Noncoding Rnas Alter Our Interpretations of Genome to Phenome

Abstract Gene transcription and protein translation are core components in the process of gene expression. Previous research on the regulation of gene expression largely focuses on events prior to translation, including epigenetic regulation, transcription, and RNA processing. However, translation acts as an additional layer of regulation that plays an important role in gene expression and function. Highly expressed genes are thought to be codon-biased to support efficient translation, in which the encoded codons correspond to highly abundant tRNAs. Further, synonymous SNPs were once considered to be silent due to the degeneracy of the genetic code. However, synonymous SNPs may disturb protein abundance and function through alterations in translational efficiency and suboptimal pairing to lowly abundant tRNAs. Our previous study identified variation in tRNA expression within bovine liver and muscle tissue, suggesting tissue-specific modulation of translation. In addition, advances in sequencing technologies have recently permitted the study of the translatome, which refers to the entire population of mRNA associated with ribosomes for protein synthesis and can be investigated through ribosome profiling. Here, we applied Quantitative Mature tRNA sequencing (QuantM-tRNA-seq) and ribosome profiling to investigate the relationship between tRNA expression and translational stalling events. Moreover, we have identified translationally regulated genes underlying tissue-specific biological processes and found that many upregulated and downregulated genes coincided with high and low translational efficiency respectively. We have also successfully defined stalling sites that depict the regulatory information encoded within the coding sequence of transcripts, which could control translation rate and facilitate proper protein folding. This work offers an atlas of distinctive stalling sites across bovine tissues, which provides an opportunity to predict codon optimality and understand tissue-specific mechanisms of regulating protein synthesis.