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，拷贝数变异占人群中观察到的大部分遗传变异，并且发现拷贝数变异（CNV）与疾病（包括复杂表型）之间存在强相关性。然而，环境对CNV的贡献仍然是未知的，部分原因是CNV的大小仅随着全测序基因组数量的增加而被认识到，并且因为很少有动物模型可用于环境基因组学研究，其试图了解基因组结构和功能如何响应环境变化而进化。因此，我们的建议采用研究使用最近添加的和理想的NIH模式生物，水蚤，以测试的中心假设，暴露于环境污染物增加的突变率引起CNV，这种变化有功能的基因表达，表型和健身和人口结构的后果。在不存在和存在镉的情况下衍生的突变累积（MA）系将用于定义CNV的光谱，并测量它们在个体中自发出现的每代速率。将调查三个独立复制的镉适应人群的CNV，评估基因表达，并测定适应性，以表征CNV的大小、分布、功能后果和进化路径。最后，将进行数量性状基因座实验，通过建立拷贝数变异和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影响自发性CNV的风险，并在其对影响耐受性的个体健康参数（即，适应、易感性）和疾病。这些问题的答案对人类的长期健康有着深远的影响，人类的寿命更长，而且在越来越多的诱变环境中也是如此。 公共卫生相关性：最近的研究表明，拷贝数变异占人类群体中观察到的遗传变异的大部分，并且已经发现拷贝数变异（CNV）与疾病（包括复杂表型）之间存在强关联。这些研究将定量评估环境暴露是否影响自发性CNV的风险，并在其对影响耐受性的个体健康参数（即，适应、易感性）和疾病。这些问题的答案对人类的长期健康有着深远的影响，人类的寿命更长，而且在越来越多的诱变环境中也是如此。

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.