Complexity and evolution of splicing-regulatory networks

剪接调控网络的复杂性和演化

• 批准号: 10706471
• 负责人: Chaolin Zhang
• 金额: $ 90.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706471
• 关键词: Address; Affect; Alternative Splicing; Biological Models; Code; Computing Methodologies; Disease; Event; Evolution; Experimental Models; Genes; Genetic; Genetic Diseases; Genetic Variation; Health; Human; Learning; Malignant Neoplasms; Mammals; Maps; Molecular; Mutation; Nature; Pan Genus; Pattern; Phenotype; Population; Predisposition; Process; Protein Isoforms; Quantitative Trait Loci; RNA Splicing; RNA-Binding Proteins; Regulation; Regulatory Element; Research; Source; Transcript; Work; driving force; experimental study; genetic information; innovation; insight; mammalian genome; multidisciplinary; nervous system disorder; new technology; programs; technology development; trait

Complexity and evolution of splicing-regulatory networks Project Summary Alternative splicing (AS) generates multiple transcript isoforms from single genes and contributes critically to the molecular, 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. Indeed, divergent AS events are pervasive in different mammalian species, as well as in human populations as evident from widespread splicing quantitative trait loci (sQTLs). Despite remarkable progress in studies of splicing-regulatory networks over the past decade, our understanding of the splicing code remains very incomplete, leaving critical questions such as 1) which evolutionary splicing changes in different species or in human populations have functional implications? 2) what are the underlying mutations/genetic variations that led to the divergent splicing patterns? Building on our previous work on splicing-regulatory networks, this research program aims to address these questions. We will develop computational methods and experimental model systems to identify AS events under adaptive selection in specific lineages and map mutations leading to changes in splicing-regulatory elements that underlie splicing divergence. Insights learned from evolutionary changes that represent nature’s experiments will be leveraged to develop a more predictive splicing code. In these studies, computational and experimental approaches including new technology development are closely integrated by our multidisciplinary team. If successful, this study will provide tremendous insights into the contribution of AS evolution to potential phenotypic differences among different mammalian species, to health and disease in humans, and to fundamental understanding of RNA splicing regulation.

剪接调控网络的复杂性和演化 项目概要 选择性剪接 (AS) 从单个基因生成多个转录亚型，并对 哺乳动物的分子、细胞和表型复杂性受到 RNA 结合的严格调控。 识别其目标转录物中特定调节元件的蛋白质（RBP）是一个长期存在的问题。 从进化的角度来看，AS 调节的变化是由于顺式调节的突变引起的。 序列提供了哺乳动物物种形成的主要驱动力，包括密切相关的物种，例如 事实上，不同的哺乳动物物种以及黑猩猩中普遍存在不同的 AS 事件。 从广泛的剪接数量性状位点（sQTL）可以看出，尽管这一点很显着。 过去十年剪接调控网络研究的进展，我们对剪接代码的理解 仍然非常不完整，留下了一些关键问题，例如 1）进化剪接在不同的情况下会发生变化 物种或人类群体有功能影响吗？ 2）潜在的突变/遗传是什么？ 导致不同剪接模式的变异？建立在我们之前的剪接监管工作的基础上？ 网络，这个研究计划旨在解决这些问题，我们将开发计算方法和 用于识别特定谱系和图谱中适应性选择下的 AS 事件的实验模型系统 突变导致剪接调节元件发生变化，而剪接调节元件是剪接分歧的基础。 来自代表自然实验的进化变化将被用来开发更具预测性的 在这些研究中，计算和实验方法包括新技术。 如果成功，这项研究将由我们的多学科团队紧密结合。 深入了解 AS 进化对不同物种之间潜在表型差异的贡献 哺乳动物物种、人类健康和疾病以及对 RNA 剪接的基本了解 规定。