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Article: Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease

TitleWhole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease
Authors
Issue Date2020
PublisherCold Spring Harbor Laboratory Press: Genome Research. The Journal's web site is located at http://genome.cshlp.org/
Citation
Genome Research, 2020, v. 30 n. 11, p. 1618-1632 How to Cite?
AbstractIt is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage–specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain.
Persistent Identifierhttp://hdl.handle.net/10722/294596
ISSN
2021 Impact Factor: 9.438
2020 SCImago Journal Rankings: 9.556
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFu, AX-
dc.contributor.authorLUI, KNC-
dc.contributor.authorTang, CSM-
dc.contributor.authorNg, RK-
dc.contributor.authorLai, FPL-
dc.contributor.authorLau, ST-
dc.contributor.authorLI, Z-
dc.contributor.authorGarcia-Barcelo, MM-
dc.contributor.authorSham, PC-
dc.contributor.authorTam, PKH-
dc.contributor.authorNgan, ESW-
dc.contributor.authorYip, KY-
dc.date.accessioned2020-12-08T07:39:12Z-
dc.date.available2020-12-08T07:39:12Z-
dc.date.issued2020-
dc.identifier.citationGenome Research, 2020, v. 30 n. 11, p. 1618-1632-
dc.identifier.issn1088-9051-
dc.identifier.urihttp://hdl.handle.net/10722/294596-
dc.description.abstractIt is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage–specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain.-
dc.languageeng-
dc.publisherCold Spring Harbor Laboratory Press: Genome Research. The Journal's web site is located at http://genome.cshlp.org/-
dc.relation.ispartofGenome Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleWhole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease-
dc.typeArticle-
dc.identifier.emailTang, CSM: claratang@hku.hk-
dc.identifier.emailLai, FPL: laifrank@hku.hk-
dc.identifier.emailLau, ST: cynlau@hku.hk-
dc.identifier.emailGarcia-Barcelo, MM: mmgarcia@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.emailTam, PKH: paultam@hku.hk-
dc.identifier.emailNgan, ESW: engan@hku.hk-
dc.identifier.authorityTang, CSM=rp02105-
dc.identifier.authorityNg, RK=rp00273-
dc.identifier.authorityGarcia-Barcelo, MM=rp00445-
dc.identifier.authoritySham, PC=rp00459-
dc.identifier.authorityTam, PKH=rp00060-
dc.identifier.authorityNgan, ESW=rp00422-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1101/gr.264473.120-
dc.identifier.pmid32948616-
dc.identifier.pmcidPMC7605255-
dc.identifier.scopuseid_2-s2.0-85095461468-
dc.identifier.hkuros320414-
dc.identifier.volume30-
dc.identifier.issue11-
dc.identifier.spage1618-
dc.identifier.epage1632-
dc.identifier.isiWOS:000586893200007-
dc.publisher.placeUnited States-

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