Short sequence motifs, overrepresented in mammalian conserved non-coding sequences.
Short sequence motifs, overrepresented in mammalian conserved non-coding sequences.
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DOI：
10.1186/1471-2164-8-378
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发表时间：
2007-10-18
期刊：
影响因子：
4.4
通讯作者：
Dubchak, Inna
中科院分区：
文献类型：
--
作者：
Minovitsky, Simon;Stegmaier, Philip;Kel, Alexander;Kondrashov, Alexey S;Dubchak, Inna
多细胞真核生物的非编码DNA序列的相当大的一部分是在选择性约束。特别是，约5%的人类基因组由保守的非编码序列（CNSs）组成。CNSs与其他基因组序列的核苷酸组成不同，必须发挥重要的功能作用，这大多仍然是模糊的。我们研究了人/小鼠全基因组比对中存在的所有人CNSs中短序列基序的相对丰度与三组背景序列：（i）弱保守或不保守的非编码序列（ii）近启动子序列（相对于转录起始，位于核苷酸-500和-1500之间）;和（iii）具有与CNS相同的核苷酸组成的随机序列。当与非CNSs和近启动子序列相比时，CNSs具有过量的富含AT的基序，通常含有相同的核苷酸。相比之下，当与随机序列相比时，CNSs含有过量的富含GC的基序，然而，缺乏CpG二核苷酸。因此，人类CNS中短序列基序的丰度，作为一个整体，主要是由它们的整体组成特性决定的，而不是由任何特定的短基序的过度表达决定的。这些属性是：（i）CNS的高AT含量，（ii）可能由于上下文依赖性突变，A和T聚集的趋势，（iii）短GC富集区的存在，和（iv）由于它们的超突变性，避免CpG上下文。只有少量的短基序，在所有的人类CNSs中过度代表的是类似的FOX家族的转录因子的结合位点。人类中枢神经系统作为一个整体似乎是太广泛的一类序列，拥有任何短序列特异性功能的强大足迹。这种足迹应该在CNS的功能亚类水平上进行研究，例如那些具有特定表达模式的侧翼基因。CNSs的整体特性受突变模式的影响，这表明导致其保守性的选择并不总是很强。
A substantial fraction of non-coding DNA sequences of multicellular eukaryotes is under selective constraint. In particular, ~5% of the human genome consists of conserved non-coding sequences (CNSs). CNSs differ from other genomic sequences in their nucleotide composition and must play important functional roles, which mostly remain obscure. We investigated relative abundances of short sequence motifs in all human CNSs present in the human/mouse whole-genome alignments vs. three background sets of sequences: (i) weakly conserved or unconserved non-coding sequences (non-CNSs); (ii) near-promoter sequences (located between nucleotides -500 and -1500, relative to a start of transcription); and (iii) random sequences with the same nucleotide composition as that of CNSs. When compared to non-CNSs and near-promoter sequences, CNSs possess an excess of AT-rich motifs, often containing runs of identical nucleotides. In contrast, when compared to random sequences, CNSs contain an excess of GC-rich motifs which, however, lack CpG dinucleotides. Thus, abundance of short sequence motifs in human CNSs, taken as a whole, is mostly determined by their overall compositional properties and not by overrepresentation of any specific short motifs. These properties are: (i) high AT-content of CNSs, (ii) a tendency, probably due to context-dependent mutation, of A's and T's to clump, (iii) presence of short GC-rich regions, and (iv) avoidance of CpG contexts, due to their hypermutability. Only a small number of short motifs, overrepresented in all human CNSs are similar to binding sites of transcription factors from the FOX family. Human CNSs as a whole appear to be too broad a class of sequences to possess strong footprints of any short sequence-specific functions. Such footprints should be studied at the level of functional subclasses of CNSs, such as those which flank genes with a particular pattern of expression. Overall properties of CNSs are affected by patterns in mutation, suggesting that selection which causes their conservation is not always very strong.