Unified framework for non-coding mutation analysis based on information theory

基于信息论的非编码突变分析统一框架

• 批准号: RGPIN-2015-06290
• 负责人: Rogan, Peter
• 金额: $ 2.77万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=687244
• 关键词: Unified; framework; non; coding; mutation

My research program develops bioinformatic methods for interpreting genomic sequence variation, specifically DNA or RNA elements that regulate transcription and post-transcriptional processes.There is an acute need for better approaches that distinguish deleterious variants from benign sequence changes. This proposal develops a unified framework, based on information theory, for interpretation of variants of unknown significance (VUS) in complete gene sequences and genomes. Changes in information contents of nucleic acid binding sites are a surrogate measure of affinity and can be used to accurately predict deleterious mutant binding sites. We have produced software to determine information changes at individual sites efficiently in complete genomes. Mutations that alter exon definition can be inferred with multipartite information models that account for multiple binding sites and intersite distances (ie. gap surprisal). We validate predicted gene expression changes by comparing abnormal splice isoforms in genomes containing predicted mutations causing missplicing with controls lacking these variants. This proposal develops a system for interpreting non-coding VUS, regardless of the type of binding event. Mutations affecting transcription factor binding, and RNA-binding protein stabilization of mRNA, and exon definition comprising multiple RNA binding events will be modeled. Information position weight matrices (PWM) are computed for each protein-nucleic acid interaction. These models will be cross-validated using chromatin immunoprecipitation data (from the International Epigenome Consortium) from multiple cell lines with the same transcription factors to eliminate low affinity, non-specific binding events. RNA binding sequences are processed similarly from protein cross-linking (public I- and PAR-CLIP) data. The PWMs are used to detect mutations based on information changes. Combinatorial analysis of cooperative regulation and overlapping or adjacent sites will be evaluated using information densities of site clusters, gap surprisal, or mixed models. Mutations will then be reanalyzed with these combinatorial methods for changes that correspond to promoter strength. After predicting deleterious single nucleotide variants, we will modify our case-control gene expression validation methods by computing the likelihood that a variant produces steady state changes in expression of all genes with predicted transcription factor or RNA binding site mutations, relative to controls lacking these mutations. The project will culminate with development of a system to make this unified information theory-based framework broadly available. This software will generate an abbreviated set of potentially deleterious mutations from gene panels and complete genome sequences.**

我的研究项目开发了生物信息学方法来解释基因组序列变异，特别是调节转录和转录后过程的DNA或RNA元件。迫切需要更好的方法来区分有害变异和良性序列变化。该建议开发了一个统一的框架，基于信息论，在完整的基因序列和基因组中的未知意义的变异（VUS）的解释。核酸结合位点信息含量的变化是亲和力的替代指标，可用于准确预测有害突变结合位点。我们已经开发了软件，可以有效地确定完整基因组中各个位点的信息变化。改变外显子定义的突变可以用解释多个结合位点和位点间距离（即，gap approximsal）。我们验证预测的基因表达变化，通过比较异常剪接异构体的基因组中含有预测的突变，导致错误剪接与控制缺乏这些变种。该提案开发了一个用于解释非编码VUS的系统，无论绑定事件的类型如何。将对影响转录因子结合和mRNA的RNA结合蛋白稳定性以及包含多个RNA结合事件的外显子定义的突变进行建模。计算每个蛋白质-核酸相互作用的信息位置权重矩阵（PWM）。这些模型将使用来自具有相同转录因子的多个细胞系的染色质免疫沉淀数据（来自国际表观基因组联盟）进行交叉验证，以消除低亲和力、非特异性结合事件。RNA结合序列从蛋白质交联（公共I-和PAR-CLIP）数据类似地处理。PWM用于基于信息变化检测突变。组合分析的合作监管和重叠或相邻的网站将评估使用的信息密度的网站集群，间隙的替代品，或混合模型。然后用这些组合方法重新分析突变，以确定对应于启动子强度的变化。预测有害的单核苷酸变异后，我们将修改我们的病例对照基因表达验证方法，计算的可能性，变异产生稳定状态变化的所有基因的表达与预测的转录因子或RNA结合位点突变，相对于控制缺乏这些突变。该项目最终将开发一个系统，使这一统一的信息理论为基础的框架广泛提供。该软件将从基因组和完整的基因组序列中生成一组简短的潜在有害突变。**