Analysis of the Functional Impact of Coding region SNPs

描述（由申请人提供）： 在目前的资助期间，我们已经开发了两种模型的错义SNP对蛋白质功能的影响在体内。通过这项工作，以及其他人的工作，我们现在对导致单基因疾病的分子机制有了更清楚的了解。我们还开发了一个网络资源，将我们的结果与大量其他与疾病相关的信息相结合。下一阶段的目标分为三个方面：（1）利用现有的结果来解决有关遗传变异与疾病之间关系的基本问题。具体而言：错义SNPs影响蛋白质功能的机制分布情况如何;上位性有多常见具有相同蛋白质分子和跨蛋白质-蛋白质界面的SNP之间的（非线性）相互作用;与所有其他蛋白质相比，涉及单基因疾病的约1500种蛋白质的特征是什么;哪些SNPs在直接或间接影响特定生物过程和对常见疾病的易感性方面最重要？(2)改进和扩展SNP分析方法，以获得更广泛和可靠的一组有害的错义SNP，并包括通过其他过程影响疾病易感性的SNP分析。将开发新的模型，用于转录，信息处理和翻译的影响。现有数据库信息将通过文献分析和 征求科学界适当成员的意见。(3)维护和加强网络资源，以提高其效用的研究社区。将扩展功能，使用户能够输入自己的单核苷酸多态性，并从两个模型接收真实的时间分析;将开发用户注释界面，以获取关于氨基酸改变的错义单核苷酸多态性的作用的知识，以及哪些基因与疾病最相关，以及哪些缓冲机制保护表型不受特定有害单核苷酸多态性的影响;将纳入其他信息来源，包括其他人的SNP分析。 与公共卫生的相关性：许多常见的人类疾病，如心脏病发作，阿尔茨海默病，哮喘和糖尿病，部分是通过特定的DNA特征遗传的。目前，还没有一种常见疾病的遗传机制被了解。这项工作将提供对一些疾病的具体见解，并提高对遗传过程的理解。

DESCRIPTION (provided by applicant): During the current grant period, we have developed two models of the impact of missense SNPs on protein function in vivo. Through this work, and that of others, we now have a clearer understanding of the molecular mechanisms that lead to monogenic disease. We have also developed a web resource which integrates our results with a large range of other information relevant to disease. Goals for next phase fall into three categories: (1) Exploiting the present results to address basic questions concerning the relationship between genetic variation and disease. Specifically: What is the distribution of mechanisms by which mis-sense SNPs influence protein function; how common are epistatic (non-linear) interactions between SNPs with the same protein molecule and across protein-protein interfaces; what are the characteristics of the approximately 1500 proteins involved in monogenic disease, versus all the others; which SNPs are most significant in directly and indirectly affecting particular biological processes and susceptibility to common diseases? (2) Improving and extending SNP analysis methods, both to obtain a more extensive and reliable set of deleterious mis-sense SNPs, and to include analysis of SNPs that influence disease susceptibility through other processes. New models will be developed for effects on transcription, message processing and translation. Available database information will be augmented by a combination of literature analysis and soliciting input from appropriate members of the scientific community. (3) Maintain and enhance the web resource to increase its utility to the research community. Functionality will be extended to allow users to input their own SNPs and receive a real time analysis from both models; a user annotation interface will be developed, to capture knowledge on the role of amino acids altered mis-sense SNPs, as well as which genes are most relevant to disease, and what buffering mechanisms shield the phenotype from particular deleterious SNPs; additional information sources will be incorporated, including SNP analysis by others. Relevance to public health: Many common human diseases, such as heart attack, Alzheimer, asthma and diabetes, are partly inherited, through specific DNA features. At present, there is no common disease for which these inheritance mechanisms are understood. This work will provide specific insight into a number of diseases, and improved understanding of the inheritance process.