Owing to the degeneracy of the genetic code, a protein sequence can be encoded by many different synonymous mRNA coding sequences. Synonymous codon usage was once thought to be functionally neutral, but evidence now indicates it is shaped by evolutionary selection and affects other aspects of protein biogenesis beyond specifying the amino acid sequence of the protein. Synonymous rare codons, once thought to have only negative impacts on the speed and accuracy of translation, are now known to play an important role in diverse functions, including regulation of cotranslational folding, covalent modifications, secretion, and expression level. Mutations altering synonymous codon usage are linked to human diseases. However, much remains unknown about the molecular mechanisms connecting synonymous codon usage to efficient protein biogenesis and proper cell physiology. Here we review recent literature on the functional effects of codon usage, including bioinformatics approaches aimed at identifying general roles for synonymous codon usage.


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Literature Cited

  1. Anfinsen CB. 1.  1973. Principles that govern the folding of protein chains. Science 181:223–30 [Google Scholar]
  2. Angov E, Hillier CJ, Kincaid RL, Lyon JA. 2.  2008. Heterologous protein expression is enhanced by harmonizing the codon usage frequencies of the target gene with those of the expression host. PLOS ONE 3:e2189 [Google Scholar]
  3. Angov E, Legler PM, Mease RM. 3.  2011. Adjustment of codon usage frequencies by codon harmonization improves protein expression and folding. Methods Mol. Biol. 705:1–13 [Google Scholar]
  4. Bahir I, Fromer M, Prat Y, Linial M. 4.  2009. Viral adaptation to host: a proteome-based analysis of codon usage and amino acid preferences. Mol. Syst. Biol. 5:311 [Google Scholar]
  5. Baker D, Agard DA. 5.  1994. Influenza hemagglutinin: kinetic control of protein function. Structure 2:907–10 [Google Scholar]
  6. Ban N, Nissen P, Hansen J, Moore PB, Steitz TA. 6.  2000. The complete atomic structure of the large ribosomal subunit at 2.4 Å resolution. Science 289:905–20 [Google Scholar]
  7. Bartoszewski RA, Jablonsky M, Bartoszewska S, Stevenson L, Dai Q. 7.  et al. 2010. 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. 285:28741–48 [Google Scholar]
  8. Bennetzen JL, Hall BD. 8.  1982. Codon selection in yeast. J. Biol. Chem. 257:3026–31 [Google Scholar]
  9. Bentele K, Saffert P, Rauscher R, Ignatova Z, Blüthgen N. 9.  2013. Efficient translation initiation dictates codon usage at gene start. Mol. Syst. Biol. 9:675 [Google Scholar]
  10. Berg OG, Kurland CG. 10.  1997. Growth rate-optimised tRNA abundance and codon usage. J. Mol. Biol. 270:544–50 [Google Scholar]
  11. Borgia MB, Borgia A, Best RB, Steward A, Nettels D. 11.  et al. 2011. Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins. Nature 474:662–65 [Google Scholar]
  12. Braselmann E, Chaney JL, Clark PL. 12.  2013. Folding the proteome. Trends Biochem. Sci. 38:337–44 [Google Scholar]
  13. Brunak S, Engelbrecht J. 13.  1996. Protein structure and the sequential structure of mRNA: alpha-helix and beta-sheet signals at the nucleotide level. Proteins 25:237–52 [Google Scholar]
  14. Bulmer M. 14.  1991. The selection-mutation-drift theory of synonymous codon usage. Genetics 129:897–907 [Google Scholar]
  15. Burmann BM, Knauer SH, Sevostyanova A, Schweimer K, Mooney RA. 15.  et al. 2012. An α-helix to β-barrel domain switch transforms the transcription factor RfaH into a translation factor. Cell 150:291–303 [Google Scholar]
  16. Charneski CA, Hurst LD. 16.  2013. Positively charged residues are the major determinants of ribosomal velocity. PLOS Biol. 11:e1001508 [Google Scholar]
  17. Chartier M, Gaudreault F, Najmanovich R. 17.  2012. Large-scale analysis of conserved rare codon clusters suggests an involvement in co-translational molecular recognition events. Bioinformatics 28:1438–45 [Google Scholar]
  18. Chen C, Stevens B, Kaur J, Cabral D, Liu H. 18.  et al. 2011. Single-molecule fluorescence measurements of ribosomal translocation dynamics. Mol. Cell 42:367–77 [Google Scholar]
  19. Chen SL, Lee W, Hottes AK, Shapiro L, McAdams HH. 19.  2004. Codon usage between genomes is constrained by genome-wide mutational processes. PNAS 101:3480–85 [Google Scholar]
  20. Chevance FF, Le Guyon S, Hughes KT. 20.  2014. The effects of codon context on in vivo translation speed. PLOS Genet. 10:e1004392 [Google Scholar]
  21. Chursov A, Frishman D, Shneider A. 21.  2013. Conservation of mRNA secondary structures may filter out mutations in Escherichia coli evolution. Nucleic Acids Res. 41:7854–60 [Google Scholar]
  22. Clark PL. 22.  2004. Protein folding in the cell: reshaping the folding funnel. Trends Biochem. Sci. 29:527–34 [Google Scholar]
  23. Clark PL, Ugrinov KG. 23.  2009. Measuring cotranslational folding of nascent polypeptide chains on ribosomes. Methods Enzymol. 466:567–90 [Google Scholar]
  24. Clarke TF, Clark PL. 24.  2008. Rare codons cluster. PLOS ONE 3:e3412 [Google Scholar]
  25. Clarke TF, Clark PL. 25.  2010. Increased incidence of rare codon clusters at 5′ and 3′ gene termini: implications for function. BMC Genomics 11:118 [Google Scholar]
  26. Cortazzo P, Cervenansky C, Marin M, Reiss C, Ehrlich R, Deana A. 26.  2002. Silent mutations affect in vivo protein folding in Escherichia coli. Biochem. Biophys. Res. Commun. 293:537–41 [Google Scholar]
  27. Curran JF. 27.  1995. Decoding with the A-I wobble pair is inefficient. Nucleic Acids Res. 23:683–88 [Google Scholar]
  28. Daidone V, Gallinaro L, Grazia Cattini M, Pontara E, Bertomoro A. 28.  et al. 2011. An apparently silent nucleotide substitution (c.7056C>T) in the von Willebrand factor gene is responsible for type 1 von Willebrand disease. Haematologica 96:881–87 [Google Scholar]
  29. Dees ND, Zhang Q, Kandoth C, Wendl MC, Schierding W. 29.  et al. 2012. MuSiC: identifying mutational significance in cancer genomes. Genome Res. 22:1589–98 [Google Scholar]
  30. Dittmar KA, Goodenbour JM, Pan T. 30.  2006. Tissue-specific differences in human transfer RNA expression. PLOS Genet. 2:e221 [Google Scholar]
  31. Doerfel LK, Wohlgemuth I, Kothe C, Peske F, Urlaub H, Rodnina MV. 31.  2013. EF-P is essential for rapid synthesis of proteins containing consecutive proline residues. Science 339:85–88 [Google Scholar]
  32. Dong H, Nilsson L, Kurland CG. 32.  1996. Co-variation of tRNA abundance and codon usage in Escherichia coli at different growth rates. J. Mol. Biol. 260:649–63 [Google Scholar]
  33. dos Reis M, Savva R, Wernisch L. 33.  2004. Solving the riddle of codon usage preferences: a test for translational selection. Nucleic Acids Res. 32:5036–44 [Google Scholar]
  34. Dreher TW. 34.  2010. Viral tRNAs and tRNA-like structures. Wiley Interdiscip. Rev. RNA 1:402–14 [Google Scholar]
  35. Drummond DA, Wilke CO. 35.  2008. Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution. Cell 134:341–52 [Google Scholar]
  36. Du YZ, Dickerson C, Aylsworth AS, Schwartz CE. 36.  1998. A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS). J. Med. Genet. 35:456–62 [Google Scholar]
  37. Duncan CD, Mata J. 37.  2011. Widespread cotranslational formation of protein complexes. PLOS Genet. 7:e1002398 [Google Scholar]
  38. Elena C, Ravasi P, Castelli ME, Peirú S, Menzella HG. 38.  2014. Expression of codon optimized genes in microbial systems: current industrial applications and perspectives. Front. Microbiol. 5:21 [Google Scholar]
  39. Elf J, Nilsson D, Tenson T, Ehrenberg M. 39.  2003. Selective charging of tRNA isoacceptors explains patterns of codon usage. Science 300:1718–22 [Google Scholar]
  40. Ermolaeva MD. 40.  2001. Synonymous codon usage in bacteria. Curr. Issues Mol. Biol. 3:91–97 [Google Scholar]
  41. Evans MS, Ugrinov KG, Frese M-A, Clark PL. 41.  2005. Homogeneous stalled ribosome nascent chain complexes produced in vivo or in vitro. Nat. Methods 2:757–62 [Google Scholar]
  42. Faa′ V, Coiana A, Incani F, Costantino L, Cao A, Rosatelli MC. 42.  2010. A synonymous mutation in the CFTR gene causes aberrant splicing in an Italian patient affected by a mild form of cystic fibrosis. J. Mol. Diagn. 12:380–83 [Google Scholar]
  43. Fedyunin I, Lehnhardt L, Böhmer N, Kaufmann P, Zhang G, Ignatova Z. 43.  2012. tRNA concentration fine tunes protein solubility. FEBS Lett. 586:3336–40 [Google Scholar]
  44. Firnberg E, Labonte JW, Gray JJ, Ostermeier M. 44.  2014. A comprehensive, high-resolution map of a gene's fitness landscape. Mol. Biol. Evol. 31:1581–92 [Google Scholar]
  45. Frenkel-Morgenstern M, Danon T, Christian T, Igarashi T, Cohen L. 45.  et al. 2012. Genes adopt non-optimal codon usage to generate cell cycle-dependent oscillations in protein levels. Mol. Syst. Biol. 8:572 [Google Scholar]
  46. Friedman R, Ely B. 46.  2012. Codon usage methods for horizontal gene transfer detection generate an abundance of false positive and false negative results. Curr. Microbiol. 65:639–42 [Google Scholar]
  47. Fuglsang A. 47.  2003. Codon optimizer: a freeware tool for codon optimization. Protein Expr. Purif. 31:247–49 [Google Scholar]
  48. Fung KL, Pan J, Ohnuma S, Lund PE, Pixley JN. 48.  et al. 2014. MDR1 synonymous polymorphisms alter transporter specificity and protein stability in a stable epithelial monolayer. Cancer Res. 74:598–608 [Google Scholar]
  49. Garcia-Vallve S, Guzman E, Montero MA, Romeu A. 49.  2003. HGT-DB: a database of putative horizontally transferred genes in prokaryotic complete genomes. Nucleic Acids Res. 31:187–89 [Google Scholar]
  50. Gardin J, Yeasmin R, Yurovsky A, Cai Y, Skiena S, Futcher B. 49a.  2014. Measurement of average decoding rates of the 61 sense codons in vivo. Elife 3:e03735 [Google Scholar]
  51. Ghaemmaghami S, Huh WK, Bower K, Howson RW, Belle A. 50.  et al. 2003. Global analysis of protein expression in yeast. Nature 425:737–41 [Google Scholar]
  52. Goetz RM, Fuglsang A. 51.  2005. Correlation of codon bias measures with mRNA levels: analysis of transcriptome data from Escherichia coli. Biochem. Biophys. Res. Commun. 327:4–7 [Google Scholar]
  53. Gonzalez-Paredes FJ, Ramos-Trujillo E, Claverie-Martin F. 52.  2014. Defective pre-mRNA splicing in PKD1 due to presumed missense and synonymous mutations causing autosomal dominant polycystic disease. Gene 546:243–49 [Google Scholar]
  54. Goodman DB, Church GM, Kosuri S. 53.  2013. Causes and effects of N-terminal codon bias in bacterial genes. Science 342:475–79 [Google Scholar]
  55. Gouy M, Gautier C. 54.  1982. Codon usage in bacteria: correlation with gene expressivity. Nucleic Acids Res. 10:7055–74 [Google Scholar]
  56. Grantham R, Gautier C, Gouy M. 55.  1980. Codon frequencies in 119 individual genes confirm consistent choices of degenerate bases according to genome type. Nucleic Acids Res. 8:1893–912 [Google Scholar]
  57. Grantham R, Gautier C, Gouy M, Mercier R, Pave A. 56.  1980. Codon catalog usage and the genome hypothesis. Nucleic Acids Res. 8:r49–r62 [Google Scholar]
  58. Grote A, Hiller K, Scheer M, Münch R, Nörtemann B. 57.  et al. 2005. JCat: a novel tool to adapt codon usage of a target gene to its potential expression host. Nucleic Acids Res. 33:W526–31 [Google Scholar]
  59. Guo FB, Ye YN, Zhao HL, Lin D, Wei W. 58.  2012. Universal pattern and diverse strengths of successive synonymous codon bias in three domains of life, particularly among prokaryotic genomes. DNA Res. 19:477–85 [Google Scholar]
  60. Gustafsson C, Govindarajan S, Minshull J. 59.  2004. Codon bias and heterologous protein expression. Trends Biotechnol. 22:346–53 [Google Scholar]
  61. Gyles C, Boerlin P. 60.  2014. Horizontally transferred genetic elements and their role in pathogenesis of bacterial disease. Vet. Pathol. 51:328–40 [Google Scholar]
  62. Hurst LD. 61.  2002. The Ka/Ks ratio: diagnosing the form of sequence evolution. Trends Genet. 18:486 [Google Scholar]
  63. Ikemura T. 62.  1985. Codon usage and transfer-RNA content in unicellular and multicellular organisms. Mol. Biol. Evol. 2:13–34 [Google Scholar]
  64. Ikemura T, Ozeki H. 63.  1983. Codon usage and transfer RNA contents: organism-specific codon-choice patterns in reference to the isoacceptor contents. Cold Spring Harb. Symp. Quant. Biol. 47:Pt. 21087–97 [Google Scholar]
  65. Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS. 64.  2009. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324:218–23 [Google Scholar]
  66. Ingolia NT, Lareau LF, Weissman JS. 65.  2011. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147:789–802 [Google Scholar]
  67. Ito K, Chiba S, Pogliano K. 66.  2010. Divergent stalling sequences sense and control cellular physiology. Biochem. Biophys. Res. Commun. 393:1–5 [Google Scholar]
  68. Jha S, Komar AA. 67.  2011. Birth, life and death of nascent polypeptide chains. Biotechnol. J. 6:623–40 [Google Scholar]
  69. Kane JF. 68.  1995. Effects of rare codon clusters on high-level expression of heterologous proteins in Escherichia coli. Curr. Opin. Biotechnol. 6:494–500 [Google Scholar]
  70. Karakozova M, Kozak M, Wong CC, Bailey AO, Yates JR 3rd. 69.  et al. 2006. Arginylation of β-actin regulates actin cytoskeleton and cell motility. Science 313:192–96 [Google Scholar]
  71. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM. 70.  et al. 2007. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–28 [Google Scholar]
  72. Kimura M. 71.  1980. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J. Mol. Evol. 16:111–20 [Google Scholar]
  73. Komar AA. 72.  2009. A pause for thought along the co-translational folding pathway. Trends Biochem. Sci. 34:16–24 [Google Scholar]
  74. Komar AA, Lesnik T, Reiss C. 73.  1999. Synonymous codon substitutions affect ribosome traffic and protein folding during in vitro translation. FEBS Lett. 462:387–91 [Google Scholar]
  75. Kramer EB, Farabaugh PJ. 74.  2007. The frequency of translational misreading errors in E. coli is largely determined by tRNA competition. RNA 13:87–96 [Google Scholar]
  76. Kramer G, Boehringer D, Ban N, Bukau B. 75.  2009. The ribosome as a platform for co-translational processing, folding and targeting of newly synthesized proteins. Nat. Struct. Mol. Biol. 16:589–97 [Google Scholar]
  77. Kudla G, Murray AW, Tollervey D, Plotkin JB. 76.  2009. Coding-sequence determinants of gene expression in Escherichia coli. Science 324:255–58 [Google Scholar]
  78. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K. 77.  et al. 2013. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–18 [Google Scholar]
  79. Lazrak A, Fu LW, Bali V, Bartoszewski R, Rab A. 78.  et al. 2013. The silent codon change I507-ATC → ATT contributes to the severity of the ΔF508 CFTR channel dysfunction. FASEB J. 27:4630–45 [Google Scholar]
  80. Letzring DP, Dean KM, Grayhack EJ. 79.  2010. Control of translation efficiency in yeast by codon-anticodon interactions. RNA 16:2516–28 [Google Scholar]
  81. Li GW, Oh E, Weissman JS. 80.  2012. The anti-Shine-Dalgarno sequence drives translational pausing and codon choice in bacteria. Nature 484:538–41 [Google Scholar]
  82. Lu JL, Deutsch C. 81.  2008. Electrostatics in the ribosomal tunnel modulate chain elongation rates. J. Mol. Biol. 384:73–86 [Google Scholar]
  83. Luo XL, Tang ZY, Xia GH, Wassmann K, Matsumoto T. 82.  et al. 2004. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat. Struct. Mol. Biol. 11:338–45 [Google Scholar]
  84. Mahlab S, Linial M. 83.  2014. Speed controls in translating secretory proteins in eukaryotes–an evolutionary perspective. PLOS Comput. Biol. 10:e1003294 [Google Scholar]
  85. Malaby HLH, Kobertz WR. 84.  2013. Molecular determinants of co- and post-translational N-glycosylation of type I transmembrane peptides. Biochem. J. 453:427–34 [Google Scholar]
  86. Meijer J, Nakajima Y, Zhang C, Meinsma R, Ito T, Van Kuilenburg AB. 85.  2013. Identification of a novel synonymous mutation in the human β-ureidopropionase gene UPB1 affecting pre-mRNA splicing. Nucleosides Nucleotides Nucleic Acids 32:639–45 [Google Scholar]
  87. Meunier J, Duret L. 86.  2004. Recombination drives the evolution of GC-content in the human genome. Mol. Biol. Evol. 21:984–90 [Google Scholar]
  88. Mitarai N, Sneppen K, Pedersen S. 87.  2008. Ribosome collisions and translation efficiency: optimization by codon usage and mRNA destabilization. J. Mol. Biol. 382:236–45 [Google Scholar]
  89. Mueller S, Papamichail D, Coleman JR, Skiena S, Wimmer E. 88.  2006. Reduction of the rate of poliovirus protein synthesis through large-scale codon deoptimization causes attenuation of viral virulence by lowering specific infectivity. J. Virol. 80:9687–96 [Google Scholar]
  90. Musto H, Naya H, Zavala A, Romero H, Alvarez-Valín F, Bernardi G. 89.  2004. Correlations between genomic GC levels and optimal growth temperatures in prokaryotes. FEBS Lett. 573:73–77 [Google Scholar]
  91. Muto A, Osawa S. 90.  1987. The guanine and cytosine content of genomic DNA and bacterial evolution. PNAS 84:166–69 [Google Scholar]
  92. Nakamura Y, Gojobori T, Ikemura T. 91.  2000. Codon usage tabulated from international DNA sequence databases: status for the year 2000. Nucleic Acids Res. 28:292 [Google Scholar]
  93. Novoa EM, Ribas de Pouplana L. 92.  2012. Speeding with control: codon usage, tRNAs, and ribosomes. Trends Genet. 28:574–81 [Google Scholar]
  94. Oh E, Becker AH, Sandikci A, Huber D, Chaba R. 93.  et al. 2011. Selective ribosome profiling reveals the cotranslational chaperone action of trigger factor in vivo. Cell 147:1295–308 [Google Scholar]
  95. Park C, Zhou S, Gilmore J, Marqusee S. 94.  2007. Energetics-based protein profiling on a proteomic scale: identification of proteins resistant to proteolysis. J. Mol. Biol. 368:1426–37 [Google Scholar]
  96. Parmley JL, Huynen MA. 95.  2009. Clustering of codons with rare cognate tRNAs in human genes suggests an extra level of expression regulation. PLOS Genet. 5:e1000548 [Google Scholar]
  97. Pechmann S, Frydman J. 96.  2013. Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding. Nat. Struct. Mol. Biol. 20:237–43 [Google Scholar]
  98. Pedersen S. 97.  1984. Escherichia coli ribosomes translate in vivo with variable rate. EMBO J. 3:2895–98 [Google Scholar]
  99. Pfeifer GP. 98.  2006. Mutagenesis at methylated CpG sequences. Curr. Top. Microbiol. Immunol. 301:259–81 [Google Scholar]
  100. Purvis IJ, Bettany AJ, Santiago TC, Coggins JR, Duncan K. 99.  et al. 1987. The efficiency of folding of some proteins is increased by controlled rates of translation in vivo. A hypothesis. J. Mol. Biol. 193:413–17 [Google Scholar]
  101. Raghavan R, Kelkar YD, Ochman H. 100.  2012. A selective force favoring increased G+C content in bacterial genes. PNAS 109:14504–7 [Google Scholar]
  102. Rocha EPC, Danchin A. 101.  2002. Base composition bias might result from competition for metabolic resources. Trends Genet. 18:291–94 [Google Scholar]
  103. Rosenblum G, Chen C, Kaur J, Cui X, Zhang H. 102.  et al. 2013. Quantifying elongation rhythm during full-length protein synthesis. J. Am. Chem. Soc. 135:11322–29 [Google Scholar]
  104. Sander IM, Chaney JL, Clark PL. 103.  2014. Expanding Anfinsen's principle: contributions of synonymous codon selection to rational protein design. J. Am. Chem. Soc. 136:858–61 [Google Scholar]
  105. Sauna ZE, Kimchi-Sarfaty C. 104.  2011. Understanding the contribution of synonymous mutations to human disease. Nat. Rev. Genet. 12:683–91 [Google Scholar]
  106. Saunders R, Deane CM. 105.  2010. Synonymous codon usage influences the local protein structure observed. Nucleic Acids Res. 38:6719–28 [Google Scholar]
  107. Schauder B, McCarthy JEG. 106.  1989. The role of bases upstream of the Shine-Dalgarno region and in the coding sequence in the control of gene expression in Escherichia coli: translation and stability of messenger RNAs in vivo. Gene 78:59–72 [Google Scholar]
  108. Sharp PM, Li WH. 107.  1986. Codon usage in regulatory genes in Escherichia coli does not reflect selection for ‘rare’ codons. Nucleic Acids Res. 14:7737–49 [Google Scholar]
  109. Sharp PM, Li WH. 108.  1987. The codon adaptation index—a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res. 15:1281–95 [Google Scholar]
  110. Shpaer EG. 109.  1986. Constraints on codon context in Escherichia coli genes. Their possible role in modulating the efficiency of translation. J. Mol. Biol. 188:555–64 [Google Scholar]
  111. Siller E, DeZwaan DC, Anderson JF, Freeman BC, Barral JM. 110.  2010. Slowing bacterial translation speed enhances eukaryotic protein folding efficiency. J. Mol. Biol. 396:1310–18 [Google Scholar]
  112. Sinclair JF, Ziegler MM, Baldwin TO. 111.  1994. Kinetic partitioning during protein-folding yields multiple native states. Nat. Struct. Biol. 1:320–26 [Google Scholar]
  113. Smith NGC, Eyre-Walker A. 112.  2001. Why are translationally sub-optimal synonymous codons used in Escherichia coli?. J. Mol. Evol. 53:225–36 [Google Scholar]
  114. Sørensen MA, Kurland CG, Pedersen S. 113.  1989. Codon usage determines translation rate in Escherichia coli. J. Mol. Biol. 207:365–77 [Google Scholar]
  115. Sørensen MA, Pedersen S. 114.  1991. Absolute in vivo translation rates of individual codons in Escherichia coli. The two glutamic acid codons GAA and GAG are translated with a threefold difference in rate. J. Mol. Biol. 222:265–80 [Google Scholar]
  116. Spencer PS, Siller E, Anderson JF, Barral JM. 115.  2012. Silent substitutions predictably alter translation elongation rates and protein folding efficiencies. J. Mol. Biol. 422:328–35 [Google Scholar]
  117. Strauss BS. 116.  1998. Hypermutability and silent mutations in human carcinogenesis. Semin. Cancer Biol. 8:431–38 [Google Scholar]
  118. Subramaniam AR, DeLoughery A, Bradshaw N, Chen Y, O'Shea E. 117.  et al. 2013. A serine sensor for multicellularity in a bacterium. Elife 2:e01501 [Google Scholar]
  119. Sun L, Petrounia IP, Yagasaki M, Bandara G, Arnold FH. 118.  2001. Expression and stabilization of galactose oxidase in Escherichia coli by directed evolution. Protein Eng. 14:699–704 [Google Scholar]
  120. Supek F, Miñana B, Valcárcel J, Gabaldón T, Lehner B. 119.  2014. Synonymous mutations frequently act as driver mutations in human cancers. Cell 156:1324–35 [Google Scholar]
  121. Syvanen M. 120.  2012. Evolutionary implications of horizontal gene transfer. Annu. Rev. Genet. 46:341–58 [Google Scholar]
  122. Takyar S, Hickerson RP, Noller HF. 121.  2005. mRNA helicase activity of the ribosome. Cell 120:49–58 [Google Scholar]
  123. Talkad V, Schneider E, Kennell D. 122.  1976. Evidence for variable rates of ribosome movement in Escherichia coli. J. Mol. Biol. 104:299–303 [Google Scholar]
  124. Taylor RC, Webb Robertson B-J, Markillie LM, Serres MH, Linggi BE. 123.  et al. 2013. Changes in translational efficiency is a dominant regulatory mechanism in the environmental response of bacteria. Integr. Biol. 5:1393–406 [Google Scholar]
  125. Thanaraj TA, Argos P. 124.  1996. Protein secondary structural types are differentially coded on messenger RNA. Protein Sci. 5:1973–83 [Google Scholar]
  126. Thanaraj TA, Argos P. 125.  1996. Ribosome-mediated translational pause and protein domain organization. Protein Sci. 5:1594–612 [Google Scholar]
  127. Thomas JO, Kolb A, Szer W. 126.  1978. Structure of single-stranded nucleic acids in the presence of ribosomal protein S1. J. Mol. Biol. 123:163–76 [Google Scholar]
  128. Tindle RW. 127.  2002. Immune evasion in human papillomavirus-associated cervical cancer. Nat. Rev. Cancer 2:59–65 [Google Scholar]
  129. Tu C, Tzeng TH, Bruenn JA. 128.  1992. Ribosomal movement impeded at a pseudoknot required for frameshifting. PNAS 89:8636–40 [Google Scholar]
  130. Tuinstra RL, Peterson FC, Kutlesa S, Elgin ES, Kron MA, Volkman BF. 129.  2008. Interconversion between two unrelated protein folds in the lymphotactin native state. PNAS 105:5057–62 [Google Scholar]
  131. Tuller T, Carmi A, Vestsigian K, Navon S, Dorfan Y. 130.  et al. 2010. An evolutionarily conserved mechanism for controlling the efficiency of protein translation. Cell 141:344–54 [Google Scholar]
  132. Ude S, Lassak J, Starosta AL, Kraxenberger T, Wilson DN, Jung K. 131.  2013. Translation elongation factor EF-P alleviates ribosome stalling at polyproline stretches. Science 339:82–85 [Google Scholar]
  133. Walter P, Blobel G. 132.  1981. Translocation of proteins across the endoplasmic reticulum III. Signal recognition protein (SRP) causes signal sequence-dependent and site-specific arrest of chain elongation that is released by microsomal membranes. J. Cell Biol. 91:557–61 [Google Scholar]
  134. Wang HC, Susko E, Roger AJ. 133.  2006. On the correlation between genomic G+C content and optimal growth temperature in prokaryotes: data quality and confounding factors. Biochem. Biophys. Res. Commun. 342:681–84 [Google Scholar]
  135. Wickner W, Schekman R. 134.  2005. Protein translocation across biological membranes. Science 310:1452–56 [Google Scholar]
  136. Wiedmann M, Huth A, Rapoport TA. 135.  1986. A signal sequence is required for the functions of the signal recognition particle. Biochem. Biophys. Res. Commun. 134:790–96 [Google Scholar]
  137. Wohlgemuth I, Brenne S, Beringer M, Rodnina MV. 136.  2008. Modulation of the rate of peptidyl transfer on the ribosome by the nature of substrates. J. Biol. Chem. 283:32229–35 [Google Scholar]
  138. Woolhead CA, McCormick PJ, Johnson AE. 137.  2004. Nascent membrane and secretory proteins differ in FRET-detected folding far inside the ribosome and in their exposure to ribosomal proteins. Cell 116:725–36 [Google Scholar]
  139. Woolstenhulme CJ, Parajuli S, Healey DW, Valverde DP, Petersen EN. 138.  et al. 2013. Nascent peptides that block protein synthesis in bacteria. PNAS 110:E878–87 [Google Scholar]
  140. Xia K, Manning M, Hesham H, Lin Q, Bystroff C, Colón W. 139.  2007. Identifying the subproteome of kinetically stable proteins via diagonal 2D SDS/PAGE. PNAS 104:17329–34 [Google Scholar]
  141. Xie T, Ding D. 140.  1998. The relationship between synonymous codon usage and protein structure. FEBS Lett. 434:93–96 [Google Scholar]
  142. Xu Y, Ma PJ, Shah P, Rokas A, Liu Y, Johnson CH. 141.  2013. Non-optimal codon usage is a mechanism to achieve circadian clock conditionality. Nature 495:116–20 [Google Scholar]
  143. Yusupov MM, Yusupova GZ, Baucom A, Lieberman K, Earnest TN. 142.  et al. 2001. Crystal structure of the ribosome at 5.5 Å resolution. Science 292:883–96 [Google Scholar]
  144. Zalucki YM, Beacham IR, Jennings MP. 143.  2009. Biased codon usage in signal peptides: a role in protein export. Trends Microbiol. 17:146–50 [Google Scholar]
  145. Zhang FL, Saha S, Shabalina SA, Kashina A. 144.  2010. Differential arginylation of actin isoforms is regulated by coding sequence-dependent degradation. Science 329:1534–37 [Google Scholar]
  146. Zhang G, Hubalewska M, Ignatova Z. 145.  2009. Transient ribosomal attenuation coordinates protein synthesis and co-translational folding. Nat. Struct. Mol. Biol. 16:274–80 [Google Scholar]
  147. Zhang G, Ignatova Z. 146.  2009. Generic algorithm to predict the speed of translational elongation: implications for protein biogenesis. PLOS ONE 4:e5036 [Google Scholar]
  148. Zhang W, Xiao W, Wei H, Zhang J, Tian Z. 147.  2006. mRNA secondary structure at start AUG codon is a key limiting factor for human protein expression in Escherichia coli. Biochem. Biophys. Res. Commun. 349:69–78 [Google Scholar]
  149. Zhao Z, Jiang C. 148.  2010. Features of recent codon evolution: a comparative polymorphism-fixation study. J. Biomed. Biotechnol. 2010:202918 [Google Scholar]
  150. Zhou M, Guo JH, Cha J, Chae M, Chen S. 149.  et al. 2013. Non-optimal codon usage affects expression, structure and function of clock protein FRQ. Nature 495:111–15 [Google Scholar]
  151. Zhou T, Weems M, Wilke CO. 150.  2009. Translationally optimal codons associate with structurally sensitive sites in proteins. Mol. Biol. Evol. 26:1571–80 [Google Scholar]

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