":"7222","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254390"},{"key":"7223","doi-asserted-by":"publisher","DOI":"10.1109\/GCE.2010.5676129"},{"key":"7224","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7998.1872.tb08571.x"},{"key":"7225","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-16-0066"},{"key":"7226","doi-asserted-by":"publisher","DOI":"10.1159\/000110495"},{"key":"7227","doi-asserted-by":"publisher","DOI":"10.1016\/s0079-6123(08)63445-7"},{"key":"7228","doi-asserted-by":"crossref","unstructured":"Owens DW, Gern WA: The pineal gland and melatonin in sea turtles. In: Lofts, B., Holmes, W.N. (Eds.), Current Trends in Comparative Endocrinology.Hong Kong University Press, Hong Kong,1985; 645\u2013648.","DOI":"10.2307\/jj.40271869.168"},{"key":"7229","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygcen.2012.04.012"},{"key":"7230","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.25884"},{"key":"7231","doi-asserted-by":"publisher","DOI":"10.1016\/j.ympev.2017.05.008"},{"key":"7232","doi-asserted-by":"publisher","DOI":"10.3402\/fnr.v56i0.17252"},{"key":"7233","doi-asserted-by":"publisher","DOI":"10.1007\/BF00229159"},{"key":"7234","doi-asserted-by":"publisher","DOI":"10.1007\/BF00223214"},{"key":"7235","unstructured":"Phillips JA, Harlow HJ: Elevation of upper voluntary temperatures after shielding the parietal eye of horned lizards ( Phrynosoma douglassi). Herpetologica. 1981; 37(4): 199\u2013205. Reference Source (https:\/\/www.jstor.org\/stable\/3891803)"},{"key":"7236","doi-asserted-by":"publisher","DOI":"10.1016\/0300-9629(86)90433-0"},{"key":"7237","doi-asserted-by":"publisher","DOI":"10.1139\/z82-084"},{"key":"7238","doi-asserted-by":"publisher","DOI":"10.1038\/nature15697"},{"key":"7239","doi-asserted-by":"publisher","DOI":"10.1007\/BF01253102"},{"key":"7240","doi-asserted-by":"publisher","DOI":"10.1007\/BF01451040"},{"key":"7241","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-6395.1985.tb00647.x"},{"key":"7242","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2005.02.005"},{"key":"7243","unstructured":"Reppert SM, Sagar SM: Characterization of the day-night variation of retinal melatonin content in the chick. Invest Ophthalmol Vis Sci. 1983; 24(3): 294\u2013300. https:\/\/pubmed.ncbi.nlm.nih.gov\/6832906"},{"key":"7244","doi-asserted-by":"publisher","DOI":"10.1126\/science.7423204"},{"key":"7245","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat7244"},{"key":"7246","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-416021-7.00005-5"},{"key":"7247","doi-asserted-by":"publisher","DOI":"10.1016\/j.ympev.2015.05.022"},{"key":"7248","doi-asserted-by":"publisher","DOI":"10.1016\/j.ympev.2015.11.002"},{"key":"7249","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu033"},{"key":"7250","unstructured":"Stebbins RC, Eakin RM: The role of the \u201cthird eye\u201d in reptilian behavior. Am Museum Noitates. 1958; 1\u201340. Reference Source (https:\/\/digitallibrary.amnh.org\/handle\/2246\/4659)"},{"key":"7251","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-079x.2001.300408.x"},{"key":"7252","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2012-13-1-415"},{"key":"7253","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705768114"},{"key":"7254","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12336"},{"key":"7255","doi-asserted-by":"publisher","DOI":"10.3390\/ijms150915858"},{"key":"7256","doi-asserted-by":"publisher","DOI":"10.1016\/0016-6480(84)90063-7"},{"key":"7257","doi-asserted-by":"publisher","DOI":"10.1007\/s00239-021-10025-1"},{"key":"7258","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314702110"},{"key":"7259","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msm088"},{"key":"7260","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msab125"},{"key":"7261","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00249"},{"key":"7262","doi-asserted-by":"publisher","DOI":"10.1016\/j.ympev.2015.10.009"}],"container-title":["Open Research Europe"],"original-title":[],"link":[{"URL":"https:\/\/open-research-europe.ec.europa.eu\/articles\/1-75\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ore.eu\/ore\/article\/download\/75\/version\/147\/293","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ore.eu\/ore\/article\/download\/75\/version\/147\/294","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ore.eu\/ore\/article\/download\/75\/version\/147\/293","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:11:12Z","timestamp":1793380272000},"score":1,"resource":{"primary":{"URL":"https:\/\/ore.eu\/ore\/article\/view\/75\/version\/147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,13]]},"references-count":112,"URL":"https:\/\/doi.org\/10.12688\/openreseurope.13795.2","relation":{"is-version-of":[{"id-type":"doi","id":"10.12688\/openreseurope.13795.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.21956\/openreseurope.15466.r28164","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/openreseurope.15466.r28165","asserted-by":"object"}]},"ISSN":["2732-5121"],"issn-type":[{"value":"2732-5121","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,13]]},"assertion":[{"value":"2021-12-13","name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}},{"value":"This project has received funding from the European Union\u2019s Horizon 2020 research and innovation programme under the European Research Council (ERC) grant agreement No [683257]. This research was also supported by a National Science Foundation (NSF) Postdoctoral Research Fellowship in Biology (award no. 1523943; C.A.E.), an NSF Postdoctoral Fellow Research Opportunities in Europe award (C.A.E.), the People Programme (Marie Curie Actions) of the European Union\u2019s Seventh Framework Programme (FP7\/2007-2013) under REA grant agreement no. PCOFUND-GA-2013-609102, through the PRESTIGE programme coordinated by Campus France (C.A.E.) and an NSF DEB- 1457735 grant to J.G and M.S.S.\n\n                    The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","name":"funding_statement","label":"Funding Statement","group":{"name":"funding_information","label":"Funding Information"}}],"article-number":"75"}}