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 该项目的中心目标是开发广泛适用的计算工具和资源， 研究前mRNA选择性剪接（AS）和mRNA异构体变异。AS是一种普遍的机制， 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显子基因都会发生AS， 导致mRNA的外显子组成不同。AS的广泛变化发生在发育、细胞 分化和疾病。然而，许多问题仍然存在的模式，监管和功能， 如.大规模RNA-seq数据在公共存储库中的快速积累，新的长读 转录组分析的测序策略，以及深度学习技术的最新进展， 令人兴奋的机会，组学和大数据方法，以揭示新的监管和功能特点， 如.为了充分利用这些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方面有着出色的记录， 用于表征AS和mRNA同种型变异的计算工具。在这个R 01项目中， 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-一个仍然很差的 了解人类细胞中的基因调控机制-并表征基因调控内含子 在人群中的保留事件（目的1），并描绘AS模式和mRNA亚型变异 使用大量组织（Aim 2）和单细胞（Aim 3）的长读段RNA-seq数据。由此产生的用户友好， 可扩展的工具以及相关的数据资源将大大提高生物医学的能力， 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， 病态的环境在这个项目中开发的所有软件将开放源代码，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， 加强这些计算工具的开发、测试和传播。我们的努力将被整合 我们长期以来对AS生物学和mRNA亚型调控的兴趣，确保我们的工作 解决重要的生物医学问题，满足尚未满足的技术需求。重要的是，在每个目标中， 计算工具和资源的发展将与它们在解决有关人类健康问题上的应用协同作用。 AS的变异、调节和功能。总的来说，我们预计我们提出的R 01项目将提供强大的 和广泛使用的计算工具和资源，用于研究哺乳动物转录组中的AS。