Discussion

Variation in any regulatory layer of gene expression can confer susceptibility to complex diseases. However, the magnitude of the contribution of post-transcriptional regulation to phenotypic variation remains a matter of debate. In order to get insights into the molecular mechanisms underlying cardiovascular as well as metabolic traits, we performed Ribo-seq and RNA-seq in heart and liver tissues of the spontaneously hypertensive rat (SHR) and the BN normotensive reference strain. We observe that, while there is limited evidence of translational buffering, strain-specific differences at the transcriptional level tend to be equally apparent at the translational level. Remarkably, Ribo-seq data also expose strain-specific differences in translation, which 1) are invisible at the transcriptome level, 2) influence cellular protein abundance, and 3) almost double the number of differentially expressed genes between the two strains. We identified miRNA expression, 3UTR variation, RNA binding protein motif signatures associated with translational regulation. Moreover, several human GWASs candidates were found to be primarily translationally regulated in the rat model. These data indicate that studying variation between individuals at the level of the translatome and understanding its regulation will clarify our view of basic biological processes as well as unravel mechanisms underlying complex disease phenotypes.