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Integrative analysis of tissue-specific alternative splicing regulation under adaptive selection

适应性选择下组织特异性选择性剪接调控的综合分析

基本信息

批准号：
10402926
负责人：
Chaolin Zhang
金额：
$ 51.67万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-07 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402926
关键词：
Adult Affect Alternative Splicing Bioinformatics Biological Assay Biology Brain Cebidae Code Comparative Genomic Analysis DNA Data Data Element Development Elements Event Evolution Exons Family Frontotemporal Dementia Genes Genetic Genetic Diseases Goals Human In Vitro Knowledge Link Malignant Neoplasms Mammals Maps Methods Modeling Molecular Monkeys Motor Neurons Mus Mutate Mutation Neurons Nucleic Acid Regulatory Sequences Pan Genus Phenotype Phylogenetic Analysis Phylogeny Predisposition Prevalence Primates Process Protein Binding Domain Protein Splicing Proteins RNA Splicing RNA-Binding Proteins RNA-Protein Interaction Recording of previous events Regulation Regulatory Element Reporter Role Series Site Source Speed Spinal Statistical Models Tissue Model Tissues Transcript Untranslated RNA Validation axon growth brain tissue causal variant cell type comparative driving force experience experimental study fitness genetic information genomic signature human disease induced pluripotent stem cell innovation insight interdisciplinary approach mRNA Precursor mammalian genome nervous system disorder species difference trait transcriptome sequencing

项目摘要

Integrative analysis of tissue-specific alternative splicing regulation under adaptive selection PROJECT SUMMARY Tissue-specific alternative splicing (AS) generates multiple transcripts from single genes and contributes critically to the cellular and phenotypic complexity of mammals. This process is tightly regulated by RNA-binding proteins (RBPs) which recognize specific regulatory elements in their target transcripts. A long-standing hypothesis from the evolutionary perspective is that changes of AS regulation due to mutations in cis-regulatory sequences provide a major driving force of speciation in mammals, including closely related species such as human and Chimpanzee. While recent studies convincingly demonstrated the pervasive species difference of AS in multiple tissues, two fundamental questions remain: 1) which evolutionary splicing changes are under adaptive selection in specific lineages because of acquired fitness advantages? 2) what are the underlying mutations that led to the shifted selective regimes? These challenges are associated with the intrinsic degeneracy of the splicing code and lack of effective computational and experimental approaches for direct comparative analysis. The primary goal of this project is to overcome these limitations, so that we can identify divergent AS events under adaptive selection and the causal mutations affecting important cis-regulatory elements. To achieve this overarching goal, we formulated three specific aims. In Aim 1, we will use phylogenetic genetic methods to detect lineage- specific changes in selection intensity and adaptive evolution of AS and map AS regulatory regions experiencing lineage-specific adaptive evolution. In Aim 2, to elucidate the underlying regulatory mechanisms that led to splicing divergence, we will systematically map divergent protein-RNA interactions and reconstruct the evolutionary history in the phylogeny through a combination of CLIP footprints, perturbation of RBPs and comparative genomic analysis. In Aim 3, we will focus on MAPT alternative exon 10, which is implicated in frontotemporal dementia (FTD), and perform detailed analysis to reveal the mechanism of its divergent splicing in primates and the associated functions at the cellular level. If successful, this study will advance our understanding of the contribution of AS evolution to potential phenotypic differences among different mammalian species and the underlying mechanisms. The strategy established in this study will also provide a new and generalizable paradigm to better understand the splicing code.

自适应选择下组织特异性选择性剪接调控的综合分析