Computational and Biochemical Analysis of Microsatellite Life Cycle

微卫星生命周期的计算和生化分析

基本信息

  • 批准号:
    7894687
  • 负责人:
  • 金额:
    $ 34.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-16 至 2013-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Microsatellite sequences are abundant in the human genome and have mutation rates orders of magnitude higher than any other genomic sequences. As a result, microsatellites are frequently used as markers in forensics and population genetics. Importantly, microsatellites influence genome functions by being part of protein-coding regions or by regulating gene expression, and allele-length polymorphisms at microsatellites are implicated as genetic risk factors in several diseases. Because the full impact of microsatellite changes on genome function has yet to be elucidated, it is of utmost importance to gain knowledge about how microsatellite arise, mutate, and eventually cease to exist at individual loci in the human genome. The evolution of each microsatellite has been presented theoretically as a life cycle, with the stages of birth, active dynamic mutation activity, and death. However, the concept of the microsatellite life cycle has not been previously investigated in detail. The goal of this interdisciplinary proposal is to elucidate mechanisms defining microsatellite life cycle in the human genome. This will be accomplished by a combination of computational and biochemical approaches, and follows the NIH roadmap themes of Interdisciplinary research and Bioinformatics and computational biology. Specific Aim 1 is to determine the mechanisms of microsatellite birth. We will use biochemical experiments to determine the microsatellite threshold in terms of the minimal number of repeats (or length) required for dynamic mutations to occur. These thresholds will be determined for various motifs, and will be used in computational analyses to examine mechanisms and densities of new microsatellite births. The results of this aim will allow us for the first time to derive a regression model explaining variation in microsatellite birth densities across the genome. Specific Aim 2 will examine microsatellite interruption and death. Our preliminary studies demonstrate that microsatellite interruptions can be observed frequently in the human genome, and that DNA polymerases can directly produce such interruptions in vitro. This aim will use computational and biochemical techniques to measure the mutational consequences of interruptions and the extent to which they contribute to microsatellite death. Specific Aim 3 is to computationally determine the mechanisms contributing to variation in mature microsatellite mutation rates among and within individual human genomes, and to biochemically determine specific mechanisms contributed by intrinsic features. Overall, the results of this project will be of considerable significance for our understanding of the dynamics of genome evolution. Additionally, our research proposal has direct relevance to the issues of public health and clinical genetics. The new information gained by our research can be used to predict the probability of each microsatellite to undergo mutation or cease to exist, and the probability of any genomic region to bear a new microsatellite. This will have major importance for assessing an individual's disease risks, especially in the era when individual human genomes are being rapidly sequenced. PUBLIC HEALTH RELEVANCE: Repetitive DNA sequences, called microsatellites, are characteristic of primate genomes and are known to regulate gene expression, and mutations within microsatellite sequences are causally linked to the development of several human diseases. Our interdisciplinary project will elucidate the mechanisms whereby microsatellites arise, mutate, and disappear at distinct loci in individual human genomes. This research could have major consequences for predicting the risk of diseases caused by microsatellites.
描述(由申请人提供):微卫星序列在人类基因组中丰富,突变率比任何其他基因组序列高几个数量级。因此,微卫星经常被用作法医和人口遗传学中的标记物。重要的是,微卫星通过成为蛋白质编码区域的一部分或通过调节基因表达来影响基因组功能,微卫星的等位基因长度多态性与几种疾病的遗传风险因素有关。由于微卫星变化对基因组功能的全面影响尚未阐明,因此了解微卫星如何在人类基因组的单个位点上产生、突变并最终停止存在至关重要。每个微卫星的演化在理论上被描述为一个生命周期,包括诞生、活跃的动态突变活动和死亡阶段。然而,微卫星生命周期的概念以前没有被详细研究过。本跨学科建议的目标是阐明人类基因组中定义微卫星生命周期的机制。这将通过计算和生化方法的结合来完成,并遵循NIH跨学科研究和生物信息学和计算生物学的路线图主题。具体目的1是确定微卫星分娩的机制。我们将使用生化实验来确定微卫星阈值,即动态突变发生所需的最小重复次数(或长度)。这些阈值将根据不同的母题确定,并将用于计算分析,以检查新的微卫星出生的机制和密度。这一目标的结果将使我们第一次推导出一个回归模型来解释微卫星出生密度在整个基因组中的变化。专项目标2将检查微卫星中断和死亡。我们的初步研究表明,在人类基因组中可以经常观察到微卫星中断,并且DNA聚合酶可以直接在体外产生这种中断。这一目标将使用计算和生化技术来衡量中断的突变后果及其对微卫星死亡的影响程度。具体目标3是通过计算确定导致人类个体基因组之间和内部成熟微卫星突变率变化的机制,并通过生物化学方法确定由内在特征贡献的特定机制。总的来说,这个项目的结果将对我们理解基因组进化的动力学具有相当重要的意义。此外,我们的研究计划与公共卫生和临床遗传学问题直接相关。我们的研究获得的新信息可以用来预测每个微卫星发生突变或停止存在的概率,以及任何基因组区域产生新微卫星的概率。这对于评估个体疾病风险具有重要意义,特别是在人类个体基因组正在快速测序的时代。公共卫生相关性:称为微卫星的重复DNA序列是灵长类基因组的特征,已知可调节基因表达,微卫星序列内的突变与几种人类疾病的发展有因果关系。我们的跨学科项目将阐明微卫星在个体人类基因组中不同位点产生、突变和消失的机制。这项研究可能对预测微卫星引起的疾病风险产生重大影响。

项目成果

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Kristin A Eckert其他文献

Kristin A Eckert的其他文献

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{{ truncateString('Kristin A Eckert', 18)}}的其他基金

Penn State Research training in Oncology and Medicine to Inspire Student Engagement (PROMISE)
宾夕法尼亚州立大学肿瘤学和医学研究培训激发学生参与(承诺)
  • 批准号:
    10693934
  • 财政年份:
    2022
  • 资助金额:
    $ 34.61万
  • 项目类别:
Penn State Research training in Oncology and Medicine to Inspire Student Engagement (PROMISE)
宾夕法尼亚州立大学肿瘤学和医学研究培训激发学生参与(承诺)
  • 批准号:
    10494494
  • 财政年份:
    2022
  • 资助金额:
    $ 34.61万
  • 项目类别:
Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions
生理复制应激条件下基因组复制过程中人类 DNA 聚合酶 eta 和 kappa 的促肿瘤功能
  • 批准号:
    9899218
  • 财政年份:
    2019
  • 资助金额:
    $ 34.61万
  • 项目类别:
Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions
生理复制应激条件下基因组复制过程中人类 DNA 聚合酶 eta 和 kappa 的促肿瘤功能
  • 批准号:
    10369670
  • 财政年份:
    2019
  • 资助金额:
    $ 34.61万
  • 项目类别:
Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions
生理复制应激条件下基因组复制过程中人类 DNA 聚合酶 eta 和 kappa 的促肿瘤功能
  • 批准号:
    10594039
  • 财政年份:
    2019
  • 资助金额:
    $ 34.61万
  • 项目类别:
Computational and Biochemical Analysis of Microsatellite Life Cycle
微卫星生命周期的计算和生化分析
  • 批准号:
    8071627
  • 财政年份:
    2009
  • 资助金额:
    $ 34.61万
  • 项目类别:
Computational and Biochemical Analysis of Microsatellite Life Cycle
微卫星生命周期的计算和生化分析
  • 批准号:
    8277920
  • 财政年份:
    2009
  • 资助金额:
    $ 34.61万
  • 项目类别:
DNA replication, DNA repair and microsatellite stability
DNA 复制、DNA 修复和微卫星稳定性
  • 批准号:
    6993555
  • 财政年份:
    2005
  • 资助金额:
    $ 34.61万
  • 项目类别:
DNA replication, DNA repair and microsatellite stability
DNA 复制、DNA 修复和微卫星稳定性
  • 批准号:
    7535534
  • 财政年份:
    2005
  • 资助金额:
    $ 34.61万
  • 项目类别:
DNA replication, DNA repair and microsatellite stability
DNA 复制、DNA 修复和微卫星稳定性
  • 批准号:
    7325814
  • 财政年份:
    2005
  • 资助金额:
    $ 34.61万
  • 项目类别:

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非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
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