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A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion

dc.contributor.authorWitte, Franziska
dc.contributor.authorRuiz Orera, Jorge
dc.contributor.authorCiolli Mattioli, Camilla
dc.contributor.authorBlachut, Susanne
dc.contributor.authorAdami, Eleonora
dc.contributor.authorFelicitas Schulz, Jana
dc.contributor.authorSchneider-Lunitz, Valentin
dc.contributor.authorHummel, Oliver
dc.contributor.authorPatone, Giannino
dc.contributor.authorMücke, Michael Benedikt
dc.contributor.authorŠilhavý, Jan
dc.contributor.authorHeinig, Matthias
dc.contributor.authorBottolo, Leonardo
dc.contributor.authorSanchis, Daniel
dc.contributor.authorVingron, Martin
dc.contributor.authorChekulaeva, Marina
dc.contributor.authorPravenec, Michal
dc.contributor.authorHubner, Norbert
dc.contributor.authorVan Heesch, Sebastiaan
dc.date.accessioned2021-10-13T10:53:04Z
dc.date.available2021-10-13T10:53:04Z
dc.date.issued2021
dc.identifier.issn1474-760X
dc.identifier.urihttp://hdl.handle.net/10459.1/72050
dc.description.abstractBackground: Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines. Results: We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates. Conclusions: We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease.ca_ES
dc.description.sponsorshipS.v.H. was supported by an EMBO long-term fellowship (ALTF 186-2015, LTFCOFUND2013, GA-2013-609409). N.H. is the recipient of an ERC advanced grant under the European Union Horizon 2020 Research and Innovation Program (grant agreement AdG788970) and is supported by a grant from the Leducq Foundation (16CVD03). M.P. was supported by Praemium Academiae award (AP1502) of the Czech Academy of Sciences. D.S. was funded by Grant 20153810 from Fundació La Marató de TV3. Open Access funding enabled and organized by Projekt DEAL.ca_ES
dc.language.isoengca_ES
dc.publisherBMCca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1186/s13059-021-02397-wca_ES
dc.relation.ispartofGenome Biology, 2021, vol. 22, 191ca_ES
dc.rightscc-by (c) Witte et al., 2021ca_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectGenetic variationca_ES
dc.subjecttrans QTL mappingca_ES
dc.subjectTranslational efficiencyca_ES
dc.subjectRibosome profilingca_ES
dc.titleA trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashionca_ES
dc.typeinfo:eu-repo/semantics/articleca_ES
dc.identifier.idgrec032002
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.identifier.doihttps://doi.org/10.1186/s13059-021-02397-w
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/788970/EU/CodingHeart


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Except where otherwise noted, this item's license is described as cc-by (c) Witte et al., 2021