Transcription profiling of mouse hippocampus, lung and liver for expression quantitative trait analysis

A proportion of the genetic variants underlying complex phenotypes do so through their effects on gene expression, so an important challenge in complex trait analysis is to discover the genetic basis for the variation in transcript abundance. So far, the potential of mapping both quantitative trait loci (QTLs) and expression quantitative trait loci (eQTLs) in rodents has been limited by the low mapping resolution inherent in crosses between inbred strains. We provide a megabase resolution map of thousands of eQTLs in hippocampus, lung, and liver samples from heterogeneous stock (HS) mice in which 843 QTLs have also been mapped at megabase resolution. We exploit dense mouse SNP data to show that artifacts due to allele-specific hybridization occur in _30% of the cis-acting eQTLs and, by comparison with exon expression data, we show that alternative splicing of the 3_ end of the genes accounts for <1% of cis-acting eQTLs. Approximately one third of cis-acting eQTLs and one half of trans-acting eQTLs are tissue specific. We have created an important systems biology resource for the genetic analysis of complex traits in a key model organism.部分调控复杂表型的遗传变异是通过影响基因表达发挥作用的，因此复杂性状分析中的一项重要挑战，是揭示转录本丰度变异的遗传基础。迄今为止，在啮齿类动物中定位数量性状位点（quantitative trait loci, QTLs）与表达数量性状位点（expression quantitative trait loci, eQTLs）的潜力，一直受限于近交系杂交固有的低定位分辨率。本研究构建了远交群（heterogeneous stock, HS）小鼠海马、肺与肝脏组织样本中数千个eQTL的兆碱基分辨率定位图谱，其中843个QTL也已实现兆碱基分辨率定位。我们利用高密度小鼠单核苷酸多态性（single nucleotide polymorphism, SNP）数据，证实约30%的顺式作用eQTL存在等位基因特异性杂交伪影；同时通过与外显子表达数据比对，发现基因3'端的可变剪接仅能解释不足1%的顺式作用eQTL。约三分之一的顺式作用eQTL与二分之一的反式作用eQTL具有组织特异性。本研究为这一关键模式生物的复杂性状遗传分析提供了一项重要的系统生物学资源。