Profiles

With the completion of the human genome project, it has become clear that the sheer number of genes cannot account for the complexity of the human proteome. Among several proposed mechanisms, alternative pre-mRNA splicing is considered to be one of the most efficient and widespread avenues to generate multiple protein isoforms from individual genes. Current estimates indicate that over 90% of all human genes undergo alternative splicing, thus greatly increasing the coding potential of our genome. In addition, defects in splicing have been linked with a variety of human genetic diseases. Understanding the basic mechanisms of pre-mRNA splicing and splice site recognition is therefore fundamental to understanding the expression of genes and human diseases. Research in the Hertel laboratory focuses on elucidating the mechanisms of splice site selection with the long-term goal of generating a splicing code that permits alternative splicing predictions based on sequence analysis. We are taking several biochemical and computational approaches (1) to determine the mechanisms whereby the binding location of splicing regulatory proteins positively or negatively influence exon recognition, (2) to derive methods to determine if single nucleotide changes elicit differences in exon selection and inclusion, and (3) to test the hypothesis that aberrant expression of splicing regulators triggers cancer-specific alternative splicing. Our long-term goals are to use the knowledge of splice-site recognition mechanisms to classify intronic and exonic mutations, thus paving the way for the design of therapeutic approaches to combat splicing-associated disease.