{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T20:13:11Z","timestamp":1780085591902,"version":"3.54.0"},"reference-count":37,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T00:00:00Z","timestamp":1766275200000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["M\u00e9diterran\u00e9e\u2010Infection 10\u2010IAHU\u201003"],"award-info":[{"award-number":["M\u00e9diterran\u00e9e\u2010Infection 10\u2010IAHU\u201003"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["APMIS"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    RNA hairpins may constitute a foundation of genetic evolution both in viruses and other organisms. Stem\u2010loops theoretically comprise a stable part, the double\u2010stranded stem, and a single\u2010stranded loop allowing evolution. Here we tested for SARS\u2010CoV\u20102 if \u201cfertile\u201d mutations were in loops while mutations in stems were poorly tolerated and rarely found in consensus genomes. We combined information on the frequencies of mutations, either \u201cfertile\u201d (present in \u2265\u200950 genomes) or \u201cnon\u2010fertile\u201d (neutral, weakly deleterious or lethal) in 61,397 SARS\u2010CoV\u20102 genomes, and on whether these mutations occurred at positions where nucleotides were predicted to be either paired or unpaired. The proportion of positions harboring \u201cfertile\u201d mutations was significantly higher in loops than in stems for the whole genome (11.6% vs. 7.6%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001, Yates\u2010corrected chi\u2010square test). This was also the case in the RNA\u2010dependent RNA polymerase gene (10.0% vs. 4.9%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0003) or in the spike gene (12.3% vs. 8.9%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0049). All four most frequent mutations in our set of genomes were located in loops. Thus, apart from some observations in \u201caccessory\u201d genes, evolution in SARS\u2010CoV\u20102 predominantly occurred in loops while mutations in stems were relatively \u201cnon\u2010fertile.\u201d These stems could be potential antiviral targets, possibly through their disruption by RNA interference.\n                  <\/jats:p>","DOI":"10.1111\/apm.70113","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T02:31:05Z","timestamp":1766370665000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\u201cFertile\u201d Mutations in\n                    <scp>SARS<\/scp>\n                    \u2010\n                    <scp>CoV<\/scp>\n                    \u20102\n                    <scp>RNA<\/scp>\n                    More Frequently Occurred in Hairpin Loops That Determine Virus Evolution"],"prefix":"10.1111","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6285-0308","authenticated-orcid":false,"given":"Philippe","family":"Colson","sequence":"first","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection  Marseille France"},{"name":"Microbes Evolution Phylogeny and Infections (MEPHI) Aix\u2010Marseille Universit\u00e9  Marseille France"},{"name":"Assistance Publique\u2010H\u00f4pitaux de Marseille (AP\u2010HM)  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Pontarotti","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection  Marseille France"},{"name":"Microbes Evolution Phylogeny and Infections (MEPHI) Aix\u2010Marseille Universit\u00e9  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Fantini","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Centre National de la Recherche 16 Scientifique (CNRS)  Marseille France"},{"name":"INSERM UMR UA 16 Aix\u2010Marseille Universit\u00e9  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2989-7539","authenticated-orcid":false,"given":"Anthony","family":"Levasseur","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection  Marseille France"},{"name":"Risques Infectieux Tropicaux, Microorganismes Emergents (RITMES) Aix\u2010Marseille Universit\u00e9  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Devaux","sequence":"additional","affiliation":[{"name":"IHU M\u00e9diterran\u00e9e Infection  Marseille France"},{"name":"Department of Biological Sciences Centre National de la Recherche 16 Scientifique (CNRS)  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0633-5974","authenticated-orcid":false,"given":"Didier","family":"Raoult","sequence":"additional","affiliation":[{"name":"Aix\u2010Marseille Universit\u00e9  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00593\u201016"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2104241118"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2024.106150"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2024.2368211"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010020\u201002344\u20106"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.043"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201022785\u2010x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01661\u201020"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/20.21.5785"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/gbe\/evx273"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.076141.120"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.est.1c01255"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716689115"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/gch2.1018"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102249\u20101"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29146"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2407731121"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.11.5153"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.7.5787\u20105794.1999"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.24.5079"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01946\u201021"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201080240\u20105"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010virology\u2010092917\u2010043315"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/v9060137"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.10.011"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00644\u201011"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa9266"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2017.11.025"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2117198119"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02493\u201024"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1238"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2020.104525"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot080788"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102164\u20109\u2010S1\u2010S17"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot080804"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20106753\u20107_13"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010022\u201001908\u2010x"}],"container-title":["APMIS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apm.70113","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/apm.70113","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apm.70113","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T12:04:25Z","timestamp":1772971465000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apm.70113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":37,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1111\/apm.70113"],"URL":"https:\/\/doi.org\/10.1111\/apm.70113","archive":["Portico"],"relation":{},"ISSN":["0903-4641","1600-0463"],"issn-type":[{"value":"0903-4641","type":"print"},{"value":"1600-0463","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-06-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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