Genetic association studies identify the genotypes that correlate with specific phenotypes. A significant portion of the Single Nucleotide Polymorphisms (SNPs) that associate with human disease phenotypes map outside of the protein coding regions of genes. In these cases, the precise molecular mechanism of the disease etiology is not immediately apparent. This proposal focuses specifically on SNPs that map to non-coding and UnTranslated Regions (UTRs) of genes. If these SNPs alter the structure of the RNA, they are classified as a riboSNitch. We will experimentally validate eight novel, computationally predicted riboSNitches associated with the human diseases amyotrophic lateral sclerosis, breast and colorectal cancer, dyskeratosis, Hirschsprung's disease, lipase deficiency, microcephalic dwarfism, and schizophrenia. Our work will leverage significant advances in the throughput and accuracy of chemical structure probing techniques in combination with next generation sequencing. Furthermore, these techniques now enable us to probe RNA structure in vivo allowing us to further understand how the cellular environment affects RNA folding and the function of riboSNitches. We will also perform quantitative luciferase reporter assays and leverage Tet-off inducible systems to study the functional consequences of validated riboSNitches on translation and RNA stability to establish disease causality. Together, our findings will establish SNP-induced RNA structure change in multiple new human diseases and broaden understanding of RNA structure in shaping human phenotype.
This project aims to understand the effects of disease-associated mutations on the structure and function of RNA (RiboNucleic Acid). Mutations are copied from DNA into RNA and, in some cases, they cause the RNA to misfold, resulting in aberrant regulation and disease. We will develop and experimentally validate computer algorithms that are highly predictive of the effects of mutations on RNA structure in living human cells, to identify novel genetic mechanisms of disease caused by RNA structure change.
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