Genomic and epigenomic mechanisms of pediatric ocular disorders

医学遗传学和眼科基因组学实验室推进了研究计划的目标和目的如下： 1.使用CRISPR/Cas9基因编辑和发育，分子和细胞生物学研究在斑马鱼，小鼠和体外模拟眼部综合征与编码基因变异的新关联，以阐明疾病机制。我们目前正在动物和细胞模型中模拟几种新的人类疾病基因。两个例子是CSDE 1（Guo et al，Science Advances，2019），编码含有RNA结合蛋白的冷休克结构域，和UBA 2（Schur，Yousaf，Liu et al，Genetics in Medicine，2021），编码SUMO化关键蛋白。我们已经证明，在这两种情况下，人类单倍不足导致独特的和可识别的神经发育障碍。我们的小组最近还合作确定了多个新的疾病基因关联，包括SMPD 4，BMPR 1A和MYRF（见参考书目），以及前几年的多个其他关联。 2.使用功能基因组学技术确定非编码基因组和眼组织中的疾病关联。使用RNAseq、ATACseq和Hi-C，沿着单细胞测序技术，我们正在绘制来自诱导多能细胞系的人眼细胞中的活性基因组，以根据人类测序数据进行变体优先排序。这些转录组学的努力促成了eyeIntegration，这是一个用于眼组织人类测序数据的公共数据库，并使用机器学习生成预测网络（eyeintegration.nei.nih.gov;参见参考书目）。

The Medical Genetics and Ophthalmic Genomics Laboratory has advanced the goals and objectives of the research program as follows: 1. Modeling novel associations of ocular syndromes with coding gene variation in zebrafish, mouse, and in vitro using CRISPR/Cas9 gene editing and developmental, molecular, and cellular biology investigations to elucidate disease mechanisms. We are currently modeling several new human disease genes in animal and cellular models. Two examples are CSDE1 (Guo et al, Science Advances, 2019), encoding a cold-shock domain containing RNA-binding protein, and UBA2 (Schur, Yousaf, Liu etc al, Genetics in Medicine, 2021), encoding a protein critical in SUMOylation. We have shown that, in both cases, haploinsufficiency in humans cause unique and recognizable neurodevelopemental disorders. Our group has also acted in collaboration to recently define multiple additional new disease-gene associations, including SMPD4, BMPR1A, and MYRF (see bibliography), in addition to multiple others in previous years. 2. Defining disease-associations in the noncoding genome and in eye tissues using functional genomics techniques. Using RNAseq, ATACseq, and Hi-C, along with single-cell sequencing technologies, we are mapping the active genome in human ocular cells derived from induced pluripotent cell lines for variant prioritization from human sequencing data. These transcriptomic efforts contributed to eyeIntegration, a public database for human sequencing data from ocular tissues and generation of predictive networks using machine learning (eyeintegration.nei.nih.gov; see bibliography).