# Evolution of cis-regulatory sequences

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $308,000

## Abstract

PROJECT SUMMARY
The goal of the proposed research is to determine how changes in cis-regulatory sequences alter
transcriptional dynamics. Whereas transcription factors are well known to determine when a gene is
turned on and off, cis-regulatory sequences have the ability to fine-tune how a gene responds to these
signals. The precise timing and rate of gene activation/repression are key to a cell's ability to
appropriately respond to it's biotic and abiotic environment. In microbes, which must survive and
compete in ever changing environments, fitness may depend more on gene expression dynamics than
expression levels under steady state conditions.
To ascertain how changes in cis-regulatory sequences modulate gene expression dynamics we will
use a high-throughput reporter system capable of testing hundreds of cis-regulatory variants in yeast.
We will map causal variants upstream of genes that exhibit allele-specific differences in their gene
expression dynamics. Our preliminary studies demonstrate that there is extensive variation in gene
expression dynamics in yeast and this allelic variation can be recapitulated in our reporter system. In
the first aim we will map SNPs and InDels between strains of Saccharomyces cerevisiae that alter
expression dynamics following depletion of glucose. By characterizing causal cis-regulatory variants
we will specifically test whether insertions and deletions that change the position of known regulatory
motifs is a major mode by which gene expression dynamics are altered, and more generally whether
changes within or outside of transcription factor binding sites are more often responsible for altered
expression levels or dynamics. In the second aim we will map substitutions between Saccharomyces
species that alter the heat shock response. Because compensatory changes are a common feature of
cis-regulatory divergence between species, expression levels and dynamics may not evolve
independently of one another. We will test whether coincident divergence in expression levels and
dynamics is a consequence of mutation or co-evolution. By including random promoter mutants as
part of our investigation we will generate expected patterns of divergence in the absence of constraint,
enabling us to measure the extent to which divergence in gene expression levels and dynamics are
constrained during evolution. The completion of these aims will fill an important gap in our
understanding of which noncoding variants alter gene expression and how cis-regulatory sequences
evolve.

## Key facts

- **NIH application ID:** 9859405
- **Project number:** 5R01GM080669-13
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Justin C Fay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2007-08-10 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859405

## Citation

> US National Institutes of Health, RePORTER application 9859405, Evolution of cis-regulatory sequences (5R01GM080669-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859405. Licensed CC0.

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