Decoding mechanisms by which silent codon changes influence protein biogenesis and function

Abstract

Scope Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. Purpose This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. Physiological and medical relevance Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies.

Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD

“…These diseases include cystic fibrosis, amyotrophic lateral sclerosis (ALS), and Crohn's disease (Bartoszewski et al 2010;Lazrak et al 2013;Bali and Bebok 2015;Liu et al 2016). A single synonymous SNP in the form of a rare codon in the human multidrug resistance 1 (MDR1) gene was found to result in altered drug and inhibitor interactions (Kimchi-Sarfaty et al 2007).…”

The roles of RNA processing in translating genotype to phenotype

“…As exonic splicing elements overlap with protein-coding information, both synonymous and non-synonymous variants can have phenotypic effects owing to altered splicing 16–18 . A phenotypic effect of a non-synonymous variant is most likely to be due to the consequences of the amino acid substitution rather than an effect on splicing.…”

Synonymous codons influencing gene expression in organisms

“…36 Several review articles have described the influence of synonymous codons on gene expression. 34,[37][38][39][40] In this review, we give an account of the recent evidences from ribosome profiling, in vivo translation, and heterologous expression experiments on the influence of synonymous codons on gene expression. In his famous in vitro experiment, Anfinsen 41 (in 1973) observed the successful refolding of an unfolded ribonuclease A (RNase A).…”