Alternative splicing and RNA selection pressure — evolutionary consequences for eukaryotic genomes

Global analyses of alternative splicing indicate that it is widespread in human and other multicellular eukaryotic organisms. ESTs and microarray data suggest that nearly three-quarters of human multi-exon genes are alternatively spliced.The frequency of transcript inclusion is an important determinant of the evolution of an alternatively spliced exon. Most minor-form alternative exons are 'young', suggesting that alternative splicing is associated with an increased rate of new exon creation in mammalian genomes.Alternative splicing provides a general strategy for relaxing negative selection pressure against evolutionary changes. It can open near-neutral pathways for evolution of gene structure and recruitment of novel protein-coding sequences.The frequency of alternative splicing in a multi-gene family is negatively correlated with the size of the family, indicating that alternative splicing and gene duplication are inversely correlated evolutionary mechanisms.Evolutionarily conserved alternatively spliced exons have greatly reduced synonymous substitution rates, and have highly conserved flanking intronic regions. Tissue-specific exons exhibit a similar pattern. These data provide evidence for widespread RNA selection pressure in mammalian genes owing to constraints of alternative splicing regulation.Genome-wide analyses of synonymous and non-synonymous substitution rates indicate that two types of selection pressure — selection on protein function and selection on RNA splicing — act very differently on alternatively spliced exons.Splicing mutations have important roles in human diseases.