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的两种形式的自然遗传变异：1）小插入和缺失（indels）的尺寸范围为1 bp至10,000 bp的尺寸范围，而2 bp）插入插座，这些插入也会在此尺寸范围内产生小indels。尽管这些形式的自然遗传变异在人类基因组中很丰富，但它们的关注较少，而结构变异的较大形式。但是，很明显，小的indels和transposon插入经常改变基因，因此可能会对人类健康产生重大影响。因此，需要开发围绕人类自然遗传变异形式的其他资源。在这种竞争性更新的目标1中，我们将对研究界发现的小型indels进行广泛的验证研究。我们将利用我们最近开发的Indel基因分型技术来检查已发现的200,000个小型indels的战略抽样。我们的研究将包括来自DBSNP中所有最大的小型Indels，个人基因组项目和1000个基因组项目的小型储蓄者。这些研究将使我们能够检查这些重要的社区资源的质量，并研究已使用的主要发现方法的相对准确性。在AIM 2中，我们将使用研究界发现的indels产生以基因为中心的新资源，这些资源将促进人类遗传学研究。我们将专注于研究界在RefSeq基因中发现但尚未将其纳入GWAS研究使用的插图图中。因此，通过将新颖的基因中心插入纳入参考归合图中，我们将与可能不会被研究的Indels多样化并扩展这些地图。我们预计我们的扩展地图将加强GWAS研究的努力，以鉴定影响人类健康的基因基因座和变体。在AIM 3中，我们将研究人类新indel差异的主要来源：人类转座子。我们将使用我们实验室开发的新型“ Transposon-Seq”技术来确定在正常和癌症基因组中生产新的转座子插入的频率。除了为研究界创造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。 公共卫生相关性：我们正在研究人类基因组中的两种自然遗传变异类别，称为indels和transposon插入。这些差异类别可能会影响人类健康的许多方面，因此与NIH的广泛使命有关。我们的项目将有助于了解这些形式的自然遗传变异如何影响包括癌症在内的人类特征和疾病。