Highly conserved non-coding sequences are associated with vertebrate development.
Highly conserved non-coding sequences are associated with vertebrate development.
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DOI：
10.1371/journal.pbio.0030007
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发表时间：
2005-01
期刊：
影响因子：
9.8
通讯作者：
Elgar G
中科院分区：
文献类型：
--
作者：
Woolfe A;Goodson M;Goode DK;Snell P;McEwen GK;Vavouri T;Smith SF;North P;Callaway H;Kelly K;Walter K;Abnizova I;Gilks W;Edwards YJ;Cooke JE;Elgar G
除了蛋白质编码序列外，人类基因组还包含大量的调控DNA，这些DNA的识别在计算机和功能方法中都被证明是有些困难的。比较序列分析是一种已经成功使用的方法，通过比较来自不同生物体的等效基因组区域，以确定相似性和差异性。一般来说，高度分化的生物体之间序列的相似性意味着功能约束。我们对人类和河豚进行了全基因组比较，鉴定出近1400个高度保守的非编码序列。考虑到这些物种之间的进化差异，这些序列很可能存在于所有脊椎动物中，而且对所有脊椎动物都是必不可少的。这些序列中的大多数，可能是全部，都位于作为发育调节因子的基因内或周围。其中一些序列在500多个碱基上的相似性超过90%，比这两个物种之间的编码序列具有更高的保守性。尽管如此，我们在无脊椎动物基因组中找不到任何类似的序列。为了开始对这组序列进行功能测试，我们使用了斑马鱼胚胎快速体内检测系统，可以识别组织特异性增强子活性。我们提供了与四个不相关的发育调节因子（SOX21, PAX6， HLXB9和SHH）相关的高度保守的非编码序列的功能数据，以证明该筛选适用于广泛的基因和表达模式。在这四个基因周围测试的25个序列元素中，23个在一个或多个组织中显示出显著的增强子活性。我们已经确定了一组在脊椎动物中高度保守的非编码序列。它们在整个人类基因组中被发现，主要围绕着与发育调节有关的基因，包括许多转录因子。这些高度保守的非编码序列很可能构成了独特定义脊椎动物发育的基因组电路的一部分。脊椎动物基因组中高度保守的非编码序列通常位于与发育有关的基因周围，在功能分析中可以指导组织特异性基因的表达。
In addition to protein coding sequence, the human genome contains a significant amount of regulatory DNA, the identification of which is proving somewhat recalcitrant to both in silico and functional methods. An approach that has been used with some success is comparative sequence analysis, whereby equivalent genomic regions from different organisms are compared in order to identify both similarities and differences. In general, similarities in sequence between highly divergent organisms imply functional constraint. We have used a whole-genome comparison between humans and the pufferfish, Fugu rubripes, to identify nearly 1,400 highly conserved non-coding sequences. Given the evolutionary divergence between these species, it is likely that these sequences are found in, and furthermore are essential to, all vertebrates. Most, and possibly all, of these sequences are located in and around genes that act as developmental regulators. Some of these sequences are over 90% identical across more than 500 bases, being more highly conserved than coding sequence between these two species. Despite this, we cannot find any similar sequences in invertebrate genomes. In order to begin to functionally test this set of sequences, we have used a rapid in vivo assay system using zebrafish embryos that allows tissue-specific enhancer activity to be identified. Functional data is presented for highly conserved non-coding sequences associated with four unrelated developmental regulators (SOX21, PAX6, HLXB9, and SHH), in order to demonstrate the suitability of this screen to a wide range of genes and expression patterns. Of 25 sequence elements tested around these four genes, 23 show significant enhancer activity in one or more tissues. We have identified a set of non-coding sequences that are highly conserved throughout vertebrates. They are found in clusters across the human genome, principally around genes that are implicated in the regulation of development, including many transcription factors. These highly conserved non-coding sequences are likely to form part of the genomic circuitry that uniquely defines vertebrate development. Highly conserved non-coding sequences in vertebrate genomes are frequently located around genes involved in development and can direct tissue-specific gene expression in functional assays.
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