Global importance of RNA secondary structures in protein-coding sequences

Abstract

Motivation: The protein-coding sequences of messenger RNAs are the linear template for translation of the gene sequence into protein. Nevertheless, the RNA can also form secondary structures by intramolecular base-pairing.

Results: We show that the nucleotide distribution within codons is biased in all taxa of life on a global scale. Thereby, RNA secondary structures that require base-pairing between the position 1 of a codon with the position 1 of an opposing codon (here named RNA secondary structure class c1) are under-represented. We conclude that this bias may result from the co-evolution of codon sequence and mRNA secondary structure, suggesting that RNA secondary structures are generally important in protein-coding regions of mRNAs. The above result also implies that codon position 2 has a smaller influence on the amino acid choice than codon position 1.

Supplementary information: Supplementary data are available at Bioinformatics online.

Fig. 1.

(A) Three base pair/RNA secondary structure classes that represent all possible base-pairs between positions 1, 2 and 3 of one codon with positions 1, 2 and 3 of an opposing codon in RNA secondary structures. The classes are based on the following groups c₁={1:1, 2:3, 3:2}, c₂={1:3, 2:2, 3:1} and c₃={1:2, 2:1, 3:3}. (B) An artificial example RNA secondary structure with the different classes corresponding to A. Shifts between the different classes are possible, introduced through loops and bulges

Fig. 2.

Distribution of class c₁, c₂ and c₃ within all selected coding sequences (sCDS, see methods for selection procedure) except mitochondria and chloroplasts for each taxonomic group. #species – number of different species; #CDS – number of coding sequence (CDS); #sCDS – number of selected CDS; #nt/sCDS – number of nucleotides per selected CDS

Fig. 3.

(A) Class distribution and (B) nucleotide distribution of each codon positions of all human mRNAs with less stable (mean MFE>−8 kcal/mol over all folding windows, #7104 mRNAs, TOP) and rather stable (mean MFE $\le$ −8 kcal/mol over all folding windows, #15022 mRNAs, BOTTOM) RNA secondary structures. The nucleotide distributions in codon positions 2 and 3 of the less stable mRNAs are similar, since base-pairings of 2:3 and 3:2 are likely. In contrast, mRNAs with more stable RNA secondary structure show an increased GC content at codon position 1 and in particular at position 3. This increases the G:C and C:G base-pairings 1:3, 3:1 and 3:3 (Supplementary Fig. S6) and consequently increases the frequency of classes c₂ and c₃

Fig. 4.

Base pair/RNA secondary structure class distribution in mitochondria and chloroplasts