How did alternative splicing evolve?

Abstract

Alternative splicing contributes significantly to human proteome complexity and explains the numerical disparity between the low number of human protein-coding genes and the number of human proteins. The appearance of multi-intron genes probably predates that of alternative splicing, and constitutive splicing probably predates exon skipping. Most of the higher eukaryotic organisms use alternative splicing, but some lower eukaryotes do not. Our understanding of the origins of alternative splicing has been limited until recently; however, two theories — one sequence based, the other trans-factor based — have now been proposed. Comparative analysis has recently provided important insights into the differences between alternative and constitutive sites, giving us hints about the steps involved in the evolution of alternative splicing. The 5′ splice site reveals major differences between unicellular organisms such as yeasts and multicellular organisms such as mammals. These differences indicate that three positions in the intronic portion of the 5′ss are less conserved in mammals than in yeasts, whereas the last three positions of the exon are more conserved. These differences are directly related to the plasticity of the 5′ splice sites of multicellular eukaryotes: 5′ss can be used in both constitutive and alternative splicing and for the regulation of the inclusion/skipping ratio in alternative splicing. Alternative splicing might have originated as a result of relaxation of 5′ splice site recognition in organisms that originally could support only constitutive splicing.