MODELING THE EFFECTS OF STRUCTURAL VARIATION IN GTEX DATA AND MENDELIAN DISEASE

描述（由申请人提供）：少数突变过程在人类生殖系上运行，形成小的插入和缺失（indels），大拷贝数变异（cnv），倒位，易位和更复杂的染色体结构变化。这些不同的突变统称为结构变异（SV）。评估疾病中单基因和罕见结构变异的功能和致病影响是当今人类遗传学中最紧迫和研究不足的问题之一。在这里，我们描述了将结构变异整合到eQTL研究中的方法创新，然后将从GTEx数据中获得的知识转化为可被广泛研究人员使用的概率致病性评估工具。我们将试点将sv和单核苷酸变异（snv）整合到一个连贯框架中的新方法。这一整合努力的核心将是一种新的基于模型的致病性评估方法，该方法将整合(1)从GTEx分析中收集的知识，(2)孟德尔疾病基因分类的最新突破，以及(3)从基于阵列和测序的严重孟德尔疾病和其他儿科疾病的研究中迅速扩展的已知疾病突变集。该方法将是第一个用于SVs和snv通用功能评估的工具，并将解释影响编码区和/或非编码区的变异。

DESCRIPTION (provided by applicant): A handful of mutation processes operate on the human germline to form small insertions and deletions (indels), large copy number variants (CNVs), inversions, translocations and more complex changes in chromosome structure. These diverse mutations are collectively referred to as structural variation (SV). Assessing the functional and pathogenic impact of singleton and rare structural variants in disease is one of the most pressing and understudied problems in human genetics today. Here we describe methodological innovations for integrating structural variation into eQTL studies, and then transforming knowledge learned from GTEx data into a probabilistic pathogenicity assessment tool that can be used by a wide range of researchers. We will pilot new approaches for integrating SVs and single nucleotide variants (SNVs) in a coherent framework. The centerpiece of this integrative effort will be a new model- based pathogenicity assessment method that will integrate (i) knowledge gleaned from GTEx analyses, (ii) recent breakthroughs in classification of Mendelian disease genes, and (iii) the rapidly expanding set of known disease mutations matriculating from array- and sequencing-based studies of severe Mendelian and other pediatric diseases. This method will be the first tool for generic functional assessment of both SVs and SNVs and will interpret variation affecting coding and/or non-coding regions.