Genome-tagged mice to identify behavior genes

描述（由申请人提供）：理解行为的遗传学仍然是一个具有重要实际意义的难题。为了便于绘制行为特征，我们使用了基因组标记小鼠（GTMs）。这些重叠的“速度”同源小鼠品系跨越整个基因组，提供了优越的绘图能力和可重复性的可能性。我们研究了60株GTM菌株中的4株，这些菌株由~23 cM DBA/2J基因组间隔组成，渗入到C57BL/6J背景上。选择这4个菌株是因为从复杂的性状图谱中鉴定出相应的基因组区域含有学习和记忆基因座。利用GTMs分析证实了学习和记忆位点的存在，并将3号染色体上的1个位点精细定位到8.8 cM的区域。与感觉运动门控、焦虑、抑郁和疼痛敏感相关的行为基因座也通过一系列测试进行了定位。在这个建议中，我们描述了两个具体目标。(1)第一个目标是确定3号染色体的学习记忆位点。(i)高分辨率F2制图将使用相关的GTMs作为亲本菌株。由此产生的遗传背景简化将提供出色的制图能力。（ii）为了进一步精确定位位点，将使用标记辅助育种构建亚同源菌株。（iii）选择同源菌株的海马表达谱将用于促进位点的定位克隆。（iv） 8.8 cM关键区域的生物信息学研究有助于候选等位基因的鉴定。转基因研究将证实负责突变的特性。(2)第二个目标是使用一系列行为测试分析整个GTMs集，并在全基因组范围内定位其他感兴趣的位点。

DESCRIPTION (provided by applicant): Understanding the genetics of behavior remains a difficult problem with important practical implications. To facilitate mapping of behavioral traits, we have employed genome-tagged mice (GTMs). These overlapping sets of "speed" congenic mouse strains span the whole genome and offer the possibilities of superior mapping power and reproducibility. We investigated 4 GTM strains from a set of 60 consisting of ~23 cM DBA/2J genomic intervals introgressed onto a C57BL/6J background. These 4 strains were chosen because the corresponding genomic regions had been identified from complex trait mapping as containing loci for learning and memory. The analysis using the GTMs confirmed the presence of learning and memory loci and fine mapped 1 locus on chromosome 3 to an 8.8 cM region. Loci for behaviors related to sensorimotor gating, anxiety, depression and pain sensitivity were also localized using a battery of tests. In this proposal, we describe 2 specific aims. (1) The first aim is to identify the chromosome 3 learning and memory locus. (i) High resolution F2 mapping will use the relevant GTMs as parental strains. The resulting simplification of genetic background should provide excellent mapping power. (ii) For additional fine mapping of the locus, subcongenic strains will be constructed using marker assisted breeding. (iii) Expression profiling of the hippocampus from selected congenic strains will be employed to facilitate positional cloning of the locus. (iv) Bioinformatics study of the 8.8 cM critical region will help identify candidate alleles. (v) Transgenic studies will confirm the identity of the responsible mutation. (2) The second aim is to analyze the entire set of GTMs using the battery of behavioral tests and localize additional loci of interest genome-wide.