2/2 - Identification and Validation of Expression Quantitative Trait Loci (eQTLs) in discrete cell types across human brain development

摘要 对发育中的人类大脑的功能基因组分析揭示了高度动态的时空 产前和产后早期发育过程中的基因表达模式和表观遗传变化， 在大脑的各个区域。这些发育动态过程的中断与以下因素有关： 对多种神经发育和神经精神疾病的病因进行了大量补充分析， 紊乱表达数量性状基因座（eQTL），沿着剪接数量性状基因座（sQTL）， 结构变异数量性状基因座（svQTL）是个体间存在差异的基因组变异， 这些差异与基因表达或剪接行为的功能变化相关。许多这些 QTL对组织、脑区、发育阶段或细胞类型表现出特异性，并有一定比例的重叠 与已知的人类疾病的遗传风险因素。在此，我们建议追求三个综合目标， 包括全基因组测序以及大量组织和单核RNA测序， 基因组变异，eQTL/sQTL/svQTL，以及基因表达模式和两个区域的共表达， 人类大脑从胎儿中期发育到青春期。此外，我们将采用新颖的和 新开发的计算工具将这些QTL与特定的细胞类型和基因座或基因相关联 与神经精神疾病有关通过这样做，我们将增加，并显着扩大， 致力于了解QTL及其在神经发育、功能和神经精神障碍中的作用。

ABSTRACT Functional genomic analyses of the developing human brain have revealed highly dynamic spatiotemporal patterns of gene expression and epigenetic changes during prenatal and early postnatal development and across brain regions. Disruptions of these developmentally dynamic processes have been implicated by numerous complementary analyses in the etiology of multiple neurodevelopmental and neuropsychiatric disorders. Expression quantitative trait loci (eQTLs), along with splicing quantitative trait loci (sQTLs) and structural variant quantitative trait loci (svQTLs), are genomic variants that differ between individuals, with these differences correlating with functional changes to gene expression or splicing behavior. Many of these QTLs show specificity to tissues, brain regions, developmental stages, or cell types, and a proportion overlap with known genetic risk factors of human disorders. Here, we propose to pursue three integrated Aims, including whole-genome sequencing and both bulk tissue and single-nuclei RNA sequencing, to identify genomic variants, eQTL/sQTL/svQTLs, and patterns of gene expression and co-expression in two regions of the human brain across mid-fetal development through to adolescence. In addition, we will apply novel and newly developed computational tools to associate these QTLs with specific cell types and loci or genes implicated in neuropsychiatric disorders. By so doing we will augment, and dramatically expand upon, earlier efforts to understand QTLs and their roles in neural development, function, and neuropsychiatric disorders.