Effects of environmental contamination on gene copy number variation: Molecular b

描述（由申请人提供）：最近的研究表明，拷贝数变异占人类群体中观察到的大部分遗传变异，并揭示了拷贝数变异（CNV）与疾病（包括复杂表型）之间的强烈关联。然而，环境对CNV的贡献仍然未知，部分原因是CNV的大小只有在越来越多的完全测序的基因组中才被认识到，而且很少有动物模型可用于环境基因组学研究，这些研究旨在了解基因组结构和功能如何随着环境变化而进化。因此，我们的建议采用最近添加的和理想的NIH模式生物水蚤进行研究，以验证暴露于环境污染物会增加导致CNV的突变率的中心假设，并且这种变异对基因表达，表型，适应性和种群结构具有功能后果。在缺乏和存在镉的情况下获得的突变积累（MA）系将用于确定CNV的光谱，并测量它们在个体中自发产生的每一代速率。研究人员将对三个独立复制的镉适应种群进行CNV调查，评估基因表达，并分析适应度，以表征CNV的大小、分布、功能后果和进化路径。最后，将进行数量性状位点实验，通过建立拷贝数变异与表型之间的因果关系来确定CNV的功能意义。总的来说，这些研究将定量评估环境暴露是否会影响自发CNV的风险，并在其对影响耐受性（即适应、易感性）和疾病的个人健康参数的贡献的背景下进行。这些问题的答案对人类的长期健康有着深远的影响，因为人类的寿命越来越长，而且生活在日益突变的环境中。

DESCRIPTION (provided by applicant): Recent studies indicate copy number variation accounts for the majority of the genetic variation observed in the human populations and have uncovered strong associations between copy number variation (CNV) and disease, including complex phenotypes. However, the environmental contributions to CNV remain unknown, in part because the magnitude of CNV has only been realized with the growing number of fully sequenced genomes and because there are few animal models available for environmental genomics studies, which seek to understand how genome structure and function evolve in response to environmental change. Accordingly, our proposal employs studies using the recently added and ideal NIH model organism, Daphnia, to test the central hypothesis that exposure to environmental contaminants increase the rate of mutations giving rise to CNV, and that this variation has functional consequences on gene expression, phenotype, and fitness and population structure. Mutation accumulation (MA) lines derived in the absence and presence of cadmium will be used to define the spectra of CNV and measure the per generation rate at which they spontaneously arise in individuals. Three independently replicated, cadmium-adapted populations will be surveyed for CNV, gene- expression assessed, and fitness assayed to characterize the magnitude, distribution, functional consequences, and evolutionary path of CNV. Finally, quantitative trait loci experiments will be conducted to determine the functional significance of CNV by establishing cause and effect relationships between copy number variants and phenotype. Collectively, these studies will quantitatively assess whether environmental exposure affects the risk for spontaneous CNV, and do so in context of their contributions to individual health parameters that influence tolerance (i.e., adaptation, susceptibility) and disease. Answers to these questions have profound implications for the long-term health of human populations that are living longer and doing so in increasingly mutagenic environments. PUBLIC HEALTH RELEVANCE: Recent studies indicate copy number variation accounts for the majority of the genetic variation observed in the human populations and have uncovered strong associations between copy number variation (CNV) and disease, including complex phenotypes. These studies will quantitatively assess whether environmental exposure affects the risk for spontaneous CNV, and do so in context of their contributions to individual health parameters that influence tolerance (i.e., adaptation, susceptibility) and disease. Answers to these questions have profound implications for the long-term health of human populations that are living longer and doing so in increasingly mutagenic environments.