Genome-wide Investigation of cis-splicing between Adjacent Genes NOSI Admin Supplement

项目总结 结构变异体的研究阐明了它们在医学和分子生物学中的重要性， 确定它们在基因表达调控、疾病中的含义和种族多样性中的作用。而当 对SVS的大规模研究已经编目了全球人口的广泛变异，发现的通常是 关于它们生产什么产品以及它们可能产生的潜在生物影响的未知后果 原因。与此同时，我们和其他人在患病和正常的人身上发现了大量的嵌合RNA 生理组织和细胞。这些RNA融合的一个子集是SVS的结果，我们称之为SVS 区别于通过基因间剪接形成的非规范嵌合RNA的典型嵌合RNA。我们 因此，我开发了一种自下而上的方法，使用在GTEx数据集中发现的嵌合RNA来识别 产生基因融合转录本的SVS。因此，它们在功能和表型上都得到了丰富 对将SVS归类为多态的传统SV预测方法的影响。每一个都可以用作 为Phewas找到相关的临床变量或患者特征提供基础，并且可以很容易地起到作用 用于个性化医疗的可检测生物标记物。在我们的初步研究中，我们发现了90多个这样的嵌合体 RNA及其相关的SVS，其中42个已在全血或淋巴细胞中被预测，这进一步 支持它们作为生物标志物的可及性。一个这样的嵌合RNA]，SUZ12P1-CRLF3，是一个复合体的结果 17q11.2上的重排，并呈现在具有非洲血统的个体中。父母的基因位于一个 在1型神经纤维瘤病(NF1)患者的子集中，区域缺失与重排本身相交 具有已知的断点删除。我们从有限的临床数据中观察到这种嵌合RNA(和 心动过速(SV)与急性脑血管疾病和身材较小有关，而且相关性较弱 有胃肠道出血，所有这些都是NF1的迹象。我们计划利用丰富的基因组集 并在全美临床数据计划中实现以下两个目标。Aim1，利用我们所有人的力量 评估SUZ12P1-CRLF3 chRNA与供者表型的相关性，包括NF1和其他临床 参数。AIM2，对剩余的92个典型嵌合RNA及其相关的SVS执行Phewas。 这些发现不仅将验证我们在识别功能性SVS方面的自下而上的方法，而且还将导致新的 对大量新奇SVS的临床洞察。

PROJECT SUMMARY Research on structural variants (SVs) has elucidated their importance to medicine and molecular biology, establishing their roles in regulation of gene expression, implications in diseases, and ethnic diversity. While large-scale studies of SVs have catalogued extensive variation in global populations, those found are often of unknown consequence in terms of what products they produce and what potential biological effects they may cause. In parallel, we and others have discovered a large number of chimeric RNAs in diseased and normal physiological tissues and cells. A subset of these RNA fusions are a consequence of SVs, which we call them canonical chimeric RNAS differentiating from the non-canonical chimeric RNAs made by intergenic splicing. We have therefore developed a bottom-up approach, using chimeric RNAs found in the GTEx dataset, to the identify SVs which produce gene fusion transcripts. These are therefore enriched for functionality and phenotypic impacts over traditional SV prediction methods, which catalogue SVs as polymorphisms. Each can be used as basis for PheWAS to find associated clinical variables or patient characteristics, and can serve as easily detectable biomarkers for personalized medicine. In our preliminary study, we uncovered over 90 such chimeric RNAs and their associated SVs, 42 of which have been predicted in whole blood or lymphocytes, which further supports their accessibility as biomarkers. One such chimeric RNA], SUZ12P1-CRLF3, is the result of a complex rearrangement on 17q11.2 and presents in individuals with African ancestry. The parental genes lie within a region deleted in a subset of type 1 neurofibromatosis (NF1) patients, and the rearrangement itself, intersects with known breakpoint deletions. We have observed from our limited clinical data that this chimeric RNA (and SV) is associated with acute cerebrovascular disease and smaller stature, and also exhibits a weaker association with gastrointestinal hemorrhage, all of which are indications of NF1. We plan to leverage the rich set of genomic and clinical data in All Of US program to achieve the following two goals. Aim1, Utilize the All of Us cohort to assess associations of the SUZ12P1-CRLF3 chiRNA with donor phenotypes, including NF1 and other clinical parameters. Aim2, Perform PheWAS on the remaining 92 canonical chimeric RNAs and their associated SVs. The findings will not only validate our bottom-up approach in identifying functional SVs, but also lead to novel clinical insights on a large number of novel SVs.