RUI: Understanding how de novo evolved genes evolve protein interactions and regulatory mechanisms in Drosophila reproduction

RUI：了解果蝇繁殖中从头进化的基因如何进化蛋白质相互作用和调节机制

• 批准号: 2212972
• 负责人: Geoffrey Findlay
• 金额: $ 66.24万
• 依托单位: College of the Holy Cross
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2212972&HistoricalAwards=false
• 关键词: RUI; Understanding; how; de; novo

Newly evolved genes, which are non-essential at first, can acquire essential roles over time, but how they do so is currently unclear. This project will use the tractable fruit fly model system to investigate how three young genes, which have gained essential functions in male fertility, evolved novel capabilities, including physical binding partners and complex expression patterns. Ultimately, these findings will shed light on the kinds of genetic changes a new gene requires to gain functionality. This project will also enhance the research capacity of an exclusively undergraduate institution, thus providing opportunities for students to conduct original research. The PI’s lab will participate in an immersive, paid summer research program for second- and third-year students and a cohort-based mentoring program for first-year students designed to bolster the persistence of first-year students from backgrounds historically underrepresented in STEM fields. The host department’s bioinformatic curriculum will be expanded through the development of a lab-based genomics course that will provide a course-based research experience to undergraduates who may not otherwise participate in original research.This project will explore how newly evolved genes that likely arose from non-protein-coding DNA sequences acquire essential functions. It will use as case studies of three genes shown previously to be essential for spermatogenesis in Drosophila melanogaster. First, an evolutionary approach will be used to estimate when each gene became essential for reproduction and to identify key amino acids stretches important for the function of the encoded protein. Specifically, the ability of both extant orthologous protein sequences and inferred ancestral sequences to rescue D. melanogaster flies lacking an endogenous copy of the gene will be measured. These experiments will generate testable hypotheses about which sequence features are required for these proteins’ essential functions in extant D. melanogaster flies. Second, to investigate how newly evolved proteins evolve functions in existing cellular networks and gain interactions with other molecules, a combination of biochemical and genetic approaches will be used to identify interacting partners of each focal protein. Third, this project will investigate how newly evolved genes gain post-transcriptional mechanisms of gene regulation and thus evolve spatiotemporal patterns of expression. These experiments will compare transcript and protein localization patterns and investigate genetically the role of different upstream and downstream regulatory regions on new gene expression.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.

新进化的基因，最初是非必需的，随着时间的推移可以获得重要的作用，但目前还不清楚它们是如何做到这一点的。该项目将使用易处理的果蝇模型系统来研究三个在雄性生育中获得重要功能的年轻基因如何进化出新的能力，包括物理结合伴侣和复杂的表达模式。最终，这些发现将揭示新基因获得功能所需的遗传变化。 该项目还将增强纯本科院校的研究能力，从而为学生提供进行原创性研究的机会。 PI的实验室将参加一个沉浸式的，付费的暑期研究计划，为二年级和三年级的学生和一个基于队列的辅导计划，为一年级的学生，旨在加强一年级学生的持久性从背景历史上代表性不足在干领域。 本项目将通过开发以实验室为基础的基因组学课程，为可能无法参与原创性研究的本科生提供基于课程的研究体验，从而扩展主办部门的生物信息学课程。本项目将探索可能来自非蛋白质编码DNA序列的新进化基因如何获得基本功能。它将作为案例研究的三个基因显示以前是必不可少的精子发生在果蝇。 首先，将使用进化方法来估计每个基因何时成为繁殖所必需的，并确定对编码蛋白质功能重要的关键氨基酸。 具体而言，现存的正向同源蛋白序列和推断的祖先序列拯救D.将测量缺乏该基因的内源拷贝的黑腹果蝇。 这些实验将产生可验证的假设，即这些蛋白质在现存的D.黑腹果蝇 其次，为了研究新进化的蛋白质如何在现有的细胞网络中进化功能并与其他分子相互作用，将使用生物化学和遗传学方法的组合来识别每个焦点蛋白质的相互作用伙伴。 第三，这个项目将研究新进化的基因如何获得基因调控的转录后机制，从而进化时空表达模式。 这些实验将比较转录本和蛋白质定位模式，并从遗传学上研究不同上游和下游调控区域对新基因表达的作用。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。