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PMID: 20808897 Published · epublish English Journal Article Research Support, N.I.H., Extramural

Disease-associated mutations that alter the RNA structural ensemble.

PLoS genetics ·Vol. 6 ·No. 8 ·2010-08-19 ·Pages e1001074

Halvorsen M, Martin JS, Broadaway S, Laederach A

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.

MeSH Terms
Disease/genetics Genome, Human Genome-Wide Association Study Humans Mutation Nucleic Acid Conformation Polymorphism, Single Nucleotide RNA/chemistry,genetics Untranslated Regions
Chemicals
Untranslated Regions RNA
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Halvorsen Matthew
Biomedical Sciences Department, University at Albany, Albany, New York, USA.
Martin Joshua S
Broadaway Sam
Laederach Alain
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1001074
Published
2010-08-19
Epub
2010-00-19
Pages
e1001074
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2924325
Subset
IM
Grants
NIGMS NIH HHS · R00 GM079953 · United States
NIMH NIH HHS · R21 MH087336 · United States
Corrections
CommentIn
PMID: 20820181
External Links
PubMed source DOI: 10.1371/journal.pgen.1001074 PMC Full Text View journal details
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