Skip to main content
SpringerLink
Log in
Book cover

Single Nucleotide Polymorphisms pp 23–39Cite as

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

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 578))

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.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Collins, F. S., Brooks, L. D. and Chakravarti, A. (1998) A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 8, 1229–1231.

    PubMed  CAS  Google Scholar 

  2. Glazier, A. M., Nadeau, J. H. and Aitman, T. J. (2002) Finding genes that underlie complex traits. Science 298, 2345–2349.

    Article  PubMed  CAS  Google Scholar 

  3. Goldstein, D. B. and Weale, M. E. (2001) Population genomics: Linkage disequilibrium holds the key. Curr. Biol. 11, R576–579.

    Article  PubMed  CAS  Google Scholar 

  4. Gumus-Akay, G., Rustemoglu, A., Karadag, A. and Sunguroglu, A. (2008) Genotype and allele frequencies of MDR1 gene C1236T polymorphism in a Turkish population. Genet. Mol. Res. 7, 1193–1199.

    Article  PubMed  CAS  Google Scholar 

  5. Sauvage, C., Bierne, N., Lapegue, S. and Boudry, P. (2007) Single nucleotide polymorphisms and their relationship to codon usage bias in the pacific oyster crassostrea gigas. Gene 406, 13–22.

    Article  PubMed  CAS  Google Scholar 

  6. Wang, E. T., Sandberg, R., Luo, S., Khrebtukova, I., Zhang, L., Mayr, C., Kingsmore, S. F., Schroth, G. P. and Burge, C. B. (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476.

    Article  PubMed  CAS  Google Scholar 

  7. Hart, M. C. and Cooper, J. A. (1999) Vertebrate isoforms of actin capping protein beta have distinct functions in vivo. J. Cell. Biol. 147, 1287–1298.

    Article  PubMed  CAS  Google Scholar 

  8. Xing, Y., Xu, Q. and Lee, C. (2003) Widespread production of novel soluble protein isoforms by alternative splicing removal of transmembrane anchoring domains. FEBS Lett. 555, 572–578.

    Article  PubMed  CAS  Google Scholar 

  9. Egan, M. F., Straub, R. E., Goldberg, T. E., Yakub, I., Callicott, J. H., Hariri, A. R., Mattay, V. S., Bertolino, A., Hyde, T. M., Shannon-Weickert, C., Akil, M., Crook, J., Vakkalanka, R. K., Balkissoon, R., Gibbs, R. A., Kleinman, J. E. and Weinberger, D. R. (2004) Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc. Natl. Acad. Sci. U.S.A. 101, 12604–12609.

    Article  PubMed  CAS  Google Scholar 

  10. Marti, S. B., Cichon, S., Propping, P. and Nothen, M. (2002) Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am. J. Med. Genet. 114, 46–50.

    Article  PubMed  Google Scholar 

  11. Norton, N., Williams, H. J., Dwyer, S., Ivanov, D., Preece, A. C., Gerrish, A., Williams, N. M., Yerassimou, P., Zammit, S., O'Donovan, M. C. and Owen, M. J. (2005) No evidence for association between polymorphisms in GRM3 and schizophrenia. BMC Psychiatry 5, 23.

    Article  PubMed  Google Scholar 

  12. Sartorius, L. J., Weinberger, D. R., Hyde, T. M., Harrison, P. J., Kleinman, J. E., and Lipska, B. K. (2008) Expression of a GRM3 splice variant is increased in the dorsolateral prefrontal cortex of individuals carrying a schizophrenia risk SNP. Neuropsychopharmacology 33, 2626–2634.

    Article  PubMed  CAS  Google Scholar 

  13. Nielsen, K. B., Sorensen, S., Cartegni, L., Corydon, T. J., Doktor, T. K., Schroeder, L. D., Reinert, L. S., Elpeleg, O., Krainer, A. R., Gregersen, N., Kjems, J. and Andresen, B. S. (2007) Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: A synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am. J. Hum. Genet. 80, 416–432.

    Article  PubMed  CAS  Google Scholar 

  14. Yakub, I., Lillibridge, K. M., Moran, A., Gonzalez, O. Y., Belmont, J., Gibbs, R. A. and Tweardy, D. J. (2005) Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNAse L in patients hospitalized with West Nile virus infection. J. Infect. Dis. 192, 1741–1748.

    Article  PubMed  CAS  Google Scholar 

  15. Cartegni, L., Chew, S. L. and Krainer, A. R. (2002) Listening to silence and understanding nonsense: Exonic mutations that affect splicing. Nat. Rev. Genet. 3, 285–298.

    Article  PubMed  CAS  Google Scholar 

  16. Fedetz, M., Matesanz, F., Caro-Maldonado, A., Fernandez, O., Tamayo, J. A., Guerrero, M., Delgado, C., Lopez-Guerrero, J. A. and Alcina, A. (2006) OAS1 gene haplotype confers susceptibility to multiple sclerosis. Tissue Antigens 68, 446–449.

    Article  PubMed  CAS  Google Scholar 

  17. Solis-Anez, E., Delgado-Luengo, W., Borjas-Fuentes, L., Zabala, W., Arraiz, N., Pineda, L., Portillo, M. G., Gonzalez-Ferrer, S., Chacin, J. A., Pena, J., Montiel, C., Morales, A., Rojas de Atencio, A., Canizales, J., Gonzalez, R., Miranda, L. E., Abreu, N., and Delgado, J. (2007) [Molecular analysis of the GABRB3 gene in autistic patients: An exploratory study]. Invest Clin. 48, 225–242.

    PubMed  Google Scholar 

  18. Ross, J. (1995) mRNA stability in mammalian cells. Microbiol. Rev. 59, 423–450.

    PubMed  CAS  Google Scholar 

  19. Capon, F., Allen, M. H., Ameen, M., Burden, A. D., Tillman, D., Barker, J. N. and Trembath, R. C. (2004) A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum. Mol. Genet. 13, 2361–2368.

    Article  PubMed  CAS  Google Scholar 

  20. Jones, P. M. and George, A. M. (2004) The abc transporter structure and mechanism: Perspectives on recent research. Cell. Mol. Life. Sci. 61, 682–699.

    Article  PubMed  CAS  Google Scholar 

  21. Niemi, M., Arnold, K. A., Backman, J. T., Pasanen, M. K., Godtel-Armbrust, U., Wojnowski, L., Zanger, U. M., Neuvonen, P. J., Eichelbaum, M., Kivisto, K. T. and Lang, T. (2006) Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics. Pharmacogenet. Genomics 16, 801–808.

    Article  PubMed  CAS  Google Scholar 

  22. Shen, L. X., Basilion, J. P. and Stanton, V. P., Jr. (1999) Single-nucleotide polymorphisms can cause different structural folds of mRNA. Proc. Natl. Acad. Sci. U.S.A. 96, 7871–7876.

    Article  PubMed  CAS  Google Scholar 

  23. Diatchenko, L., Slade, G. D., Nackley, A. G., Bhalang, K., Sigurdsson, A., Belfer, I., Goldman, D., Xu, K., Shabalina, S. A., Shagin, D., Max, M. B., Makarov, S. S., and Maixner, W. (2005) Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum. Mol. Genet. 14, 135–143.

    Article  PubMed  CAS  Google Scholar 

  24. Nackley, A. G., Shabalina, S. A., Tchivileva, I. E., Satterfield, K., Korchynskyi, O., Makarov, S. S., Maixner, W. and Diatchenko, L. (2006) Human catechol-o-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314, 1930–1933.

    Article  PubMed  CAS  Google Scholar 

  25. Anfinsen, C. B. (1973) Principles that govern the folding of protein chains. Science 181, 223–230.

    Article  PubMed  CAS  Google Scholar 

  26. Kimura, M. (1977) Preponderance of synonymous changes as evidence for the neutral theory of molecular evolution. Nature 267, 275–276.

    Article  PubMed  CAS  Google Scholar 

  27. Chamary, J. V., Parmley, J. L. and Hurst, L. D. (2006) Hearing silence: Non-neutral evolution at synonymous sites in mammals. Nat. Rev. Genet. 7, 98–108.

    Article  PubMed  CAS  Google Scholar 

  28. Drummond, D. A. and Wilke, C. O. (2008) Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution. Cell 134, 341–352.

    Article  PubMed  CAS  Google Scholar 

  29. Purvis, I. J., Bettany, A. J., Santiago, T. C., Coggins, J. R., Duncan, K., Eason, R. and Brown, A. J. (1987) The efficiency of folding of some proteins is increased by controlled rates of translation in vivo. A hypothesis. J. Mol. Biol. 193, 413–417.

    Article  PubMed  CAS  Google Scholar 

  30. Komar, A. A., Lesnik, T. and Reiss, C. (1999) Synonymous codon substitutions affect ribosome traffic and protein folding during in vitro translation. FEBS Lett. 462, 387–391.

    Article  PubMed  CAS  Google Scholar 

  31. Kimchi-Sarfaty, C., Oh, J. M., Kim, I. W., Sauna, Z. E., Calcagno, A. M., Ambudkar, S. V. and Gottesman, M. M. (2007) A “Silent” Polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525–528.

    Article  PubMed  CAS  Google Scholar 

  32. Ivanov, I. G., Saraffova, A. A. and Abouhaidar, M. G. (1997) Unusual effect of clusters of rare arginine (AGG) codons on the expression of human interferon alpha 1 gene in Escherichia coli. Int. J. Biochem. Cell. Biol. 29, 659–666.

    Article  PubMed  CAS  Google Scholar 

  33. Parmley, J. L. and Hurst, L. D. (2007) How do synonymous mutations affect fitness? Bioessays 29, 515–519.

    Article  PubMed  CAS  Google Scholar 

  34. Bukau, B., Weissman, J. and Horwich, A. (2006) Molecular chaperones and protein quality control. Cell 125, 443–451.

    Article  PubMed  CAS  Google Scholar 

  35. Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I. and Gottesman, M. M. (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39, 361–398.

    Article  PubMed  CAS  Google Scholar 

  36. Pauli-Magnus, C. and Kroetz, D. L. (2004) Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharm. Res. 21, 904–913.

    Article  PubMed  CAS  Google Scholar 

  37. Kimchi-Sarfaty, C., Marple, A. H., Shinar, S., Kimchi, A. M., Scavo, D., Roma, M. I., Kim, I. W., Jones, A., Arora, M., Gribar, J., Gurwitz, D., and Gottesman, M. M. (2007) Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene. Pharmacogenomics 8, 29–39.

    Article  PubMed  CAS  Google Scholar 

  38. Tsai, C. J., Sauna, Z. E., Kimchi-Sarfaty, C., Ambudkar, S. V., Gottesman, M. M. and Nussinov, R. (2008) Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J. Mol. Biol. 383, 281–291.

    Article  PubMed  CAS  Google Scholar 

  39. Komar, A. A. (2009) A pause for thought along the co-translational folding pathway. Trends Biochem. Sci. 34, 16–24.

    Article  PubMed  CAS  Google Scholar 

  40. Clarke, D. T., Doig, A. J., Stapley, B. J. and Jones, G. R. (1999) The alpha-helix folds on the millisecond time scale. Proc. Natl. Acad. Sci. U.S.A. 96, 7232–7237.

    Article  PubMed  CAS  Google Scholar 

  41. Kiho, Y. and Rich, A. (1964) Induced enzyme formed on bacterial polyribosomes. Proc. Natl. Acad. Sci. U.S.A. 51, 111–118.

    Article  PubMed  CAS  Google Scholar 

  42. Fedorov, A. N. and Baldwin, T. O. (1995) Contribution of cotranslational folding to the rate of formation of native protein structure. Proc. Natl. Acad. Sci. U.S.A. 92, 1227–1231.

    Article  PubMed  CAS  Google Scholar 

  43. Fedorov, A. N. and Baldwin, T. O. (1997) Cotranslational protein folding. J. Biol. Chem. 272, 32715–32718.

    Article  PubMed  CAS  Google Scholar 

  44. Batey, S., Scott, K. A. and Clarke, J. (2006) Complex folding kinetics of a multidomain protein. Biophys. J. 90, 2120–2130.

    Article  PubMed  CAS  Google Scholar 

  45. Kowarik, M., Kung, S., Martoglio, B. and Helenius, A. (2002) Protein folding during cotranslational translocation in the endoplasmic reticulum. Mol. Cell. 10, 769–778.

    Article  PubMed  CAS  Google Scholar 

  46. Sauna, Z. E., Kimchi-Sarfaty, C., Ambudkar, S. V. and Gottesman, M. M. (2007) The sounds of silence: Synonymous mutations affect function. Pharmacogenomics 8, 527–532.

    Article  PubMed  CAS  Google Scholar 

  47. Schumacher, M. A. and Brennan, R. G. (2003) Deciphering the molecular basis of multidrug recognition: Crystal structures of the staphylococcus aureus multidrug binding transcription regulator QacR. Res. Microbiol. 154, 69–77.

    Article  PubMed  CAS  Google Scholar 

  48. Keller, I., Bensasson, D. and Nichols, R. A. (2007) Transition-transversion bias is not universal: A counter example from grasshopper pseudogenes. PLoS Genet. 3, e22.

    Article  PubMed  Google Scholar 

  49. Cargill, M., Altshuler, D., Ireland, J., Sklar, P., Ardlie, K., Patil, N., Shaw, N., Lane, C. R., Lim, E. P., Kalyanaraman, N., Nemesh, J., Ziaugra, L., Friedland, L., Rolfe, A., Warrington, J., Lipshutz, R., Daley, G. Q. and Lander, E. S. (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238.

    Article  PubMed  CAS  Google Scholar 

  50. Risch, N. and Merikangas, K. (1996) The future of genetic studies of complex human diseases. Science 273, 1516–1517.

    Article  PubMed  CAS  Google Scholar 

  51. Lander, E. S. (1996) The new genomics: Global views of biology. Science 274, 536–539.

    Article  PubMed  CAS  Google Scholar 

  52. Lazarou, J., Pomeranz, B. H. and Corey, P. N. (1998) Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 279, 1200–1205.

    Article  PubMed  CAS  Google Scholar 

  53. Higgs, P. G. and Ran, W. (2008) Coevolution of codon usage and tRNA genes leads to alternative stable states of biased codon usage. Mol. Biol. Evol. 25, 2279–2291.

    Article  PubMed  CAS  Google Scholar 

  54. Hurst, L. D. (2002) The ka/ks ratio: Diagnosing the form of sequence evolution. Trends Genet. 18, 486.

    Article  PubMed  Google Scholar 

  55. Schattner, P. and Diekhans, M. (2006) Regions of extreme synonymous codon selection in mammalian genes. Nucleic Acids Res. 34, 1700–1710.

    Article  PubMed  CAS  Google Scholar 

  56. Charmary, J. V. and Hurst, L. D. (2009) How Trivial DNA Changes Can Hurt Health. Sci Am. 30, 46–53.

    Google Scholar 

Download references

Acknowledgments

This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Special thanks are expressed to George Leiman, NCI, NIH, and Geetha S., CBER, FDA, for editorial assistance.

Author information

Authors and Affiliations

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

    Ryan Hunt, Zuben E. Sauna & Chava Kimchi-Sarfaty

  2. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Suresh V. Ambudkar & Michael M. Gottesman

Authors
  1. Ryan Hunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zuben E. Sauna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suresh V. Ambudkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael M. Gottesman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chava Kimchi-Sarfaty
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Gene Regulation in, Cleveland State University, Euclid Ave. 2121, Cleveland, 44115, U.S.A.

    Anton A. Komar

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC 2003

About this protocol

Cite this protocol

Hunt, R., Sauna, Z.E., Ambudkar, S.V., Gottesman, M.M., Kimchi-Sarfaty, C. (2009). Silent (Synonymous) SNPs: Should We Care About Them?. In: Komar, A. (eds) Single Nucleotide Polymorphisms. Methods in Molecular Biology™, vol 578. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-411-1_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-411-1_2

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60327-410-4

  • Online ISBN: 978-1-60327-411-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation