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Title: A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion
Authors: Witte, 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
Keywords: Cardiac hypertrophy
Complex disease
Genetic variation
HXB/BXH rat recombinant inbred panel
Ribosome biogenesis
Ribosome profiling
Spontaneously hypertensive rats (SHR)
trans QTL mapping
Translational efficiency
Issue Date: 28-Jun-2021
Publisher: BioMed Central Ltd
Citation: Witte, 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.
Rights: Attribution 4.0 International
Abstract: Background: 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).
Source Title: Genome Biology
ISSN: 1474-7596
DOI: 10.1186/s13059-021-02397-w
Rights: Attribution 4.0 International
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