Statistical and high-throughput models of enhancer function and evolution

增强子功能和进化的统计和高通量模型

• 批准号: 10550177
• 负责人: SCOTT V. EDWARDS
• 金额: $ 56.4万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-22 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550177
• 关键词: Acceleration; Bayesian Modeling; Biological; Biological Assay; Birds; Chickens; Chromatin; Communities; Complex; DNA; Data; Data Set; Development; Disease; Electroporation; Elements; Emu species; Enhancers; Epigenetic Process; Evolution; Exhibits; Flying body movement; Forelimb; Gene Expression; Gene Expression Regulation; Genes; Genetic Diseases; Genetic Enhancer Element; Genetic Polymorphism; Genome; Genomics; Genotype; Health; Heterogeneity; Hindlimb; Human; Human Genetics; Lead; Libraries; Limb structure; Link; Malignant Neoplasms; Measures; Methods; Modeling; Morphology; Mutation; Nucleotides; Open Reading Frames; Organ; Phenotype; Phylogenetic Analysis; Phylogenetic Pattern; Phylogeny; Play; Population; Population Genetics; Process; Relaxation; Research Personnel; Role; Sampling; Scientist; Sorting; Source; Statistical Methods; Statistical Models; Study models; System; Testing; Trees; Untranslated RNA; Validation; Variant; Work; candidate identification; comparative; comparative genomics; epigenetic profiling; genome sequencing; genome wide association study; genome-wide; genomic signature; genomic variation; high throughput screening; improved; in vivo; loss of function; model development; novel; predictive modeling; rate of change; tool; trait; transcriptome sequencing; user-friendly; whole genome

PROJECT SUMMARY Enhancers are an important class of noncoding loci regulating gene expression and play important roles in modulating diverse phenotypes and disease states. However, our understanding of the role of enhancers in phenotypic evolution is limited and we lack a detailed understanding of the relationship between sequence change within and between species, epigenetic states and variation in enhancer function. Moreover, we have few statistical models that allow researchers to connect evolutionary changes in enhancer sequences within and between species to phenotypic variation, and we often cannot unambiguously determine the causes of observed changes in evolutionary rate of enhancers along lineages. Finally, most studies of enhancer evolution thus far have studied only small numbers of enhancers and genome-wide assays of enhancer variation and function are rare. Here we propose to develop statistical models linking phylogenetic patterns of enhancer evolution with phenotypic variation between species, and to leverage within-species variation across multiple species – “comparative population genomics” – to disentangle the sources of rate changes observed in enhancers across species. We will also functionally test diverse enhancers on a large-scale, using the developing fore- and hindlimb of volant and flightless birds as a model of development and gene expression. Specifically, in Aim 1 we will extend a recently developed Bayesian phylogenetic model for detecting rate changes in noncoding DNA, phyloAcc, to improve its biological realism by incorporating stochastic gene tree heterogeneity and the ability to associate sequence change with both binary and continuous traits. Building on a novel data set of comparative gene expression and chromatin states across multiple species and developmental stages, we will also develop methods to associate genome-wide variation in chromatin states between species with binary and continuous traits. In Aim 2 we will develop additional statistical models to leverage information from sequence variation within species to better understand the evolutionary forces contributing to rate variation in noncoding DNA observed between species. The models developed in Aims 1 and 2 will be refined and made available to the broader community in a user-friendly format for use on diverse systems and species. In Aim 3 we will functionally validate large numbers of candidate enhancers identified in Aims 1 and 2 as having evolved new functions or found in altered chromatin states in the developing fore- and hindlimb of volant and flightless birds. Using high-throughput assays in chicken, emu and other birds we will study the relationship between within- and between-species sequence variation of enhancers and their ability to drive gene expression. Together these aims will provide a number of tools that will benefit the community of researchers using comparative genomics to understand links between genotype and phenotype, and will extend the kinds of phenotypic traits and genomic signatures that will inform this emerging paradigm.

项目摘要 增强子是一类重要的调控基因表达的非编码基因座， 调节不同的表型和疾病状态。然而，我们对增强子在 表型进化是有限的，我们缺乏对序列之间关系的详细了解， 种内和种间的变化、表观遗传状态和增强子功能的变化。而且我们 一些统计模型，使研究人员能够连接增强子序列的进化变化， 物种之间的表型变异，我们往往不能明确确定的原因， 观察到增强子沿着谱系进化速率的变化。最后，大多数增强剂的研究 进化至今只研究了少量的增强子和增强子的全基因组测定 变异和功能是罕见的。在这里，我们建议建立统计模型， 增强子进化与物种之间的表型变异，并利用跨物种的物种内变异 多个物种--“比较种群基因组学”--以解开观察到的速率变化的来源 在不同物种的增强子中。我们还将在大规模上对不同的增强子进行功能测试，使用 作为发育和基因表达模型的能飞和不能飞的鸟类的前肢和后肢的发育。 具体来说，在目标1中，我们将扩展最近开发的贝叶斯系统发育模型，用于检测率 通过引入随机基因树，改变非编码DNA，以提高其生物真实性 异质性以及将序列变化与二元和连续性状相关联的能力。基础上 一个新的数据集比较基因表达和染色质状态在多个物种和 发育阶段，我们还将开发方法，以关联全基因组的染色质状态的变化 在具有二元和连续性状的物种之间。在目标2中，我们将开发更多的统计模型， 利用物种内序列变异的信息，更好地理解进化的力量 导致物种间观察到的非编码DNA的速率变化。目标1中开发的模型 和2将加以完善，并以用户友好的格式提供给更广泛的社区，供各种 系统和物种。在目标3中，我们将在功能上验证大量的候选增强子， 目的1和2是在发育中的前体细胞中进化出新的功能或在改变的染色质状态中发现， 能飞而不会飞的鸟的后肢。使用高通量检测鸡，鸸鹋和其他鸟类，我们将 研究增强子的种内和种间序列变异与其能力的关系 to drive驱动gene基因expression表达.这些目标将共同提供一些工具，使社区受益。 研究人员使用比较基因组学来了解基因型和表型之间的联系，并将 扩展了表型特征和基因组特征的种类，这将为这种新兴的范式提供信息。