Sequence variations in the genomes give rise to numerous phenotypic differences. However, this DNA variation does not explain all differences, such as distinct tissues and cell types from a single person where the genome is presumably identical throughout the body. In fact, the variations in the RNA are a lot more diverse and dynamic as a means to increase complexity and diversity of higher organisms. Not only the variations from the genomic DNA reflect onto the RNA, RNA bears its own variations. For example, a same gene can be expressed at different level and spliced in different ways, under spatial and temporal manner.

We are in particular interested in RNA editing, a fine-tuning mechanism that introduces variations in RNA at the post-transcriptional level. One type of RNA editing common in metazoa, Adenosine-to-Inosine (A-to-I), is catalyzed by adenosine deaminases acting on RNA (ADAR). RNA editing is critical to life as the ADRA knockout mouse is embryonically lethal. Alteration in editing level of an individual substrate can also lead to serious pathological consequences as exemplified by the glutamate receptor GluR2 (Brusa et al., Science 1995, 270:1677-1680). However, very few editing targets were identified in the nonrepetitive regions of the human transcriptome, which became one of the major barriers in the field.

Technological advance in DNA sequencing in the past several years has offered tremendous opportunities in the RNA editing field. It allowed us to discover hundreds of new genes with A-to-I editing sites (Li et al., Science 2009, 324:1210-1213). This has increased the human RNA "editome" by over a magnitude, but may still be tip of the iceberg. We will continue to comprehensively search for new editing substrates, by taking full advantage of new DNA sequencing technologies.

The next big question is whether the RNA editing events are functional, and if so, what their specific roles are. We plan to perform a series of functional assays to screen many of the newly identified RNA editing genes, in both physiological and pathological contexts.

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