Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype-phenotype maps

TL;DR

This paper uses biophysically-realistic simulations of genotype-phenotype maps to explore the long-term evolution and connectivity of regulatory DNA sequences, addressing fundamental questions in gene regulation evolution.

Contribution

It introduces a simulation framework based on a global, quantitative GP map for regulatory DNA, enabling long-term evolutionary studies of CREs.

Findings

CREs can evolve de novo over long timescales

Regulatory sequence space contains multiple functional regions

Evolutionary pathways are highly connected and evolvable

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 first of a two-part series, we briefly review the pertinent modeling and simulation efforts for a unique system that enables close, quantitative, and mechanistic links between biophysics, as well as systems, synthetic, and evolutionary biology.