Structural and functional consequences of disease SNPs on 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年；Lee等人。2008年；Mathew 2008；Glinskii等人。2009年)。在许多情况下，特别是当相关的基因型映射到基因组的非编码区时，单靠遗传数据并不能揭示疾病的分子原因(Glinskii等人。2009年)。在大多数情况下，基因组的非编码区被转录成RNA(核糖核酸)(Weinstock 2007)，如果与疾病相关的突变改变了转录本的结构，这可能会产生功能后果(Halvorsen等人)。2010)。我们最近在mRNA转录本的调节区中发现了与疾病相关的SNPs(单核苷酸多态)，它显著改变了转录本的折叠。与细菌RiBoswitch非常相似(Tucker和Breaker，2005)，如果存在特定的SNP，RiboSNitch采用显著改变的构象(Halvorsen等人。2010)。此外，我们还表明，二次突变和基因特异性锁定核酸(LNAs)的结合可以挽救RNA的结构和调节功能。我们假设，特定的单倍型(处于高连锁不平衡的SNPs组合)将稳定某些转录本。我们建议使用我们的预测性SNPold(Halvorsen等人)。2010)算法(对可能的RNA构象集合进行建模)，以识别人类基因组中稳定RNA结构的单倍型，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影响。

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.