Functional characterization of enhancer evolution in the primate lineage.

Area of Science:

• Evolutionary biology
• Genomics
• Molecular biology

Background:

• Enhancers regulate gene expression, influencing evolution and speciation.
• Previous studies on primate enhancer evolution lacked detailed molecular insights.
• Large-scale genomic changes in enhancers are known, but evolutionary steps are unclear.

Purpose of the Study:

• To characterize the evolutionary and functional trajectories of primate liver enhancers.
• To understand the molecular mechanisms driving enhancer evolution.
• To identify specific mutations and evolutionary forces shaping enhancer activity.

Main Methods:

• Identified hominoid-specific liver enhancers using H3K27ac ChIP-seq data.
• Synthesized orthologous and ancestral sequences for 233 enhancers across 11 primates.
• Assessed regulatory activity of all sequences using STARR-seq in HepG2 cells.

Main Results:

• Observed coherent evolutionary trajectories in enhancer activity, often explained by single gain/loss events.
• Quantified the correlation between mutation accumulation and changes in enhancer function.
• Identified 84 mutations linked to functional changes, enriched for CpG deamination.

Conclusions:

• Characterized evolutionary-functional paths for hundreds of primate liver enhancers.
• Demonstrated that subsets of enhancers gained or lost activity during primate evolution.
• Highlighted CpG deamination as a significant factor in primate enhancer evolution.