A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure

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.

Perspectives of Molecularly Imprinted Polymer-Based Drug Delivery Systems in Cancer Therapy

“…The list of metals that have been used in the imprinting process as pivots is quite short, being restricted to several transitional metals such as: Co(II), Co(III), Cu(II), Ni(II), Zn(II), Cd(II), Fe(II), and Fe(III) [44]. Cadmium does not occur naturally in biological systems and is an exceptionally toxic heavy metal [79], thus it cannot be used in DDS development. The other listed metals are essential trace elements and they are generally required as cofactors for enzymatic reactions; in relatively large amounts however, they are harmful or toxic.…”

Cloudy with a Chance of Insights: Context Dependent Gene Regulation and Implications for the Evolution of Gene Expression

“…Many studies exploring the molecular basis of differences in physiological and life-history traits followed by functional validation have confirmed an underlying polygenic architecture [12,33,34]. Nevertheless, few studies reached the resolution to narrow down genetic variation to the level of individual loci.…”

Lead Modulates trans- and cis-Expression Quantitative Trait Loci (eQTLs) in Drosophila melanogaster Heads

“…One of the biggest challenges in biology is to understand how genetic variation alters gene expression, which is also known as genetical genomics (Mackay et al, 2009 ; Massouras et al, 2012 ; Lagarrigue et al, 2013 ). Genetics of gene expression has been studied in various species, such as maize (Schadt et al, 2003 ), yeast (Brem et al, 2002 , 2005 ; Yvert et al, 2003 ; Bing and Hoeschele, 2005 ), roundworms (Francesconi and Lehner, 2014 ), flies (Gupta et al, 2007 ; Massouras et al, 2012 ; Zhou et al, 2016 , 2017 ), mice (Schadt et al, 2003 ; Huang et al, 2009 ), and humans (Schadt et al, 2003 ; Mangravite et al, 2013 ; Zhang et al, 2014 ). Expression Quantitative Trait Loci (eQTL) analyses, which search for genomic loci that are responsible for the differential gene expression levels, has shed light on the genetic structure of transcriptional regulation.…”