Franziska Witte1,2, Jorge Ruiz-Orera1, Camilla Ciolli Mattioli3,4, Susanne Blachut1, Eleonora Adami1,5, Jana Felicitas Schulz1, Valentin Schneider-Lunitz1, Oliver Hummel1, Giannino Patone1, Michael Benedikt Mücke1,6,7, Jan Šilhavý8, Matthias Heinig9,10, Leonardo Bottolo11,12,13, Daniel Sanchis14, Martin Vingron15, Marina Chekulaeva3, Michal Pravenec8, Norbert Hubner16,17,18, Sebastiaan van Heesch19,20. 1. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany. 2. Present Address: NUVISAN ICB GmbH, Lead Discovery-Structrual Biology, 13353, Berlin, Germany. 3. Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany. 4. Present Address: Department of Biological Regulation, Weizmann Institute of Science, 7610001, Rehovot, Israel. 5. Present Address: Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore, 169857, Singapore. 6. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany. 7. Charité-Universitätsmedizin, 10117, Berlin, Germany. 8. Institute of Physiology of the Czech Academy of Sciences, 4, 142 20, Praha, Czech Republic. 9. Institute of Computational Biology (ICB), HMGU, Ingolstaedter Landstr. 1, 85764 Neuherberg, Munich, Germany. 10. Department of Informatics, Technische Universitaet Muenchen (TUM), Boltzmannstr. 3, 85748 Garching, Munich, Germany. 11. Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK. 12. The Alan Turing Institute, London, NW1 2DB, UK. 13. MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK. 14. Institut de Recerca Biomedica de Lleida (IRBLLEIDA), Universitat de Lleida, Edifici Biomedicina-I. Av. Rovira Roure, 80, 25198, Lleida, Spain. 15. Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany. 16. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany. nhuebner@mdc-berlin.de. 17. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany. nhuebner@mdc-berlin.de. 18. Charité-Universitätsmedizin, 10117, Berlin, Germany. nhuebner@mdc-berlin.de. 19. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany. s.vanheesch@prinsesmaximacentrum.nl. 20. Present Address: The Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. s.vanheesch@prinsesmaximacentrum.nl.
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.
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.
Authors: Sebastiaan van Heesch; Franziska Witte; Valentin Schneider-Lunitz; Jana F Schulz; Eleonora Adami; Allison B Faber; Marieluise Kirchner; Henrike Maatz; Susanne Blachut; Clara-Louisa Sandmann; Masatoshi Kanda; Catherine L Worth; Sebastian Schafer; Lorenzo Calviello; Rhys Merriott; Giannino Patone; Oliver Hummel; Emanuel Wyler; Benedikt Obermayer; Michael B Mücke; Eric L Lindberg; Franziska Trnka; Sebastian Memczak; Marcel Schilling; Leanne E Felkin; Paul J R Barton; Nicholas M Quaife; Konstantinos Vanezis; Sebastian Diecke; Masaya Mukai; Nancy Mah; Su-Jun Oh; Andreas Kurtz; Christoph Schramm; Dorothee Schwinge; Marcial Sebode; Magdalena Harakalova; Folkert W Asselbergs; Aryan Vink; Roel A de Weger; Sivakumar Viswanathan; Anissa A Widjaja; Anna Gärtner-Rommel; Hendrik Milting; Cris Dos Remedios; Christoph Knosalla; Philipp Mertins; Markus Landthaler; Martin Vingron; Wolfgang A Linke; Jonathan G Seidman; Christine E Seidman; Nikolaus Rajewsky; Uwe Ohler; Stuart A Cook; Norbert Hubner Journal: Cell Date: 2019-05-30 Impact factor: 41.582
Authors: Roel Hermsen; Joep de Ligt; Wim Spee; Francis Blokzijl; Sebastian Schäfer; Eleonora Adami; Sander Boymans; Stephen Flink; Ruben van Boxtel; Robin H van der Weide; Tim Aitman; Norbert Hübner; Marieke Simonis; Boris Tabakoff; Victor Guryev; Edwin Cuppen Journal: BMC Genomics Date: 2015-05-06 Impact factor: 3.969
Authors: Sonal Dahale; Jorge Ruiz-Orera; Jan Silhavy; Norbert Hübner; Sebastiaan van Heesch; Michal Pravenec; Santosh S Atanur Journal: Life Sci Alliance Date: 2022-01-07