Computational tools and resources to study alternative splicing and mRNA isoform variation

研究选择性剪接和 mRNA 亚型变异的计算工具和资源

• 批准号: 10669330
• 负责人: Yi Xing
• 金额: $ 56.88万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669330
• 关键词: Address; Adopted; Adoption; Algorithmic Software; Algorithms; Alternative Splicing; Atlases; Big Data; Bioinformatics; Biology; Cell Differentiation process; Cells; Communities; Computer software; Data; Data Set; Development; Disease; Ensure; Event; Exons; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genomics; Genotype-Tissue Expression Project; Heterogeneity; Human; Human Development; Immune; Introns; Length; Mammalian Cell; Measurement; Medicine; Messenger RNA; Molecular; Molecular Analysis; Mus; Pattern; Performance; Phenotype; Population; Protein Isoforms; Protocols documentation; RNA; RNA Splicing; Regulation; Research; Research Personnel; Resolution; Scientist; Techniques; Technology; Testing; Tissues; Transcriptional Regulation; Variant; Work; base; brain tissue; computerized tools; computing resources; data resource; deep learning; deep learning model; epigenomics; genetic variant; human disease; improved; interest; mRNA Precursor; mammalian genome; nanopore; neuron development; novel; open source; predictive tools; programs; public repository; single cell analysis; single-cell RNA sequencing; software development; tool; trait; transcriptome; transcriptome sequencing; transcriptomics; user-friendly

PROJECT SUMMARY The central objective of this project is to develop broadly applicable computational tools and resources for studying pre-mRNA alternative splicing (AS) and mRNA isoform variation. AS is a prevalent mechanism for generating regulatory and functional diversity. Almost all multi-exon genes in mammalian genomes undergo AS, resulting in mRNAs that vary in their exon composition. Widespread changes in AS occur in development, cell differentiation, and disease. However, many questions remain about the patterns, regulation, and functions of AS. Rapid accumulation of large-scale RNA-seq data in public repositories, emergence of new long-read sequencing strategies for transcriptome analysis, and recent advances in deep learning techniques create exciting opportunities for omics and big data approaches to uncover new regulatory and functional features of AS. To make full use of these powerful datasets and technologies, new computational tools are urgently needed. Our lab has an outstanding track record in developing and disseminating widely adopted algorithms and computational tools for characterizing AS and mRNA isoform variation. In this R01 project, building on that expertise, we will develop new computational tools and resources to study intron retention – a still poorly understood mechanism of gene regulation in human cells – and characterize genetically regulated intron retention events in the human population (Aim 1), and to delineate AS patterns and mRNA isoform variation using long-read RNA-seq data of bulk tissues (Aim 2) and single cells (Aim 3). The resulting user-friendly, scalable tools as well as associated data resources will substantially enhance the ability of biomedical researchers to study AS and transcriptome complexity using in-house and public datasets in diverse normal and diseased contexts. All software developed in this project will be made open source and freely available to the research community. We will leverage our extensive network of expert collaborators and broad user base to enhance the development, testing, and dissemination of these computational tools. Our efforts will be integrated with our long-standing interest in the biology of AS and mRNA isoform regulation, ensuring that our work addresses important biomedical questions and serves unmet technological needs. Importantly, in each aim the development of computational tools and resources will synergize with their applications to questions about the variation, regulation, and functions of AS. Overall, we expect that our proposed R01 project will provide powerful and widely used computational tools and resources for studying AS in mammalian transcriptomes.

项目摘要 该项目的核心目的是开发广泛适用的计算工具和资源 研究MRNA前替代剪接（AS）和mRNA同工型变异。正如普遍的机制 产生监管和功能多样性。哺乳动物基因组中几乎所有的多外结果基因都经历了AS， 导致mRNA在其外显子组成中有所不同。开发中发生的宽度变化，细胞发生 分化和疾病。但是，关于模式，法规和功能的许多问题仍然存在 作为。公共存储库中大规模RNA-seq数据的快速积累，新的长阅读的出现 对转录组分析的测序策略，以及深度学习技术的最新进展创造 OMIC和大数据方法的激动人心的机会，以发现新的调节和功能功能 作为。为了充分利用这些功能强大的数据集和技术，迫切需要新的计算工具。 我们的实验室在开发和传播广泛采用的算法和 表征AS和mRNA同工型变化的计算工具。在这个R01项目中，以此为基础 专业知识，我们将开发新的计算工具和资源来研究内含子保留 - 仍然很差 了解人类细胞中基因调节的机制，并表征遗传调节的内含子 人口中的保留事件（AIM 1），并将其描述为模式和mRNA同工型变异 使用散装组织（AIM 2）和单个细胞（AIM 3）的长阅读RNA-seq数据。由此产生的用户友好， 可扩展工具以及相关的数据资源将大大增强生物医学的能力 研究人员使用内部和公共数据集研究AS和转录组的复杂性， 患病的情况。该项目中开发的所有软件都将成为开源，并免费提供给 研究社区。我们将利用我们广泛的专家合作者网络和广泛的用户基础来进行 增强这些计算工具的开发，测试和传播。我们的努力将被整合 我们对AS和mRNA同工型调节的生物学长期兴趣，以确保我们的工作 解决重要的生物医学问题，并满足了未满足的技术需求。重要的是，在每个目标中 计算工具和资源的开发将与他们的应用程序协同为有关 AS的变化，调节和功能。总体而言，我们预计我们拟议的R01项目将提供强大的 以及广泛使用的计算工具和资源，用于研究哺乳动物的转录组。