Howard Hughes Medical Institute, Philadelphia, Pennsylvania, USA.
PLoS Biol. 2010 Sep 14;8(9):e1000480. doi: 10.1371/journal.pbio.1000480.
Expression levels of human genes vary extensively among individuals. This variation facilitates analyses of expression levels as quantitative phenotypes in genetic studies where the entire genome can be scanned for regulators without prior knowledge of the regulatory mechanisms, thus enabling the identification of unknown regulatory relationships. Here, we carried out such genetic analyses with a large sample size and identified cis- and trans-acting polymorphic regulators for about 1,000 human genes. We validated the cis-acting regulators by demonstrating differential allelic expression with sequencing of transcriptomes (RNA-Seq) and the trans-regulators by gene knockdown, metabolic assays, and chromosome conformation capture analysis. The majority of the regulators act in trans to the target (regulated) genes. Most of these trans-regulators were not known to play a role in gene expression regulation. The identification of these regulators enabled the characterization of polymorphic regulation of human gene expression at a resolution that was unattainable in the past.
人类基因的表达水平在个体之间存在广泛差异。这种变异性使得在遗传研究中可以将表达水平作为定量表型进行分析，在遗传研究中，可以在没有监管机制先验知识的情况下扫描整个基因组以寻找监管因子，从而能够识别未知的监管关系。在这里，我们使用大量样本进行了这样的遗传分析，并鉴定了大约 1000 个人类基因的顺式和反式作用多态性调节因子。我们通过对转录组（RNA-Seq）进行测序来验证顺式作用调节因子的差异等位基因表达，并通过基因敲低、代谢测定和染色体构象捕获分析来验证反式调节因子。大多数调节因子以反式作用于靶（调节）基因。这些反式调节因子中的大多数以前并不被认为在基因表达调控中发挥作用。这些调节因子的鉴定使我们能够以过去无法达到的分辨率来描述人类基因表达的多态性调节。
