Research

The research in my laboratory is directed at understanding the processes involved in specifying the sites of splicing within a pre-mRNA and the mechanism of the splicing reactions.

A few years ago, we identified a previously unsuspected second class of introns within eukaryotic genes. Subsequent work has shown that this second class is widely distributed in nature and must have been present in the eukaryotic genome for at least a billion years. More recent work has led us to argue that both classes of introns were present in one of the earliest ancestors of eukaryotic organisms.

In modern organisms, these introns are spliced in a spliceosome composed of four snRNAs unique to this class of introns and one snRNA which is common to both classes of introns. The spliceosomal proteins are also likely to contain a mixture of unique and shared proteins. The splicing mechanisms and many of the RNA-RNA interactions involved in the formation and function of the spliceosome are strikingly similar in both classes of introns which suggests that they probably share a common origin.

Over the last several years, we have been mapping the RNA- RNA interactions involved in the splicing of this new class of introns using genetic and biochemical techniques. These studies are directed toward understanding the structure and function of the spliceosome and gaining insights into how these introns are identified by the splicing machinery in the primary RNA transcripts of genes.

Recently, we have focused on the function of a small RNA element in the spliceosome which may be involved in the catalysis of the splicing reactions. We have shown that this element can be functionally replaced by a similar RNA element from a class of self-splicing RNA introns (the Group II introns). This finding suggests that both the spliceosome and these self-splicing introns use similar catalytic mechanisms and supports the idea that spliceosomal introns evolved from self-splicing introns. We are now pursuing structural studies of these RNA elements to further define their functions in splicing.

We are also extending our studies of the minor class spliceosome to the investigation of the proteins involved in the splicing of these unusual introns. We will determine the overlap of protein factors between the two splicing systems and identify proteins unique to the newly discovered spliceosome.  

We are also beginning a new project that focuses on a class of unusual human genes that are characterized by intron lengths in excess of 100 kibobases. These genes, which we call Large, Exon Poor (LEP) genes are typically larger than 1 megabase in genomic length yet code for mature mRNAs of 1-2 kilobases using only a few exons.   These genes include several putative tumor suppressor genes and are also frequently found at common chromosomal fragile sites. We are examining the transcriptional program of these genes and their physical arrangement in interphase nuclei to determine if they are expressed according to the standard model or if they might represent a new class of genes.