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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019324-05
Application #
8641358
Study Section
Special Emphasis Panel (ZES1-TN-J (R))
Program Officer
Shaughnessy, Daniel
Project Start
2010-08-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$343,459
Indirect Cost
$120,434
Name
Indiana University Bloomington
Department
None
Type
Other Domestic Higher Education
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Shaw, Joseph R; Hampton, Thomas H; King, Benjamin L et al. (2014) Natural selection canalizes expression variation of environmentally induced plasticity-enabling genes. Mol Biol Evol 31:3002-15
De Coninck, Dieter I M; Asselman, Jana; Glaholt, Stephen et al. (2014) Genome-wide transcription profiles reveal genotype-dependent responses of biological pathways and gene-families in Daphnia exposed to single and mixed stressors. Environ Sci Technol 48:3513-22
Asselman, Jana; Shaw, Joseph R; Glaholt, Stephen P et al. (2013) Transcription patterns of genes encoding four metallothionein homologs in Daphnia pulex exposed to copper and cadmium are time- and homolog-dependent. Aquat Toxicol 142-143:422-30
Asselman, J; Glaholt, S P; Smith, Z et al. (2012) Functional characterization of four metallothionein genes in Daphnia pulex exposed to environmental stressors. Aquat Toxicol 110-111:54-65