Scope of collateral fitness effects and their mechanisms
附带适应性效应的范围及其机制
基本信息
- 批准号:2113019
- 负责人:
- 金额:$ 99.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Standard Grant
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Understanding the effects of protein mutations is fundamentally important in the study of molecular evolution. Harmful mutations are generally understood to cause negative effects by disrupting the normal functions of the affected protein. However, the deleterious effects of mutations might also arise from causing the mutated protein to do things it should not do, such as interfere with unrelated biological processes. This project is a systematic study of the effects of all possible mutations in three proteins. This will contribute to the understanding of how proteins evolve and the mechanisms by which mutations can affect cell physiology. Such knowledge is important for understanding human disease and the evolution of antibiotic resistance. Each year of this research, three graduate students, two undergraduates, and one high school student will be trained in research. The graduate students will present research at scientific conferences and gain mentorship experience supervising the undergraduate and high school students. The distribution of fitness effects of mutations plays a central role in setting protein evolution rates, but the molecular underpinnings of this constraint are unclear. One possibility is that mutant proteins misfold or misinteract with other proteins with deleterious consequences. Such effects are examples of collateral fitness effects, as opposed to primary fitness effects that derive from changes in the physiological function of the protein. Very little is known about the frequency, magnitude, and mechanisms of collateral fitness effects, but such information is critical for understanding protein evolution. This research will comprehensively determine the collateral fitness effects of mutations in three proteins using growth competition and next-generation sequencing techniques in Escherichia coli. Molecular biology techniques will be used to discover the mechanisms behind select mutational effects. This study will generate a wealth of data from which to understand the contribution of collateral fitness effects to evolution.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.
了解蛋白质突变的影响在分子进化研究中至关重要。有害突变通常被理解为通过破坏受影响蛋白质的正常功能而引起负面影响。然而,突变的有害影响也可能来自于导致突变蛋白质做它不应该做的事情,例如干扰无关的生物过程。该项目是对三种蛋白质中所有可能突变的影响的系统研究。这将有助于理解蛋白质如何进化以及突变影响细胞生理学的机制。这些知识对于了解人类疾病和抗生素耐药性的演变非常重要。每年的研究,三名研究生,两名本科生,一名高中生将在研究培训。 研究生将在科学会议上展示研究成果,并获得指导本科生和高中生的指导经验。突变的适应性效应的分布在设定蛋白质进化速率中起着核心作用,但这种约束的分子基础尚不清楚。一种可能性是突变蛋白质错误折叠或与其他蛋白质错误相互作用,从而产生有害后果。这种效应是附带适应性效应的例子,与来自蛋白质生理功能变化的主要适应性效应相反。关于附带适应性效应的频率、大小和机制知之甚少,但这些信息对于理解蛋白质进化至关重要。这项研究将全面确定在大肠杆菌中使用生长竞争和下一代测序技术的三种蛋白质突变的附带适应性效应。分子生物学技术将用于发现选择突变效应背后的机制。 这项研究将产生丰富的数据,从中了解的贡献,附带健身效果evolution.This奖项反映了NSF的法定使命,并已被认为是值得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的支持。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Marc Ostermeier其他文献
Finding Cinderella's slipper—proteins that fit
寻找灰姑娘的拖鞋——合适的蛋白质
- DOI:
10.1038/10850 - 发表时间:
1999-07-01 - 期刊:
- 影响因子:41.700
- 作者:
Marc Ostermeier;Stephen J. Benkovic - 通讯作者:
Stephen J. Benkovic
Marc Ostermeier的其他文献
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{{ truncateString('Marc Ostermeier', 18)}}的其他基金
Frequency, magnitude, and mechanisms of collateral fitness effects of mutations
突变的附带适应性影响的频率、幅度和机制
- 批准号:
1817646 - 财政年份:2018
- 资助金额:
$ 99.21万 - 项目类别:
Standard Grant
UNS: Collaborative Research: Targeted CpG Methylation
UNS:合作研究:靶向 CpG 甲基化
- 批准号:
1510652 - 财政年份:2015
- 资助金额:
$ 99.21万 - 项目类别:
Standard Grant
Alternative pathways in directed evolution
定向进化的替代途径
- 批准号:
1402101 - 财政年份:2014
- 资助金额:
$ 99.21万 - 项目类别:
Standard Grant
The distribution of epistatic effects within and between genes
基因内部和基因之间上位效应的分布
- 批准号:
1353143 - 财政年份:2014
- 资助金额:
$ 99.21万 - 项目类别:
Standard Grant
The fitness landscape of genes and proteins
基因和蛋白质的适应度景观
- 批准号:
0950939 - 财政年份:2010
- 资助金额:
$ 99.21万 - 项目类别:
Continuing Grant
Structure-function Studies of the Allosteric Mechanisms of Protein Switches
蛋白质开关变构机制的结构功能研究
- 批准号:
0919377 - 财政年份:2009
- 资助金额:
$ 99.21万 - 项目类别:
Continuing Grant
Revealing protein switch design principles through directed evolution
通过定向进化揭示蛋白质开关设计原理
- 批准号:
0828724 - 财政年份:2008
- 资助金额:
$ 99.21万 - 项目类别:
Standard Grant
CAREER: Engineering a Protein Molecular Switch
职业:设计蛋白质分子开关
- 批准号:
0239088 - 财政年份:2003
- 资助金额:
$ 99.21万 - 项目类别:
Continuing Grant
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