Understanding the effect of adaptive mutations on the three-dimensional structure of RNA

Single-nucleotide polymorphisms (SNPs) are variations in the genome where one base pair can differ between individuals.1 SNPs occur throughout the genome and can correlate to a disease-state if they occur in a functional region of DNA.1According to the central dogma of molecular biology, any variation in the DNA sequence will have a direct effect on the RNA sequence and will potentially alter the identity or conformation of a protein product. A single RNA molecule, due to intramolecular base pairing, can acquire a plethora of 3-D conformations that are described by its structural ensemble. One SNP, rs12477830, which was previously shown to harbor signatures of positive selection by Sugden et. al,3 was passed through multiple RNA folding algorithms. The results of SNPfold 2 demonstrate that the SNP significantly alters the structural ensemble, and the significance of this change offers a potential explanation of SWIF(r)’s result.3 Furthermore, the RNAfold Webserver 4-6reveals that the mutant RNA molecule is more stable than the wild-type with a more negative free energy and a higher frequency. These loci of variation should be studied in order to understand the potentially induced conformational changes that could significantly alter the functional capacity of an RNA molecule. Future work aims to assess conformational changes elicited by SNPs previously shown to harbor signatures of positive selection using ancestry-specific reference genomes to better understand motivations behind a locus experiencing positive selective pressure