Genome-tagged mice to identify behavior genes

描述（由申请人提供）：了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，我们采用了基因组标记小鼠（GTM）。这些重叠的“speed”同源小鼠品系组跨越整个基因组，并提供了上级作图能力和再现性的可能性。我们研究了来自一组60株GTM菌株中的4株，该组由渗入到C57 BL/6 J背景上的~23 cM DBA/2 J基因组间隔组成。选择这4个菌株是因为已经从复杂性状作图中鉴定出相应的基因组区域含有用于学习和记忆的基因座。使用GTM的分析证实了学习和记忆基因座的存在，并将3号染色体上的1个基因座精细定位到8.8cM区域。与感觉运动门控、焦虑、抑郁和疼痛敏感性相关的行为位点也使用一系列测试进行定位。在本建议中，我们描述了两个具体目标。(1)第一个目标是确定3号染色体的学习和记忆位点。(i)高分辨率F2图谱将使用相关GTM作为亲本菌株。由此产生的遗传背景的简化应该提供极好的绘图能力。(ii)对于基因座的额外精细定位，将使用标记辅助育种构建亚同源菌株。(iii)将采用来自所选同源株的海马的表达谱分析来促进基因座的定位克隆。(iv)8.8cM关键区域的生物信息学研究将有助于确定候选等位基因。(v)转基因研究将确认负责突变的身份。(2)第二个目标是使用行为测试的电池来分析GTM的整个集合，并且在全基因组范围内定位感兴趣的附加位点。

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.