Mutational bias and the protein code shape the evolution of splicing enhancers

Area of Science:

• Evolutionary biology
• Molecular genetics
• Bioinformatics

Background:

• Exonic splicing enhancers (ESEs) are crucial regulatory sequences that promote accurate gene splicing.
• The enrichment of ESE motifs in exons over introns presents an evolutionary puzzle, as their recognition evolved later.

Purpose of the Study:

• To investigate the evolutionary mechanisms driving the enrichment of ESE motifs in exons.
• To test the hypothesis that mutational bias and purifying selection on protein sequences created ESE enrichment prior to splicing factor evolution.

Main Methods:

• Computational simulations to model evolutionary forces.
• Genomic analyses to assess motif distribution in exons and introns.
• High-throughput splicing assays to experimentally validate findings.

Main Results:

• Simulations and genomic data support the hypothesis of mutational bias and purifying selection shaping ESEs.
• Evidence shows an overlap between sequences encoding protein information and splicing regulatory information within ESEs.
• Experimental assays confirm the functional significance of these overlapping motifs.

Conclusions:

• Mutational bias coupled with selection for protein function is a key driver for the initial enrichment of ESEs in exons.
• This co-evolutionary process demonstrates how regulatory elements can emerge and persist before the evolution of their recognition machinery.
• Findings suggest mutational bias plays a broader role in the evolution of other cis-regulatory elements.