# Improved methods for inference of genotype-specific response to environmental toxins

> **NIH NIH R01** · PRINCETON UNIVERSITY · 2020 · $712,764

## Abstract

PROJECT SUMMARY
Why do some individuals appear to be more sensitive than others to environmental perturbation? The answer to
this question has broad implications ranging from our ability to make predictions about disease risk from
genotype, to our ability to identify the drivers of inter-individual variability. Here, we propose to study the broad
question of how the interplay between genetic and environmental variation mediates disease risk
following a toxic environmental exposure. Specifically, we will examine the consequences of
environmental exposure to hexavalent chromium [Cr(VI)] a ubiquitous environmental pollutant. Cr(VI) is
a potent carcinogen and its toxicity extends far beyond its genotoxic effects, including neurotoxicity,
mitochondrial defects, immune aberrations, and reproductive defects, to list a few. Although Cr(VI) is a common
environmental and major health hazard, we know little about how genetic variation drives differential
susceptibility to its toxicity, or the molecular pathways involved. Exploring the contribution of genotype-by-
environment interactions to individual variation has been very challenging in humans. To address this problem
we created a new community resource to study the genetic basis of complex trait variation in Drosophila
melanogaster made of large, synthetic outbred populations. With this new and versatile community resource, we
can rear thousands of genetically unique flies drawn from a common genetic pool, expose them to a range of
different environments [here, Cr(VI)], and contrast the ensuing genetic architectures. We have simultaneously
developed a new high throughput protocols to sequence the DNA and assay the transcriptome of thousands of
flies at very low cost allowing for advance systems genetics analysis. Using this platform, in aim 1, we will
phenotype thousands of individual flies for a variety of traits know to be impacted by Cr(VI) exposure. This
combination of design improvements and technological advances produces a large boost in both statistical power
and genetic resolution. It allows us to ask if the shift in sensitivity some individuals experience under
environmental stress can be explained by the release of genetic susceptibility through of GxE. In aims 2, we will
use a systems genetic approach study variation in sensitivity from the perspective of the regulatory systems
disruption. Individuals more sensitive to environmental stress appear to have decreased transcriptional
robustness for many genes. This variation in robustness appears to be under genetic control and we have
developed an analytical framework to identify such context-dependent transcriptional networks and their genetic
regulators. Finally, in aim 3, we examine how environmentally sensitive alleles are background-dependent, and
what genetic factors modulate their penetrance? We will use CRISPR/Cas9 to knock-out and knock-in alleles
into targeted genes identified in aim 1 and will crossed these transgenic lines to the sy...

## Key facts

- **NIH application ID:** 9858331
- **Project number:** 5R01ES029929-02
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Julien Ayroles
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $712,764
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858331

## Citation

> US National Institutes of Health, RePORTER application 9858331, Improved methods for inference of genotype-specific response to environmental toxins (5R01ES029929-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858331. Licensed CC0.

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