Genome Research：调控DNA数量超过预想

生物谷

    人类染色体组中，围绕着遗传基因，存在着大量的“神秘”DNA，其中大量被认为是“垃圾”，另有一些被称为调控DNA（regulatory  DNA），有助于基因的开启或关闭。美国科学家近日研究发现，这种调控DNA的量可能要比我们认识到的多得多。相关论文12月10日在线发表于《基因组研究》（Genome  Research）上。

    领导这一研究的是美国约翰·霍普金斯大学医学院的Andrew  McCallion。他的小组以与神经发育有关的phox2b基因为研究对象，运用新的实验方法，分析了大量的DNA片断。结果发现，常规方法检出的phox2b调控DNA量大约只是新方法的29%至61%。

    McCallion表示，此次研究支持了这样一种观点，即许多调控蛋白的DNA序列并没有被保留下来。他同时希望新结果能说明类似的研究是有价值的。

    而在接下来的研究中，McCallion计划分析其它神经细胞的基因。他说：“我认为我们刚刚开始认识到DNA调控片断的重要性和丰富性，通过调节每个细胞内基因的活性，它们协助创造了人体内丰富的细胞类型。”（科学网  梅进/编译）

原始出处:

Published online before print December 10, 2007
Genome Research, DOI: 10.1101/gr.6929408

Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b

David M. McGaughey1, Ryan M. Vinton1, Jimmy Huynh1, Amr Al-Saif1, Michael A. Beer1,2, and Andrew S. McCallion1,3,4

1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 2 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Despite its recognized utility, the extent to which evolutionary sequence conservation-based approaches may systematically overlook functional noncoding sequences remains unclear. We have tiled across sequence encompassing the zebrafish phox2b gene, ultimately evaluating 48 amplicons corresponding to all noncoding sequences therein for enhancer activity in zebrafish. Post hoc analyses of this interval utilizing five commonly used measures of evolutionary constraint (AVID, MLAGAN, SLAGAN, phastCons, WebMCS) demonstrate that each systematically overlooks regulatory sequences. These established algorithms detected only 29%–61% of our identified regulatory elements, consistent with the suggestion that many regulatory sequences may not be readily detected by metrics of sequence constraint. However, we were able to discriminate functional from nonfunctional sequences based upon GC composition and identified position weight matrices (PWM), demonstrating that, in at least one case, deleting sequences containing a subset of these PWMs from one identified regulatory element abrogated its regulatory function. Collectively, these data demonstrate that the noncoding functional component of vertebrate genomes may far exceed estimates predicated on evolutionary constraint.

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