人类基因组遗传变异与核小体定位的相互作用研究

Genome variation and nucleosome positioning are the genetic and epigenetic factors, respectively. The interplay between the variation and the positioning can alter gene expression mode, thus modify phenotype. In this project, the patterns of nucleosomes in the vicinity of human genome variation sites will be figured out. The role of nucleosome positioning in shapping genome variation will be revealed. The effect of the variation on nucleosome stability will be evaluated; and a DNA sequence feature-based quantitative model will be constructed to predict the effect. A database about human disease-associated variants will be constructed. The molcluar mechanism will be found to elucidate the relationship between the disease phenotype and the interplay between the variant and the positioning. Before that, the applicant developed two new methods of predicting nucleosomes,investigated the patterns of nucleosome distribution in human, and resolved the role of the positioning in gene regulation. Thus, we have a good start. After the completion, the interplay between the positioning and the variation will be revealed and the biological implication will be elucidated. Those variants which lead to disease phenotype by affecting nucleosomes will be identified and the mechanism will be drawn out. The project is the foundational part in studying interaction between genetics and epigenetics, moreover, it is an essential step from identifying disease-associated variants to clinical diagnosis and treatment.

基因组变异和核小体定位分别是遗传和表观遗传的因素，两者可相互影响，相互作用，改变基因表达模式，进而影响表型。项目拟分析人类基因组变异位点周围核小体定位的模式，阐明定位在变异形成中的作用；评估变异对核小体稳定性的影响并建立基于DNA序列特征的定量预测模型；建立人类疾病关联变异信息数据库，解析变异和定位之间相互作用与疾病表型之间的关联。此前，申请者建立了两种基于序列的核小体预测技术，研究了人类基因组核小体定位模式，分析了定位在基因转录调节中的作用，具有良好的研究基础。项目完成后，将阐明核小体定位与变异之间的相互作用及生物学意义，查明通过改变核小体定位来影响疾病表型的变异和分子机制。该研究是分析遗传和表观遗传相互作用的重要内容，也是将疾病关联变异应用于临床诊断和治疗过程中的必然步骤。

项目拟分析人类基因组变异位点周围核小体定位的模式，阐明定位在变异形成中的作用；建立人类疾病关联变异的识别模型，解析变异和定位之间相互关联。目前，已经完成了如下研究(超过总任务90%)。研究的主要结论包括：1,核小体对单核苷酸多态性(SNP)位点分布的塑造(shaping)作用具有基因组位置特异性，编码区SNP(无论是否同义)富集于核小体上；而内含子SNP都富集于核小体排开区域(NDR)。2，编码区SNP周围富集组蛋白乙酰化修饰，而内含子SNP周围排开组蛋白乙酰化修饰；疾病关联SNP周围富集组蛋白乙酰化酶和去乙酰化酶。3，同义编码SNP具有更低的颠换频率(P<10-11)；且其周围具有GC-content无明显改变，而中性的SNP周围，GC-content明显高(P<10-7)。疾病关联的SNP的具有低甲基化水平。4，SNP位点的表观状态具有跨细胞系特征(在CD4+ T 和淋巴母细胞(GM12878)中验证)。5，SNP的在高表达基因体区域出现的频率更低。6，组蛋白修饰水平可以判定SNP的致病风险(ROC曲线AUC=0.72)。7，SNP左右1个碱基位置处，新发突变率比平均值高1.4倍(P<3.210-5)；而在SNP上再次突变的概率低(P=1.3510-9)。此外，项目还研究了基因组Poly-A位点的核小体定位以及与可变剪切的关系；分析了基因组转座原件与MiRAN分布的产生的关系；研究了Htz1、Chz1、Spt16等与核小体定位的关系。截止2013年12月，项目总计：发表SCI学术论文3篇；2篇接收；投稿2篇。培养硕士研究生1名。