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, 34 (8), 2428-37

A Periodic Pattern of mRNA Secondary Structure Created by the Genetic Code

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A Periodic Pattern of mRNA Secondary Structure Created by the Genetic Code

Svetlana A Shabalina et al. Nucleic Acids Res.

Abstract

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.

Figures

Figure 1
Figure 1
Profiles of nucleotide involvement in secondary structures, free energy of secondary structure formation and sequence conservation around the start codon (A) and the stop codon (B) in human mRNAs. Positions from −30 to −1 correspond to 5′-UTRs and positions from 1 to 60 correspond to CDSs (A). Positions from −60 to −1 correspond to CDSs and positions from 1 to 30 correspond to 3′-UTRs (B). Blue, sequence conservation in 6919 orthologous human and mouse mRNAs. Red, base paired nucleotides in 19 317 human mRNAs. Green, free Gibbs energy of base pairing in 19 317 human mRNAs.
Figure 2
Figure 2
Profiles of nucleotide base pairing around the start codon (A, C and E) and the stop codon (B, D and F) for 19 317 human mRNAs (A and B), for sequences with randomly chosen synonymous codons (C and D), and sequences with randomly shuffled nucleotides and the same nucleotide composition as native mRNAs (E and F). Blue, guanine; red, cytosine; green, adenosine; orange, uridine.
Figure 3
Figure 3
The three phases of nucleotide base pairing in the mRNA CDS. The numbers denote codon sites.
Figure 4
Figure 4
Profiles of base pairing for nucleotides around the start codon (A, C and E) and the stop codon (B, D and F) with different codon sites for 19 317 human mRNAs (A and B), for sequences with randomly chosen synonymous codons (C and D), and sequences with randomly shuffled nucleotides and the same nucleotide composition as native mRNAs (E and F). Nucleotides paired with codon sites 1, 2 and 3 are shown in blue, red and green, respectively.
Figure 5
Figure 5
Profiles of base pairing for nucleotides around the start codon (A) and the stop codon (B) with different mRNA structural domains. Blue, nucleotides paired with the 5′-UTRs; red, nucleotides paired with the CDSs; green, nucleotides paired with the 3′-UTRs. Data for 19 317 human mRNAs.

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