Population Genetics of Mobile Elements

描述（由申请人提供）：散布的重复元件，包括Alu和LINE1（LI）元件，占人类基因组的45%，但关于它们的起源和动力学仍有许多未知之处。有证据表明，这些元素影响基因组中遗传多样性的分布，因为它们影响重组等过程。该项目的目标是建立在从上一个资助期获得的知识，以追求的Alu和LI元素的起源及其对基因组多样性模式的影响的问题。利用一系列的PCR和测序实验，我们将评估基因转换对Alu多样性的影响。我们将评估50个基因组区域的连锁不平衡模式，以检验Alu元件介导同源重组的假设。我们将进行人类和黑猩猩基因组的比较，以测试的假设，铝元素是不平等的交叉事件，删除和复制基因的重要调解人。我们预测，LI元素，因为它们的观察到的分布和它们在基因组中的密度较低，功能不太频繁的介质不平等的交叉。我们设计了一系列实验来验证Alu元件以不依赖核酸内切酶的方式插入基因组中并因此可能参与双链DNA断裂的修复的假设。最后，我们将应用新开发的方法，以确定是否自然选择一直在人类基因组中的Alu和LI元素。 基因转换和重组等因素对基因组多样性模式产生重要影响，进而影响基因组中的连锁不平衡模式。拟议的研究，这将有助于探索重复元件对基因组多样性的影响，因此将有重要的意义，在定位致病基因的连锁不平衡的使用。我们对遗传疾病的理解也将通过更好地理解这些元件在DNA修复和基因复制和缺失中的作用而得到加强。

DESCRIPTION (provided by applicant): Interspersed repetitive elements, including Alu and LINE1 (LI) elements, make up 45% of the human genome, yet much remains unknown about their origins and dynamics. There is evidence that these elements affect the distribution of genetic diversity across the genome because of their influence on processes like recombination. The goals of this project are to build upon the knowledge gained from the previous funding period in order to pursue questions about the origins of Alu and LI elements and about their effects on patterns of genomic diversity. Using a series of PCR and sequencing experiments, we will evaluate the effects of gene conversion on Alu diversity. We will assess linkage disequilibrium patterns in 50 genomic regions to test the hypothesis that Alu elements mediate homologous recombination. We will undertake comparisons of human and chimpanzee genomes to test the hypothesis that Alu elements are important mediators of unequal crossover events, deleting and duplicating genes. We predict that LI elements, because of their observed distribution and their lower density in the genome, function less frequently as mediators of unequal crossover. We have designed a series of experiments to test the hypothesis that Alu elements insert into the genome in an endonuclease-independent fashion and may therefore participate in the repair of double-stranded DNA breaks. Finally, we will apply newly developed methods to determine whether natural selection has been operating on Alu and LI elements in the human genome. Factors like gene conversion and recombination exert important effects on patterns of genomic diversity, which in turn influence patterns of linkage disequilibrium in the genome. The proposed research, which will help to explore the influence of repetitive elements on genomic diversity, will thus have important implications for the use of linkage disequilibrium in localizing disease-causing genes. Our understanding of genetic disease will also be enhanced by a better understanding of the role of these elements in DNA repair and in gene duplication and deletion.