Phenomic analysis of the murine hippocampus

描述(申请人提供)：老鼠和人类的基因组现在已经测序，但将基因与功能联系起来的任务才刚刚开始。我们将结合新旧技术，作为将遗传基因与功能联系起来的普遍方法，也作为一种将不同的功能相互联系的方法。拟议的项目依赖于过去一个世纪小鼠遗传学家所创造的资源的存在，包括大量的近交系、重组近交系(RI)、共生体和同源品系。这些资源是遗传多样性的丰富来源，基本上仍未被用于中枢神经系统的研究。在这个项目中，我们将利用这种遗传多样性来开始定义构成“海马体表型”的一组特征，也就是可以称为海马体“表型”的特征。我们称这种方法为“现象学分析”。这个项目将集中在成年神经发生和海马体形态和发育中涉及品系间差异的特征。总的策略将是：1)识别在一组近交系中不同的多个遗传性状，并使用网络结构(即，一种由一系列统计方法和数据可视化技术组成的新方法)来产生关于这些不同性状之间潜在关系的假设(具体目标1)；2)利用现有的小鼠遗传资源，即RI品系和共生品系，来检验从网络分析中产生的假设，并同时定位与所识别的特征有关的遗传位点(具体目标2)；以及3)通过对成年动物识别出的特征进行网络分析，确定被识别为显著的和/或可能相关的特征的发育基础(具体目标3)。正如初步结果所描述的，我们在这些步骤中的每一步都取得了一些进展，很明显，我们将能够同时研究和绘制许多遗传特征。这种“中等吞吐量”的方法，实际上提供了对海马体结构、功能和发育的遗传解剖。

DESCRIPTION (provided by applicant): The mouse and human genomes have now been sequenced, but the task of linking genes to functions is just beginning. We will combine old and new technologies as a generalized method of linking genetic loci to functions and also as a method of linking disparate functions to each other. The proposed project depends on the existence of resources that have been produced by mouse geneticists over the past century, including the numerous inbred, recombinant inbred (RI), consomic, and congenic strains. These resources are a rich source of genetic diversity that remains essentially untapped for studies of the central nervous system. In this project we will exploit this genetic diversity to begin to define the set of traits that comprise the "hippocampal phenotype," i.e., what might be termed the hippocampal "phenome." We call this approach a "phenomic analysis." This project will focus on traits that involve inter-strain variation in adult neurogenesis and in hippocampal morphology and development. The general strategy will be to: 1) Identify multiple genetic traits that vary among a set of inbred strains and to use network construction (i.e., a novel approach consisting of a collection of statistical methods and data visualization techniques) to generate hypotheses about the potential relationships among these diverse traits (Specific Aim 1); 2) exploit existing mouse genetic resources, i.e., RI strains and consomic strains, to test the hypotheses generated from the network analysis and simultaneously to map the genetic loci responsible for the identified traits (Specific Aim 2); and 3) to determine the developmental basis for the traits identified as significant and/or possible related from the network analysis of the traits identified in adult animals (Specific Aim 3). As described in Preliminary Results, we have made some progress towards each of these steps, and it is clear that there are numerous genetic traits that we will be able to study and map simultaneously. This "moderate throughput" approach, in effect, provides a genetic dissection of hippocampal structure, function, and development