{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:13:07Z","timestamp":1788545587435,"version":"build-2803163510"},"reference-count":98,"publisher":"National Academy of Sciences","issue":"37","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000011","name":"HHMI","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008510","name":"University of Maryland","doi-asserted-by":"publisher","award":["Andrew and Mary Balo and Nicholas and Susan Simon Endowed Professorship"],"award-info":[{"award-number":["Andrew and Mary Balo and Nicholas and Susan Simon Endowed Professorship"]}],"id":[{"id":"10.13039\/100008510","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>\n                    Evolutionary innovation is a catalyst for the colonization of new environments and the adaptive radiations of major groups. Novel traits typically evolve through the modification of preexisting characters, but the genetic paths underlying their origin have been challenging to trace, and the general requirements for and relative order of different kinds of gene mutations have been difficult to assess. Here, we trace the genomic origins of four procoagulant venom toxins (factor X, factor V, group I phospholipase A\n                    <jats:sub>2<\/jats:sub>\n                    , and Kunitz-type toxins) that collectively underlie a novel, especially potent blood-clotting venom type in the recently evolved Australian brown snake and taipan clade. We find evidence for a previously unknown fifth toxin, coagulation factor VII, and show that the toxins evolved through two distinct genetic paths. The factor X and factor V toxins evolved through the sequential de novo co-option of ancestral clotting factor proteins that entailed their heterotopic expression in the venom gland, the fixation of segmental duplications containing each locus, and subsequent gain-of-function mutations that rendered factor X and factor V constitutively active. In contrast, the phospholipase A\n                    <jats:sub>2<\/jats:sub>\n                    and Kunitz-type toxins evolved by modifying the functions of neurotoxins that were part of the venom arsenal. Our findings support models in which innovative mutations in single-copy genes precede gene duplication in the evolution of novel proteins and offer a rare view into the genesis of a complex trait that has played a central role in a major adaptive radiation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2621054123","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:37:20Z","timestamp":1788543440000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["The genomic origins and evolutionary path to a key innovation in the world\u2019s most venomous snakes"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5187-7342","authenticated-orcid":false,"given":"Jory","family":"van Thiel","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/047s2c258","id-type":"ROR","asserted-by":"publisher"}],"name":"HHMI, University of Maryland","place":["College Park"]},{"id":[{"id":"https:\/\/ror.org\/047s2c258","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, University of Maryland","place":["College Park"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-6567","authenticated-orcid":false,"given":"Noah L.","family":"Dowell","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/047s2c258","id-type":"ROR","asserted-by":"publisher"}],"name":"HHMI, University of Maryland","place":["College Park"]},{"id":[{"id":"https:\/\/ror.org\/047s2c258","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, University of Maryland","place":["College Park"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara F.","family":"Smith","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03svjbs84","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine","place":["Liverpool, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elda E.","family":"Sanchez","sequence":"additional","affiliation":[{"name":"National Natural Toxins Research Center, Texas Agricultural and Mechanical University-Kingsville","place":["Kingsville"]},{"name":"Department of Chemistry, Texas Agricultural and Mechanical University-Kingsville","place":["Kingsville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7839-5458","authenticated-orcid":false,"given":"Sean B.","family":"Carroll","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/047s2c258","id-type":"ROR","asserted-by":"publisher"}],"name":"HHMI, University of Maryland","place":["College Park"]},{"id":[{"id":"https:\/\/ror.org\/047s2c258","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, University of Maryland","place":["College Park"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.06.030"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2009.11.010"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07891"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809668106"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08896"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1208227"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.08.005"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2016.09.020"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.028"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2108661119"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2023.03.003"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.ado1663"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2024.08.042"},{"key":"e_1_3_4_14_2","first-page":"375","volume-title":"Current Topics in Developmental Biology","author":"McQueen E.","year":"2020","unstructured":"E. McQueen, M. Rebeiz, \u201cChapter twelve\u2014On the specificity of gene regulatory networks: How does network co-option affect subsequent evolution?\u201d in Current Topics in Developmental Biology, I. S. Peter, Ed. (Academic Press, 2020), vol. 139, pp. 375\u2013405."},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03235"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233749"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-86659-3"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2482"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2808"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-026-00935-5"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tree.2012.10.020"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","unstructured":"T. Tasoulis G. K. Isbister A review and database of snake venom proteomes. Toxins (Basel) 9 290 (2017).","DOI":"10.3390\/toxins9090290"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2016.07.038"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1920011117"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-021-01191-1"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40550-0"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes13020217"},{"key":"e_1_3_4_28_2","first-page":"1","article-title":"Paleoclimatology, paleogeography, and the evolution and distribution of sea kraits (Serpentes; Elapidae; Laticauda)","volume":"31","author":"Harold H.","year":"2017","unstructured":"H. Harold, G. Alana, M. Helene, Paleoclimatology, paleogeography, and the evolution and distribution of sea kraits (Serpentes; Elapidae; Laticauda). Herpetol. Monogr. 31, 1\u201317 (2017).","journal-title":"Herpetol. Monogr."},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1420-9101.2008.01525.x"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41559-017-0355-8"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)39373-0"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)69299-3"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20020889"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH04-03-0144"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH04-07-0435"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.01969.x"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2019.08.014"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3390\/toxins8110309"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-12-3839"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH04-11-0707"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)86616-4"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2003.09.045"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001721-200006000-00011"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2002.03878.x"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2011.08.003"},{"key":"e_1_3_4_46_2","first-page":"195","article-title":"Constraints, allometry, and adaptation: Food habits and reproductive biology of Australian brownsnakes (Pseudonaja: Elapidae)","volume":"45","author":"Shine R.","year":"1989","unstructured":"R. Shine, Constraints, allometry, and adaptation: Food habits and reproductive biology of Australian brownsnakes (Pseudonaja: Elapidae). Herpetologica 45, 195\u2013207 (1989).","journal-title":"Herpetologica"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.2307\/1563782"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpc.2017.04.007"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-026-02699-0"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(79)90245-9"},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0216148","article-title":"Large-scale molecular phylogeny, morphology, divergence-time estimation, and the fossil record of advanced caenophidian snakes (Squamata: Serpentes)","volume":"14","author":"Zaher H.","year":"2019","unstructured":"H. Zaher , Large-scale molecular phylogeny, morphology, divergence-time estimation, and the fossil record of advanced caenophidian snakes (Squamata: Serpentes). PLoS One 14, e0216148 (2019).","journal-title":"PLoS One"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msi181"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/0268-960X(94)90007-8"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0040-1715441"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/icb\/23.2.411"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsos.172141"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00338-019-01833-5"},{"key":"e_1_3_4_58_2","unstructured":"D. Verhoef \u201cEvolutionary conservation of regulatory B-domain elements in blood coagulation factor V in snakes\u201d in Lessons from snake venom: New insights into the structural and functional aspects of factor V and factor X PhD thesis Leiden University Leiden Netherlands (2021); Available from universiteitleiden.nl."},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-02-202663"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4838(93)90217-F"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1976.tb10833.x"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(72)90066-9"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1995.1257"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvg187"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(25)09435-0"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/139.1.421"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/151.4.1531"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707158104"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1994.0058"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.252.5009.1078"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06151"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07092"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1226521"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.11.043"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-017-0418-y"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.105.048058"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.117.202655"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2017.05.032"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.83966"},{"key":"e_1_3_4_80_2","doi-asserted-by":"crossref","unstructured":"D. D. Almeida Tracking the recruitment and evolution of snake toxins using the evolutionary context provided by the Bothrops jararaca genome. Proc. Natl. Acad. Sci. U.S.A. 118 e2015159118 (2021).","DOI":"10.1073\/pnas.2015159118"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10607"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.3522"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.39.25393"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.21538"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam5979"},{"key":"e_1_3_4_86_2","volume-title":"Improbable Destinies: Fate, Chance, and the Future of Evolution","author":"Losos J. B.","year":"2018","unstructured":"J. B. Losos, Improbable Destinies: Fate, Chance, and the Future of Evolution (Penguin, 2018)."},{"key":"e_1_3_4_87_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-021-01208-9"},{"key":"e_1_3_4_88_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.240952.118"},{"key":"e_1_3_4_89_2","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giaf030"},{"key":"e_1_3_4_90_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-025-02465-8"},{"key":"e_1_3_4_91_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1983.tb07481.x"},{"key":"e_1_3_4_92_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2013.08.019"},{"key":"e_1_3_4_93_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054104"},{"key":"e_1_3_4_94_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH09-03-0162"},{"key":"e_1_3_4_95_2","unstructured":"J. van Thiel The origin and evolution of Australian elapid toxins. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1473678. Deposited 2 June 2026."},{"key":"e_1_3_4_96_2","unstructured":"J. van Thiel The origin and evolution of Australian elapid toxins. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1478572. Deposited 15 June 2026."},{"key":"e_1_3_4_97_2","unstructured":"J. van Thiel The origin and evolution of Australian elapid toxins. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1478565. Deposited 15 June 2026."},{"key":"e_1_3_4_98_2","doi-asserted-by":"crossref","unstructured":"J. van Thiel The genomic origins and evolutionary path to a key innovation in the world\u2019s most venomous snakes. Figshare. https:\/\/figshare.com\/projects\/The_genomic_origins_and_evolutionary_path_to_a_key_innovation_in_the_world_s_most_venomous_snakes\/279206. Deposited 27 July 2026.","DOI":"10.64898\/2026.06.23.733212"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2621054123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:37:31Z","timestamp":1788543451000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2621054123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":98,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2026,9,15]]}},"alternative-id":["10.1073\/pnas.2621054123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2621054123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]},"assertion":[{"value":"2026-06-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2621054123"}}