Mechanism of adaptive amplification

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Genetic change occurs not only by selection of preexisting variation. It also occurs adaptively. This means that the change occurs after cells are exposed to a selective environment, and is advantageous under the conditions of selection. The process of adaptive mutation in bacteria has been well studied and shown, in one system, to be a separate mechanism from spontaneous growth-dependent mutation. A second adaptive process, adaptive amplification, was recently discovered in this laboratory in the same bacterial system. In adaptive amplification, the cell makes numerous copies of a length of DNA carrying a gene that confers an advantage when expressed at a higher level. This project explores the molecular mechanism of amplification (including adaptive amplification) in Escherichia coli, using DNA sequencing, genetic manipulation and experimental intervention. The structure of amplified DNA will be defined, and the genetic requirements for adaptive amplification determined. Whether adaptive amplification is associated with other genetic instability, such as hyper-recombination and general chromosomal instability, will be tested. These results will help to define a mechanism by which DNA is amplified in response to environmental stress. The mechanism of amplification in E. coli is poorly understood at present. The results of this work will provide new insights into DNA transactions in cells under stress, and also to the general processes of chromosomal instability, and adaptation of cells to stressed environments. The results of this study will be relevant to many situations in which genetic change occurs under stress. These include the evolution of pathogenicity, the development of drug resistance in pathogens and in tumor cells, and the development of tumors. The recent discoveries of multiple different DNA repair process that are highly conserved between bacteria and humans, and the paucity of mechanistic information in the less tractable human system, underscore the relevance of this work to many aspects of human health.