Technologies for the global discovery and analysis of alternative splicing

During the past approximately 20 years, studies on alternative splicing (AS) have largely been directed at the identification and characterization of factors and mecha nisms responsible for the control of splice site selection, using model substrates and on a case by case basis. These studies have provided a wealth of information on the factors and interactions that control formation of the spliceosome. However, relatively little is known about the global regulatory properties of AS. Important questions that need to be addressed are: which exons are alternatively spliced and under which cellular contexts, what are the functional roles of AS events in different cellular contexts, and how are AS events controlled and coordinated with each other and with other levels of gene regulation to achieve cell- and development-specific functions. During the past several years, new technologies and experimental strategies have provided insight into these questions. For example, custom microarrays and data analysis tools are playing a prominent role in the discovery and analysis of splicing regulation. Moreover, several non-microarray-based technologies are emerging that will likely further fuel progress in this area. This review focuses on recent advances made in the development and application of high-throughput methods to study AS.