Diagrammatic approaches to RNA structures with trinucleotide repeats

Abstract

Trinucleotide repeat expansion disorders are associated with the overexpansion of (CNG) repeats on the genome. Messenger RNA transcripts of sequences with greater than 60–100 (CNG) tandem units have been implicated in trinucleotide repeat expansion disorder pathogenesis. In this work, we develop a diagrammatic theory to study the structural diversity of these (CNG)n RNA sequences. Representing structural elements on the chain’s conformation by a set of graphs and employing elementary diagrammatic methods, we have formulated a renormalization procedure to re-sum these graphs and arrive at a closed-form expression for the ensemble partition function. With a simple approximation for the renormalization and applied to extended (CNG)n sequences, this theory can comprehensively capture an infinite set of conformations with any number and any combination of duplexes, hairpins, multiway junctions, and quadruplexes. To quantify the diversity of different (CNG)n ensembles, the analytical equations derived from the diagrammatic theory were solved numerically to derive equilibrium estimates for the secondary structural contents of the chains. The results suggest that the structural ensembles of (CNG)n repeat sequence with n ∼60 are surprisingly diverse, and the distribution is sensitive to the ability of the N nucleotide to make noncanonical pairs and whether the (CNG)n sequence can sustain stable quadruplexes. The results show how perturbations in the form of biases on the stabilities of the various structural motifs, duplexes, junctions, helices, and quadruplexes could affect the secondary structures of the chains and how these structures may switch when they are perturbed.