Structural and functional consequences of disease SNPs on the transcriptome

疾病 SNP 对转录组的结构和功能影响

• 批准号: 8842659
• 负责人: Alain T Laederach
• 金额: $ 27.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842659
• 关键词: 5' Untranslated Regions; Accounting; Adopted; Affect; Algorithms; Base Pairing; Binding; Binding Proteins; Binding Sites; Biological Assay; Blood capillaries; Cataract; Cells; Cellular Structures; Chemical Structure; Computational algorithm; Computer Simulation; DNA Sequence Alteration; Data; Data Reporting; Detection; Development; Disease; Elements; Exons; Ferritin; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genotype; Haplotypes; Human; Human Genetics; Human Genome; Introns; Iron; Length; Light; Linkage Disequilibrium; Maps; Mediating; Messenger RNA; Modeling; Molecular; Molecular Conformation; Mutation; Nucleic Acid Regulatory Sequences; Oryctolagus cuniculus; Performance; Phenotype; Predictive Value; Probability; Process; Protein Binding; Publishing; RB1 gene; RNA; RNA-Binding Proteins; Regulation; Regulatory Element; Response Elements; Reticulocytes; Retinoblastoma; Role; Single Nucleotide Polymorphism; Structure; Syndrome; System; Techniques; Testing; Tetracyclines; Thalassemia; Transcript; Translations; Untranslated RNA; Untranslated Regions; Validation; capillary; disease phenotype; functional restoration; genetic linkage; genome wide association study; high throughput technology; human disease; improved; in vivo; interest; locked nucleic acid; mRNA Stability; next generation sequencing; novel

DESCRIPTION (provided by applicant): Large-scale genetic studies identify new associations between genotype and disease-phenotype (Benjamin et al. 2007; Lee et al. 2008; Mathew 2008; Glinskii et al. 2009). In many cases, and in particular when the associated genotype maps to a non-coding region of the genome, the genetic data alone does not reveal the molecular cause of the disease (Glinskii et al. 2009). Non-coding regions of the genome are in a majority of cases transcribed into RNA (Ribonucleic acid) (Weinstock 2007), and if a disease-associated mutation alters the structure of the transcript, this may have functional consequences (Halvorsen et al. 2010). We have recently identified disease-associated SNPs (Single Nucleotide Polymorphisms) in the regulatory regions of mRNA transcripts that significantly alter the folding of the transcript. Much like bacterial Riboswitches (Tucker and Breaker 2005), RiboSNitches adopt significantly altered conformations if a specific SNP is present (Halvorsen et al. 2010). Furthermore, we have shown that secondary mutations and binding of genotype specific locked nucleic acids (LNAs) can rescue the structure and regulatory function of the RNA. We hypothesize that specific haplotypes (combinations of SNPs in high linkage disequilibrium) will stabilize certain transcripts. We propose to use our predictive SNPfold (Halvorsen et al. 2010) algorithm (which models the ensemble of possible RNA conformations) to identify RNA structure-stabilizing haplotypes in the human genome and thus discover and experimentally validate novel posttranscriptional cellular regulatory mechanisms. We are fundamentally interested in understanding the structural consequences of common genetic variation on the function of the transcriptome.

描述（由申请人提供）：大规模遗传研究确定了基因型和疾病表型之间的新关联（Benjamin et al. 2007; Lee et al. 2008; Mathew 2008; Glinskii et al. 2009）。在许多情况下，特别是当相关基因型映射到基因组的非编码区时，单独的遗传数据并不能揭示疾病的分子原因（Glinskii et al. 2009）。在大多数情况下，基因组的非编码区转录为RNA（核糖核酸）（Weinstock 2007），如果疾病相关突变改变了转录物的结构，则可能会产生功能性后果（Halvorsen et al. 2010）。我们最近已经确定了疾病相关的SNP（单核苷酸多态性）在mRNA转录的调控区，显着改变转录的折叠。与细菌核糖开关非常相似（Tucker和Breaker 2005），如果存在特定SNP，则RiboSNitch会采用显著改变的构象（Halvorsen等人，2010）。此外，我们已经表明，二次突变和基因型特异性锁核酸（LNA）的结合可以拯救RNA的结构和调节功能。我们假设特定的单倍型（高连锁不平衡的SNP组合）将稳定某些转录本。我们建议使用我们的预测SNPfold（Halvorsen et al. 2010）算法（该算法对可能的RNA构象的集合进行建模）来识别人类基因组中的RNA结构稳定单倍型，从而发现并实验验证新的转录后细胞调控机制。我们从根本上感兴趣的是了解常见遗传变异对转录组功能的结构后果。