CAREER: Using indel rate variation to understand evolutionary constraints on distances between functional elements in the genome

职业：利用插入缺失率变化来了解基因组中功能元件之间距离的进化限制

• 批准号: 1750532
• 负责人: Mira Han
• 金额: $ 57.41万
• 依托单位: University of Nevada Las Vegas
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1750532&HistoricalAwards=false
• 关键词: CAREER; Using; indel; rate; variation

Adjacent protein domains interact to fold into a functional protein structure. Adjacent binding sites in the DNA interact with the multiprotein complex for efficient binding. Yet, both protein domains and clusters of binding sites are encoded as one-dimensional arrays in the genome. This project tests the hypothesis that, in order for specific and correct interactions to occur, there are optimal distances between these functional units and that they are maintained across evolutionary time. Since insertions and deletions of DNA (indels) change the distance between these functional units, the genome will be under evolutionary constraint against indel mutations that affect the distance. To test this hypothesis, the investigator will develop software to systematically estimate and compare the changes in distance between functional elements and statistical models to test the likelihood of the events observed. Upon project completion, the scientific community will have tools that identify distances that are conserved, and will be able to predict the effect and importance of indel mutations occurring in these genomic regions. The investigator will hold workshops for girls in grades 6-12 to develop software games that model the concept of evolutionary constraint. She will also develop undergraduate and graduate classes with hands-on activities on molecular evolution and computational sequence analysis.The goal of this project is to utilize the variation in rates of indels to infer the evolutionary constraint on the distance between functional elements in the genome. Experimental evidence has been accumulating on selection against indels in the loops and linkers within proteins, or in the space between binding sites of regulatory elements. But, studies on the evolution of these sequences are almost nonexistent, due to the difficulty in aligning these sequences. This project addresses these challenges by applying methods that can model variable indel rates across sites or methods that model length instead of relying on alignments. Using these methods, the investigator will produce phylogenetic, and quantitative estimates of indel rates on a significant proportion of the genome that has been neglected so far. In Objective 1, using a new software the investigator has developed, variable site-specific indel rates will be estimated across loops between protein motifs to identify structural motifs with strong constraints on their distance. In Objective 2, the investigator will develop a new software based on birth-death processes to estimate indel rates without relying on alignments. Using this software, she will test the hypothesis that there is stronger constraint on the distance between tandem homologous domains, compared to non-homologous domains. In Objective 3, the investigator will use the software described above to test the hypothesis that there is stronger constraint on the distance between binding sites of homodimers, compared to the distance between binding sites of heterodimers. This study will integrate the knowledge gained in the fields of structural biology and developmental biology into a phylogenomic context, and provide tools for the community to test specific evolutionary hypotheses on distance between functional elements of interest. The results of the project will be presented at https://github.com/HanLabUNLV.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

相邻的蛋白质结构域相互作用以折叠成功能性蛋白质结构。 DNA中的相邻结合位点与多蛋白络合物相互作用以有效结合。然而，将结合位点的蛋白质结构域和簇编码为基因组中的一维阵列。该项目检验了以下假设：为了进行特定和正确的相互作用，这些功能单元之间存在最佳距离，并且它们在进化时间内保持。由于DNA（Indels）的插入和缺失改变了这些功能单元之间的距离，因此基因组将在影响距离的indel突变的进化约束下。为了检验这一假设，研究者将开发软件，以系统地估计并比较功能元素和统计模型之间的距离变化，以测试观察到的事件的可能性。项目完成后，科学界将拥有识别距离的距离的工具，并能够预测这些基因组区域中发生的indel突变的效果和重要性。研究人员将在6 - 12年级的女孩举办研讨会，以开发对进化约束概念进行建模的软件游戏。她还将开发有关分子进化和计算序列分析的动手活动的本科和研究生班，该项目的目的是利用Indels速率的变化来推断基因组功能元素之间距离的进化约束。实验证据已经积累了针对蛋白质中的indels和蛋白质内部或调节元素结合位点之间的空间的选择。但是，由于难以对齐这些序列，对这些序列的演变的研究几乎不存在。该项目通过应用可以对跨站点或模型长度的方法建模的方法来解决这些挑战，而不是依靠对齐。使用这些方法，研究者将在迄今已忽略的很大一部分基因组上产生系统发育和定量估计。在目标1中，使用新软件开发了研究者，将在蛋白质基序之间估算各个循环的位点特异性Indel速率，以识别其距离对其距离有很强限制的结构基序。在目标2中，研究人员将根据出生死亡过程开发一个新软件，以估算不依赖对齐方式的Indel率。使用此软件，她将检验以下假设：与非同源域相比，串联同源域之间的距离更强。在目标3中，研究人员将使用上述软件来检验以下假设：与异二聚体的结合位点之间的距离相比，同型二聚体结合位点之间的距离更强。这项研究将将在结构生物学和发育生物学领域中获得的知识融合到系统基础上，并为社区提供工具，以测试有关感兴趣的功能元素之间距离的特定进化假设。该项目的结果将在https://github.com/hanlabunlv.this奖上介绍，这是反映了NSF的法定任务，并且使用基金会的知识分子优点和更广泛的影响评估标准，认为值得通过评估来提供支持。

项目成果

Paired-end mappability of transposable elements in the human genome

人类基因组中转座元件的双端可定位性

• DOI: 10.1186/s13100-019-0172-5
• 发表时间: 2019
• 期刊: Mobile DNA
• 影响因子: 4.9
• 作者: Sexton, Corinne E.;Han, Mira V.
• 通讯作者: Han, Mira V.

Transcriptome analyses of tumor-adjacent somatic tissues reveal genes co-expressed with transposable elements

• DOI: 10.1186/s13100-019-0180-5
• 发表时间: 2019-09-03
• 期刊: MOBILE DNA
• 影响因子: 4.9
• 作者: Chung, Nicky;Jonaid, G. M.;Han, Mira V.
• 通讯作者: Han, Mira V.