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巨大易感性。染色体1q21、15q11、15q13、16p11、22q11上的大片段(~1Mb)、杂合子、典型的从头拷贝数变化，以及最近染色体3q29上的缺失，均在SZ患者中较对照组丰富。有趣的是，这些拷贝数的变化也在自闭症和智力残疾人群中得到了丰富。然而，这些发现并没有伴随着对导致这种表型的特定基因的鉴定(S)。在埃默里，我们建立了一个由Stephen Warren、Tamara Caspary和David Weinshenker的实验室组成的跨学科团队，我们最初的目标是通过创建缺失和相互复制的小鼠模型，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，来概括人类3q29的间隔。在不同的基因组环境中确定完整的行为谱将使我们能够得出基于小鼠品系背景的差异，概括在人类中观察到的不同表型。对于微缺失，我们进一步建议在具有最健壮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低限度的缺失(因此最低限度的基因)。这一方法将使我们能够1)创建3q29缺失和重复综合征的模型，2)辨别单个基因的破坏或基因组合是否导致缺失患者表现出的SZ、ID和自闭症样特征，或者是否不同的基因导致不同的表型，以及3)识别致病基因(S)，这反过来将提供一个分子处理，通过它可以更好地理解和治疗这些神经精神疾病。使用这些小鼠模型结合行为测试，我们希望确定导致3q29缺失表型的基因，3q29缺失表型是精神分裂症、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，并提供社区推进精神病学遗传学研究所需的遗传途径的分子句柄。

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.