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High-throughput modeling of autism risk genes using zebrafish

使用斑马鱼进行自闭症风险基因的高通量建模

基本信息

批准号：
10478187
负责人：
DANIEL H GESCHWIND
金额：
$ 75.66万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478187
关键词：
Address Animal Model Autopsy Behavior Behavioral Behavioral Model Biological Assay Biological Models Brain Cells Communities Data Development Disease Disease model Drug Screening Gene Expression Genes Genetic Goals Human Image Individual Inherited Lead Literature Methods Missense Mutation Modeling Molecular Mutation Neurons Orthologous Gene Pathway Analysis Pathway interactions Pharmacology Phenotype Proteins Publishing RNA Splicing Reagent Reporting Resources Risk Role Seizures Signal Transduction Sleep Sleep disturbances Social Behavior Spliced Genes Startle Reaction System Testing Time Tissue-Specific Gene Expression Translating Variant Vertebrates Zebrafish autism spectrum disorder base behavior test behavioral phenotyping brain behavior cohort comorbidity cost cost effectiveness de novo mutation disorder risk experimental study gene function gene network genetic risk factor genetic testing genome sequencing genome wide association study genome-wide habituation high throughput analysis high throughput screening high-throughput drug screening imaging approach improved in vivo molecular phenotype mutant neurodevelopment novel novel therapeutic intervention novel therapeutics null mutation relative effectiveness risk variant screening social transcriptomics translational goal whole genome

项目摘要

Autism spectrum disorder (ASD) is caused by both environmental and genetic factors, with the genetic contribution estimated at 60-80%. Dozens of genes that increase risk for ASD have been identified, most based on de novo mutations, but these mutations are predicted to account for only 15-20% of ASD cases. Thus, the majority of the genetic contribution to ASD is predicted to result from common and rare inherited variation, but few such genes have been identified. Recently, using whole genome sequencing, we reported genome wide evidence for >60 ASD risk genes, 26 of them novel for ASD, with signals derived from inherited and de novo protein truncating or missense mutations. The functions of most of these genes are unknown, so a crucial and necessary next step is to explore their impact on neurodevelopment and neuronal function using a model organism. The current pace of translating genetic risk factors into phenotypes, mechanisms and therapies is limited in part by inefficiencies with in vivo mammalian model systems, which makes them impractical for creating and behaviorally testing large numbers of mutant lines. Here, we leverage the zebrafish, which occupies a unique niche as a vertebrate model with features amenable to both in vivo screening and mechanistic understanding, including ex utero development, transparency, small size, rapid development, a conserved yet relatively simple vertebrate brain, behaviors relevant to ASD, and cost-effectiveness relative to mammalian models. While the zebrafish cannot recapitulate ASD and has limitations for modeling a human disorder, an emerging literature supports the notion that it is a useful model to study the functions of genes that contribute to ASD risk. Rather than assess ASD-risk genes one at a time, we will accelerate progress towards mechanistic understanding via high-throughput assays and analyses. In Specific Aim 1 we will generate null mutations in the zebrafish orthologs of 24 high confidence, novel, genome-wide significant ASD risk genes, and systematically test each mutant for neurodevelopmental, behavioral, neuronal network, and transcriptomic phenotypes. In Specific Aim 2, we will use transcriptomic analyses, at the whole brain and single cell levels, to integrate ASD risk genes into functional networks, and test for convergence across genes and species, including ASD post mortem brain. We will also test for functional associations among behavioral phenotypes that are often co-morbid in ASD, such as disrupted sleep and social behavioral deficits. In Specific Aim 3 we will perform mechanistic studies to understand how mutation of specific ASD-risk genes leads to phenotypes. This project will efficiently and cost-effectively create and characterize vertebrate animal models for a large number of novel ASD risk genes. These animal models will be a valuable resource for the community, particularly for large-scale in vivo drug screens to identify new therapies for ASD.

自闭症谱系障碍（ASD）是由环境和遗传因素共同引起的，具有遗传性