{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T10:15:35Z","timestamp":1767176135038,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011747","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000}}],"reference-count":79,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["AdG 694455-ZMOD"],"award-info":[{"award-number":["AdG 694455-ZMOD"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["AdG 101021349-TAaGC"],"award-info":[{"award-number":["AdG 101021349-TAaGC"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["F32GM144223"],"award-info":[{"award-number":["F32GM144223"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK093399"],"award-info":[{"award-number":["R01DK093399"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM148348"],"award-info":[{"award-number":["R35GM148348"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Phenotypic variation is often observed in individuals with the same mutation. However, the mechanisms that contribute to this variation remain largely unknown. Fibronectin mutants in both mouse and zebrafish fail to form a functional cardiovascular system, although the penetrance and expressivity of this phenotype vary depending on the genetic background. Here we investigate the variation of the zebrafish\n                    <jats:italic>natter<\/jats:italic>\n                    phenotype, which is caused by a nonsense mutation in\n                    <jats:italic>fibronectin 1a<\/jats:italic>\n                    (\n                    <jats:italic>fn1a<\/jats:italic>\n                    ).\n                    <jats:italic>natter<\/jats:italic>\n                    \/\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutants exhibit incompletely penetrant cardia bifida, a phenotype caused by the failure of cardiac progenitors to migrate to the midline. To examine whether this variation is related to the nonsense mutation, we first generated a large deletion in\n                    <jats:italic>fn1a<\/jats:italic>\n                    that removes the proximal promoter and first 17 exons. Characterisation of this allele found that mutants display variable cardiac phenotypes indistinguishable from those observed in\n                    <jats:italic>natter<\/jats:italic>\n                    \/\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutants. As phenotypic variation is often associated with changes in paralogous gene expression, we next examined the expression of the\n                    <jats:italic>fn1a<\/jats:italic>\n                    paralogue,\n                    <jats:italic>fn1b<\/jats:italic>\n                    , and observed its upregulation specifically in the\n                    <jats:italic>natter<\/jats:italic>\n                    \/\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutants that exhibit a severe phenotype. However, overexpression and double mutant analyses suggest that\n                    <jats:italic>fn1b<\/jats:italic>\n                    expression levels do not modulate the\n                    <jats:italic>natter<\/jats:italic>\n                    \/\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutant phenotype. During these studies, we observed a small proportion of\n                    <jats:italic>natter<\/jats:italic>\n                    \/\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutants with a wild-type (WT)-like phenotype. Selectively raising WT looking mutant larvae increased the proportion of\n                    <jats:italic>natter<\/jats:italic>\n                    \/\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutants displaying the WT-like phenotype from 1.7% to 38.6% in just three generations, indicating the selection of a genetic modifier of the mutant phenotype. We mapped this modifier to the\n                    <jats:italic>integrin alpha 5<\/jats:italic>\n                    (\n                    <jats:italic>itg\u03b15<\/jats:italic>\n                    ) locus through whole-genome sequencing. Furthermore, we found that manipulating\n                    <jats:italic>itg\u03b15<\/jats:italic>\n                    expression influenced the severity of the\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutant phenotype, and that the variance in\n                    <jats:italic>itg\u03b15<\/jats:italic>\n                    expression was increased in\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutants exhibiting a severe phenotype. Taken together, these results indicate that\n                    <jats:italic>itg\u03b15<\/jats:italic>\n                    modifies the\n                    <jats:italic>fn1a<\/jats:italic>\n                    mutant phenotype.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011747","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T13:46:55Z","timestamp":1750686415000},"page":"e1011747","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A genetic modifier links integrin \u03b15 to the phenotypic variation in fibronectin 1a mutant zebrafish"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3949-4696","authenticated-orcid":true,"given":"Samuel J.","family":"Capon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5484-2164","authenticated-orcid":true,"given":"Anastasia","family":"Maroufidou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4178-8055","authenticated-orcid":true,"given":"McKenna","family":"Feltes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4945-6334","authenticated-orcid":true,"given":"Yanli","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darpan Kaur","family":"Matharoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0122-8035","authenticated-orcid":true,"given":"D\u00f6rthe","family":"J\u00fclich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott A.","family":"Holley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8037-7312","authenticated-orcid":true,"given":"Steven A.","family":"Farber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-0026","authenticated-orcid":true,"given":"Didier Y. 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