ABSTRACT
Little is known about the impact of naturally occurring genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate how genetic influences on mRNA translational efficiency are associated with complex disease phenotypes using a panel of rat recombinant inbred lines. We identify a locus for cardiac hypertrophy that is associated with a translatome-wide and protein length-dependent shift in translational efficiency. This master regulator primarily affects the translation of very short and very long protein-coding sequences, altering the physiological stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus points to altered ribosome assembly, characterized by accumulation of polysome half-mers, changed ribosomal configurations and misregulation of the small nucleolar RNA SNORA48. We postulate that this locus enhances a pre-existing negative correlation between protein length and translation initiation in diseased hearts. Our work shows that a single genomic locus can trigger a complex, translation-driven molecular mechanism that contributes to phenotypic variability between individuals.
Highlights
Genetic variability impacts protein synthesis rates in a rat model for cardiac hypertrophy
A trans locus affects stoichiometric translation rates of cardiac sarcomeric proteins
This master regulator locus induces a global, protein length-dependent shift in translation
Dysregulated ribosome assembly induces half-mer formation and affects translation initiation rate
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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