Neurogenetics of lead toxicity in Drosophila

描述（由申请人提供）：重金属中毒是一个全球性的健康问题。特别是铅暴露，由于低浓度对儿童认知发育的不利影响而引起关注。虽然铅的神经毒性机制已经得到了很好的研究，但关于人类对铅暴露影响的遗传易感性的信息以及旨在确定可能加剧或减轻暴露风险的等位基因的研究仍然缺乏。这类信息很难获得，特别是在儿童中，因为很难量化接触的开始、持续时间和程度，难以衡量在发育后期显现的铅接触的不利影响，难以评估同时接触多种通常未知的环境毒素的影响，难以在考虑人口结构的同时获得足够的人口样品量。这些问题可以通过在模型系统中识别具有人类同源物的候选风险等位基因来规避，这些等位基因随后可以应用于对人类群体的转化研究。黑腹果蝇提供了一个有利的模型，因为遗传背景和环境，包括铅暴露，都可以精确控制。本R21建议书是一项探索性可行性研究，旨在为后续的R01申请奠定基础，以开发

DESCRIPTION (provided by applicant): 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.