Testing the Reverse-splicing Model of Intron Spread with rDNA Genes

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A grant has been awarded to Dr. Debashish Bhattacharya at the University of Iowa to determine how intervening sequences (so-called "introns") spread into novel sites in genes. Introns compose a significant portion of genomes (about 16% in humans) and play important roles in gene expression and disease, yet their means of spread remains unknown. This is because few proven cases of recent and widespread intron spread have been documented. The finding of a wealth of recently inserted introns in the ribosomal (r)RNA genes of Euascomycetes fungi makes these organisms ideal for the study of intron spread. Previous work shows that a good candidate for the mechanism by which introns get incorporated into genes is by reversal of the splicing process. The rRNAs of a diverse group of Euascomycetes will be studied to test predictions of the "reverse-splicing" model such as the expectation that introns are preferentially retained at target gene sequences that have a high affinity for splicing factors and that introns are non-randomly distributed, with most of them clustering in regions that are not buried in RNA tertiary structure. Introns play important roles in the evolution of eukaryotic genomes and are implicated in diseases. For example, about 15% of point mutations that are linked to human genetic disease cause defects in the splicing of introns. It is surprising, therefore, that no general model of intron spread exists. In this grant, the recent finding of widespread introns in the nuclear rDNA of Euascomycetes fungi is exploited to address the issue of intron spread. An important strength of the fungal system is the availability of robust secondary and tertiary rRNA structures. This allows the testing of the role of RNA structure in determining intron distribution, an analysis that cannot be done with most pre-mRNAs which have largely unknown folding properties.