A periodic pattern of mRNA secondary structure created by the genetic code

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
Nucleic Acids Research (Impact Factor: 9.11). 02/2006; 34(8):2428-37. DOI: 10.1093/nar/gkl287
Source: PubMed


Single-stranded mRNA molecules form secondary structures through complementary self-interactions. Several hypotheses have been proposed on the relationship between the nucleotide sequence, encoded amino acid sequence and mRNA secondary structure. We performed the first transcriptome-wide in silico analysis of the human and mouse mRNA foldings and found a pronounced periodic pattern of nucleotide involvement in mRNA secondary structure. We show that this pattern is created by the structure of the genetic code, and the dinucleotide relative abundances are important for the maintenance of mRNA secondary structure. Although synonymous codon usage contributes to this pattern, it is intrinsic to the structure of the genetic code and manifests itself even in the absence of synonymous codon usage bias at the 4-fold degenerate sites. While all codon sites are important for the maintenance of mRNA secondary structure, degeneracy of the code allows regulation of stability and periodicity of mRNA secondary structure. We demonstrate that the third degenerate codon sites contribute most strongly to mRNA stability. These results convincingly support the hypothesis that redundancies in the genetic code allow transcripts to satisfy requirements for both protein structure and RNA structure. Our data show that selection may be operating on synonymous codons to maintain a more stable and ordered mRNA secondary structure, which is likely to be important for transcript stability and translation. We also demonstrate that functional domains of the mRNA [5'-untranslated region (5'-UTR), CDS and 3'-UTR] preferentially fold onto themselves, while the start codon and stop codon regions are characterized by relaxed secondary structures, which may facilitate initiation and termination of translation.

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Available from: Nikolay A Spiridonov
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    • "To obtain mRNA secondary structure from the RB1 gene sequence we have used RNAfold (Capon et al., 2004; Shabalina et al., 2006; Altschul et al., 1990; Hofacker et al., 1994; McCaskill, 1990; Zuker and Stiegler, 1981; Lorenz et al., 2011; Turner and Mathews, 2009; Bompfunewerer et al., 2008; Hofacker and Stadler, 2006; Mathews et al., 2004; Jia and Luo, 2006; Jia et al., 2004) version 2.1.7 online tool ( from Vienna RNA package 2.0 (Hofacker et al., 1994). "
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    ABSTRACT: Clinically significant 18 Single Nucleotide Polymorphisms (SNPs) from exon regions of Retinoblastoma gene (RB1) were analyzed to find out the structural variations in mRNAs. Online bioinformatic tools i.e., Vienna RNA, RNAfold were used for secondary structure analysis of mRNAs. Predicted minimum Free Energy Change (MFE) was calculated for mRNAs structures. It has been observed that the average of predicted MFE value from 13 nonsense mutations was higher (0.76 kcal/mol) in comparison to 5 missense mutations. Presumably, 13 nonsense mutations are responsible for Nonsense Mediated mRNA Decay (NMD), therefore, excluded from haplotype analysis. From the statistical analysis all the thermodynamic data obtained from four SNP haplotypes are significant (p≤0.05), followed by three-SNP haplotype data except Ensemble diversity (p≤0.10). Interestingly, MEF of Centroid Secondary Structure is highly significant (p≤0.01) in all the cases (Two-SNP haplotypes, Three-SNP haplotypes and Four-SNP haplotypes).
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    • "Moreover, a relevant biological effect can be linked to nucleotide alteration located in introns (Chorev and Carmel, 2012). The after-effects of the described genetic variation can be meaningful for changes in splicing regulatory sequences and sequence motifs, different reading of codons and for the influence on mRNA secondary structure (Shabalina et al., 2006, Parmley and Hurst, 2007, Hsu et al., 2010, Gingold and Pilpel, 2011).In the following work, the potential biological effect of nucleotide variation within the growth hormone gene in American mink is evaluated (Neovison vison Schreb., 1777) (mGH). The focus is primarily on the macromolecular phenotype, including gene expression heterogeneity and RNA phenotypes (Ferrada andWagner, 2012, Wagner, 2014). "
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    ABSTRACT: Most often, genetic variation causing phenotypical changes is calculated exclusively upon the occurrence of non-synonymous variation. However, it has been increasingly more common to state that synonymous mutations and polymorphisms, as well as nucleotide variation present in introns, can have very serious biological effects. In the following work, the potential biological effect (including molecular phenotype) of nucleotide variation within the growth hormone gene in American mink (Neovison vison Schreb., 1777) was evaluated, based on multilocus genotypes of 389 individuals (wild mink from Canada, six colour types of ranch mink, mink acquired from the natural environment in Poland and Iceland), identified by direct sequencing. The focus is on the possible occurrence of changes in a splicing regulatory sequences and sequence motifs, different reading of codons and on an influence on the mRNA secondary structure. The results obtained confirm the hypothesis that synonymity of single-nucleotide variation does not always signify its neutrality. © 2015, Pakistan Agricultural Scientists Forum. All Rights Reserved.
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    • "It is indicated that, in addition to translational selection, other factors that correlate with GC3, e.g. transcriptional selection [40,41], mRNA stability [11,12], biased gene conversion [8,9], may also have combined with translational selection to contribute to the positive correlation between CUB and gene expression level. As translational regulation rather than transcriptional regulation or mRNA stability is more pronounced in influencing protein level in mammals [42], future investigations might as well involve protein expression data to verify such strong translational selection in human HK genes and take account of translation initiation [13] and elongation as well as codon order [43]. "
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    ABSTRACT: Background Translational selection is a ubiquitous and significant mechanism to regulate protein expression in prokaryotes and unicellular eukaryotes. Recent evidence has shown that translational selection is weakly operative in highly expressed genes in human and other vertebrates. However, it remains unclear whether translational selection acts differentially on human genes depending on their expression patterns. Results Here we report that human housekeeping (HK) genes that are strictly defined as genes that are expressed ubiquitously and consistently in most or all tissues, are under stronger translational selection. Conclusions These observations clearly show that translational selection is also closely associated with expression pattern. Our results suggest that human HK genes are more efficiently and/or accurately translated into proteins, which will inevitably open up a new understanding of HK genes and the regulation of gene expression. Reviewers This article was reviewed by Yuan Yuan, Baylor College of Medicine; Han Liang, University of Texas MD Anderson Cancer Center (nominated by Dr Laura Landweber) Eugene Koonin, NCBI, NLM, NIH, United States of America Sandor Pongor, International Centre for Genetic Engineering and biotechnology (ICGEB), Italy.
    Full-text · Article · Jul 2014 · Biology Direct
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