Hippocampus RNA-seq in CD x Gtf2i*

Williams syndrome is a neurodevelopmental disorder caused by a 1.5-1.8Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of Williams syndrome include cardiovascular problems, craniofacial dysmorphology, deficits in visual spatial cognition, and a characteristic hypersocial personality. There are still no genes in the region that have been consistently linked to the cognitive and behavioral phenotypes, although human studies and mouse models have led to the current hypothesis that the general transcription factor 2 I family of genes, GTF2I and GTF2IRD1, are responsible. Here we test the hypothesis that these two transcription factors are sufficient to reproduce the phenotypes that are caused by deletion of the Williams syndrome critical region (WSCR). We compare a new mouse model with loss of function mutations in both Gtf2i and Gtf2ird1 to an established mouse model lacking the complete WSCR. We show that the complete deletion model has deficits across several behavioral domains including social communication, motor functioning, and conditioned fear that are not explained by loss of function mutations in Gtf2i and Gtf2ird1. Furthermore, transcriptome profiling of the hippocampus shows changes in synaptic genes in the complete deletion model that are not seen in the double mutants. Thus, we have thoroughly defined a set of molecular and behavioral consequences of complete WSCR deletion, and shown that other genes or combinations of genes are necessary to produce these phenotypic effects. 18 samples of total hippocamapal RNA from three genotypes, CD, Gtf2i*, and WT. There are 6 biological replicates per genotype. WT are used as the controls威廉姆斯综合征（Williams syndrome）是一种由7号染色体q11.23区域1.5~1.8 Mbp片段缺失引发的神经发育障碍，该缺失会影响26至28个基因的拷贝数。威廉姆斯综合征的表型包括心血管病变、颅面畸形、视觉空间认知缺陷，以及特征性的过度社交人格。目前该缺失区域内尚未发现与认知和行为表型存在明确关联的基因，但基于人类研究与小鼠模型的现有假说认为，通用转录因子2I家族（general transcription factor 2 I family）基因GTF2I与GTF2IRD1是致病关键基因。本研究旨在验证这两个转录因子是否足以重现威廉姆斯综合征关键区域（Williams syndrome critical region, WSCR）缺失所导致的表型。我们将一种新构建的携带Gtf2i与Gtf2ird1双功能缺失突变的小鼠模型，与已成熟的完整WSCR缺失小鼠模型进行对照比较。实验结果表明，完整WSCR缺失模型在社交沟通、运动功能与条件性恐惧等多个行为域均存在缺陷，而此类缺陷无法通过Gtf2i与Gtf2ird1的功能缺失突变来解释。此外，对海马体的转录组分析显示，完整WSCR缺失模型中存在突触相关基因的表达变化，而双突变体中未出现此类改变。综上，本研究系统阐明了完整WSCR缺失所引发的一系列分子与行为学后果，并证实需其他基因或基因组合方可产生上述表型效应。本数据集包含3种基因型（CD、Gtf2i*、野生型（Wild Type, WT））的共18份海马总RNA样本，每种基因型设置6个生物学重复，以野生型作为实验对照。