Evolution of CTCF binding sites in the human genome

Area of Science:

• Genomics
• Evolutionary Biology
• Epigenetics

Background:

• Topologically associating domains (TADs) are crucial for 3D genome organization and gene regulation, influenced by the CCCTC-binding factor (CTCF).
• The evolutionary dynamics of CTCF binding sites (CBSs) across primate species are not well understood, despite extensive studies on TAD evolution.

Purpose of the Study:

• To investigate the evolution of CBSs in five primate species: human, chimpanzee, gorilla, orangutan, and macaque.
• To identify conserved and species-specific CBSs and their impact on genome architecture and gene regulation.

Main Methods:

• Genome-wide prediction of CBSs using a deep learning model across five primate species.
• Analysis of CBS conservation, motif strength, selective constraints, and association with TAD boundaries.
• Investigation of human-specific CBSs, including de novo emergence, positive selection, and impact on gene expression and enhancer-promoter interactions.

Main Results:

• Approximately 50% of human CBSs are conserved across the studied primates.
• Conserved CBSs are located near TAD boundaries, possess stronger motifs, and show higher selective constraints.
• Human-specific CBSs exhibit signatures of positive selection, with examples of de novo emergence influencing genes like PDE9A, PRDM16, ADCY1, and RIMS1.
• Transposable elements differentially contribute to conserved and human-specific CBSs.
• Genetic variants near human CBSs are enriched for associations with complex traits and diseases.

Conclusions:

• Natural selection has significantly shaped CBS evolution in primates, balancing conservation and innovation in chromatin organization.
• Human-specific CBSs play a key role in human-specific gene expression regulation and are linked to complex traits.
• CBS evolution contributes to primate-specific regulatory evolution and genomic innovation.