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

• 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
• 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

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.

项目摘要 该R03提案描述了一项为期两年的研究计划，重点是对先前未注释的调查 微动蛋白是自闭症谱系障碍遗传病因（ASD）。稀有遗传和从头遗传 变体是ASD的重要原因，但仅解释了约20％的家庭的病因。此外，很少见 在基因组的非编码区域已经鉴定了与ASD相关的变体，但是功能 发现的人的意义在很大程度上是未知的，代表了ASD遗传学中的关键知识差距。我们 最近完成了一项研究，以介绍人脑的mRNA翻译景观（“翻译”）， 识别数千个编码假定的小蛋白<100氨基酸的小型开放式阅读框（SORFS）， 其中许多是从基因组的注释非编码区域翻译的。我们假设这一点 微蛋白代表了隐藏基因的未引人注目的缓存，该基因在疾病中的作用几乎完全是 意外。为了解决小蛋白在ASD中的潜在作用，我们将利用最大的全基因组 ASD中的测序（WGS）数据集以及我们新创建的人类脑小蛋白的地图集，以发现 基于罕见的遗传和从头序列级别和结构的小巧蛋白基因与ASD风险相关 变体（目标1）。此外，我们的初步数据表明，许多微蛋白缺乏三维 结构（本质上无序），并具有结合RNA的序列基序。基于传统序列 蛋白质的分析将在短而高度混乱的小蛋白质上表现不佳。因此，在AIM 2中，我们将 建立基于物理特征的分析范例，以预测与ASD相关的分子功能 小蛋白质。这项工作结合了发育神经科学，基因组学和计算的专家 蛋白质生物学。从该R03中获得的知识，包括识别新ASD相关的 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展 调节小脑中小蛋白质及其对ASD的贡献。我们的方法 将先前未经注释的微蛋白纳入遗传分析中，可以应用于其他神经系统和 非神学条件，从而扩大了我们对人类疾病遗传结构的理解。