Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
Genome Res. 2011 Jul;21(7):1139-49. doi: 10.1101/gr.119016.110. Epub 2011 May 31.
Plasticity of gene regulatory encryption can permit DNA sequence divergence without loss of function. Functional information is preserved through conservation of the composition of transcription factor binding sites (TFBS) in a regulatory element. We have developed a method that can accurately identify pairs of functional noncoding orthologs at evolutionarily diverged loci by searching for conserved TFBS arrangements. With an estimated 5% false-positive rate (FPR) in approximately 3000 human and zebrafish syntenic loci, we detected approximately 300 pairs of diverged elements that are likely to share common ancestry and have similar regulatory activity. By analyzing a pool of experimentally validated human enhancers, we demonstrated that 7/8 (88%) of their predicted functional orthologs retained in vivo regulatory control. Moreover, in 5/7 (71%) of assayed enhancer pairs, we observed concordant expression patterns. We argue that TFBS composition is often necessary to retain and sufficient to predict regulatory function in the absence of overt sequence conservation, revealing an entire class of functionally conserved, evolutionarily diverged regulatory elements that we term "covert."
基因调控加密的可塑性可以在不丧失功能的情况下允许 DNA 序列的差异。功能信息通过转录因子结合位点 (TFBS) 在调控元件中的组成的保守性得以保留。我们开发了一种方法，可以通过搜索保守的 TFBS 排列来准确识别进化上分化的基因座处具有功能的非编码直系同源物对。在大约 3000 个人类和斑马鱼同源基因座中，我们估计假阳性率 (FPR) 约为 5%，检测到大约 300 对可能具有共同祖先和相似调控活性的分化元件。通过分析一组经过实验验证的人类增强子，我们证明了它们预测的功能性直系同源物中有 7/8（88%）保留了体内调控控制。此外，在 5/7（71%）的增强子对中，我们观察到了一致的表达模式。我们认为，在没有明显序列保守性的情况下，TFBS 的组成通常是保留和足以预测调控功能所必需的，这揭示了一类功能保守但进化上分化的调控元件，我们称之为“隐性”。
