TY  - JOUR
A1  - Kliesmete, Zane
A1  - Orchard, Peter
A1  - Lee, Victor Yan Kin
A1  - Geuder, Johanna
A1  - Krauß, Simon M.
A1  - Ohnuki, Mari
A1  - Jocher, Jessica
A1  - Vieth, Beate
A1  - Enard, Wolfgang
A1  - Hellmann, Ines
T1  - Evidence for compensatory evolution within pleiotropic regulatory elements
Y1  - 2024/10/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1528 
EP  - 1539 
DO  - 10.1101/gr.279001.124 
VL  - 34 
IS  - 10 
UR  - http://genome.cshlp.org/content/34/10/1528.abstract 
N2  - 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. 
ER  -