Supplement: CRISPR screens of population relevant genes governing toxicant resilience

摘要 本附录的目的是通过支持残疾人来增强研究队伍的多样性。 研究生对PA-21-071的回应(促进健康相关多样性的研究副刊 研究)。这项补充将使残疾学生能够在家长助学金的PI实验室工作 通过为他提供津贴和学费支持，以及允许聘请专门的技术研究人员 为需要良好马达能力的拟议工作的组成部分提供助理。此外，导师制， 职业发展支持，有针对性的培训努力，以及合理的住宿安排将使学生能够 继续从事科学事业，同时应对残疾带来的挑战。父辈 Grant专注于GxE与外部应激源的相互作用，但假设应用于GxE与 内源性应激源，如先前存在的单基因遗传病，这是补充的重点。 我们选择了单基因疾病，弗里德里希共济失调(FRDA)，一种进行性神经退行性疾病 通常是由于Frataxin基因的三重重复突变所致。而三联体重复长度在 疾病的表现，其他未知的遗传和环境因素显然起到了作用。我们将评估 我们新的靶向功能筛选方法能够识别当被干扰时可以 调节FRDA的细胞表型。与家长赠款一样，工作重点将放在~1490 在人群中具有常见LOF突变的基因，并将通过评估 相关细胞的转录表型。如果这项工作成功，将为我们提供重要的洞察 影响Friedrich共济失调的表现和进展的常见LOF变体。此功能 使用转录表型终点的筛选方法可以普遍适用于任何基因 并能够识别潜在的重要功能和与种群相关的遗传变异 影响疾病的表型表现。

Summary The goal of this supplement is to enhance diversity in the research workforce through support of a disabled graduate student in response to PA-21-071(Research Supplement to Promote Diversity in Health-Related Research). This supplement will enable the disabled student to work in the laboratory of the PI of parent grant by providing support for his stipend and tuition, as well as allowing the hiring of a dedicated technical research assistant for the components of the proposed work requiring fine motor capabilities. In addition, mentorship, career development support, targeted training efforts, and reasonable accommodations will enable the student to continue to pursue a scientific career while navigating the challenges presented by his disability. The parent grant focuses on GXE interactions with exogenous stressors but posited application to GXE interactions with endogenous stressors, such as a pre-existing monogenic genetic disorder, which is the focus of the supplement. We selected the monogenic disorder, Friedrich’s ataxia (FRDA), a progressive neurodegenerative disorder most commonly due to triplet repeat mutations in the frataxin gene. While triplet repeat length plays a role in the disease presentation, other unknown genetic and environmental factors clearly contribute. We will assess the capability of our novel targeted functional screening approach to identify genes which when disrupted could modulate the cellular phenotype of FRDA. As with the parent grant, the work will focus on the set of ~1490 genes with common LOF mutations in the population and will assess functional effect by assessing changes in the transcriptional phenotype of relevant cells. This work if successful could provide important insight into common LOF variants that impact the presentation and progression of Friedrich’s ataxia. This functional screening approach using transcriptional phenotypic endpoints could have general applicability to any genetic disease and enable identification of potentially functionally significant and population relevant genetic variants impacting the phenotypic manifestations of the disease.