arXiv subjects

Justin Crocker

Publications and source records attributed to Justin Crocker.

3 recordsLinked to original sources

arXiv2026

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

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.

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arXiv2026

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

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.

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arXiv2010

Dynamic evolution of precise regulatory encodings creates the clustered signature of developmental enhancers

A morphogenic protein known as Dorsal patterns the embryonic dorsoventral body axis of Drosophila by binding to transcriptional enhancers across the genome. Each such enhancer activates a neighboring gene at a unique threshold concentration of Dorsal. The presence of Dorsal binding site clusters in these enhancers and of similar clusters in other enhancers has motivated models of threshold-encoding in site density. However, we found that the precise length of a spacer separating a pair of specialized Dorsal and Twist binding sites determines the threshold-response. Despite this result, the functional range determined by this spacer element as well as the role and origin of its surrounding Dorsal site cluster remained completely unknown. Here, we experiment with enhancers from diverse Drosophila genomes, including the large uncompacted genomes from ananassae and willistoni, and report three major interdependent results. First, we map the functional range of the threshold-encoding spacer variable. Second, we show that the majority of sites at the cluster are non-functional divergent elements that have been separated beyond the encoding's functional range. Third, we verify an evolutionary model involving the frequent replacement of a threshold encoding, whose precision is easily outdated by shifting accuracy. The process by which encodings are replaced by newer ones is facilitated by the palindromic nature of the Dorsal and Twist binding motifs and by intrinsic repeat-instability in the specialized Twist binding site, which critically impacts the length of the spacer linking it to Dorsal. Over time, the dynamic process of selective deprecation and replacement of encodings adds to a growing cluster of deadened elements, or necro-elements, and strongly biases local sequence composition. ... [ABSTRACT TRUNCATED]

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