Synonymous but not the same: the causes and consequences of codon bias (original) (raw)

• Zuckerkandl, E. & Pauling, L. Molecules as documents of evolutionary history. J. Theor. Biol. 8, 357–366 (1965).
  CAS PubMed Google Scholar
• Gustafsson, C., Govindarajan, S. & Minshull, J. Codon bias and heterologous protein expression. Trends Biotechnol. 22, 346–353 (2004).
  CAS PubMed Google Scholar
• Hershberg, R. & Petrov, D. A. Selection on codon bias. Annu. Rev. Genet. 42, 287–299 (2008).
  CAS PubMed Google Scholar
• 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). An excellent Review of the many surprisingly strong effects of synonymous mutations on splicing.
  CAS PubMed Google Scholar
• Duret, L. Evolution of synonymous codon usage in metazoans. Curr. Opin. Genet. Dev. 12, 640–649 (2002).
  CAS PubMed Google Scholar
• Sharp, P. M., Averof, M., Lloyd, A. T., Matassi, G. & Peden, J. F. DNA sequence evolution: the sounds of silence. Philos. Trans. R. Soc. Lond. B 349, 241–247 (1995).
  CAS Google Scholar
• Andersson, S. G. & Kurland, C. G. Codon preferences in free-living microorganisms. Microbiol. Rev. 54, 198–210 (1990). A classic, must-read paper that has framed the field of codon-usage adaptation.
  CAS PubMed PubMed Central Google Scholar
• Kimura, M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J. Mol. Evol. 16, 111–120 (1980).
  CAS PubMed Google Scholar
• Bulmer, M. The selection–mutation–drift theory of synonymous codon usage. Genetics 129, 897–907 (1991). A foundational study of both the population genetics that underlie codon bias and the biophysics of translation. This paper emphasizes that, for endogenous genes, elongation speed will not generally influence protein yield per mRNA.
  CAS PubMed PubMed Central Google Scholar
• Chen, S. L., Lee, W., Hottes, A. K., Shapiro, L. & McAdams, H. H. Codon usage between genomes is constrained by genome-wide mutational processes. Proc. Natl Acad. Sci. USA 101, 3480–3485 (2004).
  CAS PubMed PubMed Central Google Scholar
• Hurst, L. D. & Merchant, A. R. High guanine–cytosine content is not an adaptation to high temperature: a comparative analysis amongst prokaryotes. Proc. R. Soc. Lond. B 268, 493–497 (2001).
  CAS Google Scholar
• Fedorov, A., Saxonov, S. & Gilbert, W. Regularities of context-dependent codon bias in eukaryotic genes. Nucleic Acids Res. 30, 1192–1197 (2002).
  CAS PubMed PubMed Central Google Scholar
• Hildebrand, F., Meyer, A. & Eyre-Walker, A. Evidence of selection upon genomic GC-content in bacteria. PLoS Genet. 6, e1001107 (2010).
  PubMed PubMed Central Google Scholar
• Morton, B. R. Selection at the amino acid level can influence synonymous codon usage: implications for the study of codon adaptation in plastid genes. Genetics 159, 347–358 (2001).
  CAS PubMed PubMed Central Google Scholar
• Cambray, G. & Mazel, D. Synonymous genes explore different evolutionary landscapes. PLoS Genet. 4, e1000256 (2008).
  PubMed PubMed Central Google Scholar
• Plotkin, J. B. & Dushoff, J. Codon bias and frequency-dependent selection on the hemagglutinin epitopes of influenza A virus. Proc. Natl Acad. Sci. USA 100, 7152–7157 (2003).
  CAS PubMed PubMed Central Google Scholar
• Sharp, P. M. & Li, W. H. The rate of synonymous substitution in enterobacterial genes is inversely related to codon usage bias. Mol. Biol. Evol. 4, 222–230 (1987).
  CAS PubMed Google Scholar
• Eyre-Walker, A. & Bulmer, M. Synonymous substitution rates in enterobacteria. Genetics 140, 1407–1412 (1995).
  CAS PubMed PubMed Central Google Scholar
• Francino, M. P. & Ochman, H. Deamination as the basis of strand-asymmetric evolution in transcribed Escherichia coli sequences. Mol. Biol. Evol. 18, 1147–1150 (2001).
  CAS PubMed Google Scholar
• Majewski, J. Dependence of mutational asymmetry on gene-expression levels in the human genome. Am. J. Hum. Genet. 73, 688–692 (2003).
  CAS PubMed PubMed Central Google Scholar
• Duret, L. & Mouchiroud, D. Expression pattern and, surprisingly, gene length shape codon usage in Caenorhabditis, Drosophila, and Arabidopsis. Proc. Natl Acad. Sci. USA 96, 4482–4487 (1999).
  CAS PubMed PubMed Central Google Scholar
• Akashi, H. Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy. Genetics 136, 927–935 (1994). By quantifying the rates of synonymous substitutions at conserved and non-conserved positions in proteins, Akashi shows that such mutations influence translational accuracy in D. melanogaster.
  CAS PubMed PubMed Central Google Scholar
• Akashi, H. & Schaeffer, S. W. Natural selection and the frequency distributions of “silent” DNA polymorphism in Drosophila. Genetics 146, 295–307 (1997).
  CAS PubMed PubMed Central Google Scholar
• Eyre-Walker, A. Synonymous codon bias is related to gene length in Escherichia coli: selection for translational accuracy? Mol. Biol. Evol. 13, 864–872 (1996).
  CAS PubMed Google Scholar
• Stoletzki, N. & Eyre-Walker, A. Synonymous codon usage in Escherichia coli: selection for translational accuracy. Mol. Biol. Evol. 24, 374–381 (2007).
  CAS PubMed Google Scholar
• Drummond, D. A. & Wilke, C. O. Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution. Cell 134, 341–352 (2008).
  CAS PubMed PubMed Central Google Scholar
• Zhou, T., Weems, M. & Wilke, C. O. Translationally optimal codons associate with structurally sensitive sites in proteins. Mol. Biol. Evol. 26, 1571–1580 (2009).
  CAS PubMed PubMed Central Google Scholar
• Ikemura, T. Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes: a proposal for a synonymous codon choice that is optimal for the E. coli translational system. J. Mol. Biol. 151, 389–409 (1981).
  CAS PubMed Google Scholar
• Ikemura, T. Correlation between the abundance of yeast transfer RNAs and the occurrence of the respective codons in protein genes. Differences in synonymous codon choice patterns of yeast and Escherichia coli with reference to the abundance of isoaccepting transfer RNAs. J. Mol. Biol. 158, 573–597 (1982).
  CAS PubMed Google Scholar
• Post, L. E. & Nomura, M. Nucleotide sequence of the intercistronic region preceding the gene for RNA polymerase subunit α in Escherichia coli. J. Biol. Chem. 254, 10604–10606 (1979).
  CAS PubMed Google Scholar
• Moriyama, E. N. & Powell, J. R. Codon usage bias and tRNA abundance in Drosophila. J. Mol. Evol. 45, 514–523 (1997).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Kanaya, S., Yamada, Y., Kinouchi, M., Kudo, Y. & Ikemura, T. Codon usage and tRNA genes in eukaryotes: correlation of codon usage diversity with translation efficiency and with CG-dinucleotide usage as assessed by multivariate analysis. J. Mol. Evol. 53, 290–298 (2001).
  CAS PubMed Google Scholar
• Sharp, P. M., Bailes, E., Grocock, R. J., Peden, J. F. & Sockett, R. E. Variation in the strength of selected codon usage bias among bacteria. Nucleic Acids Res. 33, 1141–1153 (2005).
  CAS PubMed PubMed Central Google Scholar
• Sharp, P. M. & Li, W. H. The codon Adaptation Index — a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res. 15, 1281–1295 (1987).
  CAS PubMed PubMed Central Google Scholar
• Lavner, Y. & Kotlar, D. Codon bias as a factor in regulating expression via translation rate in the human genome. Gene 345, 127–138 (2005).
  CAS PubMed Google Scholar
• Tuller, T., Waldman, Y. Y., Kupiec, M. & Ruppin, E. Translation efficiency is determined by both codon bias and folding energy. Proc. Natl Acad. Sci. USA 107, 3645–3650 (2010).
  CAS PubMed PubMed Central Google Scholar
• Bergmann, J. E. & Lodish, H. F. A kinetic model of protein synthesis. Application to hemoglobin synthesis and translational control. J. Biol. Chem. 254, 11927–11937 (1979).
  CAS PubMed Google Scholar
• Mathews, M. B., Sonenberg, N. & Hershey, J. W. B. (eds) Translational Control in Biology and Medicine (CHSL Press, New York, 2007).
  Google Scholar
• Ozbudak, E. M., Thattai, M., Kurtser, I., Grossman, A. D. & van Oudenaarden, A. Regulation of noise in the expression of a single gene. Nature Genet. 31, 69–73 (2002).
  CAS PubMed Google Scholar
• Fraser, H. B., Hirsh, A. E., Giaever, G., Kumm, J. & Eisen, M. B. Noise minimization in eukaryotic gene expression. PLoS Biol. 2, e137 (2004).
  PubMed PubMed Central Google Scholar
• Lawrence, J. G. & Ochman, H. Molecular archaeology of the Escherichia coli genome. Proc. Natl Acad. Sci. USA 95, 9413–9417 (1998).
  CAS PubMed PubMed Central Google Scholar
• Karlin, S., Campbell, A. M. & Mrazek, J. Comparative DNA analysis across diverse genomes. Annu. Rev. Genet. 32, 185–225 (1998).
  CAS PubMed Google Scholar
• Zhang, F., Saha, S., Shabalina, S. A. & Kashina, A. Differential arginylation of actin isoforms is regulated by coding sequence-dependent degradation. Science 329, 1534–1537 (2010).
  CAS PubMed PubMed Central Google Scholar
• Thanaraj, T. A. & Argos, P. Ribosome-mediated translational pause and protein domain organization. Protein Sci. 5, 1594–1612 (1996).
  CAS PubMed PubMed Central Google Scholar
• Watts, J. M. et al. Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460, 711–716 (2009).
  CAS PubMed PubMed Central Google Scholar
• Warnecke, T., Batada, N. N. & Hurst, L. D. The impact of the nucleosome code on protein-coding sequence evolution in yeast. PLoS Genet. 4, e1000250 (2008).
  PubMed PubMed Central Google Scholar
• Eskesen, S. T., Eskesen, F. N. & Ruvinsky, A. Natural selection affects frequencies of AG and GT dinucleotides at the 5′ and 3′ ends of exons. Genetics 167, 543–550 (2004).
  CAS PubMed PubMed Central Google Scholar
• Chamary, J. V. & Hurst, L. D. Biased codon usage near intron-exon junctions: selection on splicing enhancers, splice-site recognition or something else? Trends Genet. 21, 256–259 (2005).
  CAS PubMed Google Scholar
• Orban, T. I. & Olah, E. Purifying selection on silent sites — a constraint from splicing regulation? Trends Genet. 17, 252–253 (2001).
  CAS PubMed Google Scholar
• Warnecke, T. & Hurst, L. D. Evidence for a trade-off between translational efficiency and splicing regulation in determining synonymous codon usage in Drosophila melanogaster. Mol. Biol. Evol. 24, 2755–2762 (2007).
  CAS PubMed Google Scholar
• Bettany, A. J. et al. 5′-secondary structure formation, in contrast to a short string of non-preferred codons, inhibits the translation of the pyruvate kinase mRNA in yeast. Yeast 5, 187–198 (1989).
  CAS PubMed Google Scholar
• de Smit, M. H. & van Duin, J. Secondary structure of the ribosome binding site determines translational efficiency: a quantitative analysis. Proc. Natl Acad. Sci. USA 87, 7668–7672 (1990). A thorough study, supported by a convincing theoretical model, of how mRNA folding affects translation initiation.
  CAS PubMed PubMed Central Google Scholar
• Eyre-Walker, A. & Bulmer, M. Reduced synonymous substitution rate at the start of enterobacterial genes. Nucleic Acids Res. 21, 4599–4603 (1993).
  CAS PubMed PubMed Central Google Scholar
• Kudla, G., Murray, A. W., Tollervey, D. & Plotkin, J. B. Coding-sequence determinants of gene expression in Escherichia coli. Science 324, 255–258 (2009). Uses libraries of synthetic genes to isolate the effects of synonymous mutations on expression. See also references 81 and 97.
  CAS PubMed PubMed Central Google Scholar
• Gu, W., 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).
  PubMed PubMed Central Google Scholar
• Tuller, T. et al. An evolutionarily conserved mechanism for controlling the efficiency of protein translation. Cell 141, 344–354 (2010). Shows that rare codons at the beginning of genes could help prevent 'ribosomal traffic jams'. See references 9, 58 and 59 for an alternative interpretation.
  CAS PubMed Google Scholar
• Bulmer, M. Codon usage and intragenic position. J. Theor. Biol. 133, 67–71 (1988).
  CAS PubMed Google Scholar
• Qin, H., Wu, W. B., Comeron, J. M., Kreitman, M. & Li, W. H. Intragenic spatial patterns of codon usage bias in prokaryotic and eukaryotic genomes. Genetics 168, 2245–2260 (2004).
  CAS PubMed PubMed Central Google Scholar
• Zhang, S., Goldman, E. & Zubay, G. Clustering of low usage codons and ribosome movement. J. Theor. Biol. 170, 339–354 (1994).
  CAS PubMed Google Scholar
• Fredrick, K. & Ibba, M. How the sequence of a gene can tune its translation. Cell 141, 227–229 (2010).
  CAS PubMed PubMed Central Google Scholar
• Cannarozzi, G. et al. A role for codon order in translation dynamics. Cell 141, 355–367 (2010).
  PubMed Google Scholar
• Zouridis, H. & Hatzimanikatis, V. Effects of codon distributions and tRNA competition on protein translation. Biophys. J. 95, 1018–1033 (2008).
  CAS PubMed PubMed Central Google Scholar
• Huh, W. K. et al. Global analysis of protein localization in budding yeast. Nature 425, 686–691 (2003).
  CAS PubMed Google Scholar
• Lu, P., Vogel, C., Wang, R., Yao, X. & Marcotte, E. M. Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nature Biotech. 25, 117–124 (2007).
  CAS Google Scholar
• 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). References 65 and 66 describe a quantitative proteomics approach that promises new insights into the coding-sequence determinants of protein levels.
  PubMed PubMed Central Google Scholar
• Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009). A clever method for mapping the positions of ribosomes on messages with unprecedented accuracy; an essential tool for the study of translation kinetics.
  CAS PubMed PubMed Central Google Scholar
• Uemura, S. et al. Real-time tRNA transit on single translating ribosomes at codon resolution. Nature 464, 1012–1017 (2010).
  CAS PubMed PubMed Central Google Scholar
• Futcher, B., Latter, G. I., Monardo, P., McLaughlin, C. S. & Garrels, J. I. A sampling of the yeast proteome. Mol. Cell. Biol. 19, 7357–7368 (1999).
  CAS PubMed PubMed Central Google Scholar
• Schrimpf, S. P. et al. Comparative functional analysis of the Caenorhabditis elegans and Drosophila melanogaster proteomes. PLoS Biol. 7, e48 (2009).
  PubMed Google Scholar
• Taniguchi, Y. et al. Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science 329, 533–538.
  CAS PubMed PubMed Central Google Scholar
• Feng, L. & Niu, D. K. Relationship between mRNA stability and length: an old question with a new twist. Biochem. Genet. 45, 131–137 (2007).
  CAS PubMed Google Scholar
• Arava, Y., Boas, F. E., Brown, P. O. & Herschlag, D. Dissecting eukaryotic translation and its control by ribosome density mapping. Nucleic Acids Res. 33, 2421–2432 (2005).
  CAS PubMed PubMed Central Google Scholar
• Welch, M., Villalobos, A., Gustafsson, C. & Minshull, J. You're one in a googol: optimizing genes for protein expression. J. R. Soc. Interface 6 (Suppl. 4), S467–S476 (2009).
  CAS PubMed PubMed Central Google Scholar
• Gouy, M. & Gautier, C. Codon usage in bacteria: correlation with gene expressivity. Nucleic Acids Res. 10, 7055–7074 (1982).
  CAS PubMed PubMed Central Google Scholar
• Kertesz, M. et al. Genome-wide measurement of RNA secondary structure in yeast. Nature 467, 103–107 (2010).
  CAS PubMed Google Scholar
• Takyar, S., Hickerson, R. P. & Noller, H. F. mRNA helicase activity of the ribosome. Cell 120, 49–58 (2005).
  CAS PubMed Google Scholar
• Dittmar, K. A., Sorensen, M. A., Elf, J., Ehrenberg, M. & Pan, T. Selective charging of tRNA isoacceptors induced by amino-acid starvation. EMBO Rep. 6, 151–157 (2005).
  CAS PubMed PubMed Central Google Scholar
• Elf, J., Nilsson, D., Tenson, T. & Ehrenberg, M. Selective charging of tRNA isoacceptors explains patterns of codon usage. Science 300, 1718–1722 (2003). A detailed theoretical model of what happens to tRNA in cells under starvation conditions.
  CAS PubMed Google Scholar
• Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).
  CAS PubMed Google Scholar
• Welch, M. et al. Design parameters to control synthetic gene expression in Escherichia coli. PLoS ONE 4, e7002 (2009).
  PubMed PubMed Central Google Scholar
• Kudla, G., Lipinski, L., Caffin, F., Helwak, A. & Zylicz, M. High guanine and cytosine content increases mRNA levels in mammalian cells. PLoS Biol. 4, e180 (2006).
  PubMed PubMed Central Google Scholar
• Han, J. S., Szak, S. T. & Boeke, J. D. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature 429, 268–274 (2004).
  CAS PubMed Google Scholar
• Nackley, A. G. et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314, 1930–1933 (2006).
  CAS PubMed Google Scholar
• Coleman, J. R. et al. Virus attenuation by genome-scale changes in codon pair bias. Science 320, 1784–1787 (2008).
  CAS PubMed PubMed Central Google Scholar
• Hayes, C. S., Bose, B. & Sauer, R. T. Stop codons preceded by rare arginine codons are efficient determinants of SsrA tagging in Escherichia coli. Proc. Natl Acad. Sci. USA 99, 3440–3445 (2002).
  CAS PubMed PubMed Central Google Scholar
• Spanjaard, R. A. & van Duin, J. Translation of the sequence AGG-AGG yields 50% ribosomal frameshift. Proc. Natl Acad. Sci. USA 85, 7967–7971 (1988).
  CAS PubMed PubMed Central Google Scholar
• Kramer, E. B. & Farabaugh, P. J. The frequency of translational misreading errors in E. coli is largely determined by tRNA competition. RNA 13, 87–96 (2007).
  CAS PubMed PubMed Central Google Scholar
• Sorensen, M. A., Kurland, C. G. & Pedersen, S. Codon usage determines translation rate in Escherichia coli. J. Mol. Biol. 207, 365–377 (1989).
  CAS PubMed Google Scholar
• Chen, G. F. & Inouye, M. Suppression of the negative effect of minor arginine codons on gene expression; preferential usage of minor codons within the first 25 codons of the Escherichia coli genes. Nucleic Acids Res. 18, 1465–1473 (1990).
  CAS PubMed PubMed Central Google Scholar
• Angov, E., Hillier, C. J., Kincaid, R. L. & Lyon, J. A. 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 (2008).
  PubMed PubMed Central Google Scholar
• Rosenberg, A. H., Goldman, E., Dunn, J. J., Studier, F. W. & Zubay, G. Effects of consecutive AGG codons on translation in Escherichia coli, demonstrated with a versatile codon test system. J. Bacteriol. 175, 716–722 (1993).
  CAS PubMed PubMed Central Google Scholar
• Gursky, Y. G. & Beabealashvilli, R. The increase in gene expression induced by introduction of rare codons into the C terminus of the template. Gene 148, 15–21 (1994).
  CAS PubMed Google Scholar
• Burgess-Brown, N. A. et al. Codon optimization can improve expression of human genes in Escherichia coli: a multi-gene study. Protein Expr. Purif. 59, 94–102 (2008).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Supek, F. & Smuc, T. On relevance of codon usage to expression of synthetic and natural genes in Escherichia coli. Genetics 185, 1129–1134 (2010).
  CAS PubMed PubMed Central Google Scholar
• Voges, D., Watzele, M., Nemetz, C., Wizemann, S. & Buchberger, B. Analyzing and enhancing mRNA translational efficiency in an Escherichia coli in vitro expression system. Biochem. Biophys. Res. Commun. 318, 601–614 (2004).
  CAS PubMed Google Scholar
• El Hage, A., French, S. L., Beyer, A. L. & Tollervey, D. Loss of topoisomerase I leads to R-loop-mediated transcriptional blocks during ribosomal RNA synthesis. Genes Dev. 24, 1546–1558 (2010).
  CAS PubMed PubMed Central Google Scholar
• McDowall, K. J., Lin-Chao, S. & Cohen, S. N. A+U content rather than a particular nucleotide order determines the specificity of RNase E cleavage. J. Biol. Chem. 269, 10790–10796 (1994).
  CAS PubMed Google Scholar
• Nguyen, K. L. et al. Codon optimization of the HIV-1 vpu and vif genes stabilizes their mRNA and allows for highly efficient Rev-independent expression. Virology 319, 163–175 (2004).
  CAS PubMed Google Scholar
• Sokolowski, M., Tan, W., Jellne, M. & Schwartz, S. mRNA instability elements in the human papillomavirus type 16 L2 coding region. J. Virol. 72, 1504–1515 (1998).
  CAS PubMed PubMed Central Google Scholar
• Bauer, A. P. et al. The impact of intragenic CpG content on gene expression. Nucleic Acids Res. 38, 3891–3908 (2010).
  CAS PubMed PubMed Central Google Scholar
• Gutman, G. A. & Hatfield, G. W. Nonrandom utilization of codon pairs in Escherichia coli. Proc. Natl Acad. Sci. USA 86, 3699–3703 (1989).
  CAS PubMed PubMed Central Google Scholar
• Irwin, B., Heck, J. D. & Hatfield, G. W. Codon pair utilization biases influence translational elongation step times. J. Biol. Chem. 270, 22801–22806 (1995).
  CAS PubMed Google Scholar
• Cheng, L. & Goldman, E. Absence of effect of varying Thr-Leu codon pairs on protein synthesis in a T7 system. Biochemistry 40, 6102–6106 (2001).
  CAS PubMed Google Scholar
• Wang, D., Johnson, A. D., Papp, A. C., Kroetz, D. L. & Sadee, W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet. Genomics 15, 3693–3704 (2005).
  Google Scholar
• Kimchi-Sarfaty, C. et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525–528 (2007).
  CAS PubMed Google Scholar
• Foster, H. et al. Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol. Ther. 16, 1825–1832 (2008).
  CAS PubMed Google Scholar
• Arruda, V. R. et al. Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood 115, 4678–4688.
  CAS PubMed PubMed Central Google Scholar
• Fuglsang, A. The relationship between palindrome avoidance and intragenic codon usage variations: a Monte Carlo study. Biochem. Biophys. Res. Commun. 316, 755–762 (2004).
  CAS PubMed Google Scholar
• Drummond, D. A. & Wilke, C. O. The evolutionary consequences of erroneous protein synthesis. Nature Rev. Genet. 10, 715–724 (2009). A readable Review that summarizes the various types of errors that occur in protein synthesis, many of which are directly related to codon usage.
  PubMed Google Scholar
• Akashi, H., Kliman, R. M. & Eyre-Walker, A. Mutation pressure, natural selection, and the evolution of base composition in Drosophila. Genetica 102–103, 49–60 (1998).
  PubMed Google Scholar
• Marais, G. & Duret, L. Synonymous codon usage, accuracy of translation, and gene length in Caenorhabditis elegans. J. Mol. Evol. 52, 275–280 (2001).
  CAS PubMed Google Scholar
• Higgs, P. G. & Ran, W. Coevolution of codon usage and tRNA genes leads to alternative stable states of biased codon usage. Mol. Biol. Evol. 25, 2279–2291 (2008).
  CAS PubMed Google Scholar
• Shah, P. & Gilchrist, M. Effect of correlated tRNA abundances on translation errors and evolution of codon usage bias. PLoS Genet. 6, e1001128 (2010).
  PubMed PubMed Central Google Scholar
• Bernardi, G. et al. The mosaic genome of warm-blooded vertebrates. Science 228, 953–958 (1985).
  CAS PubMed Google Scholar
• Galtier, N., Piganeau, G., Mouchiroud, D. & Duret, L. GC-content evolution in mammalian genomes: the biased gene conversion hypothesis. Genetics 159, 907–911 (2001).
  CAS PubMed PubMed Central Google Scholar
• Urrutia, A. O. & Hurst, L. D. The signature of selection mediated by expression on human genes. Genome Res. 13, 2260–2264 (2003).
  CAS PubMed PubMed Central Google Scholar
• Comeron, J. M. Selective and mutational patterns associated with gene expression in humans: influences on synonymous composition and intron presence. Genetics 167, 1293–1304 (2004).
  CAS PubMed PubMed Central Google Scholar
• Karlin, S. & Mrazek, J. What drives codon choices in human genes? J. Mol. Biol. 262, 459–472 (1996).
  CAS PubMed Google Scholar
• Plotkin, J. B., Robins, H. & Levine, A. J. Tissue-specific codon usage and the expression of human genes. Proc. Natl Acad. Sci. USA 101, 12588–12591 (2004).
  CAS PubMed PubMed Central Google Scholar
• Dittmar, K. A., Goodenbour, J. M. & Pan, T. Tissue-specific differences in human transfer RNA expression. PLoS Genet. 2, e221 (2006).
  PubMed PubMed Central Google Scholar
• Semon, M., Lobry, J. R. & Duret, L. No evidence for tissue-specific adaptation of synonymous codon usage in human. Mol. Biol. Evol. 23, 523–529 (2005).
  PubMed Google Scholar
• Chamary, J. V. & Hurst, L. D. Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals. Genome Biol. 6, R75 (2005).
  CAS PubMed PubMed Central Google Scholar
• Seffens, W. & Digby, D. mRNAs have greater negative folding free energies than shuffled or codon choice randomized sequences. Nucleic Acids Res. 27, 1578–1584 (1999).
  CAS PubMed PubMed Central Google Scholar
• Duan, J. 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• dos Reis, M., Savva, R. & Wernisch, L. Solving the riddle of codon usage preferences: a test for translational selection. Nucleic Acids Res. 32, 5036–5044 (2004).
  CAS PubMed Google Scholar
• Nivinskas, R., Malys, N., Klausa, V., Vaiskunaite, R. & Gineikiene, E. Post-transcriptional control of bacteriophage T4 gene 25 expression: mRNA secondary structure that enhances translational initiation. J. Mol. Biol. 288, 291–304 (1999).
  CAS PubMed Google Scholar
• Kozak, M. Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. Proc. Natl Acad. Sci. USA 87, 8301–8305 (1990).
  CAS PubMed PubMed Central Google Scholar
• Paulus, M., Haslbeck, M. & Watzele, M. RNA stem-loop enhanced expression of previously non-expressible genes. Nucleic Acids Res. 32, e78 (2004).
  PubMed PubMed Central Google Scholar
• Zhang, G., Hubalewska, M. & Ignatova, Z. Transient ribosomal attenuation coordinates protein synthesis and co-translational folding. Nature Struct. Mol. Biol. 16, 274–280 (2009).
  CAS Google Scholar
• Nakamura, Y., Gojobori, T. & Ikemura, T. Codon usage tabulated from international DNA sequence databases: status for the year 2000. Nucleic Acids Res. 28, 292 (2000).
  CAS PubMed PubMed Central Google Scholar
• Zolotukhin, S., Potter, M., Hauswirth, W. W., Guy, J. & Muzyczka, N. A “humanized” green fluorescent protein cDNA adapted for high-level expression in mammalian cells. J. Virol. 70, 4646–4654 (1996).
  CAS PubMed PubMed Central Google Scholar
• Markham, N. R. & Zuker, M. DINAMelt web server for nucleic acid melting prediction. Nucleic Acids Res. 33, W577–W581 (2005).
  CAS PubMed PubMed Central Google Scholar
• Lesnik, E. A. et al. Prediction of rho-independent transcriptional terminators in Escherichia coli. Nucleic Acids Res. 29, 3583–3594 (2001).
  CAS PubMed PubMed Central Google Scholar
• Bernstein, J. A., Khodursky, A. B., Lin, P. H., Lin-Chao, S. & Cohen, S. N. Global analysis of mRNA decay and abundance in Escherichia coli at single-gene resolution using two-color fluorescent DNA microarrays. Proc. Natl Acad. Sci. USA 99, 9697–9702 (2002).
  CAS PubMed PubMed Central Google Scholar
• Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).
  CAS PubMed Google Scholar
• Jacobs, G. H. et al. Transterm: a database to aid the analysis of regulatory sequences in mRNAs. Nucleic Acids Res. 37, D72–D76 (2009).
  CAS PubMed Google Scholar
• Peden, J. F. Analysis of Codon Usage. Thesis, Dept of Genetics, Univ. Nottingham (1999).
  Google Scholar
• Supek, F. & Vlahovicek, K. INCA: synonymous codon usage analysis and clustering by means of self-organizing map. Bioinformatics 20, 2329–2330 (2004).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Burge, C., Campbell, A. M. & Karlin, S. Over- and under-representation of short oligonucleotides in DNA sequences. Proc. Natl Acad. Sci. USA 89, 1358–1362 (1992).
  CAS PubMed PubMed Central Google Scholar
• Villalobos, A., Ness, J. E., Gustafsson, C., Minshull, J. & Govindarajan, S. Gene Designer: a synthetic biology tool for constructing artificial DNA segments. BMC Bioinformatics 7, 285 (2006).
  PubMed PubMed Central Google Scholar