Synonymous Mutations as a Cause of Human Genetic Disease

Abstract The genetic code is degenerate, that is, several codons are translated into the same amino acid. Synonymous codon changes that do not alter the protein sequence were considered as having no functional consequence and referred to as ‘silent’. This viewpoint has changed drastically in the past decade. Studies in molecular evolution have established that in all organisms, synonymous codons are under selection pressure and consequently used with different frequencies. These observations have been complemented by biochemical, biophysical and genetic studies that provide mechanistic explanations of how such a codon bias is exploited by the translation machinery of cells to control gene expression, the efficiency of protein folding and the coordinated expression of functionally related gene families. Interest in this phenomenon has been heightened by the association between many synonymous mutations and human diseases. Thus, synonymous mutations, once considered innocuous are increasingly being demonstrated to be important in human diseases, evolution and biotechnology. Key Concepts: Synonymous codon changes do not change the amino acid sequence of the translated protein. Until recently synonymous changes were thought to have no effect on the protein and were called silent. New studies show that even synonymous nucleotide changes can affect protein folding and function. Studies in molecular evolution show that even synonymous codons are under selection pressure. Over 50 human diseases are associated with synonymous mutations. Synonymous mutations can affect the splicing of precursor mRNAs. Synonymous mutations can alter the secondary structure of the mRNA and thus affect mRNA stability. Several codons encode the same amino acid but are not used with the same frequency, this is called codon bias. Codon bias is used by the translation machinery to regulate the translation speed and accuracy.