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DNA structure trumps RNA structure

Posted by forsdyke on 31 Jul 2014 at 22:37 GMT

Yang et al. (2014) suggest that their results 'explain why highly expressed genes tend to have strong mRNA folding, slow translation elongation, and conserved protein sequences.' However, mRNA structure largely reflects the potential of the corresponding DNA to extrude similar structure, so departing from the classic duplex mode. Such stem-loop extrusion potential is widespread in genomes, is usually impaired in genic regions compared with non-genic regions, and is less impaired in conserved genes that are not evolving rapidly under positive Darwinian selection (Forsdyke, 1995a, b, c). Thus, 'strong mRNA folding' can be by default, mainly because the corresponding gene retains a potential for strong DNA folding. In protein-coding regions there is a conflict between the needs of nucleic acid structure and coding, which can often only be partially resolved by choice of alternative codons.

Within these constraints, there may indeed be sufficient flexibility to modulate translational elongation as the fine paper of Yang et al. so nicely shows, but it would seem misleading to imply that mRNA folding primarily serves this role. Furthermore, the higher conservation of the proteins of highly expressed genes could reflect their dual specific and collective roles, whereas the proteins of lowly expressed genes may mainly play specific roles (Forsdyke, 2012). Thus, there are two sources of negative selection pressure on genes with highly expressed products, and only one source of negative selection pressure on genes with lowly expressed products. Hence the greater conservation of the former.

The paper of Yang et al. (2014) concludes by noting that 'The enigmatic positive correlation between gene expression level and mRNA folding strength, at least partially results from selection for slower translational elongation of more abundant mRNAs to minimize mistranslation.' This conclusion is less dogmatic than that of an earlier paper (Park et al. 2013), which notes 'a major role of natural selection at the mRNA level in constraining protein evolution.'

Forsdyke DR (1995a) A stem-loop 'kissing' model for the initiation of recombination and the origin of introns. Mol Biol Evol 12: 949-958.
Forsdyke DR (1995b) Conservation of stem-loop potential in introns of snake venom phospholipase A2 genes: an application of FORS-D analysis. Mol Biol Evol 12: 1157-1165.
Forsdyke DR (1995c) Relative roles of primary sequence and (G+C)% in determining the hierarchy of frequencies of complementary trinucleotide pairs in DNAs of different species. J Mol Evol 41: 573-581.
Forsdyke DR (2012) Functional constraint and molecular evolution. In: Encyclopedia of Life Sciences. Chichester: John Wiley.
Park C, Chen X, Yang J-R, Zhang J (2013) Differential requirements for mRNA folding partially explain why highly expressed proteins evolve slowly. Proc Natl Acad Sci USA 110: E678-686.
Yang J-R, Chen Z, Zhang J (2014) Codon-by-codon modulation of translational speed and accuracy via mRNA folding. PLOS Biol 12: e1001910.

No competing interests declared.

RE: DNA structure trumps RNA structure

forsdyke replied to forsdyke on 09 Aug 2014 at 13:48 GMT

To an email request for clarification of the above comment, the following reply was sent:

Benefit of strong DNA folding. That there is strong DNA folding, which can be presumed to have been sustained by selection, is a fact. My bioinformatics studies seemed most in keeping with the hypothesis of Kleckner and Weiner (1993. Potential advantages of unstable interactions for pairing of chromosomes in meiotic, somatic and premeiotic cells. Cold Spring Harbor Symp. Quant. Biol. 58:553-565). This is that ‘kissing’ interactions between loops favor recombination and, since recombination is usually advantageous, there has been selection for this structure. Importantly, this involves changes in base order to support structure. This creates problems in protein-coding regions and ‘the hand of evolution’ has to arrive at a compromise that is most appropriate for an organism. As a consequence, there may be less structure-potential in coding regions than in non-coding regions, especially in genes that are rapidly evolving, where there is more pressure to keep the protein optimized, and structure-potential must either be sacrificed, or directed to neighboring introns.

Why highly expressed genes need strong DNA folding. As a secondary consequence of this, another benefit appears. If a DNA sequence has a high stem-loop potential, then it is energetically easier for the two strands of the duplex to separate. The stem-loop conformation decreases the strain imposed by negative superhelical winding, and hence should facilitate the helix-opening needed for transcription. Highly expressed genes benefit from this more than lowly expressed genes, so there is more pressure for the former to retain structure in coding regions, despite the pressure to encode a unique amino acid sequence. Another consequence of the structure-potential is that the ‘top’ non-transcribed strand is free to form duplex stems, and hence to partially protect itself from mutagenic attack. The ‘bottom’ transcribed strand is less protected in this respect. A highly expressed gene is more vulnerable, so is more in need of such protection.

No competing interests declared.