This kind of study was what I (as Director of the new Center for Environmental Genetics) had envisioned in the early-1990s that Iain Cartwright and Bob Bornschein might be able to carry out: To find genetic differences is sensitivity of Drosophila sublines to heavy metals such as lead (Pb) and cadmium (Cd), and then to delineate the genetic networks responsible for these genetic differences. Oh well, someone has now done the experiment –– just 20-25 years later.
Studies on genetic variation in susceptibility to environmental toxicants are challenging in human populations, due to: the variety of clinical symptoms; bioethical considerations; difficulty in determining which symptoms are causally the direct result of the toxicant exposure; uncontrolled environments, often with exposure to multiple toxicants (mixtures); and difficulty in relating phenotypic effect-size to toxic dose –– especially when symptoms become manifest with a substantial time lag. The fruit fly, Drosophila melanogaster, is a powerful model that enables genome-wide studies for identification of allelic variants that contribute to variation in susceptibility to environmental toxicants, because the genetic background, environmental-rearing conditions and toxic exposure can be precisely controlled. In the attached publication, authors used the Extreme Discordant Phenotype (EDP) method of analysis, i.e. extreme quantitative-trait loci (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 heavy metals that present serious health risks to humans.
Authors identified single-nucleotide polymorphism (SNP) variants associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to Pb or Cd, respectively and individually. Authors found that the effects of these SNPs were largely sex-specific. They applied mutational and RNA-interference (RNAi) analyses to 33 candidate genes, and were functionally able to validate 28 of them. Authors then constructed networks of candidate genes as blueprints for orthologous networks of human genes. The human gene networks not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate the fly as an important translational toxicogenomics gene-discovery system.
PloS Genet July 2o17; 13: e1006907