GENETICS OF SCHIZOPHRENIA-RELATED TRAITS IN MICE

在这个项目中，我们将绘制影响小鼠精神分裂症相关性状的数量性状基因座（QTL）。在研究人类精神分裂症组成部分的遗传基础方面已经取得了很大进展。然而，通过专门的育种设计和通过遗传转化在小鼠中获得的信息，可以实现比在人类中更大的统计功效。在人类中发现的几种精神分裂症相关特征，如丘脑体积、丘脑背内侧核体积、整个皮质灰质体积、海马体积、空间工作记忆和情景记忆，在小鼠中具有同源物。我们建议测量广义遗传力（具体目标 1)和遗传相关性（特定目标2），并定位这些精神分裂症相关性状的重组近交系（RI）小鼠品系，包括BXD，AXB（BXA），和LGXSM的QTL（特定目标3）。QTL区域确定后，我们将根据其效应的大小和模式选择特定的QTL进行精细定位，并在群体间进行验证。我们将使用重组近交杂交（RIX）、重组近交品系测试（RIST）和同类品系测试（视情况而定）将QTL精细定位到1.0 cM间隔（特定目标4）。将使用生物信息学方法在有限的基因组间隔中鉴定位置候选基因，然后检测亲本菌株之间的序列和表达多态性，以鉴定可能导致QTL效应的分子多态性（具体目标5）。然后将显示这种分子多态性的位置候选基因敲除，对相关的表型进行评分。敲除菌株也将用于定量互补试验，以确认所选基因负责QTL效应。将来，在Specific Aim 4中发现的小鼠QTL位置将被转移到它们的同线人类染色体位置，然后在人群中测试对精神分裂症及其组成性状的潜在影响。

In this project we will map Quantitative Trait Loci (QTLs) affecting schizophrenia-related traits in mice. Much progress has been made in studying the genetic basis for components of schizophrenia in humans. However, much more statistical power can be achieved for gene mapping through specialized breeding designs and information obtained through genetic transformation in mice than in humans. Several schizophrenia-related traits discovered in humans, such as thalamic volume, volume of the thalamus' mediodorsal nucleus, whole cortex grey matter volume, hippocampal volume, and spatial working and episodic memory, have homologues in mice. We propose to measure broad-sense heritability (Specific Aim 1) and genetic correlations (Specific Aim 2) and to map QTLs (Specific Aim 3) for these schizophrenia-related traits in recombinant inbred (RI) mouse strains, including BXD, AXB(BXA), and LGXSM. After QTL regions are identified, we will select specific QTLs for fine-mapping based on the magnitude and pattern of their effects and validation across populations. We will fine-map QTLs to a 1.0 cM interval (Specific Aim 4) using Recombinant Inbred Intercrosses (RIX), Recombinant Inbred Strain Tests (RIST), and Congenic strain tests as appropriate. Positional candidate genes will be identified in the restricted genomic interval using bioinformatic methods and then tested for sequence and expression polymorphism between the parental strains to identify molecular polymorphisms potentially responsible for the QTL effect (Specific Aim 5). Positional candidate genes displaying such molecular polymorphisms will then be knocked-out, the associated phenotypes scored. Knock-out strains will also be used in a quantitative complementation test to confirm that the selected gene is responsible for the QTL effect. In future, mouse QTL positions uncovered in Specific Aim 4 will be transferred to their syntenic human chromosome positions and then tested in human populations for potential effects on schizophrenia and its component traits.