Natural Genetic Variation in the Human Genome

人类基因组的自然遗传变异

• 批准号: 8193932
• 负责人: Scott E Devine
• 金额: $ 41.6万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193932
• 关键词: Affect; Attention; Communities; DNA Transposable Elements; Data; Disease; Gene-Modified; Genes; Genetic; Genetic Variation; Genome; Goals; Health; Human; Human Genetics; Human Genome; Knowledge; Laboratories; Malignant Neoplasms; Maps; Methods; Mission; Nature; Phase; Population; Relative (related person); Research; Resources; Retrotransposon; Sampling; Source; Technology; United States National Institutes of Health; Variant; base; cancer genome; genetic variant; genome wide association study; genotyping technology; human disease; insertion/deletion mutation; novel; tool; trait; validation studies

DESCRIPTION (provided by applicant): Our laboratory is studying two forms of natural genetic variation in humans: 1) small insertions and deletions (INDELs) in the size range of 1 bp to 10,000 bp, and 2) transposon insertions that also produce small INDELs in this size range. Although these forms of natural genetic variation are abundant in human genomes, they have received less attention than SNPs and larger forms of structural variation. However, it is becoming clear that small INDELs and transposon insertions frequently modify genes, and thus, are likely to have a major impact on human health. Therefore, there is a need to develop additional resources surrounding these abundant forms of natural genetic variation in humans. In Aim 1 of this competitive renewal we will conduct a broad validation study of the small INDELs that have been discovered by the research community. We will leverage our recently-developed INDEL genotyping technologies to examine a strategic sampling of 200,000 of the small INDELs that have been discovered. Our study will include small INDELs from all of the largest depositors of small INDELs in dbSNP, personal genome projects, and the 1000 genomes project. These studies will allow us to examine the quality of these important community resources and to examine the relative accuracies of the major discovery methods that have been used. In Aim 2, we will use the INDELs that have been discovered by the research community to generate new, gene-centered INDEL resources that will facilitate genetics studies in humans. We will focus on INDELs that have been discovered in RefSeq genes by the research community but have not yet been integrated into the imputation maps that are used by GWAS studies. Thus, by integrating novel gene-centered INDELs into reference imputation maps, we will diversify and expand these maps with INDELs that might otherwise go unstudied. We expect that our expanded maps will enhance efforts by GWAS studies to identify gene loci and variants that influence human health. In Aim 3 we will examine a major source of new INDEL variation in humans: human transposons. We will use novel "transposon-seq" technologies that were developed by our laboratory to determine how often new transposon insertions are produced in both normal and cancer genomes. In addition to generating useful tools and resources for the research community, these studies will facilitate efforts to identify genetic variants that influence human health. PUBLIC HEALTH RELEVANCE: We are studying two abundant classes of natural genetic variation in human genomes known as INDELs and transposon insertions. These classes of variation are likely to influence many aspects of human health, and are thus relevant to the broad mission of the NIH. Our project will facilitate efforts to understand how these forms of natural genetic variation affect human traits and diseases, including cancers.

描述（由申请人提供）：我们的实验室正在研究人类自然遗传变异的两种形式：1）大小范围为 1 bp 至 10,000 bp 的小插入和缺失 (INDEL)，以及 2) 也产生小 INDEL 的转座子插入在这个尺寸范围内。尽管这些形式的自然遗传变异在人类基因组中非常丰富，但它们比 SNP 和更大形式的结构变异受到的关注较少。然而，越来越明显的是，小的 INDEL 和转座子插入经常修改基因，因此可能对人类健康产生重大影响。因此，需要围绕人类这些丰富的自然遗传变异形式开发额外的资源。在本次竞争更新的目标 1 中，我们将对研究界发现的小型 INDEL 进行广泛的验证研究。我们将利用我们最近开发的 INDEL 基因分型技术对已发现的 200,000 个小型 INDEL 进行战略抽样检查。我们的研究将包括来自 dbSNP、个人基因组计划和 1000 个基因组计划中所有最大的小型 INDEL 存放者的小型 INDEL。这些研究将使我们能够检查这些重要社区资源的质量，并检查已使用的主要发现方法的相对准确性。在目标 2 中，我们将利用研究界发现的 INDEL 来生成新的、以基因为中心的 INDEL 资源，以促进人类遗传学研究。我们将重点关注研究界在 RefSeq 基因中发现但尚未整合到 GWAS 研究使用的插补图中的 INDEL。因此，通过将新的以基因为中心的 INDEL 整合到参考插补图中，我们将使用 INDEL 来多样化和扩展这些图，否则这些图可能会被忽视。我们预计，我们扩展的图谱将加强 GWAS 研究的工作，以确定影响人类健康的基因位点和变异。在目标 3 中，我们将研究人类新 INDEL 变异的主要来源：人类转座子。我们将使用我们实验室开发的新型“转座子测序”技术来确定正常和癌症基因组中产生新转座子插入的频率。除了为研究界提供有用的工具和资源外，这些研究还将促进识别影响人类健康的遗传变异的努力。 公共健康相关性：我们正在研究人类基因组中两类丰富的自然遗传变异，即 INDEL 和转座子插入。这些类别的变异可能会影响人类健康的许多方面，因此与 NIH 的广泛使命相关。我们的项目将促进了解这些形式的自然遗传变异如何影响人类特征和疾病，包括癌症。