Long-term evolution of regulatory DNA sequences. Part 2: theory and future challenges

Area of Science:

• Genomics
• Evolutionary Biology
• Systems Biology

Background:

• Cis-regulatory elements (CREs), including promoters and enhancers, control gene expression by binding transcription factors (TFs).
• Decades of research have produced models of TF-DNA interactions and their combined effects on gene regulation.

Purpose of the Study:

• To synthesize insights into a quantitative genotype-phenotype (GP) map for gene regulation, enabling simulations of CRE evolution.
• To explore fundamental questions regarding the de novo evolution of CREs, the diversity of regulatory functions, and factors influencing CRE evolvability.

Main Methods:

• Review of evolutionary concepts such as epistasis, robustness, evolvability, tunability, plasticity, and bet-hedging applied to gene regulatory sequences.
• Evaluation of the potential for a unifying theory for the evolution of regulatory sequences.

Main Results:

• The synthesis of TF-DNA interaction models into a global GP map offers a powerful tool for studying regulatory sequence evolution.
• Application of evolutionary concepts provides a framework for understanding the dynamics and constraints of CRE evolution.

Conclusions:

• A unifying theory for regulatory sequence evolution is potentially achievable by integrating biophysical models with evolutionary principles.
• Key open challenges remain in fully understanding and predicting the evolutionary trajectories of gene regulatory sequences.