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dc.contributor.authorBoukas, Leandros
dc.contributor.authorBjornsson, Hans T
dc.contributor.authorHansen, Kasper D
dc.date.accessioned2020-10-01T13:26:35Z
dc.date.available2020-10-01T13:26:35Z
dc.date.issued2020-08-14
dc.date.submitted2020-10
dc.identifier.citationBoukas L, Bjornsson HT, Hansen KD. Promoter CpG Density Predicts Downstream Gene Loss-of-Function Intolerance. Am J Hum Genet. 2020 Sep 3;107(3):487-498. doi: 10.1016/j.ajhg.2020.07.014. Epub 2020 Aug 14. PMID: 32800095; PMCID: PMC7477270.en_US
dc.identifier.pmid32800095
dc.identifier.doi10.1016/j.ajhg.2020.07.014
dc.identifier.urihttp://hdl.handle.net/2336/621540
dc.descriptionTo access publisher's full text version of this article click on the hyperlink belowen_US
dc.description.abstractThe aggregation and joint analysis of large numbers of exome sequences has recently made it possible to derive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich promoters (top 10% CpG density) have a 67.2% probability of being highly LoF intolerant, using the LOEUF metric from gnomAD. This is in contrast to 7.4% of genes downstream of the most CpG-poor (bottom 10% CpG density) promoters. Combining promoter CpG density with exonic and promoter conservation explains 33.4% of the variation in LOEUF, and the contribution of CpG density exceeds the individual contributions of exonic and promoter conservation. We leverage this to train a simple and easily interpretable predictive model that outperforms other existing predictors and allows us to classify 1,760 genes-which are currently unascertained in gnomAD-as highly LoF intolerant or not. These predictions have the potential to aid in the interpretation of novel variants in the clinical setting. Moreover, our results reveal that high CpG density is not merely a generic feature of human promoters but is preferentially encountered at the promoters of the most selectively constrained genes, calling into question the prevailing view that CpG islands are not subject to selection. Keywords: CpG density; CpG islands; GC content; dosage sensitivity; epigenetics; gnomAD; haploinsufficiency; loss-of-function; promoters; selection.en_US
dc.description.sponsorshipUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) Maryland Genetics, Epidemiology, and Medicine (MD-GEM) training program - Burroughs Wellcome Fund Louma G. Foundationen_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.urlhttps://www.sciencedirect.com/science/article/pii/S0002929720302445?via%3Dihuben_US
dc.rightsCopyright © 2020. Published by Elsevier Inc.
dc.subjectCpG densityen_US
dc.subjectCpG islandsen_US
dc.subjectGC contenten_US
dc.subjectdosage sensitivityen_US
dc.subjectepigeneticsen_US
dc.subjectgnomADen_US
dc.subjecthaploinsufficiencyen_US
dc.subjectloss-of-functionen_US
dc.subjectpromotersen_US
dc.subjectselectionen_US
dc.titlePromoter CpG Density Predicts Downstream Gene Loss-of-Function Intolerance.en_US
dc.typeArticleen_US
dc.identifier.eissn1537-6605
dc.contributor.department1Human Genetics Training Program, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA. 2Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21287, USA; Faculty of Medicine, University of Iceland, Sturlugata 8, 101 Reykjavik, Iceland; Landspitali University Hospital, Hringbraut, 101 Reykjavik, Iceland. Electronic address: hbjorns1@jhmi.edu. 3Department of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD 21205, USA. Electronic address: khansen@jhsph.edu.en_US
dc.identifier.journalAmerican journal of human geneticsen_US
dc.rights.accessOpen Access - Opinn aðganguren_US
dc.departmentcodeMAB12
dc.source.journaltitleAmerican journal of human genetics
dc.source.volume107
dc.source.issue3
dc.source.beginpage487
dc.source.endpage498
dc.source.countryUnited States
dc.source.countryUnited States


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