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Pre-mRNA splicing is an essential component of eukaryotic gene expression. Many metazoans, including humans, regulate alternative splicing patterns to generate expansions of their proteome from a limited number of genes. Importantly, a considerable fraction of human disease causing mutations manifest themselves through altering the sequences that shape the splicing patterns of genes. Nevertheless, the mechanisms by which this complex pathway is regulated remain poorly understood. Understanding how disease-causing mutations impair this ability will require improved knowledge of the mechanisms by which the spliceosome identifies and activates ‘cognate’ splice site sequences in the background of scores of ‘near-cognate’ aberrant splice sites: understanding this problem is a major focus of the work in the Pleiss lab.

In the Pleiss lab, we develop and utilize novel genetic, genomic, computational, molecular biological, and comparative evolutionary approaches geared towards understanding both the mechanistic bases of splicing regulation as well as its physiological consequences. At the simplest level, this requires understanding both: (1) the cis-regulatory elements within a transcript (or gene structure) that destine it for regulation; and (2) the mechanistic bases by which trans-regulatory factors can impart this specific regulation. Work in my lab largely focuses on addressing these questions using the budding and fission yeasts, S. cerevisiae and S. pombe. Whereas budding yeast has long been a powerful genetic system for understanding the basic mechanisms of splicing, my lab has pioneered global studies of splicing in S. pombe, an organism which has retained many features of mammalian splicing, including degenerate splice site sequences, the presence of SR-proteins, and the usage of exonic splicing enhancers, yet retains the genetic tractability of budding yeast.

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