Silent (Synonymous) SNPs: Should We Care About Them?

Abstract

One of the surprising findings of the Human Genome Project was that single nucleotide polymorphisms (SNPs), which, by definition, have a minor allele frequency greater than 1%, occur at higher rates than previously suspected. When occurring in the gene coding regions, SNPs can be synonymous (i.e., not causing a change in the amino acid) or nonsynonymous (when the amino acid is altered). It has long been assumed that synonymous SNPs are inconsequential, as the primary sequence of the protein is retained. A number of studies have questioned this assumption over the last decade, showing that synonymous mutations are also under evolutionary pressure and they can be implicated in disease. More importantly, several of the mechanisms by which synonymous mutations alter the structure, function, and expression level of proteins are now being elucidated. Studies have demonstrated that synonymous polymorphisms can affect messenger RNA splicing, stability, and structure as well as protein folding. These changes can have a significant effect on the function of proteins, change cellular response to therapeutic targets, and often explain the different responses of individual patients to a certain medication.

Synonymous single nucleotide polymorphisms in the MC4R gene that are significantly associated with milk production traits in water buffaloes

“…Genetic variations in the UTR, or synonymous mutations in exons, can affect phenotypes in animals (Hunt et al, 2009;Dubey et al, 2013;Vislovukh et al, 2014). Two linked SNPs (g.293C>G and g.129A>G) in the 5ꞌ-UTR of the MC4R gene were associated with body weight and daily gain in 6-month-old Nanyang cattle (P < 0.05) (Zhang et al, 2009).…”

A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children

“…Growing evidence indicates that synonymous variation in coding regions can alter mRNA levels by affecting mRNA stability. 35,36 An in silico analysis performed by using RNA structure software package (version 4.5) revealed that c.621C>T greatly alters the predicted PAR-2 mRNA secondary structure (Fig 3, A). The calculated minimum free energy level of the PAR-2 mRNA with the ''T'' allele at c.621 was approximately 47.16 kcal/mol lower than that of the mRNA with the ''C'' allele, leading to the expectation that PAR-2 mRNA with the ''T'' allele is more stable than the mRNA with the ''C'' allele.…”

“…However, recent studies have indicated that synonymous SNPs as well as nonsynonymous SNPs can affect mRNA stability, mRNA processing, and mRNA maturation, thereby affecting mRNA expression. 36,37 We examined whether the risk allele of c.621C>T variation affects the stability of the PAR-2 mRNA by using an in silico analysis. RNA secondary structure prediction with the RNA fold web server showed that the c.621C>T variation could greatly alter the PAR-2 mRNA secondary structure (Fig 3, A).…”

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

“…In addition, one must be aware in this context that synonymous (''silent'') mutations, although not altering the amino acid sequence of the encoded protein directly, can still influence splicing accuracy or efficiency [Cartegni et al, 2002;Gorlov et al, 2006;Hunt et al, 2009;Sanford et al, 2009;Wang and Cooper, 2007]. Recently, it has been realized that apparently silent SNPs may also become distinctly ''audible'' in the context of mRNA stability or even protein structure and function.…”