Natural Genetic Variation in the Human Genome

描述(申请人提供)：我们实验室正在研究人类自然遗传变异的两种形式：1)大小在1到10,000个碱基范围内的小插入和缺失(Indels)，以及2)转座子插入也产生这个大小范围内的小Indels。虽然这些形式的自然遗传变异在人类基因组中非常丰富，但与SNP相比，它们受到的关注较少，而且结构变异的形式更多。然而，越来越明显的是，小Indels和转座子插入经常修改基因，因此，很可能对人类健康产生重大影响。因此，有必要围绕人类这些丰富的自然遗传变异形式开发更多的资源。在这次竞争性更新的目标1中，我们将对研究界发现的小型Indels进行广泛的验证性研究。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Indels进行战略性抽样。我们的研究将包括来自数据库SNP、个人基因组计划和1000基因组计划中所有最大的小Indels储存者的小Indels。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，我们将使用研究界已经发现的Indel来生成新的、以基因为中心的Indel资源，这将促进人类的遗传学研究。我们将重点介绍研究界在RefSeq基因中发现的但尚未整合到GWAS研究使用的归属图谱中的插入序列。因此，通过将新的以基因为中心的indels整合到参考定位图中，我们将使这些图谱多样化，并扩展这些可能未被研究的indels。我们预计，我们的扩展图谱将加强GWAS研究的努力，以确定影响人类健康的基因位点和变异。在目标3中，我们将研究人类新的Indel变异的一个主要来源：人类转座子。我们将使用我们实验室开发的新的“转座子-序列”技术来确定在正常和癌症基因组中产生新的转座子插入的频率。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基因变异的努力。

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.