Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver

描述（由申请人提供）：测序成本的降低和测序效率的提高正在迅速使高通量测序可用于希望在其研究工作中使用测序作为强大工具的各个实验室。事实上，随着成本的持续下降，我们可以预期高通量测序将成为一种常用的工具，不仅在基于人类表型的测序项目中，而且在模式生物的正向遗传学应用中也是一种有效的工具，并可能用于诊断特发性疾病。然而，很少有实验室拥有计算专业知识和基础设施来理解通过这些研究确定的遗传变异。该提案的目标是通过扩展Scripps基因组注释和分布式变异解释服务器（SG-ADVISER）以及配套的数据处理和可视化工具，使高通量测序数据解释与数据生成一样容易获得。SG-ADVISER是一个基于网络服务器的工具，用于对高通量测序产生的变体进行全面、深入的注释和功能预测。注释在至少四个主要水平上形成：1）变体所在的基因组元件的注释; 2）变体对基因组元件的功能影响的预测; 3）将跨基因和/或基因组元件的变体彼此连接的分子和生物学过程的注释，以及4）基因或变体的已知临床特征的注释。SG-ADVISER目前提供的注释涵盖了这些注释级别中的许多，但并不完整。因此，我们建议扩展SG-ADVISER的功能，以涵盖尽可能多的一般有趣的注释类型，同时还扩展SG-ADVISER的功能，以模拟生物体研究。此外，我们认识到灵活性的需要，并计划通过SG-ADVISER网络服务器提供自定义注释。最后，我们觉得真正强大的数据解读只有通过可视化才能实现 大量的数据集。因此，我们提出了一个计划，通过目前可用的基因组浏览器产生简单的配套工具来处理，过滤和可视化SG-ADVISER注释。 公共卫生相关性： 识别和解释与遗传性但不强烈家族性疾病相关的变异是将人类基因组测序工作的投资转化为对公共卫生真正重大影响的关键一步。需要对变异体进行注释、优先级排序和逻辑分组，以便为测序研究带来足够的统计能力，从而可以鉴定致病变异体。

DESCRIPTION (provided by applicant): Reductions in sequencing costs and increases in sequencing efficiency are quickly making high-throughput sequencing accessible to individual laboratories looking to use sequencing as a powerful tool in their research endeavors. In fact, as costs continue to decline, we can expect high-throughput sequencing to become a commonly used tool, not only in human phenotype based sequencing projects, but also as an effective tool in forward genetics applications in model organisms, and potentially for the diagnosis idiopathic disease. However, very few laboratories have the computational expertise and infrastructure to make sense of the genetic variants identified through these studies. The goal of this proposal is to make high-throughput sequencing data interpretation as accessible as data generation through expansion of the Scripps Genome Annotation and Distributed Variant Interpretation SERver (SG-ADVISER) and companion data processing and visualization tools. SG-ADVISER is a web-server based tool for holistic, in-depth, annotations and functional predictions of variants generated from high-throughput sequencing. Annotations are formed on at least four major levels: 1) annotation of the genomic element within which a variant resides; 2) prediction of the functional impact of a variant on a genomic element; 3) annotation of molecular and biological processes which link variants across genes and/or genomic elements with one another, and 4) annotation of known clinical characteristics of the gene or variant. The annotations currently provided by SG-ADVISER cover many of these levels of annotation, but are incomplete. Therefore, we propose to expand the capabilities of SG-ADVISER to cover as many generally interesting annotation types as possible, while also extending SG-ADVISER's capabilities to model organism studies. Moreover, we recognize a need for flexibility, and have included a plan to provide customized annotations through the SG-ADVISER web-server. Finally, we feel that truly powerful data interpretation can only be achieved through visualization of massive datasets. Therefore, we propose a plan to produce simple companion tools to process, filter, and visualize SG-ADVISER annotations through currently available genome browsers. PUBLIC HEALTH RELEVANCE: Identification and interpretation of variants associated with inherited but not strongly familial disease is a crucial step in translating the investment in huma genome sequencing efforts into a truly significant impact on public health. Annotation, prioritization and grouping of variants logically will be required to bring enough statistical powe to sequencing studies so that disease causing variants can be identified.