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.

项目概要 该项目的中心目标是开发广泛适用的计算工具和资源 研究前体 mRNA 选择性剪接 (AS) 和 mRNA 同工型变异是一种常见的机制。 产生调节和功能多样性，哺乳动物基因组中几乎所有的多外显子基因都会经历 AS， 导致 mRNA 的外显子组成发生变化，在细胞发育过程中发生广泛的变化。 然而，关于其模式、调节和功能仍然存在许多问题。 AS.公共存储库中大规模RNA-seq数据的快速积累，新的长读长的出现 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了 组学和大数据方法发现新的监管和功能特征的令人兴奋的机会 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和 在此 R01 项目中，用于表征 AS 和 mRNA 同工型变异的计算工具。 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 了解人类细胞基因调控机制 - 并表征基因调控内含子 人群中的保留事件（目标 1），并描绘 AS 模式和 mRNA 亚型变异 使用大量组织（目标 2）和单细胞（目标 3）的长读长 RNA 测序数据 可扩展的工具以及相关的数据资源将大大增强生物医学的能力 研究人员使用不同正常和不同状态下的内部和公共数据集来研究 AS 和转录组复杂性 该项目中开发的所有软件都将开源并免费提供给人们。 我们将利用我们广泛的专家合作者网络和广泛的用户群来 加强这些计算工具的开发、测试和传播。 凭借我们对 AS 生物学和 mRNA 同工型调控的长期兴趣，确保我们的工作 重要的是，在每个目标中，解决重要的生物医学问题并满足未满足的技术需求。 计算工具和资源的开发将与它们在解决有关问题的应用程序中发挥协同作用 总体而言，我们预计我们提出的 R01 项目将提供强大的功能。 以及用于研究哺乳动物转录组中 AS 的广泛使用的计算工具和资源。