Chromatin structure and evolution in the human genome.
Chromatin structure and evolution in the human genome.
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DOI：
10.1186/1471-2148-7-72
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发表时间：
2007-05-09
影响因子：
3.4
通讯作者：
Semple CA
中科院分区：
文献类型：
--
作者：
Prendergast JG;Campbell H;Gilbert N;Dunlop MG;Bickmore WA;Semple CA
人类基因组中的进化速率并不恒定，但已经证明，非常接近的基因经历了类似水平的分歧和选择。染色体的高阶组织经常被用来解释这种现象，但以前没有足够的染色体结构数据来严格研究这一点。利用最近对开放和封闭的人类染色质结构进行的全基因组分析的结果，我们首次研究了分歧，选择和染色质结构之间的全球关联。在这项研究中，我们已经表明，矛盾的是，在非CpG位点的同义位点分歧（dS）是最高的开放染色质的区域，主要是由于转换的数量增加，而其他传统的突变措施（基因间，内含子和古老的重复序列分歧以及SNP密度）的比率是最高的基因组的封闭区域。跨内含子-外显子边界的人类-黑猩猩分歧的分析表明，虽然在相对开放的染色质中的基因通常在其同义位点显示很少的选择，在封闭区域中的那些在其四重简并位点处显示出比相邻内含子和基因间区域明显更低的分歧。排除已知的外显子剪接增强子六聚体对在染色质类别的四倍简并位点观察到的分歧影响不大;然而，我们发现封闭的染色质富含某些类别的ncRNA基因，其RNA二级结构可能特别重要。我们的结论是，总的来说，非CpG突变率在基因组的开放区域最低，而具有封闭染色质结构的基因组区域具有最高的背景突变率。这可能反映了开放染色质区域中较低的DNA损伤率或增强的DNA修复过程。我们的研究结果还表明，dS是突变率的一个很差的衡量标准，特别是当用于基因组的封闭区域时，因为封闭区域中的基因通常在其同义位点显示出相对较强的选择水平。
Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time. In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important. We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.
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