LAUSR

Abstract A range of heavy metals are required for normal cell function and homeostasis. However, the anthropogenic release of metal compounds into soil and water sources presents a pervasive health threat. Copper is one of many heavy metals that negatively impacts diverse organisms at a global scale. Using a combination of quantitative trait locus (QTL) mapping and RNA sequencing in the Drosophila Synthetic Population Resource, we demonstrate that resistance to the toxic effects of ingested copper in D. melanogaster is genetically complex and influenced by allelic and expression variation at multiple loci. QTL mapping identified several QTL that account for a substantial fraction of heritability. Additionally, we find that copper resistance is impacted by variation in behavioral avoidance of copper and may be subject to life-stage specific regulation. Gene expression analysis further demonstrated that resistant and sensitive strains are characterized by unique expression patterns. Several of the candidate genes identified via QTL mapping and RNAseq have known copper-specific functions (e.g., Ccs, Sod3, CG11825), and others are involved in the regulation of other heavy metals (e.g., Catsup, whd). We validated several of these candidate genes with RNAi suggesting they contribute to variation in adult copper resistance. Our study illuminates the interconnected roles that allelic and expression variation, organism life stage, and behavior play in copper resistance, allowing a deeper understanding of the diverse mechanisms through which metal pollution can negatively impact organisms.