Thermal adaptation of the secondary structure of mRNA: stability versus lability



We demonstrate that the change in free energy that occurs during the folding of secondary structures (ΔGto fold) cytosolic malate dehydrogenase messenger RNA (mRNA) varies considerably with evolutionary adaptation temperature in marine molluscs. These adaptive changes in ΔGto fold confer a physiologically important balance between the stability and the lability of the secondary structure. This balance is probably of key importance to ensure that the many functions of mRNA that depend on reversible changes in secondary structure can be carried out efficiently at normal body temperatures of different species. The synonymous changes in guanine + cytosine (G + C) content are the main driver of the adaptive change in ΔGto fold; these G + C adaptations can confer appropriate stability on mRNAs without altering the stability or function of the proteins they encode.


Macromolecular function generally involves rapidly reversible alterations in three-dimensional structure (conformation). To enable these essential conformational changes, macromolecules must possess higher order structures that are appropriately balanced between stiffness and flexibility. Due to the low stabilizing free energies (marginal stabilities) of the conformations of the macromolecules, the temperature changes have important effects on the conformation and, therefore, on the function. As is well known for proteins, during evolution, temperature adaptive sequence changes promote the maintenance of optimal marginal stability at normal physiological temperatures of a species. Here, we extend this type of analysis to messenger RNAs (mRNAs), a class of macromolecules whose stability-lability balance has not been elucidated. We employ in silico methods to determine secondary structures and estimate changes in bending free energy (ΔGto fold) for 25 orthologous mRNAs that encode the cytosolic enzyme malate dehydrogenase in marine molluscs with adaptation temperatures spanning a range of nearly 60 ° C. The change in free energy that occurs during the formation of all of the secondary mRNA structures is significantly correlated with the adaptation temperature: ΔGto fold the values ​​are all negative and their absolute values ​​increase with the adaptation temperature. A main mechanism underlying these adaptations is a significant increase in synonymous guanine + cytosine substitutions with increasing temperature. These findings open an avenue for exploration in molecular evolution and raise interesting questions about the interaction between temperature adaptive changes in the mRNA sequence and in the proteins they encode.

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