Defining functional DNA elements in the human genome
Defining functional DNA elements in the human genome
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DOI：
10.1073/pnas.1318948111
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发表时间：
2014-04-29
影响因子：
11.1
通讯作者：
Hardison, Ross C.
中科院分区：
文献类型：
--
作者：
Kellis, Manolis;Wold, Barbara;Hardison, Ross C.
随着人类基因组测序的完成，人们的注意力转向了识别和注释其功能性DNA元件。作为对遗传和比较基因组学方法的补充，启动了DNA元件百科全书项目，以提供许多细胞类型中RNA转录本、转录调节因子结合位点和染色质状态的图谱。由此产生的全基因组数据揭示了具有高位置分辨率和细胞类型特异性的生化活性位点，这些位点有助于研究与人类疾病相关的基因调控和非编码变体的解释。然而，生物化学活性区域比进化上保守的区域覆盖基因组的更大部分，这就提出了一个问题，即非保守但生物化学活性区域是否真正具有功能。在这里，我们回顾了生物化学，进化和遗传方法的优势和局限性，用于定义功能性DNA片段，估计基因组覆盖率的观察到的差异的潜在来源，以及这些差异的生物学意义。我们还分析了信号强度，基因组覆盖率和进化保守性之间的关系。我们的研究结果强化了这样一个原则，即每种方法都提供了互补的信息，我们需要使用所有三种方法的组合来阐明人类生物学和疾病中的基因组功能。
With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.