Homologous sequences and their effects on genome biology

项目摘要/摘要 人类基因组充满了在整个基因组中积累的转座残留物 哺乳动物的辐射，并在今天的人类种群中持续存在。这些序列约占人类的50% DNA，但转座元件和其他重复DNA对我们基因组的影响仍然很小 明白了。基因组如何与重复的DNA竞争是我们更好地理解基因组的关键 生物学以及了解体质和躯体障碍的疾病过程。去调查 这些问题不仅需要彻底了解重复的DNA，而且还需要彻底了解这些序列是如何 影响我们从当前的测序技术和方法中获取基因组信息的能力。 我的研究目的是揭示同源序列对哺乳动物基因组的影响以及 由重复序列培育的引导基因组不稳定性的机制。在接下来的5年里，我将主要 重点确定重复序列介导的基因组不稳定性的患病率及其机制 导致哺乳动物基因组的这种不稳定性。我假设重复在培养孩子的能力方面起着重要作用 可能导致疾病和种群变异的基因组重排。为了研究这一过程，我们将 检测可转座元件介导的重排在人类和小鼠基因组中的流行率 并调查各种测序方法和调用算法识别这些事件的能力。 我们将把我们的知识应用到体细胞串联复制中，并推断在体细胞串联复制中连接形成的机制 这些事件的产生。我们试图确定所发现的基因组重排的关键机制特征 并将检查控制重复之间异位重组的基因。 最后，为了扩展我们对这种不稳定的模型，并开发更全面的观点来了解 转座子，我们将研究转座子在基因组中的作用。 折叠和另一种拼接方式。成功完成这些调查将大大增加 现有的关于哺乳动物基因组中重复介导的重排的知识，并将扩大我们的 了解重复序列如何影响基因组生物学。

PROJECT SUMMARY / ABSTRACT The human genome is replete with the remnants of transposition that have accumulated throughout the mammalian radiation, and is ongoing in human populations today. These sequences comprise ~50% of human DNA, but the impact that transposable elements and other repetitive DNAs have on our genome remain poorly understood. How the genome contends with repetitive DNA is key to our improved understanding of genome biology as well as understanding disease processes in constitutional and somatic disorders. To investigate these questions requires thorough understanding not only of repetitive DNA, but also how these sequences impact our ability to capture genomic information from current sequencing technologies and methodologies. The goal of my research is to reveal the impacts of homologous sequences on mammalian genomes and the mechanisms that guide genomic instability fostered by repeat sequences. For the next 5 years, I will primarily focus on determining the prevalence of repetitive sequence-mediated genomic instability and the mechanisms driving this instability in mammalian genomes. I hypothesize that repeats play an important role in fostering genomic rearrangements that can lead to disease and variation in the population. To study this process, we will examine the prevalence of transposable element-mediated rearrangements in human and mouse genomes and investigate the ability of various sequencing methodologies and calling algorithms to identify these events. We will apply our knowledge to somatic tandem duplications, and infer mechanisms of junction formation in the generation of these events. We seek to identify key mechanistic features of the genomic rearrangements found to be mediated by repeats, and will also examine genes that control ectopic recombination between repeats. Finally, to extend our models of this instability and to develop a more comprehensive view of the impact of transposons on genes in which they reside, we will examine the role of transposable elements in genome folding and in alternative splicing. Successful completion of these investigations will greatly increase the existing knowledge of repeat-mediated rearrangements in mammalian genomes, and will expand our understanding of how repeats influence genome biology.