Human gene duplications in neurodevelopment and disease

项目摘要/摘要 尽管在识别人类神经发育和疾病中的重要基因方面做出了重大努力，但大量的 基因和变种的比例仍未被发现。基因组的复制部分很大程度上 由于过滤器读取映射到的参考和生物信息管道中的历史错误而研究不足 基因组中的多个位置。最近发表了一个完整的端粒到端粒的人类 基因组、基因和变种可以更有效地跨复杂的位置进行分析，但修改了计算 方法是必要的。拟议的研究将利用功能基因组学方面的不同专业知识。 和人类遗传学来检验这一假设，即人类复制的基因的子集都有助于 神经学特征和导致现代人类独有的疾病。复制的基因有 以前被证明在早期大脑发育中发挥作用，并在基因组热点中得到丰富 反复出现的拷贝数变异与神经发育障碍有关。以一个 数千个人类复制基因的综合清单，在此期间表达的基因子集的功能 将使用CRISPR敲除同源基因和表达人类Paralog来测试人类皮质生成 斑马鱼以确定其对一般形态、突触功能和大脑发育的影响。这个 并行测试数十到数百个基因的能力以及基本发育过程的保守性--如 作为神经增殖、轴突引导和突触发生-使斑马鱼成为测试这些的理想模型 基因。第二，将在人类群体队列中进行基因筛查，以确定受保护的 复制的基因。由于标准方法过滤了许多复杂基因组座位上的变异，因此改进的 利用短读数据的生物信息学方法将利用现有的测序进行设计和优化 基准。此外，将对自闭症患者的保守基因进行从头开始和罕见变异的筛查。 使用已发布的数据集。利用这种多方面的方法将能够系统地评估 复制基因及其在人类神经学特征和疾病中的推定作用。斑马鱼工具包将 一般适用于分析大脑中重要的附加(非重复)基因的功能 开发，而改进的生物信息学方法将使额外的重复基因筛查成为可能 其他疾病队列。这个项目不仅将提供对人类意味着什么的重要见解，而且 此外，它还具有发现丢失的遗传风险和阐明复杂遗传神经的病因的能力 特征和障碍。

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.