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.

Berlin Institute for Medical Systems Biology 10115 Berlin Germany

Cardiovascular and Metabolic Sciences Max Delbrück Center for Molecular Medicine in the Helmholtz Association 13125 Berlin Germany

Charité Universitätsmedizin 10117 Berlin Germany

Department of Computational Molecular Biology Max Planck Institute for Molecular Genetics 14195 Berlin Germany

Department of Informatics Technische Universitaet Muenchen Boltzmannstr 3 85748 Garching Munich Germany

Department of Medical Genetics University of Cambridge Cambridge CB2 0QQ UK

DZHK Partner Site Berlin 13347 Berlin Germany

Institut de Recerca Biomedica de Lleida Universitat de Lleida Edifici Biomedicina 1 Av Rovira Roure 80 25198 Lleida Spain

Institute of Computational Biology HMGU Ingolstaedter Landstr 1 85764 Neuherberg Munich Germany

Institute of Physiology of the Czech Academy of Sciences 4 142 20 Praha Czech Republic

MRC Biostatistics Unit University of Cambridge Cambridge CB2 0SR UK

Present Address Department of Biological Regulation Weizmann Institute of Science 7610001 Rehovot Israel

Present Address NUVISAN ICB GmbH Lead Discovery Structrual Biology 13353 Berlin Germany

Present Address Program in Cardiovascular and Metabolic Disorders Duke National University of Singapore Singapore 169857 Singapore

Present Address The Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

The Alan Turing Institute London NW1 2DB UK

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A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

Cap analysis of gene expression reveals alternative promoter usage in a rat model of hypertension

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