Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules.
Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules.
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DOI：
10.1371/journal.pgen.1002053
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发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Kreitman M
中科院分区：
文献类型：
--
作者：
He BZ;Holloway AK;Maerkl SJ;Kreitman M
转录因子结合位点（TFBS）的获得和丧失（即，周转）是顺式调节模块（CRM）进化的一个有据可查的特征，然而很少有人注意到驱动这种周转过程的进化力量。由于其广泛发生，主流观点强调补偿突变和遗传漂变的重要性。正选择，相反，虽然它已在适应性基因表达进化的特定情况下调用，并没有被认为是中性补偿进化的一般替代。在这项研究中，我们评估了这两个假设，通过分析模式的TFBS的特点CRM在两个密切相关的果蝇物种，黑腹果蝇和果蝇simulans的单核苷酸多态性。该分析的一个重要特征是根据TFBS突变对结合亲和力的预测影响方向对TFBS突变进行分类，这允许沿着两个系统发生谱系独立地评估增益和损失。观察到的多态性和分歧的模式是不兼容的中性进化的任何一类突变。相反，多线的证据是一致的，积极的选择TFBS增益和损失的贡献，以及在其维护净化选择。在讨论中，我们提出了一个模型来调和的选择驱动TFBS营业额与约束CRM功能在很长的进化时间的发现。转录因子结合位点（TFBS）的转换（即谱系特异性的获得和丢失）是真核生物顺式调控模块（CRM）中的一种有据可查的现象。广泛传播的现象和保守的表达模式的外观，为不同的orthogonal CRM导致的立场认为，所观察到的增益和损失的TFBS功能和选择性中性。相反，全基因组群体遗传学分析已经明确识别出了一般在非编码区，特别是在基因的5′和3′非转录区起作用的正选择特征。为了具体测试TFBS营业额过程的中性与选择假设，我们分析了两个密切相关的果蝇物种内和之间的自然变异模式。我们发现，两种类型的突变的分歧和多态性的模式，推断增加或减少结合亲和力分别是不兼容的中性假设。相反，多线的证据表明，积极的选择有助于获得以及TFBS在两个谱系的损失，与纯化选择保持现有的TFBS在人口中。间隔区序列也显示出负选择和正选择的特征。我们提出了一个CRM演化模型，以调和频繁的适应性变化与长期演化的约束。
Transcription factor binding site(s) (TFBS) gain and loss (i.e., turnover) is a well-documented feature of cis-regulatory module (CRM) evolution, yet little attention has been paid to the evolutionary force(s) driving this turnover process. The predominant view, motivated by its widespread occurrence, emphasizes the importance of compensatory mutation and genetic drift. Positive selection, in contrast, although it has been invoked in specific instances of adaptive gene expression evolution, has not been considered as a general alternative to neutral compensatory evolution. In this study we evaluate the two hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS of well-characterized CRM in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans. An important feature of the analysis is classification of TFBS mutations according to the direction of their predicted effect on binding affinity, which allows gains and losses to be evaluated independently along the two phylogenetic lineages. The observed patterns of polymorphism and divergence are not compatible with neutral evolution for either class of mutations. Instead, multiple lines of evidence are consistent with contributions of positive selection to TFBS gain and loss as well as purifying selection in its maintenance. In discussion, we propose a model to reconcile the finding of selection driving TFBS turnover with constrained CRM function over long evolutionary time. Transcription factor binding sites (TFBS) turnover (i.e. lineage-specific gain and loss) is a well-documented phenomenon in eukaryote cis-regulatory modules (CRM). The wide spread of the phenomenon and the appearance of conserved expression patterns for diverged orthologous CRM led to the standing view that the observed gain and loss of TFBS were functionally and selectively neutral. To the contrary, genome-wide population genetics analyses have unequivocally identified signatures of positive selection acting in noncoding regions in general, and particularly in 5′ and 3′ untranscribed regions of genes. To specifically test the neutral versus selection hypotheses for the TFBS turnover process, we analyzed natural variation patterns within and between two closely related Drosophila species. We found the patterns of divergence and polymorphism for two types of mutations—those inferred to increase or decrease the binding affinity respectively—are not compatible with a neutral hypothesis. Instead, multiple lines of evidence suggested that positive selection has contributed to gain as well as loss of TFBS in the two lineages, with purifying selection maintaining existing TFBS in the population. Spacer sequences also showed signatures of negative and positive selection. We proposed a model of CRM evolution to reconcile the finding of frequent adaptive changes with constraints on long-term evolution.