Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes

Area of Science:

• Molecular Biology
• Genetics
• Bioinformatics

Background:

• General translational cis-elements in messenger RNAs (mRNAs) influence gene expression by affecting preinitiation complex and ribosome dynamics.
• Key cis-elements include mRNA folding, upstream open reading frames, flanking nucleotides of the initiating AUG codon, coding sequence length, and codon usage.
• The precise contributions and coordination of these sequence features in controlling translation rates remain poorly understood.

Purpose of the Study:

• To quantify the impact of general sequence features on translation rates across diverse eukaryotic species.
• To elucidate the specific roles of RNA secondary structure and other cis-elements in translational control.
• To investigate the correlations between different cis-control mechanisms and their impact on translation.

Main Methods:

• Comparative analysis of mRNA sequences and translation rates across multiple species (yeast, fission yeast, thale cress, mouse, human).
• Statistical modeling to determine the percentage of variance in translation rates attributable to sequence features.
• Identification and analysis of RNA secondary structures in 5' regions of mRNAs.

Main Results:

• General sequence features account for 42-81% of the variance in translation rates across the studied species.
• RNA secondary structure, particularly folded segments in 5' regions, is a major determinant of translational control.
• Correlations were observed in tri-nucleotide frequency changes and regulation by distinct or shared biochemical processes across species.

Conclusions:

• General sequence features play a more significant role in regulating translation rates than previously recognized.
• This study provides a detailed understanding of RNA structural elements that direct translation in eukaryotes.
• Correlated regulation among cis-control features promotes efficient use of the cellular translation machinery by ensuring even distribution of translational complexes.