title: Translational regulation shapes the molecular landscape of complex disease phenotypes.
abstract: 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.
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.|National Heart Research Institute Singapore (NHRIS), National Heart Centre Singapore, Singapore 169609, Singapore.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schafer
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Adami
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.|Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Katharina E Costa
authors.initials: KEC
authors.lastname: Rodrigues
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Kreuchwig
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Silhavy
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Heesch
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Deimante
authors.initials: D
authors.lastname: Simaite
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site, 13347 Berlin, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.affiliation: Hubrecht Institute-KNAW &University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Edwin
authors.identifier: http://orcid.org/0000-0002-0400-9542
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenska 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.affiliation: National Heart Research Institute Singapore (NHRIS), National Heart Centre Singapore, Singapore 169609, Singapore.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.|Duke-National University of Singapore, Singapore 169857, Singapore.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site, 13347 Berlin, Germany.|Charité-Universitätsmedizin, 10117 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006973:Hypertension / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010641:Phenotype; D020543:Proteome; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D012270:Ribosomes / Q000378:metabolism*; D017423:Sequence Analysis, RNA
chemical_list: D020543:Proteome