Evolution of Pre-mRNA Splicing in Primates

灵长类动物中前体 mRNA 剪接的进化

• 批准号: 8055497
• 负责人: Yi Xing
• 金额: $ 28.22万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055497
• 关键词: Accounting; Affect; Alternative Splicing; Base Sequence; Binding Sites; Biological Assay; Birth; Cerebellum; Code; Collection; DNA Sequence; Data Set; Eukaryota; Event; Evolution; Exons; Gene Expression; Gene Expression Profile; Gene Structure; Genes; Genetic Variation; Genome; Genomics; Goals; Human; Individual; Knowledge; Light; Macaca mulatta; Molecular; Muscle; Pan Genus; Pattern; Primates; Process; Protein Isoforms; Proteins; RNA; RNA Splicing; RNA analysis; Regulation; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Signal Transduction; Spliced Genes; Surveys; Technology; Tissue-Specific Splicing; Tissues; Transcript; comparative; density; genome sequencing; human disease; human tissue; improved; insight; mRNA Precursor; new technology; nonhuman primate; public health relevance; research study; tool

DESCRIPTION (provided by applicant): The goal of this project is to systematically survey the evolution of pre-mRNA splicing in primates, and elucidate the molecular mechanisms that created species-specific exons and splicing patterns. Alternative splicing in higher eukaryotes generates an enormous regulatory and functional diversity from a limited repertoire of protein-coding genes. It also permits a gene to evolve a new spliced isoform, while still expressing the ancestral spliced isoform. Many genes have species-specific exons and splicing patterns that arose from either small-scale sequence changes that affected essential splicing signals, or large-scale insertions or deletions. However, despite the critical role of splicing during eukaryotic genome evolution, many questions regarding how splicing changes occurred and the evolutionary significance of such changes remain largely unexplored. We propose to combine genomic, computational, and molecular approaches to study splicing changes during primate and human evolution. The specific aims are: 1) To investigate the birth and evolution of new exons in primates, using genome alignments of vertebrate species, extensive exon-level transcriptome profiles of human genes generated by microarray and sequencing-based technologies, and molecular splicing analysis of new exons in humans and nonhuman primates. 2) To globally examine splicing differences between humans and nonhuman primates, by high-density exon junction array and RNA-seq profiling of a large panel of human and primate tissues. 3) To elucidate the mechanisms of splicing evolution in primates, via comparative analysis of splicing regulatory signals and minigene experiments. This project will improve the annotation of human and primate genomes, greatly expand the knowledge of new exons and splicing patterns that are unique to our species, and shed light on how eukaryotic genomes expand their functional repertoire via the evolution of splicing. The results of these studies will elucidate how the evolution of genomic sequences contributed to splicing differences among species. This will provide significant insight into the regulation of splicing, and how genetic variations disrupt splicing in human diseases. PUBLIC HEALTH RELEVANCE: Many human diseases are caused by aberrations in pre-mRNA splicing. This project will systematically survey the evolution of splicing in primates, and elucidate how splicing patterns change as a result of genome sequence evolution. These studies will provide significant insight into how splicing is regulated, and how genetic variations disrupt splicing in human diseases.

描述（由申请人提供）：该项目的目的是系统地调查灵长类动物中MRNA剪接的演变，并阐明产生物种特异性外显子和剪接模式的分子机制。高等真核生物中的替代剪接产生了有限的蛋白质编码基因库的巨大调节和功能多样性。它还允许基因进化新的剪接同工型，同时仍表达祖先剪接的同工型。许多基因具有特异性外显子和剪接模式，这些基因源于影响基本剪接信号的小规模序列，或者大规模插入或缺失。但是，尽管在真核基因组演化过程中剪接的作用至关重要，但有关剪接变化的发生以及此类变化的进化意义的许多问题仍然在很大程度上没有探索。我们建议结合基因组，计算和分子方法，以研究灵长类动物和人类进化过程中的剪接变化。具体目的是：1）使用脊椎动物物种的基因组比对，研究灵长类动物中新外显子的出生和演变，这是由微阵列和基于测序的技术产生的人类基因的广泛外显层转录组谱，以及基于测序的技术以及人类和非人类灵长类动物的新exons分析的分子旋转分析。 2）通过高密度外显子连接阵列和大型人类和灵长类动物组织的RNA-seq分析，在全球范围内检查人类和非人类灵长类动物之间的剪接差异。 3）通过比较剪接调节信号和小型实验的比较分析，阐明了灵长类动物中剪接演变的机制。该项目将改善人类和灵长类动物基因组的注释，大大扩展我们物种独有的新外显子和剪接模式的知识，并阐明了真核基因组如何通过剪接的演变来扩展其功能曲目。这些研究的结果将阐明基因组序列的演变如何促进物种之间的差异。这将为剪接调节以及遗传变异如何破坏人类疾病中的剪接提供重大见解。 公共卫生相关性：许多人类疾病是由MRNA剪接中的畸变引起的。该项目将系统地调查灵长类动物中剪接的演变，并阐明剪接模式因基因组序列进化而导致的变化。这些研究将对剪接的调节方式以及遗传变异如何破坏人类疾病中的剪接提供重大见解。