Exome Pool-Seq and systems biology approach to identify and characterize genes and networks in neurodevelopmental disorders

外显子组池测序和系统生物学方法来识别和表征神经发育障碍中的基因和网络

• 批准号: 422575385
• 负责人: Dr. Bernt Popp
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422575385?language=en
• 关键词: Exome; Pool; Seq; systems; biology

Neurodevelopmental disorders (NDD) are clinically and genetically extremely heterogeneous with more than 1000 underlying genes identified, so far. High throughput sequencing by Next-Generation sequencing (NGS) technologies has greatly advanced the identification and confirmation of novel disease genes. Despite these advances and despite falling costs, the current gold standard of trio-based exome or genome sequencing remains prohibitively expensive and time-consuming for large cohorts. To identify further known and novel genetics causes of NDDs on a larger scale we developed Exome Pool-Seq, an approach combining pooling of DNA samples and standard capture-based exome sequencing. This method greatly reduces sequencing costs albeit maintaining a high detection rate. We now plan to improve the method computationally and screen a larger cohort of >500 individuals with NDDs to systematically identify known and new NDD causing variants. The successful application of Exome Pool-Seq results from the synergy between the two applicants’ core skills: computational data analysis and clinical/genetic expert knowledge. We want to extend this interaction to computationally and functionally characterize genes and pathways involved in NDDs. This work will be based on the further development and improvement of our established SysID database, which contains an expert-curated list of NDD associated genes and related phenotypic and molecular information. Additionally, we will functionally characterize newly identified candidate genes by e.g. Drosophila melanogaster as a model. These integrated efforts will increase the knowledge on specific candidate genes but also common processes deregulated in NDDs. In summary, our study will provide new insights into the clinical and molecular landscape of NDDs and enable researchers and clinicians to score the validity of genotype-phenotype relationships in NDDs.

神经发育障碍（NDD）在临床和遗传学上是极其异质性的，到目前为止已鉴定出1000多个潜在基因。通过下一代测序（NGS）技术的高通量测序极大地推进了新疾病基因的鉴定和确认。尽管取得了这些进展，尽管成本下降，但目前基于trio的外显子组或基因组测序的黄金标准对于大型队列来说仍然非常昂贵和耗时。为了更大规模地鉴定NDD的进一步已知和新的遗传学原因，我们开发了外显子组池-Seq，这是一种结合DNA样品池和标准捕获外显子组测序的方法。该方法大大降低了测序成本，同时保持了高检测率。我们现在计划在计算上改进该方法，并筛选一个更大的NDD人群，其中包括>500名NDD患者，以系统地识别已知的和新的NDD致病变异。Exome Pool-Seq的成功应用源于两个申请人的核心技能之间的协同作用：计算数据分析和临床/遗传专家知识。我们希望将这种相互作用扩展到计算和功能上表征NDD中涉及的基因和途径。这项工作将基于我们建立的SysID数据库的进一步开发和改进，该数据库包含NDD相关基因和相关表型和分子信息的专家策划列表。此外，我们还将以黑腹果蝇（Drosophila melanogaster）为模型，对新发现的候选基因进行功能表征。这些综合努力将增加对特定候选基因的了解，但也会增加对NDD中解除管制的常见过程的了解。总之，我们的研究将为NDD的临床和分子景观提供新的见解，并使研究人员和临床医生能够对NDD中基因型-表型关系的有效性进行评分。