Regulation of Amino-Acid Polymorphism by Alternative Splicing

Yael Mandel-Gutfreund

Faculty of Biology, Technion-Institute of Technology, Haifa

Alternative splicing is thought to be the major mechanism for protein diversity in humans. Previous bioinformatics studies based on EST and mRNA data have identified many alternative splicing events that are conserved between human and mouse. Further classification of the conserved alternative splicing events demonstrated that ~25% of the events are related to alternative 3' and 5' splice sites. Surprisingly, 215 out of the 460 conserved alternative 3' splice site events (10% of all conserved alternative splicing events) involve exactly 3 nucleotide insertions/deletions (indels). These indels result from the presence of the NAGNAG motif at the 3' acceptor splice site, recently reported to be widely spread in the genome. However, though the NAGNAG motif is highly prevalent as a splice acceptor in human genes, only a small subset of them are confirmed to be involved in alternative splicing. We examined the NAGNAG motif and surrounding intron and exon regions in both alternative and constitutive splice sites. We observed specific features which are characteristic of alternative spliced tandem acceptor sites and can distinguish them from the constitutive 3' splice sites. Overall, our data implies that alternative splicing at the NAGNAG acceptor site is regulated by a combination of the relative strength of the NAG acceptor sites as well as specific cis splicing factors. In the end of my talk I will discuss the role of alternative splicing at tandem acceptor sites in generating amino-acid polymorphism.