BXD Mouse Liver Gene Expression

The liver is the primary site for the metabolism of nutrients, drugs, and chemical agents. Although metabolic pathways are complex and tightly regulated, genetic variation among individuals, reflected in variations in gene expression levels, introduces complexity into research on liver disease. This study dissected genetic networks that control liver gene expression through the combination of large-scale quantitative mRNA expression analysis with genetic mapping in a reference population of BXD recombinant inbred mouse strains for which extensive single-nucleotide polymorphism, haplotype, and phenotypic data are publicly available. We profiled gene expression in livers of naive mice of both sexes from C57BL/6J, DBA/2J, B6D2F1, and 41 BXD strains using Agilent oligonucleotide microarrays. These data were used to map quantitative trait loci (QTLs) responsible for variations in the expression of about 19,000 transcripts. We identified polymorphic local and distant QTLs, including several loci that control the expression of large numbers of genes in liver, by comparing the physical transcript position with the location of the controlling QTL. CONCLUSION: The data are available through a public web-based resource (www.genenetwork.org) that allows custom data mining, identification of coregulated transcripts and correlated phenotypes, cross-tissue, and cross-species comparisons, as well as testing of a broad array of hypotheses. Basal gene expression in the livers of 41 BXD strains, the parentals and the F1 cross, consisting of C57BL/6J, DBA/2J, B6D2F1, BXD1, BXD2, BXD5, BXD6, BXD8, BXD9, BXD11, BXD11TY, BXD12, BXD13, BXD14, BXD15, BXD16, BXD19, BXD21, BXD23, BXD24, BXD28, BXD29, BXD31, BXD32, BXD33, BXD34, BXD36, BXD38, BXD39, BXD40, BXD42, BXD43, BXD44, BXD45, BXD48, BXD51, BXD60, BXD62, BXD69, BXD73, BXD77, BXD85, BXD86, BXD92 pooled from 2-3 mice of the same sex and strain. The arrays were run in 8 batches, balanced by sex and strain with intra- and inter-batch replicates. Interbatch normalization was carried out using a nested analysis of variance mixed model, with samples within each batch crossed with sex and strain.肝脏是营养物质、药物及化学制剂代谢的核心场所。尽管代谢通路复杂且受严格调控，但个体间的遗传变异——体现为基因表达水平的差异——为肝脏疾病研究增添了复杂度。 本研究通过整合大规模定量mRNA表达分析与遗传定位策略，在BXD重组近交系小鼠（BXD recombinant inbred mouse strains）参考群体中解析了调控肝脏基因表达的遗传网络；该群体已公开大量单核苷酸多态性（single-nucleotide polymorphism, SNP）、单倍型及表型数据。 我们采用安捷伦寡核苷酸微阵列（Agilent oligonucleotide microarrays），对来自C57BL/6J、DBA/2J、B6D2F1品系以及41个BXD品系的未经实验干预的雌雄小鼠肝脏组织完成了基因表达谱分析。基于上述数据，我们定位了约19000个转录本表达变异相关的数量性状基因座（quantitative trait loci, QTL）。 通过比对转录本的物理位置与调控QTL的定位区域，我们鉴定出多态性的局部与远端数量性状基因座，其中包含多个可调控肝脏大量基因表达的位点。 结论：本研究数据可通过公开网络资源（www.genenetwork.org）获取，该平台支持自定义数据挖掘、共调控转录本与相关表型的鉴定、跨组织及跨物种比较，以及各类假说的广泛验证。 本数据集包含41个BXD品系、亲本品系及F1杂交后代（涵盖C57BL/6J、DBA/2J、B6D2F1、BXD1、BXD2、BXD5、BXD6、BXD8、BXD9、BXD11、BXD11TY、BXD12、BXD13、BXD14、BXD15、BXD16、BXD19、BXD21、BXD23、BXD24、BXD28、BXD29、BXD31、BXD32、BXD33、BXD34、BXD36、BXD38、BXD39、BXD40、BXD42、BXD43、BXD44、BXD45、BXD48、BXD51、BXD60、BXD62、BXD69、BXD73、BXD77、BXD85、BXD86、BXD92）的基础肝脏基因表达数据，每个品系与性别的样本均由2-3只同性别同品系的小鼠混合制备。 芯片实验分为8批开展，每批均按性别与品系进行均衡设计，并设置批内与批间重复。我们采用嵌套方差分析混合模型完成批间标准化，模型中纳入每批样本与性别、品系的交互效应。