Heavy metal toxicity is a world-wide health problem. Lead exposure, especially, is of concern due to the adverse effects of low concentrations on cognitive development in children. Whereas neurotoxic mechanisms of lead have been well studied, information regarding genetic susceptibility to the effects of lead exposure in human populations and studies aimed at identifying alleles that may exacerbate or ameliorate exposure risk are lacking. Such information is difficult to obtain, especially in children, because it is dificult to quantify the onset, duration and extent of exposure, measure adverse effects of lead exposure that become manifest at a later stage of development, assess the effects of simultaneous exposure to multiple, often unknown, environmental toxins, and obtain adequate population sample sizes while accounting for population structure. These problems can be circumvented by identifying candidate risk alleles with human orthologues in model systems, which can subsequently be applied in translational studies to human populations. Drosophila melanogaster presents an advantageous model, since both the genetic background and environment, including exposure to lead, can be controlled precisely. This R21 proposal is an exploratory feasibility study to lay the foundation for a subsequent R01 application to exploit the full power of Drosophila genetics to gain insights in the genetic underpinnings of susceptibility t lead exposure. To identify alleles associated with sensitivity to lead exposure, we will take advantage of a population of wild-derived inbred lines from a Raleigh population with fully sequenced genomes (the Drosophila melanogaster Genetic Reference Panel, DGRP) and capitalize on extensive natural variation within the DGRP panel to conduct a genome-wide association study (GWAS). The Specific Aims of this application are: (1) To identify common DNA sequence variants associated with the effects of lead exposure on development time, viability and locomotor activity in 205 inbred wild- derived lines with fully sequenced genomes; and (2) To use massively parallel bulk DNA sequencing as a complementary approach to identify both common and rare alleles associated with effects of lead exposure that segregate in an advanced intercross population derived from extreme sensitive and resistant lines. We will measure development time, viability and locomotor activity in the DGRP lines reared with and without exposure to lead acetate, and identify single nucleotide polymorphisms (SNPs) associated with variation in sensitivity to lead. A subsequent R01 award will focus on a more detailed validation and characterization of candidate alleles, epistatic interactions among them, and the link between genetic networks and neural circuitry that determine sensitivity to lead neurotoxicity. Results from these experiments will be highly relevant to human environmental health.