NSF Postdoctoral Fellowship in Biology FY 2022: Defining a New Paradigm Linking Genetic Variation in Human Population with mRNA Stability

2022 财年 NSF 生物学博士后奖学金：定义将人类遗传变异与 mRNA 稳定性联系起来的新范式

• 批准号: 2209388
• 负责人: Rachael Bakker
• 金额: $ 13.8万
• 依托单位: Bakker, Rachael A
• 依托单位国家: 美国
• 项目类别: Fellowship Award
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2209388&HistoricalAwards=false
• 关键词: NSF; Postdoctoral; Fellowship; Biology; FY

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2022, Integrative Research Investigating the Rules of Life Governing Interactions Between Genomes, Environment and Phenotypes. The fellowship supports research and training of the fellow that will contribute to the area of Rules of Life in innovative ways. Differences in the DNA sequence of genes between individuals are known as genetic variants. Scientists currently have unprecedented knowledge of human genetic variants due to advances in DNA sequencing. Genetic variants can cause the physical differences we can see between individuals, known as phenotypes. However, the mechanisms for how they do so are not completely understood.This research investigates how genetic variants impact molecules called messenger RNAs (mRNAs). mRNAs are instructions for making proteins that are copied from DNA and read by protein-making machinery. Recently, scientists discovered that some gene sequences make it harder for protein-making making machinery to read mRNAs, causing the cell to destroy the mRNA. This research seeks to identify genetic variants in humans that cause the mRNA to be destroyed in this way, ultimately causing phenotypes we observe. The overall goal of this research is to understand how genetic variants cause phenotypes by altering the properties of mRNAs. This knowledge will increase scientist’s ability to predict how genetic variants will affect individuals.To achieve this goal, the fellow will use a combination of high-throughput experimental and computational approaches to define the mechanism of missense mutations in regulating mRNA stability. Towards this goal, the research will identify amino acid motifs that alter mRNA stability by combining a novel massively parallel knock-in assay in cell culture and a machine learning model. The fellow will then define critical amino acid residues in the newly-translated protein chain and the ribosome that are essential for ribosome stalling using systematic mutations. Finally, the fellow will apply the predictive models and mechanistic insights to define human genetic variants that drive phenotypic changes by altering translation and mRNA stability. The proposed research will define a novel mechanism by which missense variants alter gene expression and lead to molecular, cellular and organismal phenotypes. It will provide a framework for predicting the functional relevance of single nucleotide variants in the human genome. Additionally, the fellow will gain training in state-of-the art techniques in DNA sequencing and machine learning. Further, the fellow will mentor undergraduate interns, and will teach a graduate course module in computational biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该行动为2022财年的生物学生物学研究金提供了一项NSF博士后研究奖学金，该研究研究了研究基因组，环境和表型之间相互作用的生活规则。奖学金支持对研究员的研究和培训，这些研究和培训将以创新的方式为生活规则做出贡献。个体之间基因DNA序列的差异称为遗传变异。由于DNA测序的进步，科学家目前对人类遗传变异的知识有前所未有的知识。遗传变异会导致我们可以在个人之间看到的物理差异，称为表型。但是，对其这样做的机制尚未完全理解。这项研究研究了遗传变异如何影响称为Messenger RNA（MRNA）的分子。 mRNA是制作从DNA复制并通过蛋白质制造机械读取的蛋白质的说明。最近，科学家发现，某些基因序列使制造蛋白质的机械难以读取mRNA，从而使细胞破坏mRNA变得更加困难。这项研究试图鉴定人类的遗传变异，从而导致mRNA被这种方式破坏，最终导致我们观察到的表型。这项研究的总体目标是了解遗传变异如何通过改变mRNA的性质引起表型。这些知识将提高科学家预测遗传变异将如何影响个体的能力。为了实现这一目标，研究员将使用高通量实验和计算方法的组合来定义调节mRNA稳定性中错义突变的机制。为了实现这一目标，该研究将通过结合细胞培养中的新型平行敲入测定和机器学习模型来确定改变mRNA稳定性的氨基酸基序。然后，该研究员将在新翻译的蛋白质链和核糖体中定义临界氨基酸残基，这对于使用系统突变的核糖体停滞至关重要。最后，研究员将应用预测模型和机械见解来定义人类遗传变异，这些变异通过改变翻译和mRNA稳定性来驱动表型变化。拟议的研究将定义一种新的机制，通过该机制，错义变体改变了基因表达并导致分子，细胞和有机表型。它将提供一个预测人基因组中单个核苷酸变体的功能相关性的框架。此外，该研究员将获得有关DNA测序和机器学习的最新技术培训。此外，该研究员将在心理本科生中实习生，并将教授计算生物学的研究生课程模块。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响评估标准来评估值得支持。