Supplement: CRISPR screens of population relevant genes governing toxicant resilience

总结 该补助金的目标是通过对残疾人的支持来增强研究人员队伍的多样性 研究生在响应PA-21-071（研究补充，以促进健康相关的多样性 研究）。这笔补助金将使残疾学生能够在家长补助金的PI实验室工作 通过提供他的津贴和学费，以及允许雇用一个专门的技术研究， 助理的组成部分，拟议的工作需要精细运动能力。此外，辅导， 职业发展支持，有针对性的培训工作和合理的住宿将使学生能够 继续追求科学事业，同时应对残疾带来的挑战。母 格兰特专注于GXE与外源性压力源的相互作用，但假定应用于GXE与 内源性压力源，如预先存在的单基因遗传疾病，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， 通常是由于共济失调蛋白基因中的三联重复突变。虽然三联体重复长度在 疾病的表现，其他未知的遗传和环境因素显然有助于。我们将评估 我们新的靶向功能筛选方法鉴定基因的能力， 调节FRDA的细胞表型。与父母补助金一样，工作将集中在~1490的一套 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。这项工作如果成功，可以提供重要的见解， 影响Friedrich共济失调的表现和进展的常见LOF变异。该功能 使用转录表型终点的筛选方法可以普遍适用于任何遗传 疾病，并能够鉴定潜在的功能上重要的和群体相关的遗传变异 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.