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Highly parallel analysis of 5' and 3' UTR variants in Autism Spectrum Disorders

自闭症谱系障碍中 5 和 3 UTR 变异的高度并行分析

基本信息

批准号：
10376785
负责人：
JOSEPH D DOUGHERTY
金额：
$ 57.98万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376785
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions ASD patient Address Affect Biological Assay Brain Categories Cell Culture Techniques Clinical Code Collection Complication Copy Number Polymorphism Disease Exons Family Gene Mutation Genes Genetic Genetic Enhancer Element Genetic Transcription Genetic Variation Genome Goals Heritability In Vitro Individual Intercistronic Region Introns Investments Measures Mental disorders Messenger RNA Methods MicroRNAs Missense Mutation Molecular Mus Mutation Mutation Analysis Neurosciences Research Patients Play Population Post-Transcriptional Regulation Proteins RNA RNA-Binding Proteins Regulator Genes Reporter Research Role Siblings Symptoms Syndrome Testing Tissues Transcript Translational Regulation Translations Triplet Multiple Birth Untranslated RNA Untranslated Regions Ursidae Family Variant autism spectrum disorder base cell type cost de novo mutation design disease-causing mutation disorder risk exome sequencing falls genetic variant genome sequencing high throughput screening in vivo innovation loss of function loss of function mutation mRNA Stability novel premature prognostic promoter tool whole genome

项目摘要

Substantial investments are being made to sequence the genomes of families with Autism Spectrum Disorder (ASD). However, identifying disease mutations outside the ~1% of protein coding sequences is challenging because 1) the ‘search space’ is so much larger, and thus many more mutations occur by chance, and 2) there is no simple code to identify deleterious mutations in non-coding sequence, and thus loss of function mutations must be defined experimentally. In addition, the consequences of mutations in non-coding (i.e. regulatory) sequences are often highly dependent on the specific cell type. Thus functional assays must be conducted in vivo, in the appropriate CNS cell types. To address the search space challenge, we propose to focus specifically on the untranslated regions (UTRs) of mRNAs. UTRs are important, conserved regulatory sequences that profoundly impact protein levels by altering translation rates or transcript stability for specific genes. Importantly, in ASD cases there is a 2-fold greater rate of UTR mutations in known ASD genes than expected by chance, indicating that roughly half of these UTR mutations may contribute to disease. To address the lack of a code for interpreting UTR mutations, we have assembled a team with a unique combination of expertise to conduct massively parallel functional analysis of UTR variants from ASD patients, in ASD-relevant cell types in vitro and in vivo. Combining two innovative but established components: post-transcriptional massively parallel reporter assays, and cell type specific translational profiling, we aim to establish a pipeline to 1) Identify UTR mutations that result in altered protein levels, 2) conduct genetic burden and association testing on these variants, and 3) define the molecular mechanisms altering protein levels for specific mutations. This pipeline will leverage the existing large investment in ASD genome sequencing by defining individual non-coding disease causing mutations in a class of sequences that has, so far, not been the focus of disease studies.

对自闭症谱系障碍家庭的基因组测序进行了大量投资