Lockwood Sarah H, Guan Anna, Yu Abigail S, Zhang Chi, Zykovich Artem, Korf Ian, Rannala Bruce, Segal David J
Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California 95616.
Genome Center and Department of Evolution and Ecology, University of California, Davis, California 95616.
G3 (Bethesda). 2014 Jun 26;4(9):1647-55. doi: 10.1534/g3.114.012195.
Variants that alter the DNA-binding specificity of transcription factors could affect the specificity for and expression of potentially many target genes, as has been observed in several tumor-derived mutations. Here we examined if such trans expression quantitative trait loci (trans-eQTLs) could similarly result from common genetic variants. We chose to focus on the Cys2-His2 class of zinc finger transcription factors because they are the most abundant superfamily of transcription factors in human and have well-characterized DNA binding interactions. We identified 430 SNPs that cause missense substitutions in the DNA-contacting residues. Fewer common missense SNPs were found at DNA-contacting residues compared with non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on zinc finger transcription factor (ZNF) DNA binding preferences also suggested that many common substitutions could potentially alter binding specificity. However, Hardy-Weinberg Equilibrium analysis and examination of seven orthologs within the primate lineage failed to find evidence of trans-eQTLs associated with the DNA-contacting positions or evidence of a different selection pressure on a contemporary and evolutionary timescales. The overall conclusion was that common SNPs that alter the DNA-contacting residues of these factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans-eQTLs in humans tend to be few and weak. Some rare SNPs might alter specificity and remained rare due to purifying selection. The study also underscores the need for large-scale eQTLs mapping efforts that might provide experimental evidence for SNPs that alter the choice of transcription factor binding sites.
改变转录因子DNA结合特异性的变体可能会影响许多潜在靶基因的特异性和表达，正如在一些肿瘤衍生突变中所观察到的那样。在这里，我们研究了这种反式表达数量性状位点（trans-eQTLs）是否同样可能由常见遗传变体导致。我们选择关注Cys2-His2类锌指转录因子，因为它们是人类中最丰富的转录因子超家族，并且具有特征明确的DNA结合相互作用。我们鉴定出430个在与DNA接触的残基中导致错义替换的单核苷酸多态性（SNPs）。与非DNA接触残基相比，在与DNA接触的残基中发现的常见错义SNPs较少（P = 0.00006），这与针对DNA接触位置的SNPs可能存在功能选择一致。基于锌指转录因子（ZNF）DNA结合偏好的功能预测也表明，许多常见替换可能会潜在地改变结合特异性。然而，哈迪-温伯格平衡分析以及对灵长类谱系内七个直系同源物的研究未能找到与DNA接触位置相关的反式eQTLs的证据，也未找到在当代和进化时间尺度上存在不同选择压力的证据。总体结论是，改变这些因子DNA接触残基的常见SNPs不太可能产生强大的反式eQTLs，这与其他人的观察结果一致，即人类中的反式eQTLs往往较少且较弱。一些罕见的SNPs可能会改变特异性，并由于纯化选择而仍然罕见。该研究还强调了大规模eQTLs图谱绘制工作的必要性，这可能为改变转录因子结合位点选择的SNPs提供实验证据。
