Characterization of the Schizophrenia-associated 3q29 Deletion in Mouse

描述（由申请人提供）： 项目摘要/摘要精神分裂症遗传学的最新进展揭示了基因组拷贝数的变化与疾病的易感性。相对于对照组，SZ患者染色体1 q21、15 q11、15 q13、16 p11、22 q11上的大（~ 1 Mb）、杂合子、典型的从头拷贝数变化以及最近染色体3q 29上的缺失都富集。有趣的是，这些拷贝数变化也在自闭症和智力残疾人群中富集。然而，这些发现并没有伴随着对负责表型的特定基因的鉴定。在埃默里大学，我们已经建立了一个跨学科的团队，由斯蒂芬·沃伦（Stephen Warren）、塔玛拉·卡斯帕里（Tamara Caspary）和大卫·温申克（David Weinshenker）的实验室组成，我们的最初目标是通过创建缺失和相互复制的小鼠模型来重现人类3q 29间隔，并使用一系列全面的测试来确定多个小鼠品系背景下的行为后果。在替代基因组背景下确定完整的行为谱将使我们能够引出基于小鼠品系背景的差异，重现在人类中观察到的可变表型。对于微缺失，我们进一步建议在具有最稳健表型的两个菌株中创建一系列较小的重叠缺失。通过这种方式，我们将建立行为表型所需的最小缺失（因此也是最小基因）。这种方法将使我们能够1）创建3q 29缺失和重复综合征的模型，2）辨别单个基因或基因组合的破坏是否负责缺失患者表现出的SZ、ID和自闭症样特征，或者不同的基因是否负责不同的表型，以及3）鉴定致病基因，这反过来将，提供了一个分子把手，通过它可以更好地理解和治疗这些神经精神疾病。使用这些小鼠模型与行为测试相结合，我们希望确定负责3q 29缺失表型的基因，这是精神分裂症，智力残疾和自闭症的主要候选基因。因此，这笔赠款将开发一个有价值的小鼠模型，并提供一个遗传途径的分子处理，社区需要推进精神病遗传研究。 公共卫生相关性： 整合沃伦、卡斯帕里和温申克实验室的专业知识将填补阻碍精神病遗传研究进展的差距。我们建议的创新在于促进人类遗传学家，小鼠转基因专家和啮齿动物行为学家之间的联系，以促进对最近发现的精神分裂症和ID相关遗传病变的理解。我们的策略旨在减少3q 29间隔，直到我们找到保留行为缺陷的最小删除。通过这种方式，我们希望确定人类3q 29间隔中的致病基因，这将构成精神病遗传学的重大进展，因为它将允许阐明精神分裂症中被破坏的特定分子途径。聚集在这里的团队是实现我们既定目标的理想组合。如果成功，我们的建议将突出像我们这样的合作的重要性，以及这种方法对推进精神病遗传研究的效用。

DESCRIPTION (provided by applicant): Project Summary/Abstract Recent exciting progress in schizophrenia genetics has revealed genomic copy number changes with large susceptibility for disease. Large (~1Mb), heterozygous, typically de novo copy number changes on chromosomes 1q21, 15q11, 15q13, 16p11, 22q11, and most recently a deletion on chromosome 3q29 are all enriched in SZ patients relative to controls. Interestingly, these copy number changes are also enriched in autism and intellectual disability cohorts. However, these discoveries have been unaccompanied by identification of the specific gene responsible for the phenotype(s). At Emory we have established an interdisciplinary team that consists of the labs of Stephen Warren, Tamara Caspary and David Weinshenker, and our initial goal is to recapitulate the human 3q29 interval by creating mouse models of the deletion and reciprocal duplication, and ascertaining the behavioral consequences on multiple mouse strain backgrounds using a comprehensive battery of tests. Ascertaining the full behavioral spectrum in alternate genomic contexts will allow us to elicit differences that are predicated on mouse strain background, recapitulating the variable phenotypes observed in humans. For the microdeletion, we further propose to create a series of smaller overlapping deletions in the two strains with the most robust phenotypes. In this way we will establish the minimal deletion (and therefore minimal genes) required for a behavioral phenotype. This approach will enable us to 1) create models of the 3q29 deletion and duplication syndromes, 2) discern whether disruption of an individual gene or combination of genes are responsible for the SZ, ID and autism-like features exhibited by deletion patients or if distinct genes are responsible for the different phenotypes and 3) identify the causative gene(s) which will, in turn, provide a molecular handle through which these neuropsychiatric conditions can be better understood and treated. Using these mouse models combined with behavioral testing, we expect to identify the gene responsible for the 3q29 deletion phenotype, a major candidate gene for schizophrenia, intellectual disability, and autism. Thus this grant will develop a valuable mouse model and provide a molecular handle of the genetic pathways that the community requires to advance psychiatric genetic research. PUBLIC HEALTH RELEVANCE: Project Narrative Integrating the expertise of the Warren, Caspary and Weinshenker labs will fill the gap that impedes advances in psychiatric genetic research. The innovation of our proposal lies in fostering an association between a human geneticist, a mouse transgenic expert, and a rodent behaviorist, to advance understanding of recently discovered schizophrenia- and ID-associated genetic lesion. Our strategy is designed to whittle down the 3q29 interval, until we find a minimal deletion that preserves behavioral deficits. In this way we expect to identify the causative gene(s) in the human 3q29 interval, which would constitute a major advance in psychiatric genetics, as it would allow elucidation of a specific molecular pathway disrupted in schizophrenia. The team assembled here is an ideal combination to achieve our stated aims. If successful, our proposal will highlight the importance of collaborations such as ours, and the utility of this approach to advance psychiatric genetic research.