Over the past decade, the Dr. Jonathan Dinman laboratory at University of Maryland, College Park has established that programmed -1 ribosomal frameshifting (-1 PRF) is a molecular mechanism that is used to control the expression of approximately 10% of the genes in higher organisms. This literally translates into thousands of candidate sequences per organism. For example, our computational methods estimate that there are 1,943 high probability -1 PRF signals in the human genome alone. We have also recently identified links between defects affecting -1 PRF and a class of human diseases called “ribosomopathies”. These are largely congenital diseases with defects in ribosomal proteins and/or biogenesis factors e.g. Diamond-Blackfan Anemia (DBA), 5q- syndrome, Schwachman-Diamond syndrome (SDS) and Treacher Collins syndrome (TCS), X-linked dyskeratosis congenita (X-DC) etc.
Because of the need to stringently establish this new paradigm, our research to this point has focused on a few, very specific RNA sequences elements. Now that these ideas have gained general acceptance, it is time to expand the scope of our studies by testing and validating as many functional PRF signals as possible. We intend to follow up with questions regarding the biological and biomedical significance of -1 PRF. While cloning and assaying of each candidate sequence in mammalian cell culture represents the best high throughput approach, it is labor intensive. We propose to capitalize on the FIRE program as a multiplier of labor and time toward this end.
This is where you come in: we will provide all the tools and training that is needed to clone and test human mRNA sequences for their ability to frameshifting. Students are trained in molecular biology, cloning, sequencing, cell culture and statistical data analysis. Though no research outcome is ever guaranteed, it is our goal that the data collected in this research stream will be published with the names of all participating students listed as authors.
What have we achieved?