Natural History and Functional Evolutionary Studies of A-to-I pre-mRNA Editing

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0091142 Robert ReenanAdenosine-to-inosine (A-to-I) pre-mRNA editing hydrolytically deaminates A-to-I in target messenger RNA through the action of adenosine deaminases that act on RNA (ADARs). Inosine is interpreted as guanosine during translation, and the resulting non-templated recoding of the genetic information can introduce single amino acid changes that have dramatic effects on protein function. The process of A-to-I pre-mRNA editing itself has been demonstrated in both invertebrates and vertebrates, primarily in transcripts encoding voltage- and ligand-gated ion channels and receptors of the nervous system. It is the goal of this project to utilize Drosophila and other insect genera to create a natural history of RNA editing. Such a record will be used to directly address three important areas of this evolutionarily conserved but mysterious process. First, DNA sequence data from different species will be compared to identify the most highly conserved sequence elements necessary to form an ADAR substrate in a pre-mRNA and to determine the distribution of editing sites among species. Secondly, because each editing site is modified at a different frequency, levels of editing for given sites between species will be quantitated, and editing efficiency will be correlated with structural elements. Lastly, these data will be employed to genetically modify editing of particular sites or subsets of sites in vivo. Such experiments will address how the modification of individual editing sites affects organismal behavior and nervous system function. The project summarized here will not only provide molecular systematic data of a novel kind, but promises to deliver a deeper understanding of the process and purpose of RNA editing. Also, a detailed phylogenetic study of RNA editing such as this may also provide ammunition for new population genetic and molecular biogeographic studies into the distribution of variation in the editing process. Moreover, such advances will serve to assist in developing methods that would apply not only to Drosophila, but also in identifying and studying RNA editing sites in humans.