The functional effects of RNA structure: from riboSNitches to translational control

Ribonucleic Acid (RNA) is a nucleotide polymer that, like Deoxyribonuclic acid (DNA), has an essential role in in the cell. RNA molecules are structurally distinct from DNA in the diversity of structures they adopt, due to stable intramolecular interactions. There exist a few well-defined cases of functional RNA structures, but many classes of RNA, including mRNA, adopt more flexible structures that are poorly characterized and unlinked to biological function. Accurate structure determination is thus essential to the study of RNAs. Much work involving RNA structure relies on computational prediction of RNA secondary structures. Here I briefly summarize RNA structure prediction and how genetic variation can alter RNA structure. By benchmarking algorithms that detect single nucleotide variant-induced structural change, we show that considering the full set of structures an RNA may adopt is crucial for the most accurate predictions. Conversely, constraining computational prediction with experimental structure probing data has been shown to greatly improve single-structure predictions. Thus incorporating structure probing data like 2'-hydroxyl acylation analyzed by primer extension mutational profiling (SHAPE-MaP) is an alternative approach for modeling structural features of RNAs. In order to explore structure-function relationships in a model RNA we gathered SHAPE-MaP structural data on a set of mRNAs derived from the human gene SERPINA1. Here I discuss the effect structure may have on mRNAs, especially during protein translation. We show with SHAPE-MaP constrained structure prediction that RNA structure has a role in determining SERPINA1 protein translation efficiency and that this effect can be quantitatively modeled.Doctor of Philosoph