{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:16:33Z","timestamp":1784139393643,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014424","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000}}],"reference-count":96,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK60047"],"award-info":[{"award-number":["R01 DK60047"]}],"id":[{"id":"10.13039\/100000062","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":["R01 DK127178"],"award-info":[{"award-number":["R01 DK127178"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["T32-HD007502"],"award-info":[{"award-number":["T32-HD007502"]}],"id":[{"id":"10.13039\/100000071","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":["1F31DK137637-01"],"award-info":[{"award-number":["1F31DK137637-01"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["T32-HD007502"],"award-info":[{"award-number":["T32-HD007502"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["GT11505"],"award-info":[{"award-number":["GT11505"]}],"id":[{"id":"10.13039\/100000011","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":["R01-DK127178-03S1"],"award-info":[{"award-number":["R01-DK127178-03S1"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Diabetes and Kidney Disease","award":["P30-DK058404"],"award-info":[{"award-number":["P30-DK058404"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Hirschsprung disease (HSCR) is characterized by absence of enteric ganglia (aganglionosis) along variable lengths of the distal intestine. This disorder results from deficient colonization of fetal intestine by enteric neural crest-derived cells (ENCDCs). HSCR exhibits complex, multifactorial inheritance with penetrance and severity varying widely even within families.\n                    <jats:italic>SOX10<\/jats:italic>\n                    is among causal genes that predispose to aganglionosis. Yet, how gene interactions influence severity of HSCR aganglionosis is not understood. Prior mapping of aganglionosis modifiers was achieved in a standard F\n                    <jats:sub>1<\/jats:sub>\n                    -intercross utilizing the\n                    <jats:italic>Sox10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>Dom<\/jats:italic>\n                    <\/jats:sup>\n                    HSCR mouse model. Here we deploy a novel strategy of genotyping an extended pedigree pedigree of\n                    <jats:italic>Sox10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>Dom<\/jats:italic>\n                    <\/jats:sup>\n                    mice on a mixed genetic background. GWAS in this pedigree points to novel aganglionosis modifier intervals with replication and refinement of prior modifier regions. Complementary omics analysis of the developing Enteric Nervous System (ENS) enabled identification of multiple high-priority candidate genes within these modifier intervals based on gene expression, chromatin accessibility, and presence of conserved SOX10 binding motifs. We implemented a prioritization pipeline for ranking potential modifiers that generated candidate lists including several well-known for effects on ENS development as well as multiple novel genes. Among the novel genes,\n                    <jats:italic>Dach1<\/jats:italic>\n                    ranked as a top priority candidate gene for modifying migration of ENCDCs and thus influencing aganglionosis severity. The results identify genome intervals with intrinsic genes that are logical candidates for modifying\n                    <jats:italic>Sox10<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>Dom<\/jats:italic>\n                    <\/jats:sup>\n                    aganglionosis severity. We also note that several human orthologs to aganglionosis modifier candidate genes are within linkage disequilibrium blocks containing genetic variants associated with human gut motility disorders, which offers opportunity for gaining biological insight into human HSCR severity.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014424","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T17:52:58Z","timestamp":1783360378000},"page":"e1014424","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combinatorial multiomic analysis from a pedigree of Sox10Dom Hirschsprung mice identifies multiple high confidence candidate modifiers of Enteric Nervous System development"],"prefix":"10.1371","volume":"22","author":[{"given":"Joseph T.","family":"Benthal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin A.","family":"Avila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4718-5869","authenticated-orcid":true,"given":"E. Michelle","family":"Southard-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"issue":"1","key":"pcbi.1014424.ref001","article-title":"Enteric nervous system development: migration, differentiation, and disease","volume":"305","author":"JI Lake","year":"2013","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"2","key":"pcbi.1014424.ref002","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1525-1470.1986.tb00501.x","article-title":"Waardenburg\u2019s syndrome with Hirschsprung\u2019s disease: a neural crest defect","volume":"3","author":"SB Mallory","year":"1986","journal-title":"Pediatr Dermatol"},{"issue":"2","key":"pcbi.1014424.ref003","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/ng0298-171","article-title":"SOX10 mutations in patients with Waardenburg-Hirschsprung disease","volume":"18","author":"V Pingault","year":"1998","journal-title":"Nat Genet"},{"issue":"6","key":"pcbi.1014424.ref004","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/oxfordjournals.jhered.a109980","article-title":"Association of megacolon with a new dominant spotting gene (Dom) in the mouse","volume":"75","author":"PW Lane","year":"1984","journal-title":"J Hered"},{"issue":"3","key":"pcbi.1014424.ref005","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1101\/gr.9.3.215","article-title":"The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome","volume":"9","author":"EM Southard-Smith","year":"1999","journal-title":"Genome Res"},{"issue":"19","key":"pcbi.1014424.ref006","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1093\/hmg\/ddh243","article-title":"Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease","volume":"13","author":"VA Cantrell","year":"2004","journal-title":"Hum Mol Genet"},{"issue":"1","key":"pcbi.1014424.ref007","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ydbio.2004.09.014","article-title":"Identification of Sox8 as a modifier gene in a mouse model of Hirschsprung disease reveals underlying molecular defect","volume":"277","author":"M Maka","year":"2005","journal-title":"Dev Biol"},{"issue":"4","key":"pcbi.1014424.ref008","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1073\/pnas.0337540100","article-title":"Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb","volume":"100","author":"AS McCallion","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pcbi.1014424.ref009","doi-asserted-by":"crossref","DOI":"10.1242\/dev.201090","article-title":"A distinct transcriptome characterizes neural crest-derived cells at the migratory wavefront during enteric nervous system development","volume":"150","author":"R Stavely","year":"2023","journal-title":"Development"},{"issue":"8","key":"pcbi.1014424.ref010","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1073\/pnas.0809630105","article-title":"Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung\u2019s disease","volume":"106","author":"M-M Garcia-Barcelo","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"pcbi.1014424.ref011","article-title":"A genome-wide association study identifies potential susceptibility loci for Hirschsprung disease","volume":"9","author":"J-H Kim","year":"2014","journal-title":"PLoS One"},{"issue":"23","key":"pcbi.1014424.ref012","first-page":"5265","article-title":"Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease","volume":"25","author":"CS-M Tang","year":"2016","journal-title":"Hum Mol Genet"},{"issue":"4","key":"pcbi.1014424.ref013","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41431-017-0053-7","article-title":"Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus","volume":"26","author":"J Fadista","year":"2018","journal-title":"Eur J Hum Genet"},{"issue":"6","key":"pcbi.1014424.ref014","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0021219","article-title":"Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease","volume":"6","author":"Q Jiang","year":"2011","journal-title":"PLoS One"},{"issue":"1","key":"pcbi.1014424.ref015","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1073\/pnas.97.1.268","article-title":"A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus","volume":"97","author":"S Bolk","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1014424.ref016","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/ajmg.10185","article-title":"Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?","volume":"108","author":"MA Parisi","year":"2002","journal-title":"Am J Med Genet"},{"issue":"8","key":"pcbi.1014424.ref017","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/humu.20517","article-title":"Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease","volume":"28","author":"L de Pontual","year":"2007","journal-title":"Hum Mutat"},{"issue":"1","key":"pcbi.1014424.ref018","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1038\/s41467-023-37928-5","article-title":"Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation","volume":"14","author":"Z Li","year":"2023","journal-title":"Nat Commun"},{"issue":"15","key":"pcbi.1014424.ref019","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1056\/NEJMoa1706594","volume":"380","author":"JM Tilghman","year":"2019","journal-title":"N Engl J Med"},{"issue":"11","key":"pcbi.1014424.ref020","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1093\/hmg\/ddi163","article-title":"Genome-wide linkage identifies novel modifier loci of aganglionosis in the Sox10Dom model of Hirschsprung disease","volume":"14","author":"SE Owens","year":"2005","journal-title":"Hum Mol Genet"},{"issue":"7","key":"pcbi.1014424.ref021","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/ng.2310","article-title":"Genome-wide efficient mixed-model analysis for association studies","volume":"44","author":"X Zhou","year":"2012","journal-title":"Nat Genet"},{"key":"pcbi.1014424.ref022","article-title":"The UCSC Genome Browser database: 2025 update","author":"G Perez","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"6734","key":"pcbi.1014424.ref023","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/20700","article-title":"The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives","volume":"399","author":"A Pattyn","year":"1999","journal-title":"Nature"},{"issue":"2","key":"pcbi.1014424.ref024","doi-asserted-by":"crossref","first-page":"111053","DOI":"10.1016\/j.celrep.2022.111053","article-title":"Mesenchymal-epithelial interaction regulates gastrointestinal tract development in mouse embryos","volume":"40","author":"L Zhao","year":"2022","journal-title":"Cell Rep"},{"issue":"4","key":"pcbi.1014424.ref025","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1534\/genetics.106.061176","article-title":"The X chromosome in quantitative trait locus mapping","volume":"174","author":"KW Broman","year":"2006","journal-title":"Genetics"},{"issue":"10","key":"pcbi.1014424.ref026","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/nmeth.1681","article-title":"FaST linear mixed models for genome-wide association studies","volume":"8","author":"C Lippert","year":"2011","journal-title":"Nat Methods"},{"issue":"2","key":"pcbi.1014424.ref027","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/ng.2876","article-title":"Advantages and pitfalls in the application of mixed-model association methods","volume":"46","author":"J Yang","year":"2014","journal-title":"Nat Genet"},{"issue":"8","key":"pcbi.1014424.ref028","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1136\/archdischild-2016-311872","article-title":"Hirschsprung\u2019s disease in the UK and Ireland: incidence and anomalies","volume":"102","author":"British Association of Paediatric Surgeons Congenital Anomalies Surveillance System","year":"2017","journal-title":"Arch Dis Child"},{"issue":"12","key":"pcbi.1014424.ref029","doi-asserted-by":"crossref","first-page":"162655","DOI":"10.1016\/j.jpedsurg.2025.162655","article-title":"Sex differences in postoperative outcomes of Hirschsprung disease: propensity score matching analysis","volume":"60","author":"W Feng","year":"2025","journal-title":"J Pediatr Surg"},{"issue":"5","key":"pcbi.1014424.ref030","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.mod.2004.12.008","article-title":"Phox2b function in the enteric nervous system is conserved in zebrafish and is sox10-dependent","volume":"122","author":"S Elworthy","year":"2005","journal-title":"Mech Dev"},{"issue":"2","key":"pcbi.1014424.ref031","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.mod.2005.11.004","article-title":"Genetic evidence does not support direct regulation of EDNRB by SOX10 in migratory neural crest and the melanocyte lineage","volume":"123","author":"RM Hakami","year":"2006","journal-title":"Mech Dev"},{"issue":"1","key":"pcbi.1014424.ref032","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ydbio.2006.03.031","article-title":"Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development","volume":"295","author":"L Stanchina","year":"2006","journal-title":"Dev Biol"},{"issue":"9","key":"pcbi.1014424.ref033","doi-asserted-by":"crossref","first-page":"3145","DOI":"10.1172\/JCI63401","article-title":"Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression","volume":"122","author":"M Nagashimada","year":"2012","journal-title":"J Clin Invest"},{"key":"pcbi.1014424.ref034","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.semcdb.2017.01.006","article-title":"Enteric nervous system development: a crest cell\u2019s journey from neural tube to colon","volume":"66","author":"N Nagy","year":"2017","journal-title":"Semin Cell Dev Biol"},{"issue":"1","key":"pcbi.1014424.ref035","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"S Jin","year":"2021","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1014424.ref036","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/s41596-024-01045-4","article-title":"CellChat for systematic analysis of cell-cell communication from single-cell transcriptomics","volume":"20","author":"S Jin","year":"2025","journal-title":"Nat Protoc"},{"issue":"1","key":"pcbi.1014424.ref037","doi-asserted-by":"crossref","first-page":"9913","DOI":"10.1038\/s41598-017-10477-w","article-title":"Effects of NRG1 polymorphisms on Hirschsprung\u2019s disease susceptibility: a meta-analysis","volume":"7","author":"M Jiang","year":"2017","journal-title":"Sci Rep"},{"issue":"14","key":"pcbi.1014424.ref038","doi-asserted-by":"crossref","first-page":"6005","DOI":"10.1523\/JNEUROSCI.22-14-06005.2002","article-title":"The projections of early enteric neurons are influenced by the direction of neural crest cell migration","volume":"22","author":"HM Young","year":"2002","journal-title":"J Neurosci"},{"issue":"2","key":"pcbi.1014424.ref039","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.ydbio.2004.03.015","article-title":"Dynamics of neural crest-derived cell migration in the embryonic mouse gut","volume":"270","author":"HM Young","year":"2004","journal-title":"Dev Biol"},{"issue":"2","key":"pcbi.1014424.ref040","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.ydbio.2006.10.017","article-title":"Cell proliferation drives neural crest cell invasion of the intestine","volume":"302","author":"MJ Simpson","year":"2007","journal-title":"Dev Biol"},{"key":"pcbi.1014424.ref041","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1741-7007-12-23","article-title":"Colonizing while migrating: how do individual enteric neural crest cells behave?","volume":"12","author":"HM Young","year":"2014","journal-title":"BMC Biol"},{"issue":"1","key":"pcbi.1014424.ref042","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ydbio.2018.11.017","article-title":"The enteric neural crest progressively loses capacity to form enteric nervous system","volume":"446","author":"D Zhang","year":"2019","journal-title":"Dev Biol"},{"issue":"1","key":"pcbi.1014424.ref043","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/dvdy.10350","article-title":"HOXB5 expression is spatially and temporarily regulated in human embryonic gut during neural crest cell colonization and differentiation of enteric neuroblasts","volume":"228","author":"M Fu","year":"2003","journal-title":"Dev Dyn"},{"issue":"4","key":"pcbi.1014424.ref044","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1053\/j.gastro.2008.01.028","article-title":"Perturbation of hoxb5 signaling in vagal neural crests down-regulates ret leading to intestinal hypoganglionosis in mice","volume":"134","author":"VCH Lui","year":"2008","journal-title":"Gastroenterology"},{"issue":"1","key":"pcbi.1014424.ref045","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ydbio.2012.11.010","article-title":"The Xenopus Tgfbi is required for embryogenesis through regulation of canonical Wnt signalling","volume":"379","author":"F Wang","year":"2013","journal-title":"Dev Biol"},{"key":"pcbi.1014424.ref046","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.biocel.2014.04.013","article-title":"HOXB5 binds to multi-species conserved sequence (MCS+9.7) of RET gene and regulates RET expression","volume":"51","author":"JJ Zhu","year":"2014","journal-title":"Int J Biochem Cell Biol"},{"issue":"4","key":"pcbi.1014424.ref047","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.bbrc.2020.05.009","article-title":"Dach1 regulates neural crest migration during embryonic development","volume":"527","author":"Y-K Kim","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"pcbi.1014424.ref048","doi-asserted-by":"crossref","first-page":"588901","DOI":"10.3389\/fphys.2020.588901","article-title":"Pdgfra and Pdgfrb genetically interact in the murine neural crest cell lineage to regulate migration and proliferation","volume":"11","author":"J Mo","year":"2020","journal-title":"Front Physiol"},{"key":"pcbi.1014424.ref049","doi-asserted-by":"crossref","first-page":"119577","DOI":"10.1016\/j.lfs.2021.119577","article-title":"m6A demethylase ALKBH5 suppresses proliferation and migration of enteric neural crest cells by regulating TAGLN in Hirschsprung\u2019s disease","volume":"278","author":"B Wang","year":"2021","journal-title":"Life Sci"},{"issue":"1","key":"pcbi.1014424.ref050","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/s41467-023-40408-5","article-title":"Epigenetic reprogramming shapes the cellular landscape of schwannoma","volume":"15","author":"SJ Liu","year":"2024","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1014424.ref051","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1186\/s12864-016-3167-3","article-title":"Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation","volume":"17","author":"C Gopinath","year":"2016","journal-title":"BMC Genom"},{"key":"pcbi.1014424.ref052","article-title":"Cis-regulatory variants affect gene expression dynamics in yeast","volume":"10","author":"C-H Shih","year":"2021","journal-title":"Elife"},{"issue":"1","key":"pcbi.1014424.ref053","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1038\/s42003-024-07255-6","article-title":"cis- and trans-regulatory contributions to a hierarchy of factors influencing gene expression variation","volume":"7","author":"S Kalra","year":"2024","journal-title":"Commun Biol"},{"issue":"4","key":"pcbi.1014424.ref054","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1002\/dvdy.21498","article-title":"A Histone2BCerulean BAC transgene identifies differential expression of Phox2b in migrating enteric neural crest derivatives and enteric glia","volume":"237","author":"JC Corpening","year":"2008","journal-title":"Dev Dyn"},{"issue":"3","key":"pcbi.1014424.ref055","article-title":"Combinatorial transcriptional profiling of mouse and human enteric neurons identifies shared and disparate subtypes in situ","volume":"160","author":"AA May-Zhang","year":"2021","journal-title":"Gastroenterology"},{"issue":"8","key":"pcbi.1014424.ref056","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/sj.ejhg.5201852","article-title":"Transcriptional regulation of TLX2 and impaired intestinal innervation: possible role of the PHOX2A and PHOX2B genes","volume":"15","author":"S Borghini","year":"2007","journal-title":"Eur J Hum Genet"},{"issue":"13","key":"pcbi.1014424.ref057","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1242\/dev.005520","article-title":"Physiological Notch signaling promotes gliogenesis in the developing peripheral and central nervous systems","volume":"134","author":"MK Taylor","year":"2007","journal-title":"Development"},{"key":"pcbi.1014424.ref058","article-title":"Loss of Tbx3 in murine neural crest reduces enteric glia and causes cleft palate, but does not influence heart development or bowel transit","author":"SH L\u00f3pez","year":"2018","journal-title":"Dev Biol"},{"issue":"3","key":"pcbi.1014424.ref059","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1053\/j.gastro.2017.10.005","article-title":"Transcription and signaling regulators in developing neuronal subtypes of mouse and human enteric nervous system","volume":"154","author":"F Memic","year":"2018","journal-title":"Gastroenterology"},{"issue":"5","key":"pcbi.1014424.ref060","doi-asserted-by":"crossref","DOI":"10.1016\/j.jcmgh.2020.12.014","article-title":"scRNA-seq reveals new enteric nervous system roles for GDNF, NRTN, and TBX3","volume":"11","author":"CM Wright","year":"2021","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"12","key":"pcbi.1014424.ref061","doi-asserted-by":"crossref","first-page":"101590","DOI":"10.1016\/j.jcmgh.2025.101590","article-title":"Single cell profiling in the Sox10Dom Hirschsprung mouse implicates Hox genes in enteric neuron trajectory allocation","volume":"19","author":"JA Avila","year":"2025","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"1","key":"pcbi.1014424.ref062","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"W McLaren","year":"2016","journal-title":"Genome Biol"},{"issue":"3","key":"pcbi.1014424.ref063","article-title":"GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome","volume":"1","author":"F Bonfiglio","year":"2021","journal-title":"Cell Genom"},{"issue":"9","key":"pcbi.1014424.ref064","doi-asserted-by":"crossref","first-page":"100168","DOI":"10.1016\/j.xgen.2022.100168","article-title":"Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes","volume":"2","author":"KJ Karczewski","year":"2022","journal-title":"Cell Genom"},{"key":"pcbi.1014424.ref065"},{"issue":"5","key":"pcbi.1014424.ref066","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1128\/MCB.21.5.1484-1490.2001","article-title":"Dach1 mutant mice bear no gross abnormalities in eye, limb, and brain development and exhibit postnatal lethality","volume":"21","author":"RJ Davis","year":"2001","journal-title":"Mol Cell Biol"},{"issue":"19","key":"pcbi.1014424.ref067","doi-asserted-by":"crossref","first-page":"6924","DOI":"10.1073\/pnas.0802085105","article-title":"Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8","volume":"105","author":"K Wu","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pcbi.1014424.ref068","article-title":"Collaborative cross mice yield genetic modifiers for Pseudomonas aeruginosa infection in human lung disease","volume":"11","author":"NI Lor\u00e8","year":"2020","journal-title":"mBio"},{"issue":"1","key":"pcbi.1014424.ref069","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1186\/s12864-021-07890-x","article-title":"Genetic mapping of novel modifiers for ApcMin induced intestinal polyps\u2019 development using the genetic architecture power of the collaborative cross mice","volume":"22","author":"A Dorman","year":"2021","journal-title":"BMC Genom"},{"issue":"11","key":"pcbi.1014424.ref070","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/nrg1206","article-title":"The nature and identification of quantitative trait loci: a community\u2019s view","volume":"4","author":"O Abiola","year":"2003","journal-title":"Nat Rev Genet"},{"key":"pcbi.1014424.ref071","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jtbi.2015.02.016","article-title":"Two-part zero-inflated negative binomial regression model for quantitative trait loci mapping with count trait","volume":"372","author":"A Moghimbeigi","year":"2015","journal-title":"J Theor Biol"},{"key":"pcbi.1014424.ref072"},{"issue":"1","key":"pcbi.1014424.ref073","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ydbio.2008.05.524","article-title":"Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro","volume":"320","author":"Y Sato","year":"2008","journal-title":"Dev Biol"},{"issue":"3","key":"pcbi.1014424.ref074","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1242\/dev.044164","article-title":"Regulation of neural crest cell fate by the retinoic acid and Pparg signalling pathways","volume":"137","author":"N Li","year":"2010","journal-title":"Development"},{"key":"pcbi.1014424.ref075","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3389\/fped.2018.00382","article-title":"Alteration of the retinoid acid-CBP signaling pathway in neural crest induction contributes to enteric nervous system disorder","volume":"6","author":"C Li","year":"2018","journal-title":"Front Pediatr"},{"issue":"1","key":"pcbi.1014424.ref076","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ydbio.2017.10.021","article-title":"Retinoic acid temporally orchestrates colonization of the gut by vagal neural crest cells","volume":"433","author":"RA Uribe","year":"2018","journal-title":"Dev Biol"},{"issue":"10","key":"pcbi.1014424.ref077","article-title":"Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system","volume":"6","author":"T Gao","year":"2021","journal-title":"JCI Insight"},{"issue":"4","key":"pcbi.1014424.ref078","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1242\/dev.010454","article-title":"Sox9 and Sox10 influence survival and migration of oligodendrocyte precursors in the spinal cord by regulating PDGF receptor alpha expression","volume":"135","author":"M Finzsch","year":"2008","journal-title":"Development"},{"key":"pcbi.1014424.ref079","article-title":"Engrafted nitrergic neurons derived from hPSCs improve gut dysmotility in mice","author":"H Majd","year":"2025","journal-title":"Nature"},{"issue":"8","key":"pcbi.1014424.ref080","article-title":"Size matters: Large copy number losses in Hirschsprung disease patients reveal genes involved in enteric nervous system development","volume":"17","author":"LE Kuil","year":"2021","journal-title":"PLoS Genet"},{"issue":"4","key":"pcbi.1014424.ref081","doi-asserted-by":"crossref","DOI":"10.1242\/dev.200082","article-title":"PRDM paralogs antagonistically balance Wnt\/\u03b2-catenin activity during craniofacial chondrocyte differentiation","volume":"149","author":"LC Shull","year":"2022","journal-title":"Development"},{"issue":"1","key":"pcbi.1014424.ref082","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/dgd.12705","article-title":"The many faces of Sox2 function in neural crest development","volume":"63","author":"Y Wakamatsu","year":"2021","journal-title":"Dev Growth Differ"},{"issue":"6","key":"pcbi.1014424.ref083","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nrg1615","article-title":"Stochasticity in gene expression: from theories to phenotypes","volume":"6","author":"M Kaern","year":"2005","journal-title":"Nat Rev Genet"},{"issue":"2","key":"pcbi.1014424.ref084","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0896-6273(00)80541-3","article-title":"GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys","volume":"21","author":"H Enomoto","year":"1998","journal-title":"Neuron"},{"key":"pcbi.1014424.ref085","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkh103","article-title":"The UCSC Table Browser data retrieval tool","volume":"32","author":"D Karolchik","year":"2004","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"pcbi.1014424.ref086","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Y Hao","year":"2024","journal-title":"Nat Biotechnol"},{"key":"pcbi.1014424.ref087"},{"issue":"1","key":"pcbi.1014424.ref088","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13059-021-02584-9","article-title":"Comparison and evaluation of statistical error models for scRNA-seq","volume":"23","author":"S Choudhary","year":"2022","journal-title":"Genome Biol"},{"key":"pcbi.1014424.ref089","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkj144","article-title":"The UCSC Genome Browser database: update 2006","volume":"34","author":"AS Hinrichs","year":"2006","journal-title":"Nucleic Acids Research"},{"key":"pcbi.1014424.ref090","doi-asserted-by":"crossref","first-page":"14049","DOI":"10.1038\/ncomms14049","article-title":"Massively parallel digital transcriptional profiling of single cells","volume":"8","author":"GXY Zheng","year":"2017","journal-title":"Nat Commun"},{"issue":"11","key":"pcbi.1014424.ref091","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/s41592-021-01282-5","article-title":"Single-cell chromatin state analysis with Signac","volume":"18","author":"T Stuart","year":"2021","journal-title":"Nat Methods"},{"issue":"12","key":"pcbi.1014424.ref092","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"I Korsunsky","year":"2019","journal-title":"Nat Methods"},{"issue":"1","key":"pcbi.1014424.ref093","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cne.10448","article-title":"Acquisition of neuronal and glial markers by neural crest-derived cells in the mouse intestine","volume":"456","author":"HM Young","year":"2003","journal-title":"J Comp Neurol"},{"issue":"9","key":"pcbi.1014424.ref094","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Y Zhang","year":"2008","journal-title":"Genome Biol"},{"issue":"14","key":"pcbi.1014424.ref095","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1093\/bioinformatics\/btp328","article-title":"rtracklayer: an R package for interfacing with genome browsers","volume":"25","author":"M Lawrence","year":"2009","journal-title":"Bioinformatics"},{"issue":"2","key":"pcbi.1014424.ref096","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/bioinformatics\/btv546","article-title":"Approximately independent linkage disequilibrium blocks in human populations","volume":"32","author":"T Berisa","year":"2016","journal-title":"Bioinformatics"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1014424","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014424","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T17:53:00Z","timestamp":1784137980000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014424"}},"subtitle":[],"editor":[{"given":"Mark","family":"Ziemann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,6]]},"references-count":96,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1014424","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,6]]}}}