A Human-Specific Gene (G72/G30) in Transgenic Mice

描述(申请人提供)：G72/G30，染色体13q33.2上的正义-反义基因复合体，也被称为DAOA(D-氨基酸氧化酶激活剂)，在多项研究中与精神分裂症和双相情感障碍有关。这种疾病关联及其作为极少数灵长类特异基因之一的特点，使G72/G30成为人类大脑和精神疾病生物学研究中非常有趣的靶点。我们最近对精神分裂症的荟萃分析表明，在亚洲人中，G72/G30中的两个SNP显示出全基因范围的显著关联。在这项应用中，我们建议对亚洲精神分裂症患者(NIMH Genetics Initiative收集的DNA)进行筛查，以寻找携带与精神分裂症相关的等位基因的个体。然后，我们将使用转化相关重组(TAR)克隆方法从选定的精神分裂症患者中分离出G72细菌人工染色体(BAC)克隆。分离的克隆将被引入小鼠基因组中，以产生转基因小鼠品系。然后，我们将对三种类型的小鼠进行生化、基因表达和行为测试：本研究中产生的新的转基因小鼠系，我们现有的携带非危险等位基因的G72转基因小鼠系，以及野生型小鼠。综合运用遗传学、功能基因组学和行为遗传学的方法，应该能帮助我们更好地理解G72在脑功能和精神分裂症易感性中的生物学作用。我们将创建一种携带人类G72/G30基因复合体和精神分裂症风险等位基因的转基因小鼠系。G72(我们指的是复合体)是与双相情感障碍和精神分裂症最一致的相关基因之一。由于G72是灵长类动物特有的基因，在人类中的表达水平很低，因此对G72在人类中的生物学研究尤其具有挑战性。有了这一应用中产生的新的转基因小鼠，以及我们现有的没有精神分裂症风险等位基因的G72转基因小鼠，我们可以在体内对G72的生物和行为功能进行测试。我们预计这些结果将最终导致更好地理解G72及其在人类正常大脑功能和精神疾病状态中的作用。

DESCRIPTION (provided by applicant): G72/G30, a sense-antisense gene complex on chromosome 13q33.2 also known as DAOA (D-amino acid oxidase activator), has been associated with schizophrenia and bipolar disorder in multiple studies. The disease association and its characteristic of being one of the very few primate-specific genes make G72/G30 a very intriguing target in the biological study of human brain and mental diseases. Our most recent meta-analysis of schizophrenia indicates that two SNPs in G72/G30 show gene-wide significant association in Asians. In this application, we propose to screen Asian schizophrenia patients (DNAs have been collected by the NIMH Genetics Initiative) for an individual carrying the allele that shows association with schizophrenia. Then, we will use the Transformation Associated Recombination (TAR) Cloning method to isolate G72 Bacterial Artificial Chromosome (BAC) clones from the selected schizophrenia patient. The isolated clone will be introduced into a mouse genome to produce a transgenic mouse line. We will then perform biochemical, gene expression, and behavioral tests on three types of mice: the new transgenic mouse line produced in this study, our existing G72 transgenic mouse line that carries the non-risk allele, and wild type mice. Comprehensive use of genetic, functional genomics and behavioral genetics approaches should lead us to an improved understanding of the biology of G72 in brain function and in schizophrenia susceptibility. We will create a transgenic mouse line that carries a human G72/G30 gene complex with a schizophrenia risk allele. G72 (as we refer to the complex) is one of the most consistently associated genes with both bipolar disorder and schizophrenia. Because G72 is a primate-specific gene with low expression levels in human, biological study of G72 in humans is particularly challenging. With the new transgenic mouse generated in this application, and our existing G72 transgenic mouse without the schizophrenia risk allele, we can perform in vivo tests on G72 biological and behavioral functions. We expect these results will ultimately lead to a better understanding of G72 and its role in both normal human brain function and psychiatric disease states.