Background: Single-stranded, negative-sense RNA (ssRNA-) serves many varied roles within the eukaryotic cell. Currently known examples include snRNA (short nuclear), snoRNA (short nucleolar), tRNA (transfer), siRNA (silencing), miRNA (micro), and others [1,2]. Unknown examples are currently being studied, also, including the long, non-coding ssRNA- found in the nuclear paraspeckle, a component of unknown function located within the eukaryotic nucleus and comprised of ssRNA- sequences transcribed from so-called ‘junk’ DNA [3,4]. While a growing list of confirmed physiological functions have been attributed to ssRNA-, additional roles likely exist and have yet to be discovered. Further, since ssRNA- is known to bind to proteins, nucleic polymers (DNA and RNA), small molecules and metallic ions, unknown roles attributable to such sequences are likely to be surprisingly diverse and of potential benefit to the modern warfighter. Unfortunately, contemporary biological assays for identifying functional ssRNA- sequences within eukaryotic cells are cumbersome, time-consuming and costly. Further, despite recent advances in software for folding ssRNA-, the computational process of folding the entire human genome remains an intractable problem.
To resolve the traditional problems associated with this process, the proposed method leverages the long-term evolution of obligate intracellular parasites with small ssRNA- genomes to reduce the size and scope of the problem domain. These species have been evolving, adapting and attenuating cellular behavior to affect human physiology over the course of eons. Recent evidence suggests inter-genomic host-parasite interactions are vital to their continuing exploitation of eukaryotic physiology and successful evasion of host immunities [5, and unpublished dissertation results]. As a result of natural, long-term experimentation, these organisms have hypothetically derived many secondary and tertiary ssRNA- structures exhibiting vital influence within human physiology. Therefore, the proposed method will use inexpensive and open source software (Rosetta or ViennaRNA) to fold various pathogenic ssRNA- genomes, isolate functional single-stranded ‘loop’ sequences among the resultant structures, and then compare these short sequences to the human transcriptome using a novel computational protocol to identify structures related to human genes of interest (e.g., genes related to physiology, toxicity or to mitigation of toxicity). The resultant RNA sequence library should provide a rich source of multi-functional molecules with diverse applications to eukaryotic cellular control and potential association with high level physiological behaviors and dynamics.
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