Analysis of Genetic Variation Indicates DNA Shape Involvement in Purifying Selection.
Analysis of Genetic Variation Indicates DNA Shape Involvement in Purifying Selection.
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遗传变异分析表明 DNA 形状参与纯化选择。
DOI：
10.1093/molbev/msy099
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发表时间：
2018
影响因子：
10.7
通讯作者：
Rohs,Remo
中科院分区：
文献类型：
--
作者：
Wang,Xiaofei;Zhou,Tianyin;Wunderlich,Zeba;Maurano,MatthewT;DePace,AngelaH;Nuzhdin,SergeyV;Rohs,Remo
非编码DNA序列在基因表达和调控中发挥着各种作用，受到进化的压力。基因调控需要特异性的蛋白质-DNA结合事件，我们以前的研究表明，DNA序列和形状读出都被转录因子（TF）用来实现DNA结合特异性。通过研究人类调控区单核苷酸多态性（SNP）的形状破坏特性，我们建立了破坏性的局部DNA形状变化和特异性TF结合丧失之间的联系。此外，我们描述了疾病相关的SNP可能通过DNA形状变化改变TF结合的情况。这种联系使我们假设TF结合位点内和周围的局部DNA形状处于选择压力下。为了验证这一假设，我们分析了来自216个自然果蝇品系的SNP数据。对于在发育的胚盘阶段活跃的黑色素瘤，我们发现功能区域内的SNP倾向于引起较小的DNA形状变异。此外，具有较高次要等位基因频率的SNPs更可能导致较小的DNA形状变异。同样的分析是基于D.来自DNA酶I可及性数据的黑素胃基因组证实了这些观察结果。综上所述，我们的研究结果表明，在功能区域的常见SNP往往保持DNA的形状，而形状破坏SNP更有可能通过纯化选择被消除。
Noncoding DNA sequences, which play various roles in gene expression and regulation, are under evolutionary pressure. Gene regulation requires specific protein–DNA binding events, and our previous studies showed that both DNA sequence and shape readout are employed by transcription factors (TFs) to achieve DNA binding specificity. By investigating the shape-disrupting properties of single nucleotide polymorphisms (SNPs) in human regulatory regions, we established a link between disruptive local DNA shape changes and loss of specific TF binding. Furthermore, we described cases where disease-associated SNPs may alter TF binding through DNA shape changes. This link led us to hypothesize that local DNA shape within and around TF binding sites is under selection pressure. To verify this hypothesis, we analyzed SNP data derived from 216 natural strains ofDrosophila melanogaster.Comparing SNPs located in functional and nonfunctional regions within experimentally validated cis-regulatory modules (CRMs) fromD. melanogasterthat are active in the blastoderm stage of development, we found that SNPs within functional regions tended to cause smaller DNA shape variations. Furthermore, SNPs with higher minor allele frequency were more likely to result in smaller DNA shape variations. The same analysis based on a large number of SNPs in putative CRMs of theD. melanogastergenome derived from DNase I accessibility data confirmed these observations. Taken together, our results indicate that common SNPs in functional regions tend to maintain DNA shape, whereas shape-disrupting SNPs are more likely to be eliminated through purifying selection.