GENETICS OF SCHIZOPHRENIA-RELATED TRAITS IN MICE

小鼠精神分裂症相关特征的遗传学

• 批准号: 7476364
• 负责人: JAMES M CHEVERUD
• 金额: $ 41.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476364
• 关键词: Affect; Anatomy; Architecture; Backcrossings; Behavior; Behavioral; Bioinformatics; Biological Assay; Biological Markers; Biometry; Brain; Brain Mapping; Breeding; Candidate Disease Gene; Cell Count; Characteristics; Chromosome Mapping; Chromosome Positioning; Communities; Complex; Congenic Strain; Data; Databases; Dorsal; Environment; Episodic memory; Etiology; Future; Gene Expression; Genes; Genetic; Genetic Complementation Test; Genetic Polymorphism; Genetic Recombination; Genetic Transformation; Genetic Variation; Genomics; Genotype; Heritability; Hippocampus (Brain); Homologous Gene; Human; Human Genome; Inbred Strains Mice; Knock-out; Letters; Link; Linkage Disequilibrium; Location; Manuals; Maps; Measures; Medial Dorsal Nucleus; Memory; Mental disorders; Methods; Molecular; Mus; National Institute of Mental Health; Neuroanatomy; Pattern; Phenotype; Population; Positioning Attribute; Principal Investigator; Production; Protocols documentation; Quantitative Trait Loci; Recombinant Inbred Strain; Recombinants; Relative (related person); Research; Resources; Schizophrenia; Score; Specific qualifier value; Staging; Structure; Testing; Thalamic structure; Time; Transcript; Ursidae Family; Validation; Variant; Water; Work; base; data management; design; disorder risk; gene function; gray matter; human population study; interest; pleiotropism; relating to nervous system; repository; tool; trait

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.

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）