Homologous sequences and their effects on genome biology

同源序列及其对基因组生物学的影响

• 批准号: 10686856
• 负责人: Christine R Beck
• 金额: $ 40.98万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686856
• 关键词: Algorithms; Alternative Splicing; Automobile Driving; Biology; Constitution; Constitutional; DNA; DNA Sequence Rearrangement; DNA Transposable Elements; Disease; Event; Fostering; Generations; Genes; Genetic Recombination; Genome; Genomic Instability; Genomics; Goals; Human; Human Genome; Investigation; Knowledge; Malignant Neoplasms; Mediating; Methodology; Modeling; Pathogenesis; Play; Population; Prevalence; Process; Radiation; Repetitive Sequence; Research; Role; Sequence Homologs; Technology; Therapeutic; Variant; human DNA; improved; mammalian genome; mouse genome; repaired

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.

项目总结/摘要 人类基因组充满了转座的残余，这些残余在整个人类基因组中积累起来。 哺乳动物的辐射，并正在进行的人口今天。这些序列包含约50%的人类 但是转座因子和其他重复DNA对我们基因组的影响仍然很小 明白基因组如何与重复DNA竞争是我们提高对基因组理解的关键 生物学以及了解体质和躯体疾病的疾病过程。探讨 这些问题不仅需要彻底理解重复的DNA， 影响我们从当前测序技术和方法中捕获基因组信息的能力。 我的研究目标是揭示同源序列对哺乳动物基因组的影响， 基因组不稳定性是由重复序列引起的。在接下来的五年里，我将主要 重点是确定重复序列介导的基因组不稳定性的患病率和机制， 导致了哺乳动物基因组的不稳定性。我假设重复在培养 基因组重排可能导致疾病和种群变异。为了研究这个过程，我们将 检查人类和小鼠基因组中转座元件介导的重排的普遍性 并研究各种测序方法和调用算法鉴定这些事件的能力。 我们将把我们的知识应用于体细胞串联重复，并推断连接形成的机制， 这些事件的产生。我们试图确定发现的基因组重排的关键机制特征 由重复序列介导，也将检查控制重复序列之间异位重组的基因。 最后，为了扩展这种不稳定性的模型， 转座子在它们所在的基因上，我们将研究转座因子在基因组中的作用。 折叠和选择性剪接。这些调查的成功完成将大大增加 现有的知识重复介导的哺乳动物基因组重排，并将扩大我们的 了解重复序列如何影响基因组生物学。

项目成果

Hotspots of Human Mutation.

• DOI: 10.1016/j.tig.2020.10.003
• 发表时间: 2021-08
• 期刊: Trends in genetics : TIG
• 作者: Nesta AV;Tafur D;Beck CR
• 通讯作者: Beck CR

Transposable element-mediated rearrangements are prevalent in human genomes.

• DOI: 10.1038/s41467-022-34810-8
• 发表时间: 2022-11-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Balachandran, Parithi;Walawalkar, Isha A.;Flores, Jacob, I;Dayton, Jacob N.;Audano, Peter A.;Beck, Christine R.
• 通讯作者: Beck, Christine R.