Physically modeling cross-hybridization error in gene expression microarrays by a novel Boltzmann partition function algorithm for probe-specific position-dependent free energy
通过针对探针特异性位置依赖自由能的新型玻尔兹曼分配函数算法对基因表达微阵列中的交叉杂交误差进行物理建模
基本信息
- 批准号:0817971
- 负责人:
- 金额:$ 19.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Standard Grant
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-01 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Cross-hybridization is singly the most important source of noise in gene expression measurements. Many current approaches to assess gene signal fit data to statistical models; in contrast, the investigators will develop a thermodynamics-based algorithm to compute the hybridization free energy between probe and specific (i.e. intended) target as well as non-specific (i.e. non-intended) target molecules. This new approach takes into consideration the fact that thermodynamics of hybridization for two molecules in aequeous solution is different that than where one molecule (probe) is tethered to a glass slide. A new probe-specific position-dependent hybridization partition function will be computed by a dynamic programming algorithm PPH using free energy parameters from labs of Turner, Santalucia, and Sugimoto. The partition function accounts for (Boltzmann-weighted) sum of all possible partial as well as complete hybridizations betwenn probe and target, including secondary structure of both probe and target. Applying PPH to all probes and all (specific and non-specific) targets is not computationally feasible, so the algorithm PPHx will be developed to compute the hybridization free energy between probe and a Markov model representing all non-specific targets. Ensemble free energies are immediately obtained from partition function values Z, and can be used to derive concentrations of messenger RNA from microarray fluorescence intensity values. High-density oligonucleotide arrays (gene-expression arrays, tiling arrays, single-nucleotide polymorphism arrays, microRNA arrays, etc.) constitute a powerful tool in molecular biology for the discovery of genes and their function, with far-reaching applications in population biology, systems biology, pathobiology and other fields. In this method, fluorescently tagged cRNA or cDNA derived from messenger RNA is washed over a glass slide to which hundreds of thousands up to millions of short cDNA probes are attached. Hybridization between fluorescently tagged molecules and probes occurs, non-hybridized molecules are removed, and fluorescence intensities are measured by an optical scanning device. Despite technical improvements in various commercial platforms, it is still not possible to infer messenger RNA concentrations from microarray fluorescence intensity values, due to noise from cross-hybridization (also called non-specific binding). A computer algorithm to compute the cross-hybridization free energy will be developed and implemented, directly allowing one to estimate cross-hybridization effects. Findings from this research will be made publicly accessible through a web server and distribution of source code, by journal publications, and presentations in meetings. Due to the prevalent use of microarray technology, this research will have a very broad impact on molecular biology (genetics, genomics, systems biology, population biology) as well as to disease pathology and drug dosage and design. Educational impact at the undergraduate and graduate level will be ensured by courses and training opportunities offered at Boston College, which provide special opportunities for females and minorities, with additional outreach provided in the weekly MIT Bioinformatics Seminar.
杂交是基因表达测量中最重要的噪声源。目前许多评估基因信号的方法符合统计模型;相反,研究人员将开发一种基于热力学的算法来计算探针与特定(即预期的)靶分子以及非特定(即非预期的)靶分子之间的杂交自由能。这种新的方法考虑到了这样一个事实,即两个分子在水溶液中的杂交热力学与一个分子(探针)拴在玻璃片上的热力学不同。使用来自Turner、Santalucia和Sugimoto实验室的自由能参数,将通过动态编程算法PPH计算新的探针特定位置依赖的杂交分配函数。配分函数考虑了探针和靶之间所有可能的部分和完全杂化的(玻尔兹曼加权)和,包括探针和靶的二级结构。将PPH应用于所有探针和所有(特定和非特定)靶在计算上是不可行的,因此将开发算法PPHx来计算探针与代表所有非特定靶的马尔可夫模型之间的杂交自由能。系综自由能立即从配分函数值Z获得,并可用于从微阵列荧光强值推导信使RNA浓度。高密度寡核苷酸阵列(基因表达阵列、平铺阵列、单核苷酸多态阵列、微RNA阵列等)是分子生物学中发现基因及其功能的有力工具,在种群生物学、系统生物学、病理生物学等领域有着深远的应用。在这种方法中,来自信使RNA的荧光标记的cRNA或cdna被清洗在玻璃片上,在玻片上附着数十万到数百万个短的cdna探针。荧光标记的分子和探针之间发生杂交,非杂交分子被移除,并通过光学扫描设备测量荧光强度。尽管在各种商业平台上进行了技术改进,但由于交叉杂交(也称为非特异性结合)产生的噪声,仍然不可能从微阵列的荧光强度值中推断信使RNA的浓度。一个计算杂交自由能的计算机算法将被开发和实现,直接允许人们估计杂交效果。这项研究的结果将通过网络服务器和源代码分发、期刊出版物和会议演示文稿向公众公布。由于微阵列技术的广泛应用,这项研究将对分子生物学(遗传学、基因组学、系统生物学、种群生物学)以及疾病病理学和药物剂量与设计产生非常广泛的影响。波士顿学院提供的课程和培训机会将确保对本科生和研究生的教育影响,这些课程和培训机会为女性和少数族裔提供特殊机会,并在每周举行的麻省理工学院生物信息学研讨会上提供额外的推广服务。
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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Peter Clote其他文献
Peter Clote的其他文献
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