ADVANCED STOCHASTIC MODELS FOR DNA MICROSATELITE SOMATIC INSTABILITY

DNA 微卫星体细胞不稳定性的高级随机模型

• 批准号: 8167541
• 负责人: Daniel James Endres
• 金额: $ 3.37万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167541
• 关键词: Age; Aging; Algorithms; Cessation of life; Characteristics; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Repair; DNA Repair Pathway; DNA lesion; Data; Data Set; Dependence; Development; Dimensions; Disease; Evaluation; Friedreich Ataxia; Funding; Gene Frequency; Generations; Genetic; Genome; Grant; Human; Huntington Disease; Hybrids; Institution; Lead; Link; Markov Chains; Measures; Methods; Microsatellite Repeats; Modeling; Mutation; Neurons; Nuclear; Play; Primates; Process; Research; Research Personnel; Resources; Role; Source; Testing; Time; Tissues; Transcript; United States National Institutes of Health; functional disability; gene repression; insight; mathematical model; nervous system disorder; novel; parallel computing; repaired; senescence; simulation; success; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Normative aging in humans and other primates leads to the accumulation of DNA lesions, progressive degeneration of DNA, and the functional impairment and death of neurons. Recent whole genome studies have found that normative human senescence includes down-regulation of genes whose transcripts play critical roles in nuclear DNA repair pathways. Erroneous DNA repair has been linked to the instability of the highly variable expanded repeat sequences causing a variety of genetically transmitted human neurological diseases. This study advances an ongoing project developing and implementing stochastic mathematical models that analyze existing allele frequency data measuring progressive mutational instability of pathogenic microsatellites in somatic tissues. Our current generation of continuous-time Markov chain models has revealed previously unknown characteristics of the mutation process by examining a single large data set for a single disease (Friedreich ataxia). This success has lead us to obtain data sets for other diseases (Huntington's and SCA 7) suitable for similar modeling analysis. The modeling process requires a complex and expensive nonlinear optimization involving repeated evaluation of model fit as parameters vary over a large, mixed continuous-discrete, feasible parameter space of from 4 to 10 dimensions. Three distinct approaches will be explored to facilitate the analysis at reduced expense: development of novel hybrid optimization algorithms that employ "natural" (e.g. "genetic' and +swarm algorithms in conjunction with traditional optimization methods, use of Monte-Carlo simulations, and high throughput (parallel) computation. The algorithms developed will be tested against several existing data sets, both suggesting new insights into the age dependence of the DNA repair process and providing new tools with which to study the repair mechanisms underlying DNA microsatellite somatic instability.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 人类和其他灵长类动物的正常衰老会导致 DNA 损伤的积累、DNA 的进行性退化以及神经元的功能损伤和死亡。最近的全基因组研究发现，正常的人类衰老包括基因的下调，这些基因的转录本在核 DNA 修复途径中发挥着关键作用。错误的 DNA 修复与高度可变的扩展重复序列的不稳定性有关，从而导致多种遗传性人类神经系统疾病。 这项研究推进了一个正在进行的项目，开发和实施随机数学模型，分析现有的等位基因频率数据，测量体细胞组织中致病性微卫星的渐进突变不稳定性。我们当前一代的连续时间马尔可夫链模型通过检查单一疾病（弗里德赖希共济失调）的单个大数据集，揭示了突变过程的先前未知的特征。这一成功使我们获得了适合类似建模分析的其他疾病（亨廷顿病和 SCA 7）的数据集。建模过程需要复杂且昂贵的非线性优化，涉及模型拟合的重复评估，因为参数在 4 到 10 维的大型、混合连续离散、可行参数空间中变化。 将探索三种不同的方法，以降低成本来促进分析：开发采用“自然”的新型混合优化算法（例如，与传统优化方法相结合的“遗传”和群体算法、蒙特卡罗模拟的使用以及高开发的算法将针对多个现有数据集进行测试，这既提出了对 DNA 修复过程的年龄依赖性的新见解，又提供了研究 DNA 微卫星体细胞不稳定性背后的修复机制的新工具。