Haplotype and Expression Mapping of Prepulse Inhibition

描述（由申请人提供）：脉冲前惊吓抑制（PPI）是一种神经生理特征，在精神分裂症患者中受损，并且在近亲繁殖的小鼠品系中有所不同。我们对C57BL/6J和A/J小鼠的染色体置换小鼠品系（经济品系）进行研究，发现含有PPI数量性状位点（qtl）的染色体，并获得了在小鼠16号染色体上存在一个或多个PPI基因的证据。自我们最初的申请以来，我们已经快速完成了交叉定位，使我们能够在16号染色体上鉴定出两个显著的PPI qtl (lod = 3.9和4.6)，大小分别为3.5 cM和5.5 cM。我们建议使用结合近交系单倍型定位和mRNA表达谱的多方面方法来鉴定小鼠16号染色体PPI基因。我们将首先使用单倍型定位方法，在已知PPI变化的多个近交小鼠品系中完善16号染色体qtl。同时，我们将对小鼠进行回交，分离每条染色体16 QTL，并测试重组自交系的PPI，以帮助改进位点。然后，我们将在C57BL/6J和16号染色体替代菌株中进行相关脑区mRNA表达研究，以确定差异表达基因作为候选PPI基因。这些数据将被翻译到我们实验室正在进行的人类研究中，以确定候选小鼠PPI基因的同源物是否与人类PPI或精神分裂症风险有关。为了实现这一目标，我们将构建通过作图和谱分析鉴定的PPI候选基因的人类单倍型图谱，然后在我们的患者样本中检测与精神分裂症和PPI的关联。这项建议是一项初步研究，旨在确定与PPI和精神分裂症有关的基因，同时也证明了这种多方面的方法可以广泛应用于复杂人类特征的研究。

DESCRIPTION (provided by applicant): Prepulse inhibition of startle (PPI) is a neurophysiological trait that is impaired in schizophrenia patients and varies among inbred mouse strains. We have studied chromosome substitution mouse strains (consomic strains) derived from C57BL/6J and A/J mice to identify chromosomes that harbor PPI quantitative trait loci (QTLs), and have obtained evidence for one or more PPI genes on mouse chromosome 16. Since our original application, we have rapidly completed intercross mapping, allowing us to identify two significant PPI QTLs on chromosome 16 (LODs = 3.9 and 4.6) that are 3.5 cM and 5.5 cM in size. We propose to identify the mouse chromosome 16 PPI genes using a multi-faceted approach that incorporates inbred strain haplotype mapping and mRNA expression profiling. We will first refine the chromosome 16 QTLs using haplotype mapping across multiple inbred mouse strains known to vary in PPI. In parallel, we will perform backcrosses of mice segregating each chromosome 16 QTL and test recombinant inbred strains for PPI to assist in refining the loci. We will then perform mRNA expression studies of relevant brain regions in the C57BL/6J and chromosome 16 substitution strains to identify differentially expressed genes as candidate PPI genes. These data will be translated into the human studies ongoing in our lab to determine whether the orthologs of the candidate mouse PPI genes are involved in human PPI or schizophrenia risk. We will carry out this aim by constructing human haplotype maps of candidate PPI genes identified by mapping and profiling, and then testing for association with schizophrenia and PPI in our patient samples. This proposal is a pilot study to identify genes involved in PPI and perhaps schizophrenia, and is also a proof-of-principle that this multi-faceted approach could be widely applicable to the study of complex human traits.