Large-Scale Methods for Assessing the Consequences of Mutations in Proteins

评估蛋白质突变后果的大规模方法

基本信息

  • 批准号:
    9323449
  • 负责人:
  • 金额:
    $ 28.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2018-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): One of the fundamental challenges in contemporary genomics lies in understanding how genomic alterations produce disease. An increasing urgency to meet this challenge has arisen owing to several factors. First, we have learned that every individual harbors a surprisingly large number of rare, protein-coding variants whose functional consequences will be difficult to address using association-based methods. Second, we have made incredible strides in understanding the genes and pathways involved in many diseases. As a result, we are tantalizingly close to being able to offer personalized, genomically-based advice to physicians, patients and casual users of genetic tests. However, we are hampered by our lack of effective methods for determining the functional consequences of the ~300 rare variants we find in the protein-coding regions of a typical human genome. Current methods for assessing the consequences of rare protein-coding variants are either experimental or computational. Experimental methods generally involve cellular or biochemical assays for protein function. Though these methods are effective, they are used on a case-by-case basis, which cannot be scaled to address the rare variants we find in each human genome. Computational methods for determining the impact of protein variants, though easily scalable, generally produce a large number of false positive and negative results. Thus, a novel approach to studying the functional consequences of protein-coding variation is needed. We propose to address this need by developing methods for directly measuring the functional consequences of all possible single mutations in a protein simultaneously using eukaryotic model systems. We can use these data to create sequence-function maps for disease-related proteins, which will enable more effective genetic diagnosis. To accomplish this goal, we will draw on our expertise in combining assays for protein function with high-throughput DNA sequencing to measure the functional consequences of hundreds of thousands of variants of a protein simultaneously. Furthermore, we will begin to dissect the complexity of mutational effects on proteins by studying the impact of mutagenesis on multiple cellular phenotypes simultaneously.
描述(由申请人提供):当代基因组学的基本挑战之一在于理解基因组改变如何产生疾病。由于若干因素,应对这一挑战的紧迫性日益增加。首先,我们已经了解到,每个人都拥有数量惊人的罕见蛋白质编码变体,其功能后果将难以使用基于关联的方法来解决。第二,我们在了解许多疾病的基因和途径方面取得了令人难以置信的进步。因此,我们非常接近能够为医生、患者和基因检测的临时用户提供个性化的、基于基因组学的建议。然而,我们缺乏有效的方法来确定我们在典型人类基因组的蛋白质编码区中发现的约300种罕见变异的功能后果,这阻碍了我们的研究。目前用于评估罕见蛋白质编码变体的后果的方法是实验性的或计算性的。实验方法通常涉及蛋白质功能的细胞或生物化学测定。虽然这些方法是有效的,但它们是在个案的基础上使用的,不能扩展到解决我们在每个人类基因组中发现的罕见变异。用于确定蛋白质变体的影响的计算方法虽然易于扩展,但通常会产生大量的假阳性和假阴性结果。因此,需要一种新的方法来研究蛋白质编码变异的功能后果。我们建议通过开发直接测量蛋白质中所有可能的单突变的功能后果的方法,同时使用真核模型系统来解决这一需求。我们可以使用这些数据来创建疾病相关蛋白质的序列功能图,这将使更有效的遗传诊断成为可能。为了实现这一目标,我们将利用我们的专业知识,将蛋白质功能测定与高通量DNA测序相结合,以同时测量数十万种蛋白质变体的功能后果。此外,我们将开始通过同时研究突变对多种细胞表型的影响来剖析突变对蛋白质影响的复杂性。

项目成果

期刊论文数量(0)
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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Douglas M Fowler其他文献

Comprehensive Characterization of Missense Variation in Coagulation Factor IX Reveals Features Necessary for Secretion and γ-Carboxylation
  • DOI:
    10.1182/blood-2022-164996
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Nicholas A Popp;Rachel L Powell;Brendan Zapp;Kerry Lannert;Jill M. Johnsen;Douglas M Fowler
  • 通讯作者:
    Douglas M Fowler

Douglas M Fowler的其他文献

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{{ truncateString('Douglas M Fowler', 18)}}的其他基金

Comprehensive Characterization of Missense Mutants in Factor IX
因子 IX 错义突变体的综合表征
  • 批准号:
    10734485
  • 财政年份:
    2022
  • 资助金额:
    $ 28.5万
  • 项目类别:
The Center for Actionable Variant Analysis; measuring variant function at scale
可行变异分析中心;
  • 批准号:
    10473870
  • 财政年份:
    2021
  • 资助金额:
    $ 28.5万
  • 项目类别:
The Center for Actionable Variant Analysis; measuring variant function at scale
可行变异分析中心;
  • 批准号:
    10840702
  • 财政年份:
    2021
  • 资助金额:
    $ 28.5万
  • 项目类别:
The Center for Actionable Variant Analysis; measuring variant function at scale
可行变异分析中心;
  • 批准号:
    10687156
  • 财政年份:
    2021
  • 资助金额:
    $ 28.5万
  • 项目类别:
The Center for Actionable Variant Analysis; measuring variant function at scale
可行变异分析中心;
  • 批准号:
    10295657
  • 财政年份:
    2021
  • 资助金额:
    $ 28.5万
  • 项目类别:
Comprehensive Characterization of Missense Mutants in Factor IX
因子 IX 错义突变体的综合表征
  • 批准号:
    10371181
  • 财政年份:
    2020
  • 资助金额:
    $ 28.5万
  • 项目类别:
Center for the Multiplexed Assessment of Phenotype
表型多重评估中心
  • 批准号:
    10115777
  • 财政年份:
    2019
  • 资助金额:
    $ 28.5万
  • 项目类别:
Center for the Multiplexed Assessment of Phenotype
表型多重评估中心
  • 批准号:
    9926906
  • 财政年份:
    2019
  • 资助金额:
    $ 28.5万
  • 项目类别:
Center for the Multiplexed Assessment of Phenotype
表型多重评估中心
  • 批准号:
    10563149
  • 财政年份:
    2019
  • 资助金额:
    $ 28.5万
  • 项目类别:
Center for the Multiplexed Assessment of Phenotype
表型多重评估中心
  • 批准号:
    10376767
  • 财政年份:
    2019
  • 资助金额:
    $ 28.5万
  • 项目类别:

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