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

项目摘要 对结构变异体（SV）的研究已经阐明了它们对医学和分子生物学的重要性， 确定它们在基因表达调控、疾病影响和种族多样性中的作用。而 对SV的大规模研究已经记录了全球人群的广泛变化，这些发现通常是 就它们产生的产物以及它们可能产生的潜在生物学效应而言， 事业与此同时，我们和其他人已经发现了大量的嵌合RNA在患病和正常的细胞中， 生理组织和细胞。这些RNA融合的一个子集是SV的结果，我们称之为SV。 典型的嵌合RNAS与通过基因间剪接产生的非典型嵌合RNA不同。我们 因此，他们开发了一种自下而上的方法，使用GTEx数据集中发现的嵌合RNA， 产生基因融合转录物的SV。因此，这些基因富含功能性和表型 传统的SV预测方法将SV归类为多态性。每个都可以用作 PheWAS发现相关临床变量或患者特征的基础，并可轻松作为 可检测的生物标志物，用于个性化医疗。在我们的初步研究中，我们发现了超过90个这样的嵌合体， RNA及其相关SV，其中42种已在全血或淋巴细胞中预测， 支持它们作为生物标志物的可访问性。一种这样的嵌合RNA，SUZ 12 P1-CRLF 3，是复合物的结果。 在17q11.2上的重排，并在具有非洲血统的个体中呈现。亲本基因位于 在1型神经纤维瘤病（NF 1）患者的一个亚组中缺失的区域，以及重排本身， 已知的断点删除。我们从我们有限的临床数据中观察到，这种嵌合RNA（和 SV）与急性脑血管病和身材矮小有关， 伴有胃肠道出血，所有这些都是NF 1的适应症。我们计划利用丰富的基因组 和临床数据，以实现以下两个目标。目标1，利用我们所有人队列， 评估SUZ 12 P1-CRLF 3 chiRNA与供体表型的关联，包括NF 1和其他临床 参数目标2，对其余92个典型嵌合RNA及其相关SV进行PheWAS。 这些发现不仅验证了我们自下而上的方法在识别功能性SV方面的有效性，而且还导致了新的 对大量新型SV的临床见解。

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.