{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:24:46Z","timestamp":1790141086857,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,9,14]],"date-time":"2019-09-14T00:00:00Z","timestamp":1568419200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01\u2010DE019638"],"award-info":[{"award-number":["R01\u2010DE019638"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["anatomypubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Developmental Dynamics"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A\/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the <jats:italic>Wnt9b<\/jats:italic> locus in clefting animals, which results in decreased <jats:italic>Wnt9b<\/jats:italic> expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three\u2010dimensional morphology for the first time. We find that methylation at the retrotransposon relates to <jats:italic>Wnt9b<\/jats:italic> expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among\u2010individual variance in facial shape.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Methylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among\u2010individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.110","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T12:13:50Z","timestamp":1567167230000},"page":"1232-1242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Nonlinear gene expression\u2010phenotype relationships contribute to variation and clefting in the A\/WySn mouse"],"prefix":"10.1002","volume":"248","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7319-0755","authenticated-orcid":false,"given":"Rebecca M.","family":"Green","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Anatomy, Alberta Children's Hospital Research Institute and McCaig Institute for Bone and Joint Health University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney L.","family":"Leach","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Alberta Children's Hospital Research Institute and McCaig Institute for Bone and Joint Health University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia M.","family":"Diewert","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose David","family":"Aponte","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Alberta Children's Hospital Research Institute and McCaig Institute for Bone and Joint Health University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"School of PA Medicine University of Lynchburg  Lynchburg Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Cheverud","sequence":"additional","affiliation":[{"name":"Department of Biology Loyola University Chicago  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles C.","family":"Roseman","sequence":"additional","affiliation":[{"name":"Department of Animal Biology University of Illinois Urbana Champaign  Champaign Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan M.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Orthopedics University of California San Francisco  San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph S.","family":"Marcucio","sequence":"additional","affiliation":[{"name":"Department of Orthopedics University of California San Francisco  San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7192-9103","authenticated-orcid":false,"given":"Benedikt","family":"Hallgrimsson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Alberta Children's Hospital Research Institute and McCaig Institute for Bone and Joint Health University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,14]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23329"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22158"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034517716914"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1597\/10-178"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e3182125f9c"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1597\/15-190"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33695"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1500523"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1090510104"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420020411"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420250313"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20106"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23320"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20788"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2005.05.016"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.075796"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14364"},{"key":"e_1_2_6_19_1","first-page":"1","article-title":"Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk","volume":"45","author":"Gonseth S","year":"2019","journal-title":"Epigenetics"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.108.086959"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/19.6.537"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02037-7"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911856107"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2013.04.004"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.129452"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11692-009-9076-5"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1999.tb03772.x"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1998.tb03690.x"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajpa.20187"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24490"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-14-31"},{"key":"e_1_2_6_32_1","volume-title":"Geometric Morphometrics for Biologists","author":"Zelditch ML","year":"2012"},{"issue":"3","key":"e_1_2_6_33_1","first-page":"141","article-title":"A morphometric analysis of craniofacial growth in cleft lip and noncleft mice","volume":"12","author":"Wang KY","year":"1992","journal-title":"J Craniofac Genet Dev Biol"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2015.09.003"},{"issue":"7","key":"e_1_2_6_35_1","first-page":"557","article-title":"Correlation and causation","volume":"20","author":"Wright S","year":"1921","journal-title":"J Agric Res"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.052340"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000434"},{"key":"e_1_2_6_38_1","volume-title":"Factors of Evolution: The Theory of Stabilizing Selection","author":"Schmalhausen II","year":"1949"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2005.03.003"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2018-1099E"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathol.1.110304.100039"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37065"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1597\/13-146"}],"container-title":["Developmental Dynamics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dvdy.110","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/dvdy.110","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/anatomypubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dvdy.110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:53:47Z","timestamp":1760363627000},"score":1,"resource":{"primary":{"URL":"https:\/\/anatomypubs.onlinelibrary.wiley.com\/doi\/10.1002\/dvdy.110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,14]]},"references-count":42,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1002\/dvdy.110"],"URL":"https:\/\/doi.org\/10.1002\/dvdy.110","archive":["Portico"],"relation":{},"ISSN":["1058-8388","1097-0177"],"issn-type":[{"value":"1058-8388","type":"print"},{"value":"1097-0177","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,14]]},"assertion":[{"value":"2019-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-08-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}