What Is Alternative Splicing?
Eukaryotic genes, primarily in multi-cellular organisms, have mRNAencoding regions called exons that are interrupted by non-coding regions named introns. This split gene structure provides a fertile ground of posttranscriptional regulation which expands transcript repertoire through usage of various exon-exon combinations (i.e. alternative splicing) resulting in multiple mRNA isoforms (i.e. splice variants) produced from a single gene. High-throughput RNA sequencing (RNA-seq) indicates that > 90% of multi-exon human genes undergo alternative splicing (AS) . More importantly, AS can change a final protein’s binding properties, modify enzymatic activity, and even reverse roles of its gene in cellular processes (e.g. two isoforms of Bcl-x through AS, the long form is anti-apoptotic, while the short one is pro-apoptotic) [4]. Besides the role of AS in normal development, evidence of pathogenesis and clinical relevance of aberrant splicing variants is growing exponentially [5], with an estimated 10% of splice site mutations (exon intron boundary) causing human inherited diseases [6-8]. Deciphering the pre-mRNA splicing code and functional characterization of splice variants will provide us new insights of pathogenesis of human diseases.
Author(s): Zhi-xiang Lu