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Adv."],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:p>\n                    The turquoise karst lakes of China\u2019s Jiuzhaigou Nature Reserve harbor among the highest natural calcium concentrations known in freshwater, around threefold higher than adjacent rivers. Yet the Jialing fish (\n                    <jats:italic toggle=\"yes\">Schizopygopsis kialingensis<\/jats:italic>\n                    ) thrives there with serum calcium levels indistinguishable from river-dwelling conspecifics. We show that this calcium tolerance arose through evolutionary loss of vitamin D signaling. Lake and river populations diverged \u223c410,000 years ago. Gill transcriptomics revealed &gt;90% suppression of vitamin D receptor b (\n                    <jats:italic toggle=\"yes\">vdrb<\/jats:italic>\n                    ) and 99% reduction of its downstream calcium transporter\n                    <jats:italic toggle=\"yes\">calb2a<\/jats:italic>\n                    in lake fish. Zebrafish knockout of either gene enhanced survival under hypercalcemia. We traced this suppression to specific mutations in a\n                    <jats:italic toggle=\"yes\">vdrb<\/jats:italic>\n                    enhancer that reduce its activity. These findings reveal that regulatory dismantling of a canonical endocrine pathway can drive vertebrate adaptation to extreme environments, providing a clear example of how cis-regulatory evolution can drive ecological adaptation.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg8398","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:58:33Z","timestamp":1791395913000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Cis-regulatory inactivation of vitamin D signaling confers extreme calcium tolerance in Jialing fish"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6559-2644","authenticated-orcid":true,"given":"Nan","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsen","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbin","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilin","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5031-8653","authenticated-orcid":true,"given":"Lingyun","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Jiuzhaigou Administration Bureau, Jiuzhaigou 623407, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai","family":"Wang","sequence":"additional","affiliation":[{"name":"Gansu Key Laboratory of Cold Water Fishes Germplasm Resources and Genetics Breeding, Gansu Fishers Research Institute, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-2124","authenticated-orcid":true,"given":"Aaron J. W","family":"Hsueh","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."},{"name":"Department of Obstetrics and Gynecology, Stanford University, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4747-6249","authenticated-orcid":true,"given":"Jianzhen","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730000, China."},{"name":"Gansu Pharmaceutical Group, Lanzhou 730000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-595X(72)80049-5"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1155"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.028"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.05910809"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2008-0004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00014.2015"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00047.2011"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu14163351"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s40494-025-01927-0"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-46838-w"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep25078"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/w12030771"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1054665"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2006.12.019"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2009-0140"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-012-9619-0"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3322"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.281.3.E558"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2063"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04843"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2202862119"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1182213"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.18331"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20069-4"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/raq.12081"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeg8398","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:59:37Z","timestamp":1791395977000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeg8398"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":25,"journal-issue":{"issue":"41","published-print":{"date-parts":[[2026,10,9]]}},"alternative-id":["10.1126\/sciadv.aeg8398"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeg8398","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"assertion":[{"value":"2026-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeg8398"}}