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Understanding the contribution of synonymous mutations to human disease

Nature Reviews Genetics volume 12, pages 683691 (2011) | Download Citation


Synonymous mutations — sometimes called 'silent' mutations — are now widely acknowledged to be able to cause changes in protein expression, conformation and function. The recent increase in knowledge about the association of genetic variants with disease, particularly through genome-wide association studies, has revealed a substantial contribution of synonymous SNPs to human disease risk and other complex traits. Here we review current understanding of the extent to which synonymous mutations influence disease, the various molecular mechanisms that underlie these effects and the implications for future research and biomedical applications.

Key points

  • Synonymous mutations, once thought to be 'silent', are now increasingly acknowledged to be able to cause changes in protein expression, conformation and function.

  • Studies of the association of genetic variants with disease have revealed a substantial contribution of synonymous mutations to human disease risk and other complex traits. This article includes a compendium of human diseases or clinical conditions associated with synonymous mutations.

  • Concomitantly, there has been substantial progress in understanding the mechanisms by which synonymous substitutions effect changes in the phenotype.

  • Synonymous mutations can affect protein conformation and function by affecting post-transcriptional processing and regulation of RNA, altering the local and global structure of the mRNA and influencing the kinetics of translation.

  • Recent estimates suggest that 5–10% of human genes contain at least one region where synonymous mutations could be harmful. Thus, synonymous SNPs identified in genome-wide association studies should be included in follow-up functional and mechanistic studies.

  • Understanding the effect (or effects) of synonymous mutations could have important implications in the practice of medicine and biotechnology.

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We thank B. Golding for helpful discussions and G. S. Pandey for comments and help in the manuscript preparation. The assistance of E. Ayalp and I. Kimchi in generating the table in box 1 and J. Sauna for the illustrations in figure 1 is gratefully acknowledged. This work was supported by funds from the Laboratory of Hemostasis (C.K.-S.) and the Center for Biologics Evaluation and Research, US Food and Drug Administration's Modernization of Science programme (Z.E.S.). The findings and conclusions in this article have not been formally disseminated by the US Food and Drug Administration and should not be construed to represent any Agency determination or policy.

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  1. Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Bethesda, Maryland 20892, USA.

    • Zuben E. Sauna
    •  & Chava Kimchi-Sarfaty


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The authors declare no competing financial interests.

Corresponding authors

Correspondence to Zuben E. Sauna or Chava Kimchi-Sarfaty.

Supplementary information

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  1. 1.

    Supplementary information S1 (table)

    Human diseases associated with synonymous mutations.

  2. 2.

    Supplementary information S2 (table)

    Changes in RSCU values due to synonymous mutations associated with human diseases.



The transcribed precursor RNA consists of exons (which encode amino acids) and introns, which must be edited out: splicing is the process by which this occurs.

Synonymous SNPs

(sSNPs). Single-nucleotide changes that do not result in a change in the amino acid in the translated protein.

Protein therapeutics

Proteins used in the treatment of human diseases that are purified from animal or human sources or, increasingly, manufactured by recombinant DNA technology.

Non-synonymous SNPs

(nsSNPs). Single-nucleotide changes that result in a change in the amino acid in the translated protein.


A complex of small nuclear RNAs and protein subunits that removes introns from the transcribed precursor mRNA.

Splicing enhancers

Short nucleotide sequences that flag the boundaries of the exon for the splicing machinery of the cell.


(miRNAs). Short RNA molecules that are post-transcriptional regulators. They bind to complementary sequences on mRNAs and result in gene repression.

Exon skipping

RNA splicing that results in one or more exons being eliminated from the final mRNA.

Relative synonymous codon usage

(RSCU). This is a simple measure of non-uniform usage of synonymous codons in a coding sequence. RSCU values show the number of times a particular codon is observed relative to the number of times that the codon would be observed if all the codons for a given amino acid had the same probability.


(Protein homeostasis). This process is necessary for normal cellular function and is maintained by a highly conserved network of biological pathways.

Codon optimization

The use of the host organism's codon bias when proteins are often expressed in a foreign host.

Optical tweezers

Highly focused laser beams that can be used to hold and move microscopic objects, sometimes at the level of a single molecule.

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