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

描述(申请人提供)：最近的研究表明，拷贝数变异是人类群体中观察到的大部分遗传变异的原因，并发现拷贝数变异(CNV)与疾病之间存在强烈的关联，包括复杂的表型。然而，环境对CNV的贡献仍然未知，部分原因是CNV的大小只有随着全序列基因组的增加才被认识到，而且环境基因组学研究试图了解基因组结构和功能如何随着环境变化而演变的动物模型很少。因此，我们的建议采用了使用最近添加的和理想的NIH模式生物Daphnia的研究来验证中心假设，即暴露在环境污染物中会增加导致CNV的突变率，并且这种变异对基因表达、表型、适合度和种群结构具有功能性影响。在没有镉和有镉存在的情况下产生的突变累积(MA)系将被用来定义CNV的光谱，并测量它们在个体中自发产生的每一代的速率。将对三个独立复制的适应镉的种群进行CNV调查，评估基因表达，并进行适合性分析，以表征CNV的大小、分布、功能后果和进化路径。最后，将通过建立拷贝数变异和表型之间的因果关系来进行数量性状基因座实验，以确定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，并根据它们对影响耐受性(即适应、易感性)和疾病的个人健康参数的贡献来这样做。这些问题的答案对人类人口的长期健康有着深远的影响，这些人活得更长，而且是在日益突变的环境中这样做的。 与公共卫生相关：最近的研究表明，拷贝数变异是人类群体中观察到的大部分遗传变异的原因，并发现拷贝数变异(CNV)与疾病之间存在很强的相关性，包括复杂的表型。这些研究将定量评估环境暴露是否影响自发性CNV的风险，并根据它们对影响耐受性(即适应、易感性)和疾病的个人健康参数的贡献来这样做。这些问题的答案对人类人口的长期健康有着深远的影响，这些人活得更长，而且是在日益突变的环境中这样做的。

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.