Evolution of transcription factor binding sites in mammalian gene regulatory regions: Conservation and turnover
Evolution of transcription factor binding sites in mammalian gene regulatory regions: Conservation and turnover
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DOI：
10.1093/oxfordjournals.molbev.a004169
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发表时间：
2002-07-01
影响因子：
10.7
通讯作者：
Clark, AG
中科院分区：
文献类型：
--
作者：
Dermitzakis, ET;Clark, AG
人类和啮齿动物DNA序列的比较被广泛用于识别调控区域（系统发育足迹）。这种基因组间比较对启动子注释的重要性正在扩大。这种比较对识别功能调控元件的有效性取决于启动子序列的进化动力学。尽管人们普遍认识到序列基序的保守性可能提供了功能的暗示，但尚不清楚人类中有多少比例的功能结合位点在远缘物种中是保守的。在本报告中。我们对51个人类基因启动子中功能已被实验证实的转录因子结合位点的进化动力学进行了分析，并将其序列与其他灵长类动物和啮齿动物的同源序列进行了比较。我们的研究结果表明，转录因子结合位点的核苷酸序列存在广泛的差异。通过对人类和啮齿类动物的20个调控位点的功能研究的直接实验数据，我们估计32%-40%的人类功能位点在啮齿类动物中不起作用。这证明转录因子结合位点存在广泛的周转。这些结果对系统发育足迹的有效性和调控序列进化模式的解释具有重要意义。
Comparisons between human and rodent DNA sequences are Widely Used for the identification of regulatory regions (phylogenetic footprinting). and the importance of such intergenomic comparisons for promoter annotation is expanding. The efficacy of Such comparisons for the identification of functional regulatory elements hinges oil the evolutionary dynamics of promoter sequences. Although it is widely appreciated that conservation of sequence motifs may provide a suggestion of function, it is not known as to what proportion of the functional binding sites in humans is conserved in distant species. In this report. we Present all analysis of the evolutionary dynamics of transcription factor binding sites whose function had been experimentally verified in promoters of 51 human genes and compare their sequence to homologous sequences in other primate species and rodents. Our results Show that there is extensive divergence within the nucleotide sequence of transcription factor binding sites. Using direct experimental data from functional studies in both human and rodents for 20 of the regulatory re,,ions, we estimate that 32%-40%, of the human functional sites are not functional in rodents. This is evidence that there is widespread turnover of transcription factor binding sites. These results have important implications for the efficacy of phylogenetic footprinting and the interpretation of the pattern of evolution in regulatory sequences.