Abstract
The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs) associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system.
Highlights
Studies on the genetics of susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag after exposure
We identified single nucleotide polymorphisms (SNPs) associated with variation in resistance to both cadmium and lead, as well as SNPs associated with variation in resistance specific to one of these two heavy metals
In order to identify variants associated with resistance to lead and cadmium exposure in D. melanogaster, we implemented an extreme QTL mapping design [48, 49, 53] in which we compared allele frequencies of three replicate samples of randomly selected flies and three replicate samples of the 10% most resistant flies from an outbred population derived from 37 D. melanogaster Genetic Reference Panel (DGRP) lines
Summary
Studies on the genetics of susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag after exposure. Drosophila melanogaster is a powerful genetic model system for the identification of allelic variants that contribute to variation in resistance to environmental toxins in populations. To explore the Drosophila system as a translational model for toxicogenomic analyses, we took advantage of natural variants that segregate in the D. melanogaster Genetic Reference Panel (DGRP), a collection of 205 wild-derived sequenced inbred lines [8, 9], and focused on individual variation in sensitivity to heavy metal exposure. Other heavy metals, including lead and cadmium, do not occur naturally in biological systems. The mechanisms of their toxicity are diverse and may include competition for endogenous enzymatic cofactors, effects on ion channels, or oxidative damage. Sequestration of heavy metals in bone and their binding to metallothioneins as well as albumin contributes to their long persistence with half-lives that can extend over many years [10, 11, 15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
