Evidence for compensatory evolution within pleiotropic regulatory elements

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zane Kliesmete, Peter Orchard, Victor Yan Kin Lee, Johanna Geuder, Simon M. Krauß, Mari Ohnuki, Jessica Jocher, Beate Vieth, Wolfgang Enard, Ines Hellmann
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引用次数: 0

Abstract

Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is due to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.
多效应调控元件补偿性进化的证据
以跨组织表达广度衡量的多义性是蛋白质序列和表达保护的最佳预测指标之一。在本研究中,我们研究了它对顺式调控元件(CRE)进化的影响。为此,我们仔细地重新分析了九种胎儿组织的表观基因组学路线图数据,为近五十万个 CREs 指定了一个多义性度量。为了评估 CRE 的功能保护,我们生成了来自人类和猕猴的 ATAC-seq 和 RNA-seq 数据。我们发现,多向性 CREs 在可及性方面表现出更大的保护性,相关基因的 mRNA 表达水平也更加保守。在分析转录因子结合库时,这种多效性程度越高,保守性越高的趋势依然存在。与此相反,物种间同源位点的简单 DNA 序列保守性在多效应 CREs 中往往比物种特异性 CREs 更低。综合各种证据,我们提出,功能保守的多效应 CRE 缺乏序列保守是由于元件内补偿进化造成的。总之,我们的研究结果表明,多效性也是预测 CREs 功能保守性的一个很好的指标,尽管多效性 CREs 的序列保守性并没有反映出这一点。
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来源期刊
Genome research
Genome research 生物-生化与分子生物学
CiteScore
12.40
自引率
1.40%
发文量
140
审稿时长
6 months
期刊介绍: Launched in 1995, Genome Research is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies. New data in these areas are published as research papers, or methods and resource reports that provide novel information on technologies or tools that will be of interest to a broad readership. Complete data sets are presented electronically on the journal''s web site where appropriate. The journal also provides Reviews, Perspectives, and Insight/Outlook articles, which present commentary on the latest advances published both here and elsewhere, placing such progress in its broader biological context.
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