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

环境污染对基因拷贝数变异的影响：分子b

• 批准号: 8247015
• 负责人: Joseph R. Shaw
• 金额: $ 35.9万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247015
• 关键词: Accounting; Affect; Animal Model; Architecture; Biological Assay; Biology; Cadmium; Chemicals; Complex; Copy Number Polymorphism; DNA Sequence Rearrangement; Daphnia; Deposition; Diapause; Disease; Disease susceptibility; Environment; Environmental Exposure; Environmental Pollution; Evolution; Exposure to; Gene Cluster; Gene Dosage; Gene Duplication; Gene Expression; Generations; Genes; Genetic Variation; Genome; Genomics; Health; Human; Individual; Life; Link; Maps; Measures; Mining; Modeling; Molecular; Mutation; Phenotype; Population; Quantitative Trait Loci; Recombinants; Reporting; Research; Risk; Role; Science; Stress; Structure; Surveys; Testing; United States National Institutes of Health; Variant; coping; defined contribution; design; egg; environmental change; fitness; genome sequencing; insertion/deletion mutation; operation; public health relevance; research study; response; toxic metal

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.

描述（由申请人提供）：最近的研究表明，拷贝数变化是人口中观察到的大多数遗传变异的副本变化，并发现了拷贝数变化（CNV）和疾病（包括复杂的表型）之间的牢固关联。但是，对CNV的环境贡献仍然未知，部分原因是CNV的大小仅随着完全测序的基因组数量的越来越多，并且很少有动物模型可用于环境基因组学研究，这些动物模型试图理解基因组结构和功能如何响应环境变化。因此，我们的提案使用最近添加和理想的NIH模型生物Daphnia进行研究，以检验中心假设，即暴露于环境污染物的人会增加突变速率，从而引起CNV，并且这种变化对基因表达，表观表达，表型以及适应性和种群结构具有功能后果。在不存在和存在镉的情况下得出的突变积累（MA）线将用于定义CNV的光谱并测量其自发出现在个体中的每一生速率。将对CNV，评估的基因表达和适应性分析的三个独立复制，适应镉适应的种群进行调查，以表征CNV的大小，分布，功能后果和进化路径。最后，将进行定量性状基因座实验，以确定CNV的功能意义，通过建立拷贝数变体和表型之间的因果关系。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，并在其对影响公差（即适应性，易感性）和疾病的个人健康参数的背景下这样做。这些问题的答案对人群的长期健康具有深远的影响，而人群的寿命更长，并且在越来越多的诱变环境中这样做。 公共卫生相关性：最近的研究表明，拷贝数变化是人群中观察到的大部分遗传变异的副本变化，并发现了拷贝数变化（CNV）和疾病（包括复杂表型）之间的强烈关联。这些研究将定量评估环境暴露是否会影响自发CNV的风险，并在其对影响公差（即适应性，易感性）和疾病的个体健康参数的背景下这样做。这些问题的答案对人群的长期健康具有深远的影响，而人群的寿命更长，并且在越来越多的诱变环境中这样做。