Human gene duplications in neurodevelopment and disease

项目概要/摘要 尽管在识别人类神经发育和疾病中重要的基因方面做出了重大努力，但大部分基因仍然存在。 基因和变异的比例仍然未被发现。基因组的重复部分主要是 由于参考和生物信息学管道中的历史错误， 基因组中的多个位置。随着最近发表的一个完整的端粒到端粒的人类 基因组、基因和变体可以在复杂的基因座上更有效地测定，但修改的计算 方法是必要的。拟议的研究将利用功能基因组学的各种专业知识 和人类遗传学来检验一个假设，即人类复制基因的一个子集都有助于 神经学特征，并导致现代人类独有的疾病。重复的基因 以前被证明在早期大脑发育中发挥作用，并在基因组热点富集， 复发性拷贝数变异与神经发育障碍有关。以开局就是 成千上万的人类重复基因的综合列表，在人类基因组中表达的基因子集的功能， 将使用直向同源物的CRISPR敲除和人旁系同源物的表达来测试人皮质生成， 斑马鱼，以确定其对一般形态，突触功能和大脑发育的影响。的 同时测试数十到数百个基因的能力，以及基本发育过程的保护， 神经增殖、轴突引导和突触发生--使斑马鱼成为测试这些功能的理想模型 基因.其次，将在人群队列中进行遗传筛查，以确定保守的 复制基因由于标准方法在许多复杂的基因组基因座上过滤变体，因此改进的方法可以在许多复杂的基因组基因座上过滤变体。 利用现有的测序技术，将设计和优化利用短读数据的生物信息学方法 基准。此外，保守的基因将筛选新生和罕见的变异，在自闭症患者 使用已发布的数据集。利用这一多方面的方法，将能够系统地评估 重复基因及其在人类神经系统特征和疾病中的假定作用。斑马鱼工具包将 通常适用于测定脑中重要的额外（非复制）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选， 其他疾病队列。这个项目不仅将提供重要的见解，了解什么是人类，但 它也有能力发现缺失的遗传风险，并阐明复杂的遗传神经系统疾病的病因。 特征和失调

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.