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.

• Keywords
• Cardiac hypertrophy, Complex disease, Genetic variation, HXB/BXH rat recombinant inbred panel, Ribosome biogenesis, Ribosome profiling, Ribosomopathy, Spontaneously hypertensive rats (SHR), Translational efficiency, trans QTL mapping,
• MeSH
• Organelle Biogenesis MeSH
• Genetic Variation MeSH
• Peptide Chain Initiation, Translational * MeSH
• Cardiomegaly genetics   metabolism   pathology   MeSH
• Rats MeSH
• Quantitative Trait Loci * MeSH
• RNA, Small Nucleolar genetics   metabolism   MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Myocardium metabolism   pathology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Rats, Inbred SHR MeSH
• Rats, Transgenic MeSH
• Gene Expression Regulation MeSH
• Ribosomal Proteins genetics   metabolism   MeSH
• Ribosomes genetics   metabolism   pathology   MeSH
• Saccharomyces cerevisiae genetics   metabolism   MeSH
• Sarcomeres metabolism   pathology   MeSH
• Gene Expression Profiling MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• RNA, Small Nucleolar MeSH
• RNA, Messenger MeSH
• Ribosomal Proteins MeSH