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，我们已经开发了两个错义SNPs对体内蛋白质功能影响的模型。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晰的理解。我们还开发了一个网络资源，将我们的结果与与疾病有关的大量其他信息整合在一起。下一阶段的目标分为三类：(1)利用目前的结果解决关于遗传变异和疾病之间关系的基本问题。具体地说：错义SNP影响蛋白质功能的机制是什么？同一蛋白质分子的SNP之间以及蛋白质-蛋白质界面之间的上位性(非线性)相互作用有多常见；单基因疾病涉及的大约1500个蛋白质相对于所有其他蛋白质的特征是什么；哪些SNP在直接和间接影响特定生物学过程和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，并包括对通过其他过程影响疾病易感性的SNP的分析。将开发新的模型来影响转录、信息处理和翻译。现有的数据库信息将通过结合文献分析和 征求科学界适当成员的意见。(3)维护和加强网络资源，增加其对研究界的效用。将扩展功能以允许用户输入他们自己的SNPs并从两个模型接收实时分析；将开发用户注释界面，以获取关于氨基酸改变的错义SNPs的作用的知识，以及哪些基因与疾病最相关，以及什么缓冲机制保护表型免受特定有害SNPs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、阿尔茨海默氏症、哮喘和糖尿病，部分是通过特定的DNA特征遗传的。目前，还没有一种常见的疾病可以理解这些遗传机制。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.