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Dark Matter: Functional Analyses of Noncanonical Transcript

We believe it is possible to extract more complete informational content from sequenced genomes and advance the operational definition of ‘genetic meaning’. We are advancing this objective through unbiased determinations of transcriptional activity at high resolution, combined with innovative functional tests available in sophisticated model systems. Toward this goal, we conducted a pilot study that applies ‘saturation tiling’ for unbiased mapping of noncanonical transcripts from a defined interval of the Drosophila genome. Our pilot study produced three salient observations. First, the scope of unannotated transcription is widespread. Second, much of this noncanonical activity was responsive to stimulus challenge. Third, stimulus-dependent RNAs were clearly linked to a master regulator that intimately regulates conventional outputs. Together, these observations provide an exciting glimpse at a potentially vast dimension of under-appreciated transcriptional activity.

To determine whether non-canonical RNAs encode authentic biologic function, we are interrogating unannotated transcripts for relevant phenotypes. Noncanonical RNAs could exert subtle activities and produce subtle phenotypes if eliminated. Consequently, as a means to both enhance sensitivity and narrow the scope of functional experiments, we are focused on stimulus-induced transcripts, since it is reasonable that some (or all) might promote adaptive responses when challenged and, accordingly, could cause stimulus-conditional phenotypes if removed. The ‘stimulus’ chosen for these studies exploits a standard protocol of radiation stress that we developed over the last decade. Tailor-made mutations that eliminate a selected collection of noncanonical RNAs are being analyzed for relevant phenotypes and other indicators of molecular activity.