Silent mutations in sight: co-variations in tRNA abundance as a key to unravel consequences of silent mutations

Abstract

Mutations that alter the amino acid sequence are known to potentially exert deleterious effects on protein function, whereas substitutions of nucleotides without amino acid change are assumed to be neutral for the protein's functionality. However, cumulative evidence suggests that synonymous substitutions might also induce phenotypic variability by affecting splicing accuracy, translation fidelity, and conformation and function of proteins. tRNA isoacceptors mediate the translation of codons to amino acids, and asymmetric tRNA abundance causes variations in the rate of translation of each single triplet. Consequently, the effect of a silent point mutation in the coding region could be significant due to differential abundances of the cognate tRNA(s), emphasizing the importance of precise assessment of tRNA composition. Here, we provide an overview of the methods used to quantitatively determine the concentrations of tRNA species and discuss synonymous mutations in the context of tRNA composition of the cell, thus providing a new twist on the detrimental impact of the silent mutations.

Novel Mutations in BMPR2, ACVRL1 and KCNA5 Genes and Hemodynamic Parameters in Patients with Pulmonary Arterial Hypertension

“…Even, these mutations may decrease the half-life of mRNA, leading to a downregulation of the protein expression [32]. Different synonymous mutations, both new and already described, were seen in 46% of our patients and the 62.5% of these synonymous mutations are considered pathogenic and were not found in controls.…”

Prediction of variable translation rate effects on cotranslational protein folding

“…For example, when coupled with models of translation rates that account for codon usage and tRNA concentrations 34 , this formalism provides a means to predict cotranslational folding behaviour of entire proteomes under varying cellular conditions and aid in the design and of synthetic transcriptomes that optimize the extent of cotranslational folding. Equations (4) and (6) also provide a way for experimentalists to map directly the results from more easily studied arrested RNCs to the realistic situation of continuous translation.…”

Are synonymous codons indeed synonymous?

“…This is not always true, however. In a recent review Czech et al (9) emphasise the importance of the precise assessment of tRNA composition and summarise the methods applicable for determining the concentrations of tRNA species. If and when such a correlation exists, an obvious consequence of this fact is that synonymous mutations could lead to a slowdown of protein synthesis.…”