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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Brem R. B., Yvert G., Clinton R. & Kruglyak L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002). PubMed

Hubner N. PubMed

Scheper G., Knaap M. & Proud C. Translation matters: protein synthesis defects in inherited disease. Nat. Rev. Genet. 8, 711–723 (2007). PubMed

Schwanhäusser B. PubMed

Li J., Bickel P. & Biggin M. System wide analyses have underestimated protein abundances and the importance of transcription in mammals. PeerJ 2, (2014). PubMed PMC

Wu L. PubMed PMC

Albert F., Treusch S., Shockley A., Bloom J. & Kruglyak L. Genetics of single-cell protein abundance variation in large yeast populations. Nature 506, 494–497 (2014). PubMed PMC

Parts L. PubMed PMC

Hause R. J. PubMed PMC

Battle A. PubMed PMC

Ingolia N., Ghaemmaghami S., Newman J. & Weissman J. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009). PubMed PMC

Li G.-W., Burkhardt D., Gross C. & Weissman J. Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources. Cell 157, 624–635 (2014). PubMed PMC

Okamoto K. & Aoki K. Development of a strain of spontaneously hypertensive rats. Japn. Circ. J. 27, 282–293 (1963). PubMed

Aitman T. J. PubMed

Pravenec M. PubMed

Pravenec M. PubMed

Petretto E. PubMed PMC

Gibbs R. A. PubMed

Atanur S. S. PubMed PMC

Atanur S. PubMed PMC

Anders S. & Huber W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010). PubMed PMC

McManus C. J., May G. E., Spealman P. & Shteyman A. Ribosome profiling reveals post-transcriptional buffering of divergent gene expression in yeast. Genome Res. 24, 422–430 (2014). PubMed PMC

Artieri C. & Fraser H. Evolution at two levels of gene expression in yeast. Genome Res. 24, 411–421 (2014). PubMed PMC

Albert F. W., Muzzey D., Weissman J. S. & Kruglyak L. Genetic influences on translation in yeast. PLoS Genet. 10, e1004692 (2014). PubMed PMC

Warton D. I., Duursma R. A., Falster D. S. & Taskinen S. smatr 3 - an R package for estimation and inference about allometric lines. Methods Ecol. Evol. 3, 257–259 (2012).

Low T. PubMed

Edwards D. Introduction to Graphical Modelling Springer (2000).

Sandberg R., Neilson J., Sarma A., Sharp P. & Burge C. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008). PubMed PMC

Mayr C. & Bartel D. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009). PubMed PMC

Ghazalpour A. PubMed PMC

Rintisch C. PubMed PMC

Richter J. D. CPEB: a life in translation. Trends Biochem. Sci. 32, 279–285 (2007). PubMed

Guo H., Ingolia N., Weissman J. & Bartel D. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010). PubMed PMC

Bazzini A., Lee M. & Giraldez A. Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Science 336, 233–237 (2012). PubMed PMC

Welter D. PubMed PMC

Hoed M. den PubMed PMC

Illig T. PubMed PMC

Hong M.-G. G. PubMed

Dixon A. L. PubMed

Langmead B. & Salzberg S. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012). PubMed PMC

Flicek P. PubMed PMC

Lowe T. M. & Eddy S. R. tRNAscan-SE: a program for improved detection of transfer RNA genes in genomic sequence. Nucleic Acids Res. 25, 955–964 (1997). PubMed PMC

Trapnell C., Pachter L. & Salzberg S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009). PubMed PMC

Kim D. PubMed PMC

Love M. I., Huber W. & Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). PubMed PMC

Warton D. & Weber N. Common slope tests for bivariate errors-in-variables models. Biom. J. 44, 161–174 (2002).

Graybill F. A. Theory and Application of the Linear Model Duxbury (2000).

Kanehisa M. & Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000). PubMed PMC

Duncan D., Prodduturi N. & Zhang B. WebGestalt2: an updated and expanded version of the Web-based Gene Set Analysis Toolkit. BMC Bioinformatics 11, P10 (2010).

Langmead B., Trapnell C., Pop M. & Salzberg S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009). PubMed PMC

Griffiths-Jones S. The microRNA registry. Nucleic Acids Res. 32, D109–D111 (2004). PubMed PMC

Griffiths-Jones S., Grocock R. J., Dongen S., van, Bateman A. & Enright A. J. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 34, D140–D144 (2006). PubMed PMC

Griffiths-Jones S., Saini H. K., van Dongen S. & Enright A. J. miRBase: tools for microRNA genomics. Nucleic Acids Res. 36, D154–D158 (2008). PubMed PMC

Schulte J. H. PubMed PMC

Benjamini Y. & Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B. 57, 289–300 (1995).

Lewis B. P., Burge C. B. & Bartel D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005). PubMed

Fisher R. A. Statistical Methods for Research Workers Oliver and Boyd (1925).

Venables W. N. & Ripley B. D. Modern Applied Statistics With S Springer (2002).

Ray D. PubMed PMC

Manke T., Heinig M. & Vingron M. Quantifying the effect of sequence variation on regulatory interactions. Hum. Mutat. 31, 477–483 (2010). PubMed

Kettunen J. PubMed PMC

Inouye M. PubMed PMC

Suhre K. PubMed PMC

Willer C. J. PubMed PMC

Teslovich T. M. PubMed PMC

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