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The role of periodic mRNA secondary structure and RNA-RNA interactions in biological regulation and complexity

mRNA carries a wealth of the structural and regulatory information in addition to the encoded amino acid sequence. This information defines mRNAs secondary structure and stability, pre-mRNA splicing efficiency, regulates rate of translation and affects folding and posttranslational modifications of the nascent polypeptide (1-3). Emerging evidence suggests important biological functions for synonymous nucleotides and “silent” mutations in the protein coding genes that do not change the amino acid sequences of the proteins. Using our software Afold, we performed the first transcriptome-wide analysis of the mRNA folding in different organisms, and demonstrated that the structure of the genetic code and the unequal use of synonymous codons create a periodic pattern of nucleotide involvement in mRNA secondary structure in the protein coding regions (CDSs) (4-5). We also showed how RNA secondary structure might regulate gene expression and suggested that a periodic pattern in the CDS is likely responsible for translation frame monitoring (Figure 1 - low centre panel, 1-2). The degenerate codon sites make the greatest contribution to mRNA stability. Our results support the hypothesis that redundancies in the genetic code enable mRNA sequences to satisfy requirements for both protein and RNA structure, and suggest that selection in favor of G and C may be operating in synonymous codons to maintain a more stable and ordered mRNA secondary structure, which is likely to be important for transcript stability and translation. Functional domains of the mRNA (5’UTR, CDS and 3’UTR) preferentially fold onto themselves, while domain boundaries are characterized by relaxed secondary structures, as compared to the overall mRNA folding. Relaxed secondary structures in the vicinity of the start and stop codon regions could facilitate the initiation and termination of translation. Comparative analysis of mRNA secondary structure patterns for eukaryotes and prokaryotes revealed the ubiquity of periodic mRNA secondary structures and RNA level selection pressure acting at the level of mRNA secondary structure in different organisms. Systematic differences in selection pressure exist between synonymous and nonsynonymous positions in mRNA coding regions (2). Selection pressure on the coding gene regions follows a three-nucleotide periodic pattern of nucleotide base pairing in