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The emergence of new genes led to the genetic variation essential in metazoan evolution, just as was gene loss, both sources of genetic variation resulting in adaptive phenotypic diversity. In this context, F12\u2010coding protein with defense and hemostatic roles emerged some 425 Mya, and it might have contributed in aquatic vertebrates to the transition from water\u2010to\u2010land. Conversely, the\n                    <jats:italic>F12<\/jats:italic>\n                    loss in marine, air\u2010breathing mammals like cetaceans has been associated with phenotypic adaptations in some terrestrial mammals in their transition to aquatic lifestyle. More recently, the advent of technological innovations in western lifestyle with blood\u2010contacting devices and harmful environmental nanoparticles, has unfolded new roles of FXII. Environment operates as either a positive or a relaxed selective pressure on genes, and consequently genes are selected or lost. FXII, an old dog facing environmental novelties can learn new tricks and teach us new therapeutic avenues.\n                  <\/jats:p>","DOI":"10.1002\/bies.202300077","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T06:09:52Z","timestamp":1695708592000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["An evolutionary history of\n                    <i>F12<\/i>\n                    gene: Emergence, loss, and vulnerability with the environment as a driver"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9672-2881","authenticated-orcid":false,"given":"Sabino","family":"Padilla","sequence":"first","affiliation":[{"name":"BTI\u2010Biotechnology Institute ImasD  Vitoria Spain"},{"name":"Eduardo Anitua Foundation for Biomedical Research  Vitoria Spain"},{"name":"University Institute for Regenerative Medicine &amp; Oral Implantology \u2013 UIRMI (UPV\/EHU\u2010Fundaci\u00f3n Eduardo Anitua)  Vitoria Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4767-7206","authenticated-orcid":false,"given":"Roberto","family":"Prado","sequence":"additional","affiliation":[{"name":"BTI\u2010Biotechnology Institute ImasD  Vitoria Spain"},{"name":"Eduardo Anitua Foundation for Biomedical Research  Vitoria Spain"},{"name":"University Institute for Regenerative Medicine &amp; Oral Implantology \u2013 UIRMI (UPV\/EHU\u2010Fundaci\u00f3n Eduardo Anitua)  Vitoria Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8386-5303","authenticated-orcid":false,"given":"Eduardo","family":"Anitua","sequence":"additional","affiliation":[{"name":"BTI\u2010Biotechnology Institute ImasD  Vitoria Spain"},{"name":"Eduardo Anitua Foundation for Biomedical Research  Vitoria Spain"},{"name":"University Institute for Regenerative Medicine &amp; Oral Implantology \u2013 UIRMI (UPV\/EHU\u2010Fundaci\u00f3n Eduardo Anitua)  Vitoria Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.68.2.173\u2010186.2004"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/rth2.12235"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000450"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92880"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201015792\u2010w"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050664"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000425"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaw6671"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/00019501\u2010199405000\u201000012"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100038\u20101647467"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2021.01.002"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009345"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00312"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2018.04.001"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2016.10.010"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/rth2.12349"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12471"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20103\u2010319\u201018603\u20100_1"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.17"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/14686996.2019.1625721"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3cs60338e"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102017\u201004\u2010569111"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102016\u201011\u2010753202"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100037\u20101613081"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102013\u201004\u2010499111"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2011.04280.x"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2008.03143.x"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002456"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12862\u2010019\u20101353\u2010z"},{"key":"e_1_2_9_31_1","volume-title":"The evolution of vertebrate blood clotting","author":"Doolittle R. 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