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. 2001 Oct;159(2):623–633. doi: 10.1093/genetics/159.2.623

The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcohol dehydrogenase genes Adh and Adhr.

D B Carlini 1, Y Chen 1, W Stephan 1
PMCID: PMC1461829  PMID: 11606539

Abstract

To gain insights into the relationship between codon bias, mRNA secondary structure, third-codon position nucleotide distribution, and gene expression, we predicted secondary structures in two related drosophilid genes, Adh and Adhr, which differ in degree of codon bias and level of gene expression. Individual structural elements (helices) were inferred using the comparative method. For each gene, four types of randomization simulations were performed to maintain/remove codon bias and/or to maintain or alter third-codon position nucleotide composition (N3). In the weakly expressed, weakly biased gene Adhr, the potential for secondary structure formation was found to be much stronger than in the highly expressed, highly biased gene Adh. This is consistent with the observation of approximately equal G and C percentages in Adhr ( approximately 31% across species), whereas in Adh the N3 distribution is shifted toward C (42% across species). Perturbing the N3 distribution to approximately equal amounts of A, G, C, and T increases the potential for secondary structure formation in Adh, but decreases it in Adhr. On the other hand, simulations that reduce codon bias without changing N3 content indicate that codon bias per se has only a weak effect on the formation of secondary structures. These results suggest that, for these two drosophilid genes, secondary structure is a relatively independent, negative regulator of gene expression. Whereas the degree of codon bias is positively correlated with level of gene expression, strong individual secondary structural elements may be selected for to retard mRNA translation and to decrease gene expression.

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Selected References

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  1. Akashi H. Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy. Genetics. 1994 Mar;136(3):927–935. doi: 10.1093/genetics/136.3.927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Antezana M. A., Kreitman M. The nonrandom location of synonymous codons suggests that reading frame-independent forces have patterned codon preferences. J Mol Evol. 1999 Jul;49(1):36–43. doi: 10.1007/pl00006532. [DOI] [PubMed] [Google Scholar]
  3. Bulmer M. The selection-mutation-drift theory of synonymous codon usage. Genetics. 1991 Nov;129(3):897–907. doi: 10.1093/genetics/129.3.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dock A. C., Lorber B., Moras D., Pixa G., Thierry J. C., Giégé R. Crystallization of transfer ribonucleic acids. Biochimie. 1984 Mar;66(3):179–201. doi: 10.1016/0300-9084(84)90063-4. [DOI] [PubMed] [Google Scholar]
  5. Ellis R. J., Hartl F. U. Principles of protein folding in the cellular environment. Curr Opin Struct Biol. 1999 Feb;9(1):102–110. doi: 10.1016/s0959-440x(99)80013-x. [DOI] [PubMed] [Google Scholar]
  6. Fitch W. M. The large extent of putative secondary nucleic acid structure in random nucleotide sequences or amino acid derived messenger-RNA. J Mol Evol. 1974;3(4):279–291. doi: 10.1007/BF01796043. [DOI] [PubMed] [Google Scholar]
  7. Fox G. E., Woese C. R. 5S RNA secondary structure. Nature. 1975 Aug 7;256(5517):505–507. doi: 10.1038/256505a0. [DOI] [PubMed] [Google Scholar]
  8. Ikemura T. Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes. J Mol Biol. 1981 Feb 15;146(1):1–21. doi: 10.1016/0022-2836(81)90363-6. [DOI] [PubMed] [Google Scholar]
  9. Kirby D. A., Muse S. V., Stephan W. Maintenance of pre-mRNA secondary structure by epistatic selection. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9047–9051. doi: 10.1073/pnas.92.20.9047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Knudsen B., Hein J. RNA secondary structure prediction using stochastic context-free grammars and evolutionary history. Bioinformatics. 1999 Jun;15(6):446–454. doi: 10.1093/bioinformatics/15.6.446. [DOI] [PubMed] [Google Scholar]
  11. Konecny J., Schöniger M., Hofacker I., Weitze M. D., Hofacker G. L. Concurrent neutral evolution of mRNA secondary structures and encoded proteins. J Mol Evol. 2000 Mar;50(3):238–242. doi: 10.1007/s002399910027. [DOI] [PubMed] [Google Scholar]
  12. Konings D. A., Gutell R. R. A comparison of thermodynamic foldings with comparatively derived structures of 16S and 16S-like rRNAs. RNA. 1995 Aug;1(6):559–574. [PMC free article] [PubMed] [Google Scholar]
  13. Mita K., Ichimura S., Zama M., James T. C. Specific codon usage pattern and its implications on the secondary structure of silk fibroin mRNA. J Mol Biol. 1988 Oct 20;203(4):917–925. doi: 10.1016/0022-2836(88)90117-9. [DOI] [PubMed] [Google Scholar]
  14. Moriyama E. N., Hartl D. L. Codon usage bias and base composition of nuclear genes in Drosophila. Genetics. 1993 Jul;134(3):847–858. doi: 10.1093/genetics/134.3.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Muse S. V. Evolutionary analyses of DNA sequences subject to constraints of secondary structure. Genetics. 1995 Mar;139(3):1429–1439. doi: 10.1093/genetics/139.3.1429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Netzer W. J., Hartl F. U. Recombination of protein domains facilitated by co-translational folding in eukaryotes. Nature. 1997 Jul 24;388(6640):343–349. doi: 10.1038/41024. [DOI] [PubMed] [Google Scholar]
  17. Noller H. F., Woese C. R. Secondary structure of 16S ribosomal RNA. Science. 1981 Apr 24;212(4493):403–411. doi: 10.1126/science.6163215. [DOI] [PubMed] [Google Scholar]
  18. Pace N. R., Smith D. K., Olsen G. J., James B. D. Phylogenetic comparative analysis and the secondary structure of ribonuclease P RNA--a review. Gene. 1989 Oct 15;82(1):65–75. doi: 10.1016/0378-1119(89)90031-0. [DOI] [PubMed] [Google Scholar]
  19. Parsch J., Braverman J. M., Stephan W. Comparative sequence analysis and patterns of covariation in RNA secondary structures. Genetics. 2000 Feb;154(2):909–921. doi: 10.1093/genetics/154.2.909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Post L. E., Strycharz G. D., Nomura M., Lewis H., Dennis P. P. Nucleotide sequence of the ribosomal protein gene cluster adjacent to the gene for RNA polymerase subunit beta in Escherichia coli. Proc Natl Acad Sci U S A. 1979 Apr;76(4):1697–1701. doi: 10.1073/pnas.76.4.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Powell J. R., Moriyama E. N. Evolution of codon usage bias in Drosophila. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7784–7790. doi: 10.1073/pnas.94.15.7784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Russo C. A., Takezaki N., Nei M. Molecular phylogeny and divergence times of drosophilid species. Mol Biol Evol. 1995 May;12(3):391–404. doi: 10.1093/oxfordjournals.molbev.a040214. [DOI] [PubMed] [Google Scholar]
  23. Savill N. J., Hoyle D. C., Higgs P. G. RNA sequence evolution with secondary structure constraints: comparison of substitution rate models using maximum-likelihood methods. Genetics. 2001 Jan;157(1):399–411. doi: 10.1093/genetics/157.1.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Seffens W., Digby D. mRNAs have greater negative folding free energies than shuffled or codon choice randomized sequences. Nucleic Acids Res. 1999 Apr 1;27(7):1578–1584. doi: 10.1093/nar/27.7.1578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sharp P. M., Li W. H. An evolutionary perspective on synonymous codon usage in unicellular organisms. J Mol Evol. 1986;24(1-2):28–38. doi: 10.1007/BF02099948. [DOI] [PubMed] [Google Scholar]
  26. Wada A., Suyama A. Local stability of DNA and RNA secondary structure and its relation to biological functions. Prog Biophys Mol Biol. 1986;47(2):113–157. doi: 10.1016/0079-6107(86)90012-x. [DOI] [PubMed] [Google Scholar]
  27. Walter A. E., Turner D. H., Kim J., Lyttle M. H., Müller P., Mathews D. H., Zuker M. Coaxial stacking of helixes enhances binding of oligoribonucleotides and improves predictions of RNA folding. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9218–9222. doi: 10.1073/pnas.91.20.9218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Workman C., Krogh A. No evidence that mRNAs have lower folding free energies than random sequences with the same dinucleotide distribution. Nucleic Acids Res. 1999 Dec 15;27(24):4816–4822. doi: 10.1093/nar/27.24.4816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Zama M. Codon usage pattern in alpha 2(I) chain domain of chicken type I collagen and its implications for the secondary structure of the mRNA and the synthesis pauses of the collagen. Biochem Biophys Res Commun. 1990 Mar 16;167(2):772–776. doi: 10.1016/0006-291x(90)92092-e. [DOI] [PubMed] [Google Scholar]

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