TSH Hypersecretion in WKY: Positional Candidate Analysis

描述(申请人提供)：低血压性脑脊髓炎与 甲亢和抑郁障碍说明了 下丘脑-垂体-甲状腺(HPT)轴对行为的影响。近亲交配 Wistar-京都(WKY)大鼠尽管TSH升高，但仍持续升高 甲状腺激素水平和对脑下垂体的正常负反馈。另外，WKY 在各种行为测试中表现不活跃，包括野外测试。 因此，该菌株是一个很好的模型，可以剖析 多基因行为特征和复杂的激素控制系统 遗传学。这些特征的遗传结构将用 数量性状座位(QTL)分析。一个F2杂交群体已经 由WKY与遗传、荷尔蒙和 行为多态的Fischer-344菌株。WKYxF344 F2代是 足以分离表型性状并创建连锁图谱以执行 QTL分析。通过展示一种极端的表达与 这些遗传图谱位置已知的表型和标记等位基因， 将被映射到单个染色体的特定区域，以及共性 行为特征和荷尔蒙特征之间的关系？基因架构将是 被揭露了。重要的感兴趣基因将被引入同源基因 使用标记和表型辅助选择的菌株，这将证实 轨迹？在表型中的作用，并允许从分离出来进行进一步分析 其他可能改变其表达的分离基因座。轨迹也将是 利用同源映射链接的位置候选方法进行分析 老鼠、小鼠和人类的基因组。这些实验将有助于 了解HPT的调节，并阐明任何可能的遗传联系 存在于这些表型之间。

DESCRIPTION (provided by applicant): The high comorbidity between hypo- and hyperthyroidism and depressive disorders illustrates the influence of hypothalamic-pituitary-thyroid (HPT) axis function on behavior. The inbred Wistar-Kyoto (WKY) rat strain has persistently elevated TSH despite elevated thyroid hormone levels and normal negative feedback to the pituitary. Also, WKY are hypoactive in a variety of behavioral tests, including the open-field test. The strain is thus an excellent model for dissecting the relationships between multigenic behavioral traits and complex hormonal control systems using forward genetics. Genetic architectures of these traits will be investigated with quantitative trait locus (QTL) analysis. An F2 intercross population has been created from reciprocal crosses between WKY and the genetically, hormonally and behaviorally polymorphic Fischer-344 strain. The WKYxF344 F2 generation is sufficient to segregate phenotypic traits and create a linkage map to perform a QTL analysis. By demonstrating an association between an extreme expression of these phenotypes and marker alleles whose genetic map position is known, loci will be mapped to specific regions of individual chromosomes, and commonalities between the behavioral and hormonal traits? genetic architectures will be revealed. Significant loci of interest will be introgressed into congenic strains using marker-and phenotype-assisted selection, which will confirm the locus? role in the phenotype and permit its further analysis in isolation from other segregating loci that may modify its expression. The loci will also be analyzed using a positional candidate approach utilizing homology maps linking rat, mouse and human genomes. These experiments will contribute to the understanding of HPT regulation, and also illuminate any genetic links that may exist between these phenotypes.