Evolution of Pre-mRNA Splicing in Primates

灵长类动物中前体 mRNA 剪接的进化

• 批准号: 8606617
• 负责人: Yi Xing
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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/8606617
• 关键词: Evolution; Pre; mRNA; Splicing; Primates

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）：该项目的目标是系统地调查灵长类动物中mRNA前体剪接的进化，并阐明产生物种特异性外显子和剪接模式的分子机制。高等真核生物中的选择性剪接从有限的蛋白质编码基因库中产生了巨大的调控和功能多样性。它还允许基因进化出新的剪接同种型，同时仍然表达祖先的剪接同种型。许多基因具有物种特异性的外显子和剪接模式，这些外显子和剪接模式是由影响基本剪接信号的小规模序列变化或大规模插入或缺失引起的。然而，尽管剪接在真核基因组进化过程中发挥着关键作用，但关于剪接变化如何发生以及此类变化的进化意义的许多问题仍然很大程度上未被探索。我们建议结合基因组、计算和分子方法来研究灵长类动物和人类进化过程中的剪接变化。具体目标是：1）利用脊椎动物物种的基因组比对、微阵列和基于测序的技术生成的人类基因的广泛外显子水平转录组图谱以及新外显子的分子剪接分析，研究灵长类动物新外显子的诞生和进化。人类和非人类灵长类动物的外显子。 2) 通过高密度外显子连接阵列和大量人类和灵长类组织的 RNA-seq 分析，全面检查人类和非人类灵长类动物之间的剪接差异。 3）通过剪接调控信号和小基因实验的比较分析，阐明灵长类动物剪接进化的机制。该项目将改善人类和灵长类基因组的注释，极大地扩展对我们物种特有的新外显子和剪接模式的了解，并揭示真核基因组如何通过剪接的进化来扩展其功能库。这些研究的结果将阐明基因组序列的进化如何导致物种之间的剪接差异。这将为剪接的调控以及遗传变异如何破坏人类疾病中的剪接提供重要的见解。 公共健康相关性：许多人类疾病是由前 mRNA 剪接异常引起的。该项目将系统地调查灵长类动物剪接的进化，并阐明剪接模式如何因基因组序列进化而变化。这些研究将为了解剪接如何调控以及遗传变异如何破坏人类疾病中的剪接提供重要见解。