Analysis of the Functional Impact of Coding Region SNPs

描述(由申请人提供)： 单核苷酸多态(SNPs)是最常见的遗传形式 人类个体之间的差异。大多数单基因疾病是 由这一机制介导，人们认为易感性 多基因疾病和个体对药物的反应也可以 在很大程度上是以这些术语理解的。大规模SNP作图正在迅速进行 增加人类群体中SNPs的可用数据量。 了解这些数据并利用它们来开发新的治疗方法 需要SNPs和功能之间联系的模型。我们建议开发 这是一个通过影响蛋白质功能发挥作用的单核苷酸多态的模型。最单基因 疾病SNP以这种方式运行，因此预计结果将 对解释和利用人类SNP信息具有广泛的适用性。 该模型是基于大量可用数据的影响 体外单个残基突变。这些数据可以从以下方面进行理解 蛋白质结构中突变的情况。突变数据， 与结构上下文一起，已经被用来制定一套规则 识别哪些编码区SNPs在体内可能有害。我们 我已经根据已知SNP的一组数据测试了该模型的第一个版本 导致人类疾病和来自人类人口的SNPs样本。这个 这些结果为SNPs的作用机制提供了洞察力。我们现在提议 开发一套能够对所有数据进行全面分析的软件 疾病相关和一般人口SNP数据。该软件将用于 分析有害的SNPs在人类人口中的程度，以及 以确定可能与多基因疾病有关的这些基因的子集。

DESCRIPTION (provided by applicant): Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation between human individuals. The majority of monogenic disease is mediated by this mechanism, and it is believed that susceptibility to polygenic diseases and individual response to medication can also be understood largely in these terms. Large scale SNP mapping is rapidly increasing the amount of data available on SNPs within the human population. To understand these data and exploit them for development of new therapies requires models of the link between SNPs and function. We propose to develop such a model for SNPs that act via effects on protein function. Most monogenic disease SNPs operate in this manner so it is expected that the results will have wide applicability for interpreting and utilizing human SNP information. The model is based on the large amount of data available on the effect of single residue mutations in vitro. Those data can be understood in terms of the situation of the mutation within the protein structure. The mutation data, together with the structural context, have been used to devise a set of rules that identify which coding region SNPs are potentially harmful in vivo. We have tested a first version of the model against a set of data on SNPs known to cause human disease and a sample of SNPs from the human population. The results provide insights into the mechanism of action of SNPs. We now propose to develop a set of software capable of performing a full analysis of all disease related and general population SNP data. The software will be used to perform an analysis of the extent of harmful SNPs in the human population, and to identify a subset of these likely to be involved in polygenetic diseases.