利用野生小家鼠来源1号染色体替换系群体进行血脂代谢的系统遗传学研究

Systems genetics are one of the powerful approaches for dissection complex trait gene networks. Traditional genetic analysis in inbred mice includes the process of crossing different inbred strains and mapping the traits of interest using linkage analysis. A serious problem has been the lack of resolution in identifying the causative gene(s) from the linkage study. However, the wild mouse chromosome 1 substituted population is very suitable for systems genetics study because of its high mapping resolution and uniform genetic background. To date, there are 24 blood lipid quantitative trait loci (QTL) having been mapped on mouse chromosome 1(5 cholesterol QTLs, 12 high-density lipoprotein QTLs and 3 triglyceride QTLs), but the quantitative trait gene (QTG) in the intervals have not been cloned. In the present study, we will construct a high blood lipid mouse model in the wild mouse chromosome 1 substituted population by high-Fat and high-Sucrose Diet. Through blood lipid measurement, liver transcriptase abundance assay and high density SNP genotyping, we will establish a blood lipid gene network to dissect the blood lipid QTL or QTG on chromosome 1, and illustrate the molecular mechanism involves blood lipid metabolism.

系统遗传学是研究复杂性状调控网络的有效方法之一。实验小鼠来源较为单一，单倍域较大，导致基因定位的分辨率低，QTL检出率也较低。野生小家鼠来源1号染色体替换系群体具有丰富的遗传多样性（1号染色体），同时具有均一的遗传背景，非常适用于系统遗传学相关研究。 目前定位在小鼠1号染色体上和血脂调控相关的QTL有24个（胆固醇相关QTL 5 个、 高密度脂蛋白相关QTL 12个、 甘油三脂相关QTL 3个 ），但相关区段内的候选基因还尚未被定位克隆和功能解析。本研究拟在已构建好的25个野生来源小家鼠1号染色体替换群体中,通过高脂高蔗糖饮食建立高脂小鼠模型，测定各血脂成分浓度和肝脏转录本丰度，以及高密度SNP基因分型，应用系统遗传学原理构建血脂调控基因网络，阐明1号染色体上血脂调控座位或基因参与血脂调控的分子机制。

利用二代测序技术，我们完成了25个一号染色体替换小鼠的全基因组测序。我们进一步进行了数据分析：注释各类序列变化（SNP、In/del、SV、CNV）；分析野生来源的1号染色体各区段的选择压力；分析各亚种来源。.利用RNA-seq技术，我们完成了25个品系肝脏样本的全转录组测序，并进行了相关数据的分析：了解与血脂相关的基因网络表达水平的变化。.我们也在1号染色体上，精细定位了血脂相关QTL并筛选了功能相关基因。.本项目的研究结果，对解析哺乳动物血脂调控相关基因及其网络，提供了进一步的信息。