Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss

One of the most interesting opportunities in comparative genomics is to compare not only genome sequences but additional phenomena, such as alternative splicing, using orthologous genes in different genomes to find similarities and differences between organisms(1,2). Recently, genomics studies have suggested that 40-60% of human genes are alternatively spliced(3-8) and have catalogued up to 30,000 alternative splice relationships in human genes(9). Here we report an analysis of 9,434 orthologous genes in human and mouse, which indicates that alternative splicing is associated with a large increase in frequency of recent exon creation and/or loss. Whereas most exons in the mouse and human genomes are strongly conserved in both genomes, exons that are only included in alternative splice forms (as opposed to the constitutive or major transcript form) are mostly not conserved and thus are the product of recent exon creation or loss events. A similar comparison of orthologous exons in rat and human validates this pattern. Although this says nothing about the complex question of adaptive benefit, it does indicate that alternative splicing in these genomes has been associated with increased evolutionary change.