Divergence of exonic splicing elements after gene duplication and the impact on gene structures

The origin of new genes and their contribution to functional novelty has been the subject of considerable interest. There has been much progress in understanding the mechanisms by which new genes originate. Here we examine a novel way that new gene structures could originate, namely through the evolution of new alternative splicing isoforms after gene duplication.

We studied the divergence of exonic splicing enhancers and silencers after gene duplication and the contributions of such divergence to the generation of new splicing isoforms. We found that exonic splicing enhancers and exonic splicing silencers diverge especially fast shortly after gene duplication. About 10% and 5% of paralogous exons undergo significantly asymmetric evolution of exonic splicing enhancers and silencers, respectively. When compared to pre-duplication ancestors, we found that there is a significant overall loss of exonic splicing enhancers and the magnitude increases with duplication age. Detailed examination reveals net gains and losses of exonic splicing enhancers and silencers in different copies and paralog clusters after gene duplication. Furthermore, we found that exonic splicing enhancer and silencer changes are mainly caused by synonymous mutations, though nonsynonymous changes also contribute. Finally, we found that exonic splicing enhancer and silencer divergence results in exon splicing state transitions (from constitutive to alternative or vice versa), and that the proportion of paralogous exon pairs with different splicing states also increases over time, consistent with previous predictions.

Our results suggest that exonic splicing enhancer and silencer changes after gene duplication have important roles in alternative splicing divergence and that these changes contribute to the generation of new gene structures.