Abstract

The ribosome is a central molecular machine that translates the genetic information into a corresponding polypeptide in an mRNA template-directed manner. Thereby, the mRNA is not a mere messenger for translating codons into amino acids. Emerging evidence places mRNA more centrally as a direct effector of a variety of processes including translation efficiency, co-translational folding, assembly and cellular localization. We use recent developments in deep sequencing technologies to probe translation on a global transcriptome-wide scale and show that mRNA bears additional layer of information that facilitates translation efficiency and is crucial for co-translational folding and expression of the encoded protein. In the context of these findings, we present a new twist of the effect of synonymous and non-synonymous mutations. We find that the type of mutation, i.e. whether along with the amino-acid exchanges it also alters translation speed at a codon, correlates with its effect on protein stability and function and highlight the central role of translation in mediating the effect of mutations. Using one of the most polymorphic genes, CFTR , implicated in cystic fibrosis pathology, we show that such effects are likely to influence the spectrum of disease symptoms, represent a mechanistic contributor to genotype-phenotype relationships, and ultimately predict therapeutic response in ‘precision’ theratyping studies.