Genomes in Eye Disease: Methods to Query Variants Across Multiple Genome-wide Dat

眼病的基因组：在多个全基因组数据集中查询变异的方法 这个应用程序，响应NEI的RFA关于集成数据分析，有两个目标。我们的第一 我们的目标是提供计算工具，以支持综合基因比较查询，这些查询利用来自 多个独立的全基因组DNA测序研究。我们的第二个目标是利用这些工具， 通过整合来自青光眼患者的300多个外显子，发现与青光眼相关的基因， 外显子组和基因组来自其他NIH资助的测序研究。 DNA置换、插入、缺失和重排的全基因组检测范围 从测量已知的单核苷酸多态性（SNP），到测序al蛋白编码外显子， 测序整个基因组一些NEI和NIH资助的研究已经产生了不同的全基因组 通过对数百或数千名患者的研究。这些研究产生了主要的和 二次（派生）数据。主要数据是来自患者DNA的高质量、未映射的读数。二次 数据是在将原始数据映射到参考人类基因组并调用 取代、插入、缺失和重排。应用于辅助数据的数据库仅限于 范围和准确性的方法来产生的主要数据和派生的次要数据。 查询辅助数据的限制在使用多个数据集时变得更加明显。 加起来由于原始派生方法的不同， 数据集有不完整或不准确的风险，并可能返回错误的答案。 我们将开发新的工具来解决查询二级数据的限制， 可以计算关于基因-疾病关联的查询的准确和有意义的答案， 多个全基因组DNA测序数据集这些工具将创建一个框架，其中每个查询驱动 从准确回答查询所需的原始数据中重新推导变体。 我们将使用这些工具询问与原发性开角型青光眼（POAG）研究相关的数据。 这些工具将应用于与青光眼相关的四个数据集： 患者，来自约5，000名POAG患者的珠阵列基因型数据，包括300个外显子组受试者，和外显子组受试者。 来自两个非眼病对照组的序列数据，每个组有超过1,000名受试者。一个对照队列 一个来自NIH Intramural ClinSeq项目;另一个来自NHLBI资助的心脏研究。 这项工作将在两个目标中完成。目标1将建立一个连贯的，质量控制的参考 来自2,800多个外显子组的数据集。Aim 2将构建工具来比较外显子组（或基因组）数据集与 目标1中建立的参考，通过罕见变异发现和检查与POAG相关的基因。

Genomes in Eye Disease: Methods to Query Variants Across Multiple Genome-wide Datasets This application, in response to the NEI's RFA on Integrative Data Analysis, has two goals. Our first goal is to provide computational tools to support integrated gene-comparison queries that draw upon data from multiple, independent genome-wide DNA sequencing studies. Our second goal is to use these tools to discover genes associated with glaucoma by integrating over 300 exomes from glaucoma patients with 2500 exomes and genomes from other NIH-funded sequencing studies. Genome-wide assays for DNA substitutions, insertions, deletions, and rearrangements range in scope from measuring known single nucleotide polymorphisms (SNP), to sequencing al protein coding exons, to sequencing entire genomes. A number of NEI- and NIH-funded studies have generated distinct genome-wide datasets through studies of hundreds, or thousands, of patients. These studies generate both primary and secondary (derived) data. Primary data are the high quality, unmapped reads from patient DNA. Secondary data are the variants identified after mapping primary data to a reference human genome and calling substitutions, insertions, deletions, and rearrangements. Queries applied to the secondary data are limited in scope and accuracy by the methods used to generate the primary data and to derive the secondary data. Limitations on querying secondary data become more pronounced when multiple datasets are combined. To the extent that the original derivation methods difered, queries acros multiple secondary datasets risk being incomplete or inaccurate and can return false answers. We will develop new tools that will addres the limitations on querying secondary data, making it possible to compute accurate and meaningful answers to queries about gene-disease associations using multiple genome-wide DNA sequencing datasets. These tools will create a framework where each query drives re-derivation of variants from just the primary data necessary to answer the query accurately. We will use the tools to interrogate data relevant to the study of primary open angle glaucoma (POAG). These tools will be applied to four datasets relevant to glaucoma: exome sequence data from 300 POAG patients, bead-array genotype data from ~5,000 POAG patients, including the 300 exome subjects, and exome sequence data from two non-eye disease control cohorts, each with over 1,000 subjects. One control cohort will be from the NIH Intramural ClinSeq project; the other will be from an NHLBI funded heart study. The work will be accomplished in two aims. Aim 1 wil build a coherent, quality-controlled reference dataset from the 2,800+ exomes. Aim 2 will build tools to compare an exome (or genome) dataset against the reference built in Aim 1 to discover and examine genes associated with POAG through rare variants.