Mathematical and Statistical Models for Nucleosome

核小体的数学和统计模型

基本信息

批准号：
7214137
负责人：
JI-PING WANG
金额：
$ 19.01万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The nucleosome is the fundamental packing unit of chromatin formed by association of DNA and histone octamer in eukaryotic chromosomes. The detailed locations of nucleosomes along genomic DNA are critical for proper gene regulation - and therefore for the health and development of humans and all other eukaryotes - yet, at present, we lack any methods for the "in-silico" prediction of nucleosome positioning sequence elements in genomes. The long-term goal of this project is to develop capability to predict nucleosome-forming propensity given DNA sequences and correlate the genome-wide distribution of nucleosome-forming sequences with chromosome function. Towards this goal, we propose to achieve the following five aims progressively in the subsequent years. (1) Experimentally collect 1000 yeast nucleosome core DNA sequences, and 1000 yeast di-nucleosome DNA sequences (two neighboring nucleosomes linked by linker DNA). These yeast nucleosome DNA sequences will form a new training set as well as a validating set for nucleosome positioning prediction across the yeast genome. (2) Develop and refine statistical methods to align nucleosome DNA sequences. A novel statistical model for nucleosorne DNA sequence alignment was proposed in the preliminary study. We will refine this model by introducing a weighting scheme based on the importance of different periodic di-nucleotide signals from free energy consideration. (3) Use the alignment in (2) to train a model to predict nucleosome positioning. An inhomogeneous Markov chain model and a "mixture train" model are under consideration to model the sequential dependent structure of nucleotides. (4) Generalize the model by incorporating knowledge in spacing properties of neighboring nucleosomes. The di-nucleosome sequences generated from (1) will provide distributional evidence for between-nucleosome space and dl1 greatly facilitate prediction of genome-wide nucleosome positioning. (5) Automate the developed tools and algorithms.

描述（申请人提供）：核小体是真核染色体中DNA和组蛋白八聚体结合形成的染色质的基本包装单位。核小体沿基因组 DNA 的详细位置对于正确的基因调控至关重要，因此对于人类和所有其他真核生物的健康和发育至关重要，然而，目前我们缺乏任何“计算机”预测核小体定位序列的方法基因组中的元素。该项目的长期目标是开发根据 DNA 序列预测核小体形成倾向的能力，并将核小体形成序列的全基因组分布与染色体功能相关联。为实现这一目标，我们建议在接下来的几年里逐步实现以下五个目标。 (1) 实验收集1000个酵母核小体核心DNA序列和1000个酵母双核小体DNA序列（两个相邻核小体通过连接DNA连接）。这些酵母核小体 DNA 序列将形成新的训练集以及用于整个酵母基因组中核小体定位预测的验证集。 (2) 开发和完善核小体 DNA 序列比对的统计方法。初步研究中提出了一种新的核仁DNA序列比对统计模型。我们将通过引入基于自由能考虑的不同周期性二核苷酸信号的重要性的加权方案来完善该模型。 (3) 使用(2)中的比对来训练模型来预测核小体定位。正在考虑使用非均质马尔可夫链模型和“混合序列”模型来模拟核苷酸的顺序依赖性结构。 (4) 通过结合邻近核小体的间隔特性的知识来推广模型。由（1）生成的双核小体序列将为核小体间空间提供分布证据，并且 dl1 极大地促进了预测全基因组核小体定位。 (5) 自动化开发的工具和算法。