The extent of translational control of gene expression in mammalian tissues remains largely unknown. Here we perform genome-wide RNA sequencing and ribosome profiling in heart and liver tissues to investigate strain-specific translational regulation in the spontaneously hypertensive rat (SHR/Ola). For the most part, transcriptional variation is equally apparent at the translational level and there is limited evidence of translational buffering. Remarkably, we observe hundreds of strain-specific differences in translation, almost doubling the number of differentially expressed genes. The integration of genetic, transcriptional and translational data sets reveals distinct signatures in 3'UTR variation, RNA-binding protein motifs and miRNA expression associated with translational regulation of gene expression. We show that a large number of genes associated with heart and liver traits in human genome-wide association studies are primarily translationally regulated. Capturing interindividual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease phenotypes.

Cardiovascular and Metabolic Sciences Max Delbrück Center for Molecular Medicine in the Helmholtz Association Robert Rossle Strasse 10 13125 Berlin Germany

Charité Universitätsmedizin 10117 Berlin Germany

Department of Computational Molecular Biology Max Planck Institute for Molecular Genetics Ihnestrasse 63 73 14195 Berlin Germany

Duke National University of Singapore Singapore 169857 Singapore

DZHK Partner Site 13347 Berlin Germany

Hubrecht Institute KNAW and University Medical Center Utrecht Uppsalalaan 8 3584 CT Utrecht The Netherlands

Institute of Physiology Academy of Sciences of the Czech Republic Vídenska 1083 142 20 Prague 4 Czech Republic

National Heart and Lung Institute Imperial College London London SW3 6NP UK

National Heart Research Institute Singapore National Heart Centre Singapore Singapore 169609 Singapore

Systems Biology of Gene Regulatory Elements Max Delbrück Center for Molecular Medicine in the Helmholtz Association Robert Rossle Strasse 10 13125 Berlin Germany

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Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat

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