title: Structural effects of linkage disequilibrium on the transcriptome.
abstract: A majority of SNPs (single nucleotide polymorphisms) map to noncoding and intergenic regions of the genome. Noncoding SNPs are often identified in genome-wide association studies (GWAS) as strongly associated with human disease. Two such disease-associated SNPs in the 5' UTR of the human FTL (Ferritin Light Chain) gene are predicted to alter the ensemble of structures adopted by the mRNA. High-accuracy single nucleotide resolution chemical mapping reveals that these SNPs result in substantial changes in the structural ensemble in agreement with the computational prediction. Furthermore six rescue mutations are correctly predicted to restore the mRNA to its wild-type ensemble. Our data confirm that the FTL 5' UTR is a "RiboSNitch," an RNA that changes structure if a particular disease-associated SNP is present. The structural change observed is analogous to that of a bacterial Riboswitch in that it likely regulates translation. These data further suggest that specific pairs of SNPs in high linkage disequilibrium (LD) will form RNA structure-stabilizing haplotypes (SSHs). We identified 484 SNP pairs that form SSHs in UTRs of the human genome, and in eight of the 10 SSH-containing transcripts, SNP pairs stabilize RNA protein binding sites. The ubiquitous nature of SSHs in the transcriptome suggests that certain haplotypes are conserved to avoid RiboSNitch formation.
authors: Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Joshua S
authors: JS
authors: Martin
authors: Matthew
authors: M
authors: Halvorsen
authors: Lauren
authors: L
authors: Davis-Neulander
authors: Justin
authors: J
authors: Ritz
authors: Chetna
authors: C
authors: Gopinath
authors: Arthur
authors: A
authors: Beauregard
authors: Alain
authors: A
authors: Laederach
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D001052:Apoferritins / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D009154:Mutation; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000737:chemistry / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; C507433:FTL protein, human; D016601:RNA-Binding Proteins; D012313:RNA; D001052:Apoferritins