Integrative analysis of tissue-specific alternative splicing regulation under adaptive selection

适应性选择下组织特异性选择性剪接调控的综合分析

• 批准号: 10402926
• 负责人: Chaolin Zhang
• 金额: $ 51.67万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-07 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402926
• 关键词: Adult; Affect; Alternative Splicing; Bioinformatics; Biological Assay; Biology; Brain; Cebidae; Code; Comparative Genomic Analysis; DNA; Data; Data Element; Development; Elements; Event; Evolution; Exons; Family; Frontotemporal Dementia; Genes; Genetic; Genetic Diseases; Goals; Human; In Vitro; Knowledge; Link; Malignant Neoplasms; Mammals; Maps; Methods; Modeling; Molecular; Monkeys; Motor Neurons; Mus; Mutate; Mutation; Neurons; Nucleic Acid Regulatory Sequences; Pan Genus; Phenotype; Phylogenetic Analysis; Phylogeny; Predisposition; Prevalence; Primates; Process; Protein Binding Domain; Protein Splicing; Proteins; RNA Splicing; RNA-Binding Proteins; RNA-Protein Interaction; Recording of previous events; Regulation; Regulatory Element; Reporter; Role; Series; Site; Source; Speed; Spinal; Statistical Models; Tissue Model; Tissues; Transcript; Untranslated RNA; Validation; axon growth; brain tissue; causal variant; cell type; comparative; driving force; experience; experimental study; fitness; genetic information; genomic signature; human disease; induced pluripotent stem cell; innovation; insight; interdisciplinary approach; mRNA Precursor; mammalian genome; nervous system disorder; species difference; trait; transcriptome sequencing

Integrative analysis of tissue-specific alternative splicing regulation under adaptive selection PROJECT SUMMARY Tissue-specific alternative splicing (AS) generates multiple transcripts from single genes and contributes critically to the cellular and phenotypic complexity of mammals. This process is tightly regulated by RNA-binding proteins (RBPs) which recognize specific regulatory elements in their target transcripts. A long-standing hypothesis from the evolutionary perspective is that changes of AS regulation due to mutations in cis-regulatory sequences provide a major driving force of speciation in mammals, including closely related species such as human and Chimpanzee. While recent studies convincingly demonstrated the pervasive species difference of AS in multiple tissues, two fundamental questions remain: 1) which evolutionary splicing changes are under adaptive selection in specific lineages because of acquired fitness advantages? 2) what are the underlying mutations that led to the shifted selective regimes? These challenges are associated with the intrinsic degeneracy of the splicing code and lack of effective computational and experimental approaches for direct comparative analysis. The primary goal of this project is to overcome these limitations, so that we can identify divergent AS events under adaptive selection and the causal mutations affecting important cis-regulatory elements. To achieve this overarching goal, we formulated three specific aims. In Aim 1, we will use phylogenetic genetic methods to detect lineage- specific changes in selection intensity and adaptive evolution of AS and map AS regulatory regions experiencing lineage-specific adaptive evolution. In Aim 2, to elucidate the underlying regulatory mechanisms that led to splicing divergence, we will systematically map divergent protein-RNA interactions and reconstruct the evolutionary history in the phylogeny through a combination of CLIP footprints, perturbation of RBPs and comparative genomic analysis. In Aim 3, we will focus on MAPT alternative exon 10, which is implicated in frontotemporal dementia (FTD), and perform detailed analysis to reveal the mechanism of its divergent splicing in primates and the associated functions at the cellular level. If successful, this study will advance our understanding of the contribution of AS evolution to potential phenotypic differences among different mammalian species and the underlying mechanisms. The strategy established in this study will also provide a new and generalizable paradigm to better understand the splicing code.

适应性选择下组织特异性选择性剪接调控的综合分析 项目总结 组织特异性选择性剪接(AS)从单个基因产生多个转录本，并在其中起关键作用 哺乳动物的细胞和表型的复杂性。这一过程受到RNA结合蛋白的严格调控。 (限制性商业惯例)，识别其目标成绩单中的特定调控要素。一个长期存在的假说来自 进化观点认为，由于顺式调控序列的突变，AS的调控发生了变化 提供哺乳动物物种形成的主要推动力，包括密切相关的物种，如人类和 黑猩猩。虽然最近的研究令人信服地证明了AS在多种疾病中的普遍物种差异 组织方面，仍然存在两个基本问题：1)在适应性选择下，哪些进化剪接变化 在特定的血统中，因为获得的健康优势？2)导致 改变了选择性政权？这些挑战与剪接代码的内在简并性有关 缺乏有效的计算和实验方法来进行直接比较分析。初级阶段 这个项目的目标是克服这些限制，这样我们就可以识别不同的事件为适应下的事件 影响重要顺式调控元件的选择和因果突变。要实现这一总体目标 目标，我们制定了三个具体目标。在目标1中，我们将使用系统发生学方法来检测血统- AS和MAP调节区经历的选择强度和适应性进化的特异性变化 特定于世系的适应性进化。在目标2中，阐明导致 剪接发散，我们将系统地映射不同的蛋白质-RNA相互作用，并重建 通过片段足迹、限制性商业惯例和限制性商业惯例的扰动在系统发育中的进化史 比较基因组分析。在目标3中，我们将重点研究MAPT替代外显子10，它与 额颞叶痴呆(FTD)，并进行详细分析，以揭示其分歧剪接的机制 在灵长类动物中以及细胞水平上的相关功能。如果成功，这项研究将推进我们的 理解AS进化对不同哺乳动物之间潜在表型差异的贡献 物种和潜在的机制。这项研究确立的战略还将提供一种新的和 可泛化的范例，以更好地理解拼接代码。