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dc.titleA 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.authorMattioli, Camilla Ciolli
dc.contributor.authorBlachut, Susanne
dc.contributor.authorAdami, Eleonora
dc.contributor.authorSchulz, Jana Felicitas
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.identifier.citationWitte, Franziska, Ruiz-Orera, Jorge, Mattioli, Camilla Ciolli, Blachut, Susanne, Adami, Eleonora, Schulz, Jana Felicitas, Schneider-Lunitz, Valentin, Hummel, Oliver, Patone, Giannino, Mücke, Michael Benedikt, Šilhavý, Jan, Heinig, Matthias, Bottolo, Leonardo, Sanchis, Daniel, Vingron, Martin, Chekulaeva, Marina, Pravenec, Michal, Hubner, Norbert, van Heesch, Sebastiaan (2021-06-28). A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion. Genome Biology 22 (1) : 191. ScholarBank@NUS Repository.
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. © 2021, The Author(s).
dc.publisherBioMed Central Ltd
dc.rightsAttribution 4.0 International
dc.sourceScopus OA2021
dc.subjectCardiac hypertrophy
dc.subjectComplex disease
dc.subjectGenetic variation
dc.subjectHXB/BXH rat recombinant inbred panel
dc.subjectRibosome biogenesis
dc.subjectRibosome profiling
dc.subjectSpontaneously hypertensive rats (SHR)
dc.subjecttrans QTL mapping
dc.subjectTranslational efficiency
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.sourcetitleGenome Biology
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