Population Genetics of Mobile Elements

描述（由申请人提供）：移动的元件构成了人类基因组的近一半。由于从头插入以及介导非同源重组和缺失，它们是遗传疾病的重要原因。我们建议建立在我们以前的研究，以进一步了解移动的元素对人类和非人类灵长类动物基因组遗传多样性的产生的影响。我们已经开发出一种新的技术，基于第二代高通量测序，同时确定和基因型的所有成员的移动元件亚家族在大样本的个人。我们将把这项技术应用于42个大的犹他州家系，首次直接估计人类基因组中Alu逆转录转座的比率。我们还将使用这些谱系来探索移动的元素和从头拷贝数变异体的产生之间的关系。我们将在500人的不同样本中对数千个Alu插入多态性进行基因分型。由于我们的新技术可以识别每个亚家族的所有成员，因此可以识别罕见的插入，从而可以分析插入多态性的无偏频谱。这些数据将使我们能够在人类基因组中寻找活跃的Alu元素，并使我们能够测试有关古代人类进化史的几个关键假设。我们将利用几个非人灵长类动物基因组序列的可用性来测试这些物种进化过程中移动的元件对基因组物质插入和缺失的影响。我们还将研究移动的元件在介导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.