Identification of intergenic trans-regulatory RNAs containing a disease-linked SNP sequence and targeting cell cycle progression/differentiation pathways in multiple common human disorders

Glinskii, Anna B.; Jun, Ma; Ma, Shuang; Grant, Denise; Lim, Chang-Uk; Sell, Stewart; Glinsky, Gennadi V.

doi:10.4161/cc.8.23.10113

Cited by 62 publications

(52 citation statements)

References 78 publications

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“…We suspect that this could be because the common disease-common variant' hypothesis ] may be much more likely to apply to noncoding sequence than to coding sequence, owing to the selectional constraints impacting upon sufficiently frequent functional variation in the latter. In similar vein, others have also estimated that 39-43% of trait/disease-associated SNPs in GWAS are located within intergenic regions [Glinskii et al, 2009;Hindorff et al, 2009]. This notwithstanding, it should be appreciated that any given variant apparently detected within a noncoding region may actually reside within a hitherto undiscovered exon .…”

Section: Mutations In Noncoding Regions Of Functional Significancementioning

confidence: 96%

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

et al. 2010

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The number of reported germline mutations in human nuclear genes, either underlying or associated with inherited disease, has now exceeded 100,000 in more than 3,700 different genes. The availability of these data has both revolutionized the study of the morbid anatomy of the human genome and facilitated “personalized genomics.” With ∼300 new “inherited disease genes” (and ∼10,000 new mutations) being identified annually, it is pertinent to ask how many “inherited disease genes” there are in the human genome, how many mutations reside within them, and where such lesions are likely to be located? To address these questions, it is necessary not only to reconsider how we define human genes but also to explore notions of gene “essentiality” and “dispensability.” Answers to these questions are now emerging from recent novel insights into genome structure and function and through complete genome sequence information derived from multiple individual human genomes. However, a change in focus toward screening functional genomic elements as opposed to genes sensu stricto will be required if we are to capitalize fully on recent technical and conceptual advances and identify new types of disease‐associated mutation within noncoding regions remote from the genes whose function they disrupt. Hum Mutat 31:631–655, 2010. © 2010 Wiley‐Liss, Inc.

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Section: Mutations In Noncoding Regions Of Functional Significancementioning

confidence: 96%

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

et al. 2010

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“…Of particular interest are RiboSNitches where the SNP or mutation is associated with a human disease (Chappell et al 2006;Kimchi-Sarfaty et al 2007;Garcia-Barcelo et al 2009;Glinskii et al 2009;Fujimoto et al 2010;Kilty et al 2010). Using the SNPfold algorithm (Halvorsen et al 2010), we predicted that two SNPs in the 59 UTR of the human FTL (Ferritin Light Chain) gene associated with hyperferritinemia cataract syndrome (a rare but dominant hereditary disorder resulting in early onset cataracts) alter the mRNA structural ensemble (Ferrari et al 2006;Sanchez et al 2006;Burdon et al 2007;Halvorsen et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Structural effects of linkage disequilibrium on the transcriptome

Martin¹,

Halvorsen²,

Davis-Neulander³

et al. 2011

RNA

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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 diseaseassociated SNPs in the 59 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 59 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.

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“…All 6,144 genes were evaluated for association with clinical and pathological variables (except survival status) using correlation analysis. Different thresholds on the P-values (0.05; 0.01; 0.001) were used for selection of gene sets with common patterns of association and concordance analysis was performed using expression profiling data of snpRNA-driven cell line-based models of prostate cancer predisposition [15,16] to identify concordant and discordant GES in cell lines and clinical samples. [17][18][19][20] GES were built based on selection of co-regulated transcripts in various experimental conditions and clinically-relevant models, including prostate cancer predisposition and longevity models.…”

Section: Patientsmentioning

confidence: 99%

Malignant field expression signatures in biopsy samples at diagnosis predict the likelihood of lethal disease in patients with localized prostate cancer

Glinsky¹

2017

JCMT

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Identification of intergenic trans-regulatory RNAs containing a disease-linked SNP sequence and targeting cell cycle progression/differentiation pathways in multiple common human disorders

Cited by 62 publications

References 78 publications

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

Structural effects of linkage disequilibrium on the transcriptome

Malignant field expression signatures in biopsy samples at diagnosis predict the likelihood of lethal disease in patients with localized prostate cancer

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