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进化