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dc.contributor.authorMorrill, Summer A.
dc.contributor.authorAmon, Angelika B
dc.date.accessioned2020-06-30T21:46:15Z
dc.date.available2020-06-30T21:46:15Z
dc.date.issued2019-05
dc.date.submitted2019-06
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttps://hdl.handle.net/1721.1/126033
dc.description.abstractHaploinsufficiency describes the decrease in organismal fitness observed when a single copy of a gene is deleted in diploids. We investigated the origin of haploinsufficiency by creating a comprehensive dosage sensitivity data set for genes under their native promoters. We demonstrate that the expression of haploinsufficient genes is limited by the toxicity of their overexpression. We further show that the fitness penalty associated with excess gene copy number is not the only determinant of haploinsufficiency. Haploinsufficient genes represent a unique subset of genes sensitive to copy number increases, as they are also limiting for important cellular processes when present in one copy instead of two. The selective pressure to decrease gene expression due to the toxicity of overexpression, combined with the pressure to increase expression due to their fitness-limiting nature, has made haploinsufficient genes extremely sensitive to changes in gene expression. As a consequence, haploinsufficient genes are dosage stabilized, showing much more narrow ranges in cell-to-cell variability of expression compared with other genes in the genome. We propose a dosage-stabilizing hypothesis of haploinsufficiency to explain its persistence over evolutionary time.en_US
dc.language.isoen
dc.publisherNational Academy of Sciencesen_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1900437116en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleWhy haploinsufficiency persistsen_US
dc.typeArticleen_US
dc.identifier.citationMorrill, Summer A. and Angelika Amon. "Why haploinsufficiency persists." Proceedings of the National Academy of Sciences 116, 24 (May 2019): 11866-11871 © 2019 National Academy of Sciencesen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentPaul F. Glenn Center for Biology of Aging Research (Massachusetts Institute of Technology)en_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2019-11-26T15:42:30Z
dspace.date.submission2019-11-26T15:42:33Z
mit.metadata.statusComplete


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