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Synonymous (“Silent”) Mutations in Health, Disease, and Personalized Medicine: Review

Ongoing discoveries into how synonymous (often erroneously referred to as “silent”) genetic mutations affect human disease could improve the practice of clinical medicine, according to a review of the field by CBER researchers. The article, by Zuben Sauna and Chava Kimchi-Sarfaty, appears in the October 2011 issue of Nature Reviews Genetics.

The authors show that research findings published over the past five years describing synonymous mutations contribute to medical practice in three important ways. The first is the recognition that synonymous mutations can cause human diseases; thus, synonymous mutations cannot be ignored in Genome Wide Association Studies (studies of all or most genes of individuals to determine the amount of genetic variation that exists among individuals).  

Second, single nucleotide polymorphisms (SNPs: variations in single DNA building blocks of a gene) represent the most common source of genetic variation in the human population; they often determine which patients are most likely to respond to or suffer adverse consequences from  specific medical treatments. The growing field of pharmacogenomics exploits the growing understanding of SNPs to develop safer and more effective therapies. Therefore, synonymous SNPs that have previously been ignored are likely to play an important role in this growing field of medical care

Finally, protein-based drugs are increasingly being bioengineered to facilitate the manufacturing process and increase yield by using tRNAs (see below) that are more abundant in the cell. Many of the bioengineering strategies now used are based on the notion that synonymous changes in the DNA will not affect the function of the protein. This review cautions that bioengineering strategies based on this concept might not always yield safe and effective therapies.

Like regular gene mutations, synonymous mutations change the DNA code that controls the production of a specific protein. However, synonymous mutations inflict their damage differently than do regular mutations. A regular gene mutation can disrupt the ability of the cell to make a specific protein by substituting one specific amino acid building block of a protein for another, or by deleting that amino acid entirely; either change could disrupt the protein’s function.  For instance, sickle-cell anemia is caused by a single mutation in which one amino acid is substituted for another.

In contrast, a synonymous mutation does not delete or substitute one amino acid for another; thus the protein produced by both the normal gene and the mutant have the identical amino acid sequence. However, it can reduce the amount of a specific protein the cell makes or cause the structure of the protein to be distorted in a manner that disrupts its functioning in the body.

The key to how a synonymous mutation can affect proteins lies in molecules called ribonucleic acid (RNA). One form of RNA (mRNA) is the decoded form of the gene’s deoxyribonucleic acid (DNA). Each specific mRNA carries the blueprint that specifies which amino acids are in a particular protein and determines the order in which they are linked together.  The folded shape of mRNA enables it to interact with the protein-making machinery of the cell—the ribosome—and guide production of a specific protein. Another type of RNA, called tRNA, carries a single, specifically-shaped amino acid to the ribosome as directed by the mRNA blueprint. Some amino acids have more than one type of tRNA that delivers them to the ribosome.

A synonymous mutation can change the shape of mRNA, disrupting its normal interaction with the ribosome and decreasing or eliminating protein production. Or, a synonymous mutation can alter the mRNA code for a specific amino acid, causing it to attract a different—and less efficient--tRNA than it usually does. This could also reduce protein production at the ribosome or cause production of a misshaped protein that fails to work properly.  In addition, some synonymous mutations disrupt the process that normally modifies newly-made mRNA so it can efficiently guide protein production. This can lead to deletion of a specific amino acid in the protein, which disrupts its shape and function.

The CBER authors compiled a list of synonymous mutations that are linked to almost fifty diseases, including diabetes, a blood clotting disorder called hemophilia B, cervical cancer, and cystic fibrosis.

Moreover, some synonymous mutations can predict how susceptible individuals are to certain diseases or how well a person is likely to respond to treatment. Such information is key to the development of personalized medicine. For example, one synonymous mutation is linked to susceptibility to a type of cardiomyopathy, a disease that enlarges and weakens the heart, reducing its ability to pump blood. The ability to predict a person’s susceptibility to this disease could enable physicians to initiate preventive care and improve patient outcome. Another such mutation is correlated with the ability of children to survive acute myeloid leukemia.

Importantly, some synonymous mutations also affect how well the body absorbs certain drugs, how well those drugs work in patients, and whether specific drugs are likely to cause significant adverse effects in patients. In all, up to 10% of human genes are estimated to contain at least one region in which a synonymous mutation could cause disease.

The CBER authors also noted that advances in understanding synonymous mutations could lead to the development of more effective antibiotics and vaccines as well as identification of risk factors that make certain populations especially susceptible to specific infections, such as tuberculosis. 

“Understanding the contribution of synonymous mutations to human disease”

Nature Reviews/Genetics 12, 683-691 (October 2011) 


Zuben E. Sauna and Chava Kimchi-Sarfaty

Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Bethesda, MD 20892