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位点（qtl）。在研究人类精神分裂症成分的遗传基础方面取得了很大进展。然而，与人类相比，通过专门的育种设计和基因转化获得的信息可以在小鼠中获得更多的基因定位统计能力。在人类身上发现的一些与精神分裂症相关的特征，如丘脑体积、丘脑中背核体积、整个皮层灰质体积、海马体积、空间工作和情景记忆，在小鼠身上都有同源物。我们建议测量广义遗传力（具体目标）

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.