Anfinsen, C. B. Principles that govern folding of protein chains. Science 181, 223–230 (1973).
Kimura, M. Preponderance of synonymous changes as evidence for neutral theory of molecular evolution. Nature 267, 275–276 (1977).
Chamary, J. V., Parmley, J. L. & Hurst, L. D. Hearing silence: non-neutral evolution at synonymous sites in mammals. Nature Rev. Genet. 7, 98–108 (2006).
This is an excellent early Review from a molecular evolution perspective that brought the importance of synonymous mutations on human health and disease to a larger audience.
Plotkin, J. B. & Kudla, G. Synonymous but not the same: the causes and consequences of codon bias. Nature Rev. Genet. 12, 32–42 (2011).
This is a recent Review that explains global patterns in codon bias and how they influence protein folding.
Cartegni, L., Chew, S. L. & Krainer, A. R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nature Rev. Genet. 3, 285–298 (2002).
Nackley, A. G. et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314, 1930–1933 (2006).
The first study to elucidate a detailed molecular mechanism based on mRNA structure for how synonymous mutations can have physiological consequences.
Kimchi-Sarfaty, C. et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525–528 (2007).
The first study to provide evidence that synonymous changes that do not affect mRNA levels have clinical consequences.
Gunderson, K. L., Steemers, F. J., Lee, G., Mendoza, L. G. & Chee, M. S. A genome-wide scalable SNP genotyping assay using microarray technology. Nature Genet. 37, 549–554 (2005).
Kennedy, G. et al. Large-scale genotyping of complex DNA. Am. J. Hum. Genet. 71, 204 (2002).
Matsuzaki, H. et al. Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nature Methods 1, 109–111 (2004).
Steemers, F. J. et al. Whole-genome genotyping with the single-base extension assay. Nature Methods 3, 31–33 (2006).
Manolio, T. A., Brooks, L. D. & Collins, F. S. A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590–1605 (2008).
Stark, K. et al. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy. PLoS Genet. 6, e1001167 (2010).
Mannisto, P. T. & Kaakkola, S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol. Rev. 51, 593–628 (1999).
Winterer, G. & Goldman, D. Genetics of human prefrontal function. Brain Res. Rev. 43, 134–163 (2003).
Ellis, P. E., Dawson, M. & Dixon, M. J. Mutation testing in Treacher Collins syndrome. J. Orthodont. 29, 293–297 (2011).
Macaya, D. et al. A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon. Am. J. Med. Genet. A 149, 1624–1627 (2009).
Bartoszewski, R. A. et al. A synonymous single nucleotide polymorphism in ΔF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein. J. Biol. Chem. 285, 28741–28748 (2010).
This paper reveals a very interesting finding. A common amino acid deletion has long been thought to be responsible for cystic fibrosis; this study shows that a coincident synonymous mutation results in a change in mRNA structure and protein level and may be responsible for the polymorphism.
Ramser, J. et al. Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy. Am. J. Hum. Genet. 82, 188–193 (2008).
O'Driscoll, M., Ruiz-Perez, V. L., Woods, C. G., Jeggo, P. A. & Goodship, J. A. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nature Genet. 33, 497–501 (2003).
Ho, P. A. et al. WT1 synonymous single nucleotide polymorphism rs16754 correlates with higher mRNA expression and predicts significantly improved outcome in favorable-risk pediatric acute myeloid leukemia: a report from the children's oncology group. J. Clin. Oncol. 29, 704–711 (2011).
Hassan, H. E., Myers, A. L., Coop, A. & Eddington, N. D. Differential involvement of P-glycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: in vitro and in vivo evaluation. J. Pharm. Sci. 98, 4928–4940 (2009).
Ambudkar, S. V., Kim, I. W. & Sauna, Z. E. The power of the pump: mechanisms of action of P-glycoprotein (ABCB1). Eur. J. Pharm. Sci. 27, 392–400 (2006).
van der Veldt, A. A. M. et al. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin. Cancer Res. 17, 620–629 (2011).
Herrlinger, K. R. et al. ABCB1 single-nucleotide polymorphisms determine tacrolimus response in patients with ulcerative colitis. Clin. Pharmacol. Ther. 89, 422–428 (2011).
Sauna, Z. E., Kim, I. W. & Ambudkar, S. V. Genomics and the mechanism of P-glycoprotein (ABCB1). J. Bioenerg. Biomembr. 39, 481–487 (2007).
Chen, R., Davydov, E. V., Sirota, M. & Butte, A. J. Non-synonymous and synonymous coding SNPs show similar likelihood and effect size of human disease association. PLoS ONE 5, e13574 (2010).
Schattner, P. & Diekhans, M. Regions of extreme synonymous codon selection in mammalian genes. Nucleic Acids Res. 34, 1700–1710 (2006).
Chamary, J. V. & Hurst, L. D. The price of silent mutations. Sci. Am. 300, 46–53 (2009).
Schwanhausser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
Vogel, C. et al. Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line. Mol. Syst. Biol. 6, 400 (2010).
Czech, A., Fedyunin, I., Zhang, G. & Ignatova, Z. Silent mutations in sight: co-variations in tRNA abundance as a key to unravel consequences of silent mutations. Mol. Biosyst. 6, 1767–1772 (2010).
Pagani, F., Raponi, M. & Baralle, F. E. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc. Natl Acad. Sci. USA 102, 6368–6372 (2005).
Wang, G. S. & Cooper, T. A. Splicing in disease: disruption of the splicing code and the decoding machinery. Nature Rev. Genet. 8, 749–761 (2007).
Friedman, R. C., Farh, K. K. H., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).
Brest, P. et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. Nature Genet. 43, 242–245 (2011).
This study demonstrates the presence of an miRNA binding site in an exon, a synonymous change in which alters suceptibility to Crohn's disease.
Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nature Genet. 39, 830–832 (2007).
Duan, J. B. et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum. Mol. Genet. 12, 205–216 (2003).
Kudla, G., Lipinski, L., Caffin, F., Helwak, A. & Zylicz, M. High guanine and cytosine content increases mRNA levels in mammalian cells. PLoS Biol. 4, 933–942 (2006).
Gu, W. J., Zhou, T. & Wilke, C. O. A universal trend of reduced mRNA stability near the translation-initiation site in prokaryotes and eukaryotes. PLoS Comput. Biol. 6, e1000664 (2010).
Kudla, G., Murray, A. W., Tollervey, D. & Plotkin, J. B. Coding-sequence determinants of gene expression in Escherichia coli. Science 324, 255–258 (2009).
This important study, which was carried out using synthetic genes, shows the importance mRNA structure near the start codon and the consequenes of synonymous mutations in this region.
Studer, S. M. & Joseph, S. Unfolding of mRNA secondary structure by the bacterial translation initiation complex. Mol. Cell 22, 105–115 (2006).
Dong, H. J., Nilsson, L. & Kurland, C. G. Co-variation of tRNA abundance and codon usage in Escherichia coli at different growth rates. J. Mol. Biol. 260, 649–663 (1996).
Duret, L. tRNA gene number and codon usage in the C. elegans genome are co-adapted for optimal translation of highly expressed genes. Trends Genet. 16, 287–289 (2000).
Zhang, G., Hubalewska, M. & Ignatova, Z. Transient ribosomal attenuation coordinates protein synthesis and co-translational folding. Nature Struct. Mol. Biol. 16, 274–280 (2009).
Bonekamp, F., Dalboge, H., Christensen, T. & Jensen, K. F. Translation rates of individual codons are not correlated with transfer-RNA abundances or with frequencies of utilization in Escherichia coli. J. Bacteriol. 171, 5812–5816 (1989).
Higgs, P. G. & Ran, W. Q. Coevolution of codon usage and tRNA genes leads to alternative stable states of biased codon usage. Mol. Biol. Evol. 25, 2279–2291 (2008).
Ikemura, T. Codon usage and transfer-RNA content in unicellular and multicellular organisms. Mol. Biol. Evol. 2, 13–34 (1985).
Komar, A. A. A pause for thought along the co-translational folding pathway. Trends Biochem. Sci. 34, 16–24 (2009).
Purvis, I. J. et al. The efficiency of folding of some proteins is increased by controlled rates of translation in vivo — a hypothesis. J. Mol. Biol. 193, 413–417 (1987).
This study presents the first challenge to the concept that only the sequence of amino acids determines the final conformation of a protein.
Komar, A. A., Lesnik, T. & Reiss, C. Synonymous codon substitutions affect ribosome traffic and protein folding during in vitro translation. FEBS Lett. 462, 387–391 (1999).
Fedorov, A. N. & Baldwin, T. O. Contribution of cotranslational folding to the rate of formation of native protein-structure. Proc. Natl Acad. Sci. USA 92, 1227–1231 (1995).
Clarke, D. T., Doig, A. J., Stapley, B. J. & Jones, G. R. The α-helix folds on the millisecond time scale. Proc. Natl Acad. Sci. USA 96, 7232–7237 (1999).
Tuller, T. et al. An evolutionarily conserved mechanism for controlling the efficiency of protein translation. Cell 141, 344–354 (2010).
Ehrenberg, M., Dennis, P. P. & Bremer, H. Maximum rrn promoter activity in Escherichia coli at saturating concentrations of free RNA polymerase. Biochimie 92, 12–20 (2010).
Powers, E. T. & Balch, W. E. Costly mistakes: translational infidelity and protein homeostasis. Cell 134, 204–206 (2008).
Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. S. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009).
Cannarrozzi, G. et al. A role for codon order in translation dynamics. Cell 141, 355–367 (2010).
Deutscher, M. P. The eukaryotic aminoacyl-transfer RNA-synthetase complex — suggestions for its structure and function. J. Cell Biol. 99, 373–377 (1984).
Kaminska, M. et al. Dynamic organization of aminoacyl-tRNA synthetase complexes in the cytoplasm of human cells. J. Biol. Chem. 284, 13746–13754 (2009).
Mirande, M., Lecorre, D. & Waller, J. P. A complex from cultured Chinese-hamster ovary cells containing 9 aminoacyl-transfer RNA-synthetases — thermolabile leucyl-transfer RNA-synthetase from the Tsh1 mutant-cell line is an integral component of this complex. Eur. J. Biochem. 147, 281–289 (1985).
Sosnick, T. R. Kinetic barriers and the role of topology in protein and RNA folding. Protein Sci. 17, 1308–1318 (2008).
Jha, S. & Komar, A. A. Birth, life and death of nascent polypeptide chains. Biotechnol. J. 6, 623–640 (2011).
Fedyukina, D. V. & Cavagnero, S. Protein folding at the exit tunnel. Annu. Rev. Biophys. 40, 337–359 (2011).
Netzer, W. J. & Hartl, F. U. Recombination of protein domains facilitated by co-translational folding in eukaryotes. Nature 388, 343–349 (1997).
Nicola, A. V., Chen, W. & Helenius, A. Co-translational folding of an alphavirus capsid protein in the cytosol of living cells. Nature Cell Biol. 1, 341–345 (1999).
Frydman, J., Erdjument-Bromage, H., Tempst, P. & Hartl, F. U. Co-translational domain folding as the structural basis for the rapid de novo folding of firefly luciferase. Nature Struct. Biol. 6, 697–705 (1999).
Tsai, C. J. et al. Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J. Mol. Biol. 383, 281–291 (2008).
Sauna, Z. E., Kimchi-Sarfaty, C., Ambudkar, S. V. & Gottesman, M. M. Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res. 67, 9609–9612 (2007).
Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).
Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R. & Morimoto, R. I. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311, 1471–1474 (2006).
Pal, C., Papp, B. & Lercher, M. J. An integrated view of protein evolution. Nature Rev. Genet. 7, 337–348 (2006).
Wilke, C. O. & Drummond, D. A. Signatures of protein biophysics in coding sequence evolution. Curr. Opin. Struct. Biol. 20, 385–389 (2010).
Drummond, D. A. & Wilke, C. O. Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution. Cell 134, 341–352 (2008).
This is an interesting global computational study conducted in a range of taxa using evolutionary simulation. It shows that selective pressures are exerted as a consequence of protein misfolding resulting from synonymous changes.
Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006).
Krejsa, C., Rogge, M. & Sadee, W. Protein therapeutics: new applications for pharmacogenetics. Nature Rev. Drug Discov. 5, 507–521 (2006).
Ward, N. J. et al. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood 117, 798–807 (2011).
Maertens, B. et al. Gene optimization mechanisms: a multi-gene study reveals a high success rate of full-length human proteins expressed in Escherichia coli. Protein Sci. 19, 1312–1326 (2010).
De Groot, A. S. & Scott, D. W. Immunogenicity of protein therapeutics. Trends Immunol. 28, 482–490 (2007).
Wang, J. H. et al. Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment. Nature Biotech. 26, 901–908 (2008).
Wen, J. D. et al. Following translation by single ribosomes one codon at a time. Nature 452, 598–603 (2008).
Eden, E. et al. Proteome half-life dynamics in living human cells. Science 331, 764–768 (2011).
Plinke, C. et al. embCAB sequence variation among ethambutol-resistant Mycobacterium tuberculosis isolates without embB306 mutation. J. Antimicrob. Chemother. 65, 1359–1367 (2010).
Dissanayeke, S. R. et al. Polymorphic variation in TIRAP is not associated with susceptibility to childhood TB but may determine susceptibility to TBM in some ethnic groups. PLoS ONE 4, e6698 (2009).
Geslain, R. & Pan, T. Functional analysis of human tRNA isodecoders. J. Mol. Biol. 396, 821–831 (2010).
Gustilo, E. M., Franck, A. P. F. & Agris, P. F. tRNA's modifications bring order to gene expression. Curr. Opin. Microbiol. 11, 134–140 (2008).
Glinskii, A. B. et al. Identification of intergenic trans-regulatory RNAs containing a disease-linked SNP sequence and targeting cell cycle progression/differentiation pathways in multiple common human disorders. Cell Cycle 8, 3925–3942 (2009).
Treutlein, J. et al. Genome-wide association study of alcohol dependence. Arch. Gen. Psychiat. 66, 773–784 (2009).
Haiman, C. A. et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nature Genet. 39, 638–644 (2007).
Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nature Genet. 39, 645–649 (2007).
Sharp, P. M., Tuohy, T. M. & Mosurski, K. R. Codon usage in yeast: cluster analysis clearly differentiates highly and lowly expressed genes. Nucleic Acids Res. 14, 5125–5143 (1986).
Bonekamp, F. & Jensen, K. F. The AGG codon is translated slowly in E. coli even at very low expression levels. Nucleic Acids Res. 16, 3013–3024 (1988).
Folley, L. S. & Yarus, M. Codon contexts from weakly expressed genes reduce expression in vivo. J. Mol. Biol. 209, 359–378 (1989).