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

TL;DR

This paper reviews the long-term evolution of regulatory DNA sequences, focusing on theoretical models, evolutionary concepts, and future challenges in understanding how gene regulatory elements evolve and adapt over time.

Contribution

It synthesizes existing models and concepts to evaluate the potential for a unifying theory of regulatory sequence evolution and highlights key open challenges.

Findings

Insights into the evolution of CREs and their regulatory functions.

Evaluation of the connectivity and evolvability of regulatory sequences.

Identification of open challenges in modeling long-term regulatory evolution.

Abstract

Promoters and enhancers are cis-regulatory elements (CREs), DNA sequences that bind transcription factor (TF) proteins to up- or down-regulate target genes. Decades-long efforts yielded TF-DNA interaction models that predict how strongly an individual TF binds arbitrary DNA sequences and how individual binding events on the CRE combine to affect gene expression. These insights can be synthesized into a global, biophysically-realistic, and quantitative genotype-phenotype (GP) map for gene regulation, a "holy grail" for the application of evolutionary theory. A global map provides a rare opportunity to simulate long-term evolution of regulatory sequences and pose several fundamental questions: How long does it take to evolve CREs de novo? How many non-trivial regulatory functions exist in sequence space? How connected are they? For which regulatory architecture is CRE evolution most rapid and evolvable? In this article, the second of a two-part series, we review the application of evolutionary concepts - epistasis, robustness, evolvability, tunability, plasticity, and bet-hedging - to the evolution of gene regulatory sequences. We then evaluate the potential for a unifying theory for the evolution of regulatory sequences, and identify key open challenges.