Changes in gene expression predictably shift and switch genetic interactions

Non-additive interactions between mutations occur extensively and also change across conditions, making genetic prediction a difficult challenge. To better understand the plasticity of genetic interactions (epistasis), we combine mutations in a single protein performing a single function (a transcri...

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Detalles Bibliográficos
Autores: Li, Xianghua, Lalić, Jasna, Baeza Centurión, Pablo, 1989-, Dhar, Riddhiman, Lehner, Ben, 1978-
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/42511
Acceso en línea:http://hdl.handle.net/10230/42511
http://dx.doi.org/10.1038/s41467-019-11735-3
Access Level:acceso abierto
Palabra clave:Computational models
Epistasis
Genetics
Systems biology
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spelling Changes in gene expression predictably shift and switch genetic interactionsLi, XianghuaLalić, JasnaBaeza Centurión, Pablo, 1989-Dhar, RiddhimanLehner, Ben, 1978-Computational modelsEpistasisGeneticsSystems biologyNon-additive interactions between mutations occur extensively and also change across conditions, making genetic prediction a difficult challenge. To better understand the plasticity of genetic interactions (epistasis), we combine mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, genetic interactions switch from positive (suppressive) to negative (enhancing) as the expression of the gene changes. These seemingly complicated changes can be predicted using a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. More generally, changes in gene expression should be expected to alter the effects of mutations and how they interact whenever the relationship between expression and a phenotype is nonlinear, which is the case for most genes. These results have important implications for understanding genotype-phenotype maps and illustrate how changes in genetic interactions can often-but not always-be predicted by hierarchical mechanistic models.This work was supported by a European Research Council (ERC) Consolidator grant (616434), the Spanish Ministry of Economy and Competitiveness (BFU2017-89488-P and SEV-2012-0208), the Bettencourt Schueller Foundation, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322.), and the CERCA Program/Generalitat de Catalunya. X. Li was supported in part by a fellowship from the Ramón Areces Foundation. We also acknowledge the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership and the Centro de Excelencia Severo Ochoa.Nature Research201920192019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/42511http://dx.doi.org/10.1038/s41467-019-11735-3reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésNature Communications. 2019;10(1):3886info:eu-repo/grantAgreement/EC/FP7/616434info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/425112026-06-12T07:21:37Z
dc.title.none.fl_str_mv Changes in gene expression predictably shift and switch genetic interactions
title Changes in gene expression predictably shift and switch genetic interactions
spellingShingle Changes in gene expression predictably shift and switch genetic interactions
Li, Xianghua
Computational models
Epistasis
Genetics
Systems biology
title_short Changes in gene expression predictably shift and switch genetic interactions
title_full Changes in gene expression predictably shift and switch genetic interactions
title_fullStr Changes in gene expression predictably shift and switch genetic interactions
title_full_unstemmed Changes in gene expression predictably shift and switch genetic interactions
title_sort Changes in gene expression predictably shift and switch genetic interactions
dc.creator.none.fl_str_mv Li, Xianghua
Lalić, Jasna
Baeza Centurión, Pablo, 1989-
Dhar, Riddhiman
Lehner, Ben, 1978-
author Li, Xianghua
author_facet Li, Xianghua
Lalić, Jasna
Baeza Centurión, Pablo, 1989-
Dhar, Riddhiman
Lehner, Ben, 1978-
author_role author
author2 Lalić, Jasna
Baeza Centurión, Pablo, 1989-
Dhar, Riddhiman
Lehner, Ben, 1978-
author2_role author
author
author
author
dc.subject.none.fl_str_mv Computational models
Epistasis
Genetics
Systems biology
topic Computational models
Epistasis
Genetics
Systems biology
description Non-additive interactions between mutations occur extensively and also change across conditions, making genetic prediction a difficult challenge. To better understand the plasticity of genetic interactions (epistasis), we combine mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, genetic interactions switch from positive (suppressive) to negative (enhancing) as the expression of the gene changes. These seemingly complicated changes can be predicted using a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. More generally, changes in gene expression should be expected to alter the effects of mutations and how they interact whenever the relationship between expression and a phenotype is nonlinear, which is the case for most genes. These results have important implications for understanding genotype-phenotype maps and illustrate how changes in genetic interactions can often-but not always-be predicted by hierarchical mechanistic models.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/42511
http://dx.doi.org/10.1038/s41467-019-11735-3
url http://hdl.handle.net/10230/42511
http://dx.doi.org/10.1038/s41467-019-11735-3
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nature Communications. 2019;10(1):3886
info:eu-repo/grantAgreement/EC/FP7/616434
info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
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repository.mail.fl_str_mv
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