HIGH RESOLUTION ANALYSIS OF THE SELECTION ON LOCAL MRNA FOLDING STRENGTH IN PROTEIN-CODING SEQUENCES ACROSS THE TREE OF LIFE

The strength of local mRNA folding can be increased or decreased at different regions of the CDS (protein-coding sequence) through the choice of synonymous codons. This modulation of local folding strength affects the interaction with the ribosome and is thought to influence many aspects of gene expression, including translation initiation rate, translation elongation rate, co-translational protein folding, mRNA aggregation and even the transcription rate.
We performed a genome-wide computational study of local mRNA folding strengths in genomes across the tree of life to see how they correlate with genomic and environmental traits, in order to shed light on the biophysical and evolutionary mechanisms involved. We compare folding strengths in native CDSs to randomized sequences maintaining the amino acid content, GC-content, and codon distributions, and argue that most of the deviation between the two folding strengths should be attributed to selection. We show that this selection changes direction along the CDS following a characteristic profile present in most bacterial (98%) and archaeal (72%) species, but not in most eukaryotes (36%). Much of the observed inter-specific variation in selection for local folding can be explained by genomic GC-content (which is non-trivial as the randomization controls for the direct effect of GC on folding strength). This correlation changes direction between regions similar to those found in the selection profile in most taxons with the exception of fungi. Growth temperature does not appear to have a clear influence on the selection on folding strength in general, but in hyperthermophilic organisms weaker selection is observed.
These results should advance the understanding of mRNA secondary structure in native proteins, and thus promote developing novel engineering approaches for controlling gene expression in non-model organisms.