Human gene duplications in neurodevelopment and disease

神经发育和疾病中的人类基因重复

基本信息

批准号：
10803027
负责人：
Megan Y Dennis
金额：
$ 69.48万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10803027
关键词：
Benchmarking Bioinformatics Biological Biological Assay Biological Models Brain Candidate Disease Gene Clustered Regularly Interspaced Short Palindromic Repeats Complement Complex Copy Number Polymorphism Coupled Data Data Set Development Developmental Process Disease Embryo Etiology Evolution Exhibits Eye Development Family Gene Duplication Genes Genetic Genetic Diseases Genetic Heterogeneity Genetic Risk Genetic Screening Genetic Variation Genome Genomics Human Human Genetics Human Genome Image Knock-out Left Life Location Maps Messenger RNA Methods Modeling Modernization Morphology Mus Mutation Neurodevelopmental Disorder Neurologic Neurons Orthologous Gene Phenotype Pongidae Population Population Control Primates Proliferating Proteins Publications Publishing Recurrence Role SRGAP2 gene Sampling Sequence Analysis Siblings Signal Transduction Societies Source Specific qualifier value Testing Time Variant Zebrafish autism spectrum disorder autistic children axon guidance bioinformatics pipeline causal variant cohort experience falls fetal frontier functional genomics gene conservation gene function genetic variant genomic locus human pangenome human reference genome improved individuals with autism spectrum disorder innovation insight mutant neural neurodevelopment paralogous gene patient screening proband rare variant reference genome single-cell RNA sequencing synaptic function synaptogenesis telomere tool trait transcriptome sequencing whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Despite significant efforts to identify genes important in human neurodevelopment and disease, a large proportion of genes and variants remain undiscovered. Duplicated parts of the genome are largely understudied due to historical errors in the reference and bioinformatic pipelines that filter reads mapping to multiple locations in the genome. With the recent publication of a complete telomere-to-telomere human genome, genes and variants can be more effectively assayed across complex loci, but modified computational approaches are necessary. The proposed study will leverage diverse expertise in functional genomics and human genetics to test the hypothesis that a subset of human duplicated genes both contribute to neurological features and cause disorders exclusive to modern-day humans. Duplicated genes have previously been shown to play a role in early brain development and are enriched at genomic hotspots where recurrent copy-number variants are associated with neurodevelopmental disorders. Starting with a comprehensive list of thousands of human duplicated genes, functions of a subset of genes expressed during human corticogenesis will be tested using CRISPR knockout of orthologs and expression of human paralogs in zebrafish to determine their effects on general morphology, synaptic function, and brain development. The ability to test tens to hundreds of genes in parallel and conservation of basic developmental processes—such as neural proliferation, axonal guidance, and synaptogenesis—make zebrafish an ideal model to test these genes. Second, a genetic screen will be performed in human population cohorts to identify conserved duplicated genes. Since standard methods filter variants across many complex genomic loci, an improved bioinformatics approach leveraging short-read data will be devised and optimized using available sequencing benchmarks. Further, conserved genes will be screened for de novo and rare variants in autistic individuals using published datasets. Leveraging this multifaceted approach will enable systematic assessment of duplicated genes and their putative roles in human neurological traits and disorders. The zebrafish toolkit will be generally applicable to assaying functions of additional (non-duplicated) genes important in brain development, while the improved bioinformatics approach will enable additional screens of duplicated genes in other disease cohorts. This project will not only provide important insights into what it means to be human, but also it has the capability to discover missing genetic risk and elucidate the etiology of complex genetic neural traits and disorders.

项目摘要/摘要尽管努力确定在人类神经发育和疾病中重要的基因，但很大基因和变体的比例仍然未被发现。基因组的重复部分主要是由于参考文献和生物信息学管道中的历史错误而对过滤器读取为基因组中的多个位置。随着最新出版的完整端粒到居组人基因组，基因和变体可以在复杂的地方更有效地分配，但是经过修改的计算方法是必要的。拟议的研究将利用潜水员的功能基因组学专家和人类遗传学以检验人类重复基因子集的假设都有助于神经功能特征并引起现代人类独有的疾病。重复的基因具有以前已显示出在早期大脑发育中发挥作用，并在基因组热点中富集反复的复制数变体与神经发育障碍有关。从A开始全面的人类重复基因的综合列表，一部分基因的功能人皮质生成将使用直系同源物的CRISPR敲除和人类旁系同源物的表达进行测试斑马鱼对它们对一般形态，突触功能和大脑发育的影响。这能够在基本发展过程中并行地测试数十个基因和数百个基因的能力 - 作为神经增殖，轴突引导和突触发生，斑马鱼是一个理想的模型来测试这些模型基因。其次，将在人群同类中进行遗传屏幕以识别保守重复的基因。由于标准方法过滤了许多复杂基因组局部的变体，因此改进了利用可用测序的生物信息学方法将设计和优化短阅读数据基准。此外，将在加速个体中对从头开始筛选保守的基因和稀有变体使用已发布的数据集。利用这种多方面方法将使系统评估重复的基因及其在人类神经系统特征和疾病中的推定作用。斑马鱼工具包将通常适用于在大脑中重要的（未塑性）基因的额外（未塑形）基因的功能开发，而改进的生物信息学方法将使重复基因的其他屏幕在其他疾病队列。该项目不仅将提供有关人类意味着什么的重要见解，而且还会提供它有能力发现缺失遗传风险并阐明复杂遗传神经的病因特质和疾病。