Disease-Associated Mutations That Alter the RNA Structural Ensemble

Abstract

Genome-wide association studies (GWAS) often identify disease-associated mutations in intergenic and non-coding regions of the genome. Given the high percentage of the human genome that is transcribed, we postulate that for some observed associations the disease phenotype is caused by a structural rearrangement in a regulatory region of the RNA transcript. To identify such mutations, we have performed a genome-wide analysis of all known disease-associated Single Nucleotide Polymorphisms (SNPs) from the Human Gene Mutation Database (HGMD) that map to the untranslated regions (UTRs) of a gene. Rather than using minimum free energy approaches (e.g. mFold), we use a partition function calculation that takes into consideration the ensemble of possible RNA conformations for a given sequence. We identified in the human genome disease-associated SNPs that significantly alter the global conformation of the UTR to which they map. For six disease-states (Hyperferritinemia Cataract Syndrome, β-Thalassemia, Cartilage-Hair Hypoplasia, Retinoblastoma, Chronic Obstructive Pulmonary Disease (COPD), and Hypertension), we identified multiple SNPs in UTRs that alter the mRNA structural ensemble of the associated genes. Using a Boltzmann sampling procedure for sub-optimal RNA structures, we are able to characterize and visualize the nature of the conformational changes induced by the disease-associated mutations in the structural ensemble. We observe in several cases (specifically the 5′ UTRs of FTL and RB1) SNP–induced conformational changes analogous to those observed in bacterial regulatory Riboswitches when specific ligands bind. We propose that the UTR and SNP combinations we identify constitute a “RiboSNitch,” that is a regulatory RNA in which a specific SNP has a structural consequence that results in a disease phenotype. Our SNPfold algorithm can help identify RiboSNitches by leveraging GWAS data and an analysis of the mRNA structural ensemble.

A global map for dissecting phenotypic variants in human lincRNAs

“…Because the precise functions of the majority of lincRNA sequences remain unknown, it is difficult to identify the molecular cause of disease-associated SNPs located in lincRNAs. Previous studies have shown that functional noncoding regions in the human genome had conserved RNA secondary structures, 44 and certain human diseases could be caused by variants inducing structural changes, 28 suggesting RNA structural change as a potential molecular cause of the disease. Our results found that some known disease-associated SNPs located in lincRNAs had significant effects on predicted RNA secondary structures, which might have causal effects on disease risk.…”

“…Furthermore, we used a significance calculation to search for the large structural changes caused by SNPs. 28 We computed a P-value for each lincRNA polymorphism, which was based on the total number of SNPs in a lincRNA divided by the rank of the SNP's MFE change in this lincRNA.…”

“…28 To investigate the effects of lincRNA polymorphisms on RNA secondary structures, we predicted the MFE (DG) changes caused by SNPs in human lincRNAs. The MFE change (DDG) distribution of all lincRNA polymorphisms is shown in Figure 2a.…”

The Role of Single Nucleotide Polymorphisms of Untranslated Regions (Utrs) in Insulin Resistance Pathogenesis in Patients with Type 2 Diabetes

“…Initially, investigators focused on genetic variants in regulatory regions as the cause of abnormities in gene expression during carcinogenesis. Next, more diseases have been correlated with changes in those regions (Conne et al, 2000;Pickering & Willis, 2005;Chen et al, 2006;Sethupathy & Collins, 2008;Halvorsen et al, 2010).…”

The long range regulation of breast cancer associated genes

“…Lam et al demonstrated that a 50% reduction in eRNA expression reduces the expression of target genes by a similar magnitude so the disruption of eRNA production may represent a novel mechanism by which risk SNPs act to alter local gene expression [232]. It is also interesting to note that SNP1 is contained within the sequence of the (+) strand eRNA raising the question whether it may represent a riboSNitch inducing a conformational change in RNA structure and hence alter the function of the eRNA [312].…”