Mutations are the ultimate source of genetic variation. Understanding the rate and environmental influence on mutation rate is therefore critical for understanding the origin of human disease and all evolutionary change. Environments, including chemical environments, are rapidly changing around the globe. Over the past seven decades, more than 140,000 novel chemicals have introduced into the market. However, less than 2% of these chemicals have been thoroughly characterized with toxicological assays.
Because the majority of germline mutations have a neutral or negative impact on fitness, pollutant-induced mutagenesis can be devastating for ecosystems and can increase the rate of human disease. However, the influence of chemicals on the rate of germline mutation has been largely ignored. We therefore utilized Daphnia pulex to, (1) characterize the rate and spectrum of genome-wide mutation, (2) measure the influence of chronic, cadmium exposure on the germline mutation rate, and (3) investigate if adaptation protects the germline from mutagenesis.
The single nucleotide mutation (SNM) rate in D. pulex is similar to other model organisms. However, the rate of large-scale de novo copy number variants is 10 to 100-fold higher than other organismal models and is identical to the estimated rate in humans. Exposure to cadmium was mutagenic in the germline, altering the genome-wide rates and spectra of multiple SNM classes and changing the SNM rates in multiple genome regions. Since drastic, pollutant-induced changes to germline mutation have not previously been described, we developed a quantitative model for predicting population response to mutagenic pollutants. Finally, with a cadmium-adapted genotype we show adaptation protects the germline from cadmium-induced mutagenesis. The knowledge gained through this research stands to have profound implications for society and the long-term health of populations, which are living longer in the presence of a growing diversity of potentially mutagenic chemicals.
|Advisor:||Shaw, Joseph R.|
|Commitee:||Brendel, Volker, Lynch, Michael, Meretsky, Vicky|
|School Location:||United States -- Indiana|
|Source:||DAI-B 80/09(E), Dissertation Abstracts International|
|Keywords:||Cadmium, Environmental genomics, Genomics, Mutagenesis, Toxicology|
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