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

转基因小鼠中的人类特异性基因 (G72/G30)

• 批准号: 8051049
• 负责人: Elliot S Gershon
• 金额: $ 20.61万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051049
• 关键词: Alleles; Amino Acid Sequence; Asians; Bacterial Artificial Chromosomes; Behavioral; Behavioral Genetics; Biochemical; Biological; Biology; Bipolar Disorder; Brain; Brain region; Characteristics; Chinese People; Chromosomes; Cloning; Complex; D-Amino Acid Dehydrogenase; DNA; DNA copy number; Data; Development; Disease; Disease Association; Family; Gene Expression; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genotype; Human; Individual; Knowledge; Lead; Location; Measurement; Measures; Mental disorders; Meta-Analysis; Methods; Mitochondria; Mus; N-Methyl-D-Aspartate Receptors; National Institute of Mental Health; Neurobiology; Orthologous Gene; Outcome; Pathway interactions; Patients; Peptide Sequence Determination; Phase; Predisposition; Primates; Procedures; Proteins; Psyche structure; Regulation; Reverse Transcription; Risk; Role; Schizophrenia; Serine; Single Nucleotide Polymorphism; Specificity; Sucrose; Swimming; Testing; Time; Transcript; Transgenic Mice; Variant; Water; Western Blotting; Wild Type Mouse; behavior test; enzyme activity; functional genomics; improved; in vivo; interest; mouse genome; phase 1 study; preference; prepulse inhibition; receptor binding; research study

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.

描述（由申请人提供）：G72/G30 是染色体 13q33.2 上的正义-反义基因复合体，也称为 DAOA（D-氨基酸氧化酶激活剂），在多项研究中已与精神分裂症和双相情感障碍相关。 G72/G30 与疾病的关联性及其作为极少数灵长类特异性基因之一的特性，使得 G72/G30 成为人脑和精神疾病生物学研究中非常有趣的目标。我们最近对精神分裂症的荟萃分析表明，G72/G30 中的两个 SNP 在亚洲人中显示出全基因范围的显着关联。在此应用中，我们建议筛查亚洲精神分裂症患者（DNA 已由 NIMH 遗传学计划收集），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：本研究中产生的新转基因小鼠系、我们现有的携带非风险等位基因的 G72 转基因小鼠系和野生型小鼠。综合利用遗传、功能基因组学和行为遗传学方法，我们应该能够更好地了解 G72 在大脑功能和精神分裂症易感性方面的生物学特性。我们将创建一个携带人类 G72/G30 基因复合物和精神分裂症风险等位基因的转基因小鼠品系。 G72（我们称之为复合体）是与躁郁症和精神分裂症最相关的基因之一。由于G72是灵长类动物特有的基因，在人类中表达水平较低，因此G72在人类中的生物学研究尤其具有挑战性。利用本申请中生成的新型转基因小鼠，以及我们现有的不含精神分裂症风险等位基因的 G72 转基因小鼠，我们可以对 G72 生物学和行为功能进行体内测试。我们预计这些结果最终将有助于更好地了解 G72 及其在正常人脑功能和精神疾病状态中的作用。