Population Genetics of Mobile Elements

描述(申请人提供)：移动元件占人类基因组的近一半。它们是遗传病的重要原因，既是从头插入的结果，也是非同源重组和缺失的中介。我们建议在以前研究的基础上，进一步了解可移动元素对人类和非人类灵长类基因组遗传多样性产生的影响。我们开发了一种基于第二代高通量测序的新技术，可以在大样本个体中同时确定移动元件亚家族的所有成员并对其进行基因分型。我们将在42个犹他州大型家系中应用这项技术，首次直接估计人类基因组中Alu逆转录转座的比率。我们还将使用这些家系来探索移动元件和从头产生拷贝数变体之间的关系。我们将在500人的不同样本中对数千个Alu插入多态进行基因分型。因为我们的新技术识别了每个亚家族的所有成员，所以将识别罕见的插入，以便能够分析插入多态的无偏频谱。这些数据将使我们能够在人类基因组中搜索活跃的Alu元素，它们将使我们能够测试关于古人类进化史的几个关键假说。我们将利用几个非人类灵长类基因组序列的可用性来测试在这些物种的进化过程中，移动元件对基因组材料插入和缺失的影响。我们还将研究移动元件在调节人类和非人类灵长类动物的转导事件中的作用，因为这是基因组中新遗传物质的重要来源。

DESCRIPTION (provided by applicant): Mobile elements make up nearly half of the human genome. They are a significant cause of genetic disease as a result of both de novo insertion as well as mediation of nonhomologous recombination and deletion. We propose to build on our previous research to further understand the effects of mobile elements on the generation of genetic diversity in human and non-human primate genomes. We have developed a new technique, based on second-generation high-throughput sequencing, to simultaneously ascertain and genotype all members of mobile-element subfamilies in large samples of individuals. We will apply this technology to 42 large Utah pedigrees to directly estimate, for the first time, the rate of Alu retrotransposition in the human genome. We will also use these pedigrees to explore the relationship between mobile elements and the generation of de novo copy number variants. We will genotype thousands of Alu insertion polymorphisms in a diverse sample of 500 humans. Because our new technique identifies all members of each subfamily, rare insertions will be identified so that an unbiased frequency spectrum of insertion polymorphisms can be analyzed. These data will allow us to search for active Alu elements in the human genome, and they will allow us to test several key hypotheses about ancient human evolutionary history. We will take advantage of the availability of several non-human primate genome sequences to test the effects of mobile elements on insertions and deletions of genomic material during the evolution of these species. We will also examine the roles of mobile elements in mediating transduction events in humans and non-human primates, as this is an important source of new genetic material in genomes.