Regulatory Genomics of Human Neurodevelopment

描述(由申请人提供)：许多神经精神障碍，包括精神分裂症、双相情感障碍和自闭症，都显示出强烈的遗传成分，但连锁和关联研究结果一直没有定论和矛盾。因此，他们观察到的遗传力的很大一部分仍然无法解释。最近的全基因组关联研究表明，非编码基因组区域显著参与了许多常见疾病，包括神经精神障碍。这项建议利用数字DNaseI图谱系统地识别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(70天至140天)的胎儿脑组织，并进一步开发新的技术来识别反式调节相互作用。这张顺式调节元件的功能图谱将被用来分析精神疾病的遗传学研究中涉及的区域。相反，转录因子编码序列中与疾病相关的变体将被系统地评估DNA序列特异性的改变，潜在地导致反式作用于下游调控元件。最后，疾病相关调控变异的反式效应将通过对培养的人类细胞进行定点基因组编辑来验证和探索。这项工作将为理解神经发育中基因调控的分子机制提供独特的资源，并将为解释在关联研究中观察到的遗传变异奠定基础。这些迅速扩大的人类基因变异目录为减轻精神疾病的负担提供了巨大的希望。这一提议的资源将通过生成可能与神经疾病相关的顺式调控元件和跨调控相互作用的高分辨率地图来充分释放这些目录的优势。研究培训计划结合了申请者主办机构和赞助商的优势，并提供了将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疾病领域的机会。

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.