RT Journal
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
JF Genome Research 
JO Genome Research 
YR 2024 
FD October 01 
VO 34 
IS 10 
SP 1528 
OP 1539 
DO 10.1101/gr.279001.124 
UL http://genome.cshlp.org/content/34/10/1528.abstract 
AB 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.