1/2 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 基因表达模式和表观遗传变化在产前和出生后早期的发展和跨 大脑区域。这些发展动态过程的中断已经被许多 多种神经发育和神经精神障碍病因学的补充分析。 表达数量性状基因座（eQTL）、沿着剪接数量性状基因座（sQTL）和结构变异体 数量性状基因座（svQTL）是个体之间存在差异的基因组变体，具有这些差异 与基因表达或剪接行为的功能变化相关。这些QTL中有许多表现出特异性 组织，大脑区域，发育阶段或细胞类型，并且一部分与已知的遗传风险重叠 人类疾病的因素。在这里，我们提出了三个综合目标，包括全基因组 测序以及大量组织和单核RNA测序，以鉴定基因组变体， eQTL/sQTL/svQTL，以及人脑两个区域的基因表达和共表达模式 从胎儿中期发育到青春期此外，我们将采用新的和新开发的 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， 神经精神障碍通过这样做，我们将加强并大大扩展早期的努力， 了解QTL及其在神经发育，功能和神经精神疾病中的作用。

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.