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      Disease-Associated Mutations That Alter the RNA Structural Ensemble

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          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.

          Author Summary

          Genome-wide association studies identify mutations in the human genome that correlate with a particular disease. It is common to find mutations associated with disease in the non-coding region of the genome. These non-coding mutations are more difficult to interpret at a molecular level, because they do not affect the protein sequence. In this study, we analyze disease-associated mutations in non-coding regions of our genome in the context of their structural effect on the message of genetic information in our cells, Ribonucleic Acid (RNA). We focus in particular on the regulatory parts of our genes known as untranslated regions. We find that certain disease-associated mutations in these regulatory untranslated regions have a significant effect on the structure of the RNA message. We call these elements “RiboSNitches,” because they act like switches turning on and off genes, but are caused by Single Nucleotide Polymorphisms (SNPs), which are single point mutations in our genome. The RiboSNitches we identify are potentially a new class of pharmaceutical targets, as it is possible to change the structure of RNA with small drug-like molecules.

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          Most cited references61

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          Common regulatory variation impacts gene expression in a cell type-dependent manner.

          Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiling and association with genetic variants (single-nucleotide polymorphisms) on three cell types of 75 individuals. We detected cell type-specific genetic effects, with 69 to 80% of regulatory variants operating in a cell type-specific manner, and identified multiple expressive quantitative trait loci (eQTLs) per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type-specific eQTLs were found at larger distances from genes and at lower effect size, similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell-type specificity.
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            The UCSC Genome Browser Database: 2008 update

            The University of California, Santa Cruz, Genome Browser Database (GBD) provides integrated sequence and annotation data for a large collection of vertebrate and model organism genomes. Seventeen new assemblies have been added to the database in the past year, for a total coverage of 19 vertebrate and 21 invertebrate species as of September 2007. For each assembly, the GBD contains a collection of annotation data aligned to the genomic sequence. Highlights of this year's additions include a 28-species human-based vertebrate conservation annotation, an enhanced UCSC Genes set, and more human variation, MGC, and ENCODE data. The database is optimized for fast interactive performance with a set of web-based tools that may be used to view, manipulate, filter and download the annotation data. New toolset features include the Genome Graphs tool for displaying genome-wide data sets, session saving and sharing, better custom track management, expanded Genome Browser configuration options and a Genome Browser wiki site. The downloadable GBD data, the companion Genome Browser toolset and links to documentation and related information can be found at: http://genome.ucsc.edu/.
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              Sfold web server for statistical folding and rational design of nucleic acids.

              The Sfold web server provides user-friendly access to Sfold, a recently developed nucleic acid folding software package, via the World Wide Web (WWW). The software is based on a new statistical sampling paradigm for the prediction of RNA secondary structure. One of the main objectives of this software is to offer computational tools for the rational design of RNA-targeting nucleic acids, which include small interfering RNAs (siRNAs), antisense oligonucleotides and trans-cleaving ribozymes for gene knock-down studies. The methodology for siRNA design is based on a combination of RNA target accessibility prediction, siRNA duplex thermodynamic properties and empirical design rules. Our approach to target accessibility evaluation is an original extension of the underlying RNA folding algorithm to account for the likely existence of a population of structures for the target mRNA. In addition to the application modules Sirna, Soligo and Sribo for siRNAs, antisense oligos and ribozymes, respectively, the module Srna offers comprehensive features for statistical representation of sampled structures. Detailed output in both graphical and text formats is available for all modules. The Sfold server is available at http://sfold.wadsworth.org and http://www.bioinfo.rpi.edu/applications/sfold.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                August 2010
                August 2010
                19 August 2010
                : 6
                : 8
                : e1001074
                Affiliations
                [1 ]Biomedical Sciences Department, University at Albany, Albany, New York, United States of America
                [2 ]Developmental Genetics and Bioinformatics, Wadsworth Center, Albany, New York, United States of America
                National Institute of Genetics, Japan
                Author notes

                Conceived and designed the experiments: MH AL. Performed the experiments: MH JSM. Analyzed the data: MH JSM SB. Wrote the paper: MH JSM AL.

                Article
                10-PLGE-RA-NV-2665R2
                10.1371/journal.pgen.1001074
                2924325
                20808897
                b2c3f481-06d9-42a7-8500-a86f96764f9a
                Halvorsen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 24 February 2010
                : 15 July 2010
                Page count
                Pages: 11
                Categories
                Research Article
                Genetics and Genomics/Bioinformatics
                Genetics and Genomics/Epigenetics
                Genetics and Genomics/Genetics of Disease
                Genetics and Genomics/Population Genetics

                Genetics
                Genetics

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