Recording silence-accurate annotation of the genetic sequence is required to better understand how synonymous coding affects protein structure and disease

The term silent mutation is commonly used to describe (1) a change in the DNA sequence that does not result in an observable effect on the organism's phenotype; and (2) a synonymous mutation where the nucleotide change leaves the translated amino acid sequence unchanged. When Christian Anfinsen showed that a folded and active protein could be denatured to lose structure and activity and then subsequently renatured to regain the same structure and activity it appeared that the native, thermodynamically stable, structure of a protein depends only on the amino acid sequence and solution conditions (Anfinsen and Haber 1961). This experiment suggested that, once translated, proteins carry no memory of the genetic sequence and led to one of the most erroneous assumptions in modern science; synonymous codons were long considered silent, a mutation of the type that has no effect on an organism's phenotype.