Synonymous but not the same- The new view of synonymous mutation

The classic view assumed that what are termed “silent” mutations were inconsequential to health, because such changes in DNA would not alter the composition of the proteins encoded by genes. Proteins function in
virtually every process carried out by cells, from catalyzing biochemical reactions to recognizing foreign invaders. Hence, the thinking went, if a protein’s makeup ends up being correct, any small glitches in the process leading to its construction could not do a body harm.

For example if one codon GGG is has point mutation to GGA, both still encode for acid amino glycine. So by classic view assumption, the silent or synonymous mutation is not cause any harm. By researches, scientists have proved that the assumption is totally wrong.

By researches, the evidences of the harmful silent mutation can be explained by 3 evidence, (may be have more), the evidence of bias, silent mutation that disrupt protein manufactured, and also some synonymously mutation affect pain sensitivity.

The evidence of bias: In the 1980s did scientists realize that silent mutations could also affect protein production—at least in bacteria and yeast. A key discovery at the time was that the genes of those organisms did not use synonymous codons in equal numbers. When the bacterium E-coli specifies the amino acid asparagine, for instance, the codon AAC appears in its DNA much more often than AAT. The reason for this biased usage of codons soon became apparent: cells were preferentially employing certain codons because those choices enhanced the rate or accuracy of protein synthesis.

It turned out that tRNAs corresponding to those synonymous codons typically are not equally abundant within the cell. Most important, then, a gene that contains more of the codons matching the relatively abundant tRNAs would be translated faster, because the higher concentration of those tRNAs would make them more likely to be present when needed. In other cases, a single tRNA variety matches more than one synonymous codon but binds more readily to one codon in particular, so the use of that codon maximizes the accuracy of translation. Consequently, a cell has good reasons not to use all codons equally. As expected, in bacteria and yeast the genes that encode especially abundant proteins exhibit the greatest codon bias, with the preferred codons matching the most common or better-binding tRNAs.

Later observations in other organisms—including plants, flies and worms—revealed similar biases. With such a diverse array of species employing this technique to improve the efficiency of protein production, it seemed likely that mammals would, too. Analyses of mammalian genes did indeed reveal tendencies toward favoring certain codons. The similarity between simple organisms and mammals, however, proved to be only superficial. For reasons not yet fully understood, mammalian genomes are organized into large blocks, each with a distinctively skewed nucleotide content: some regions are rich in G and C bases, whereas others are enriched for A and T. As a result, genes residing in a GC rich region of the genome tend to have many codons containing those bases. Our genes, then, do show a bias for using certain codons, but unlike simpler organisms, the mammalian pattern does not obviously suggest that the reason is to optimize protein synthesis.

In principle, any mutation that does not affect an organism is invisible to the force of natural selection,
which preserves variations that are beneficial.According to the thinking at the time, regions invisible to selection would include sites of silent mutations within genes as well as the 98 percent of the genome that does not specify protein—the noncoding DNA. Yet when scientists began looking at whether silent sites in genes evolved at the same rate as noncoding regions, they unexpectedly found differences—a sign that silent mutations could affect physiology after all.

Initially researchers had no idea how such mutations could disturb protein manufacture in mammals. Lately, however, studies of human disease have provided not just one mechanism but many. Silent disease-causing mutations interfere with several stages of the protein-making process, from DNA transcription all the way through to the translation of mRNA into proteins.

One example involves silent mutations changing how a gene transcript is edited. Shortly after a gene is transcribed into RNA form, that transcript is trimmed to remove noncoding regions known as introns. Like a movie editor who cuts out unwanted film, cellular splicing machinery needs to find the good bits that encode amino acids, known as exons, and then splice them together to produce the final mRNA version of the gene. Human genes are especially rich in introns, with each gene having an average of eight long intronic stretches, so the splicing machinery needs a way to tell where each exon starts and ends.

Research over the past few years has revealed that exons not only specify amino acids, they also contain within their sequences cues necessary for intron removal. Chief among these are exonic splicing enhancer (ESE) motifs—short sequences of about three to eight nucleotides that sit near the ends of the exons and define the exon for the cellular splicing machinery. The need for such motifs can in fact explain a preference
for certain nucleotides in human genes. Although the codons GGA and GGG, which encode glycine, can both occur in splicing enhancers, the former codon acts as a more potent enhancer, leading to more efficient splicing.GGA is also correspondingly more common close to the ends of exons.


In support of the view that preserving codon sequence in splicing enhancers matters, research of  University of Bath  J. V. Chamary , Laurence D. Hurst and Joanna L. Parmley has shown that exonic motifs that apparently function as splicing enhancers show slower evolution in their synonymous codons than do neighboring sequences uninvolved in splicing. This slow evolution indicates that natural selection has kept enhancer motifs relatively unchanged because their specific sequences are so significant. Silent alteration to codons containing these enhancers,although they do not change an amino acid, can nonetheless have a major effect on a protein simply because they disrupt the proper removal of introns.


The long explanation can be visualized in the figure below:

Another evidence is synonymously mutation that affect pain sensitivity A synonymous mutation was found to affect pain sensitivity by changing the amount of an important enzyme that cells produced. The difference results from alterations in the shape of mRNA that can influence how easily ribosomes are able to unpackage and read the strand. The folded shape is caused by base-pairing of the mRNA’s nucleotides; therefore,
a synonymous mutation can alter the way nucleotides match up.

To date, some 50 genetic disorders have been linked to silent mutations, many of which also appear to interfere with intron removal. Splicing enhancers can overlap with a considerable length of a gene’s protein-coding sequence, imposing significant limitations on where a silent mutation would be tolerated. A striking example of the damage a mutation in a splicing enhancer can do was recently documented by Francisco Baralle of the International Center for Genetic Engineering and Biotechnology in Trieste, Italy. The investigators found that 25 percent of the silent mutations they induced in one exon of the cystic fibrosis transmembraneconductance regulator (CFTR) gene disrupted splicing and presumably would thus contribute to cystic fibrosis or related disorders.

As a conclusion, this post mainly about to expose to reader to recent view about silent mutations. Silent mutation doesn't means we just ignored it, silent does not mean nothing, thanks to researches. From researches they give us data, from data after interpretation and process they give us knowledge. Knowledge is power.