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, beta-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.

• Authors: Matthew Halvorsen, Joshua S Martin, Sam Broadaway, Alain Laederach
• Journal: PLoS genetics (PLoS Genet) Vol. 6 Issue 8 Pg. e1001074 (Aug 19 2010) ISSN: 1553-7404 [Electronic] United States
• PMID: 20808897 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Untranslated Regions
• RNA

Topics

• Disease (genetics)
• Genome, Human
• Genome-Wide Association Study
• Humans
• Mutation
• Nucleic Acid Conformation
• Polymorphism, Single Nucleotide
• RNA (chemistry, genetics)
• Untranslated Regions