Discovery of Novel Autism-Associated Variation in Brain Miniproteins

发现大脑微蛋白中与自闭症相关的新变异

基本信息

批准号：
10574820
负责人：
Brian Kalish
金额：
$ 5.4万
依托单位：
HOSPITAL FOR SICK CHLDRN (TORONTO)
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-02 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10574820
关键词：
Address Affect Amino Acids Atlases Base Sequence Bioinformatics Biology Brain Calcium Signaling Cell Differentiation process Child Clinical Code Collection Complex Genetic Trait Computer Models Data Data Set Development Disease Etiology Family Foundations Future Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genome Genomics Goals Grant Heritability Human Impairment Individual Infrastructure Inherited Investigation Knowledge Longevity Modeling Molecular Nervous System Neurobiology Neurodevelopmental Disorder Neurologic Neurons Neurosciences Nucleotides Open Reading Frames Phenotype Protein Analysis Protein Truncation Proteins RNA Binding Regulation Research Role Social Interaction Specificity Translating Translations Twin Studies United States Untranslated RNA Variant Work autism spectrum disorder brain tissue cell type cohort computational pipelines de novo mutation disorder risk dosage experimental study genetic analysis genetic architecture genetic variant genome annotation genome sequencing genome wide association study human disease insertion/deletion mutation interest large datasets mRNA Translation mitochondrial metabolism neuropsychiatric disorder novel polygenic risk score programs repetitive behavior research clinical testing ribosome profiling social communication three dimensional structure trait translatome transmission process whole genome

项目摘要

PROJECT SUMMARY This R03 proposal describes a two-year research plan focused on the investigation of previously unannotated miniproteins to the genetic etiology of Autism Spectrum Disorder (ASD). Rare inherited and de novo genetic variants are important causes of ASD, but explain the etiology in only ~20% of families. Furthermore, rare ASD-associated variants have been identified in noncoding regions of the genome, but the functional significance of those found is largely unknown, representing a critical knowledge gap in ASD genetics. We recently completed a study to profile the mRNA translational landscape (the “translatome”) of the human brain, identifying thousands of small open reading frames (sORFs) encoding putative miniproteins <100 amino acids, many of which are translated from annotated noncoding regions of the genome. We hypothesize that miniproteins represent an unappreciated cache of hidden genes whose role in disease is almost entirely unexplored. To address the potential role of miniproteins in ASD, we will leverage the largest whole-genome sequencing (WGS) dataset in ASD, as well as our newly created atlas of human brain miniproteins, to discover miniprotein genes associated with ASD risk based on rare inherited and de novo sequence-level and structural variants (Aim 1). Additionally, our preliminary data suggest that many miniproteins lack three-dimensional structure (intrinsically disordered) and are rich in sequence motifs that bind RNA. Traditional sequence-based analysis of proteins will perform poorly on short, highly disordered miniproteins. Therefore, in Aim 2, we will build physical feature-based analysis paradigms to predict the molecular function of ASD-associated miniproteins. This work combines expertise in developmental neuroscience, genomics, and computational protein biology. The knowledge gained from this R03, including the identification of new ASD-associated genes, will form the basis of future studies to characterize the function, cell type-specificity, and developmental regulation of miniproteins in the human brain, as well as their contribution to ASD. Our approach to incorporating previously unannotated miniproteins in genetic analysis can be applied to other neurologic and non-neurologic conditions, thereby expanding our understanding of the genetic architecture of human disease.

项目概要这个 R03 提案描述了一个为期两年的研究计划，重点是调查以前未注释的微蛋白与自闭症谱系障碍（ASD）的遗传病因学相关。变异是 ASD 的重要原因，但仅能解释约 20% 的家庭的病因。此外，这种情况很少见。与 ASD 相关的变异已在基因组的非编码区域中被发现，但功能性变异这些发现的意义在很大程度上尚不清楚，这代表了自闭症谱系障碍遗传学方面的一个关键知识空白。最近完成了一项研究，旨在描绘人脑的 mRNA 翻译景观（“翻译组”），识别数千个小的开放阅读框（sORF），编码<100个氨基酸的推定微型蛋白，其中许多是从基因组注释的非编码区域翻译而来的。微型蛋白代表了未受重视的隐藏基因，其在疾病中的作用几乎完全是为了解决小蛋白在自闭症谱系障碍中的潜在作用，我们将利用最大的全基因组。自闭症谱系障碍 (ASD) 测序 (WGS) 数据集，以及我们新创建的人脑微型蛋白图谱，以发现基于罕见遗传和从头序列水平和结构的与 ASD 风险相关的小蛋白基因此外，我们的初步数据表明许多微型蛋白缺乏三维结构。结构（本质上无序）并且富含结合 RNA 的序列基序。蛋白质分析对于短的、高度无序的微型蛋白质来说效果不佳，因此，在目标 2 中，我们将进行分析。建立基于物理特征的分析范式来预测 ASD 相关的分子功能这项工作结合了发育神经科学、基因组学和计算方面的专业知识。从 R03 中获得的知识，包括新的 ASD 相关蛋白的鉴定。基因，将构成未来研究的基础，以表征功能、细胞类型特异性和发育人脑中微蛋白的调节及其对 ASD 的贡献。之前在遗传分析中纳入未注释的微型蛋白可以应用于其他神经系统和非神经系统疾病，从而扩大我们对人类疾病遗传结构的理解。