Regulatory Genomics of Human Neurodevelopment

描述（由申请人提供）：许多神经精神疾病，包括精神分裂症、双相情感障碍和自闭症，都有很强的遗传成分的证据，但连锁和关联研究结果并不确定且相互矛盾。因此，他们观察到的遗传性的一个很大的组成部分仍然无法解释。最近的全基因组关联研究表明，非编码基因组区域在一些常见疾病，包括神经精神疾病的显着参与。该建议利用数字DNaseI图谱系统鉴定和表征与人类神经发育相关的顺式调节元件，以分析不同发育时间点的胎儿脑组织（70至140天），并进一步发展了新的技术，以确定在反式调节相互作用。这一地图的功能顺式-调控元件将被用于分析与精神疾病的遗传学研究有关的区域。相反，将系统地评估转录因子编码序列中的疾病相关变体的DNA序列特异性改变，可能导致对下游调控元件的反式影响。最后，将使用培养的人类细胞的位点特异性基因组编辑来验证和探索疾病相关调节变体的反式效应。这项工作将为了解神经发育中基因调节的分子机制提供独特的资源，并将建立一个基线来解释关联研究中观察到的遗传变异。这些迅速扩大的人类遗传变异目录为减轻精神障碍的负担提供了巨大的希望。这一拟议的资源将通过生成可能与神经系统疾病相关的顺式调控元件和反式调控相互作用的高分辨率地图来释放这些目录的全部优势。研究培训计划结合了申请人的主办机构和赞助商的优势，并提供了一个机会，将ENCODE项目和路线图表观基因组学计划等大规模监管绘图工作的结果转化为特定的疾病领域。

DESCRIPTION (provided by applicant): Many neuropsychiatric disorders, including schizophrenia, bipolar disorder, and autism show evidence of a strong genetic component, yet linkage and association study results have been inconclusive and contradictory. Thus a large component of their observed heritability remains unexplained. Recent genome wide association studies suggest the prominent involvement of noncoding genomic regions in a number of common diseases, including neuropsychiatric disorders. This proposal takes advantage of the systematic identification and characterization of cis-regulatory elements relevant to human neurological development using digital DNaseI mapping to analyze fetal brain tissues at different developmental time points (between 70 and 140 days), and further develops novel techniques to identify regulatory interaction in trans. This map of functional cis-regulatory elements will be used to analyze regions implicated in genetic studies of psychiatric disorders. Conversely, disease-associated variants in transcription factor coding sequence will be systematically evaluated for altered DNA sequence specificity, potentially leading to effects in trans on downstream regulatory elements. Finally, the trans effects of disease-associated regulatory variants will be validated and explored using site-specific genome editing of cultured human cells This work will provide a unique resource for understanding the molecular mechanisms of gene regulation in neural development, and will establish a baseline for interpreting genetic variation observed in association studies. These rapidly expanding catalogs of human genetic variation offer great promise for reducing the burden of mental disorders. This proposed resource will unlock the full advantage of these catalogs by generating high-resolution maps of cis-regulatory elements and trans-regulatory interactions likely relevant to neurological disease. The research training program combines the strengths of the applicant's host institution and sponsor, and offers an opportunity to translate thee results of large-scale regulatory mapping efforts such as the ENCODE project and the Roadmap Epigenomics program to a specific disease area.