Evidence for compensatory evolution within pleiotropic regulatory elements

Area of Science:

• Genomics
• Evolutionary Biology
• Regulatory Biology

Background:

• Pleiotropy, defined as gene expression across multiple tissues, is a known predictor of protein sequence and expression conservation.
• The impact of pleiotropy on the evolution of cis-regulatory elements (CREs) remains less understood.

Purpose of the Study:

• To investigate the effect of pleiotropy on the evolutionary dynamics of cis-regulatory elements (CREs).
• To determine if pleiotropy influences the functional conservation of CREs.

Main Methods:

• Reanalyzed Epigenomics Roadmap data for nine fetal tissues to quantify the pleiotropic degree of nearly 500,000 CREs.
• Generated ATAC-seq and RNA-seq data from human and macaque samples to assess CRE functional conservation.
• Analyzed transcription factor binding repertoires and DNA sequence conservation of orthologous sites.

Main Results:

• CREs with higher pleiotropy exhibited greater conservation in chromatin accessibility and associated gene expression.
• This trend of increased functional conservation with higher pleiotropy extended to transcription factor binding patterns.
• Conversely, pleiotropic CREs showed lower DNA sequence conservation compared to species-specific CREs.

Conclusions:

• Pleiotropy is a significant predictor of functional conservation in cis-regulatory elements (CREs).
• The apparent lack of sequence conservation in functionally conserved pleiotropic CREs may be due to within-element compensatory evolution.
• Functional conservation of CREs, influenced by pleiotropy, is not always reflected in direct DNA sequence conservation.