Hasin-Brumshtein Yehudit, Hormozdiari Farhad, Martin Lisa, van Nas Atila, Eskin Eleazar, Lusis Aldons J, Drake Thomas A
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
BMC Genomics. 2014 Jun 13;15(1):471. doi: 10.1186/1471-2164-15-471.
The simplest definition of cis-eQTLs versus trans, refers to genetic variants that affect expression in an allele specific manner, with implications on underlying mechanism. Yet, due to technical limitations of expression microarrays, the vast majority of eQTL studies performed in the last decade used a genomic distance based definition as a surrogate for cis, therefore exploring local rather than cis-eQTLs.
In this study we use RNAseq to explore allele specific expression (ASE) in adipose tissue of male and female F1 mice, produced from reciprocal crosses of C57BL/6J and DBA/2J strains. Comparison of the identified cis-eQTLs, to local-eQTLs, that were obtained from adipose tissue expression in two previous population based studies in our laboratory, yields poor overlap between the two mapping approaches, while both local-eQTL studies show highly concordant results. Specifically, local-eQTL studies show ~60% overlap between themselves, while only 15-20% of local-eQTLs are identified as cis by ASE, and less than 50% of ASE genes are recovered in local-eQTL studies. Utilizing recently published ENCODE data, we also find that ASE genes show significant bias for SNPs prevalence in DNase I hypersensitive sites that is ASE direction specific.
We suggest a new approach to analysis of allele specific expression that is more sensitive and accurate than the commonly used fisher or chi-square statistics. Our analysis indicates that technical differences between the cis and local-eQTL approaches, such as differences in genomic background or sex specificity, account for relatively small fraction of the discrepancy. Therefore, we suggest that the differences between two eQTL mapping approaches may facilitate sorting of SNP-eQTL interactions into true cis and trans, and that a considerable portion of local-eQTL may actually represent trans interactions.
顺式表达数量性状基因座（cis-eQTLs）与反式表达数量性状基因座（trans-eQTLs）的最简单定义是，影响等位基因特异性表达的遗传变异，这对潜在机制有影响。然而，由于表达微阵列的技术限制，过去十年中进行的绝大多数eQTL研究使用基于基因组距离的定义作为顺式的替代，因此探索的是局部而非顺式eQTLs。
在本研究中，我们使用RNA测序来探索由C57BL/6J和DBA/2J品系的正反交产生的雄性和雌性F1小鼠脂肪组织中的等位基因特异性表达（ASE）。将鉴定出的顺式eQTLs与从我们实验室之前两项基于群体的研究中的脂肪组织表达获得的局部eQTLs进行比较，发现两种定位方法之间的重叠性较差，而两项局部eQTL研究显示出高度一致的结果。具体而言，局部eQTL研究之间显示出约60%的重叠，而只有15 - 20%的局部eQTLs被ASE鉴定为顺式，并且在局部eQTL研究中回收的ASE基因不到50%。利用最近发表的ENCODE数据，我们还发现ASE基因在DNase I超敏位点的单核苷酸多态性（SNP）流行率上表现出显著的偏差，且这种偏差是ASE方向特异性的。
我们提出了一种新的等位基因特异性表达分析方法，该方法比常用的费舍尔或卡方统计更灵敏和准确。我们的分析表明，顺式和局部eQTL方法之间的技术差异，如基因组背景或性别特异性的差异，仅占差异的相对较小部分。因此，我们认为两种eQTL定位方法之间的差异可能有助于将SNP - eQTL相互作用分为真正的顺式和反式，并且相当一部分局部eQTL实际上可能代表反式相互作用。
