Evidence for compensatory evolution within pleiotropic regulatory elements
- Zane Kliesmete1,
- Peter Orchard1,2,
- Victor Yan Kin Lee1,3,
- Johanna Geuder1,
- Simon M. Krauß1,4,
- Mari Ohnuki1,5,
- Jessica Jocher1,
- Beate Vieth1,
- Wolfgang Enard1 and
- Ines Hellmann1
- 1Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians Universität München, 82152 Munich, Germany;
- 2Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109-2218, USA;
- 3Section for Molecular Ecology and Evolution, Globe Institute, University of Copenhagen, 1350 Copenhagen, Denmark;
- 4Department of Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, 04103 Leipzig, Germany;
- 5Faculty of Medicine, Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan
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 owing 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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279001.124.
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Freely available online through the Genome Research Open Access option.
- Received January 17, 2024.
- Accepted August 19, 2024.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
