Both Maintenance and Avoidance of RNA-Binding Protein Interactions Constrain Coding Sequence Evolution.

Area of Science:

• Evolutionary biology
• Genomics
• Molecular biology

Background:

• Coding sequences (CDSs) evolve under selection for protein function.
• CDSs must also maintain interactions with RNA-binding proteins (RBPs) for gene expression.
• The evolutionary impact of maintaining RBP interactions is not fully understood.

Purpose of the Study:

• To investigate if CDSs are evolutionarily constrained by the need to specify RBP binding motifs.
• To determine the proportion of mutations affected by RBP interaction constraints.
• To assess if CDS evolution is constrained by avoiding motifs that attract unwanted RBP binding.

Main Methods:

• Scanned human CDSs for experimentally validated RBP binding motifs.
• Analyzed motif enrichment and depletion relative to nucleotide-controlled null models.
• Correlated motif evolution rates with RBP binding specificities.

Main Results:

• Observed both enriched and depleted sets of RBP binding motifs within human CDSs.
• Depleted motifs were enriched for those recognized by non-CDS binding RBPs.
• Enriched motifs showed slower evolutionary rates, indicating selection to preserve them.
• Synonymous evolution rate reduced by 2-3% in primates and rodents due to selection to preserve motifs.
• Stronger motif depletion correlated with stronger selection against motif gain.

Conclusions:

• CDS evolution is constrained by the dual needs to attract functional RBPs and avoid non-functional ones.
• Selection to preserve RBP binding motifs reduces synonymous evolution rates.
• CDS evolution balances RBP interactions with protein structure-based selection pressures.