Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064022-03
Application #
6619687
Study Section
Genetics Study Section (GEN)
Program Officer
Wolfe, Paul B
Project Start
2001-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$225,750
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Wimberly, Hallie; Shee, Chandan; Thornton, P C et al. (2013) R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli. Nat Commun 4:2115
Moore, J M; Wimberly, Hallie; Thornton, P C et al. (2012) Gross chromosomal rearrangement mediated by DNA replication in stressed cells: evidence from Escherichia coli. Ann N Y Acad Sci 1267:103-9
Rosenberg, Susan M; Shee, Chandan; Frisch, Ryan L et al. (2012) Stress-induced mutation via DNA breaks in Escherichia coli: a molecular mechanism with implications for evolution and medicine. Bioessays 34:885-92
Al Mamun, Abu Amar M; Lombardo, Mary-Jane; Shee, Chandan et al. (2012) Identity and function of a large gene network underlying mutagenic repair of DNA breaks. Science 338:1344-8
Carvalho, Claudia M B; Ramocki, Melissa B; Pehlivan, Davut et al. (2011) Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 43:1074-81
Lin, Dongxu; Gibson, Ian B; Moore, Jessica M et al. (2011) Global chromosomal structural instability in a subpopulation of starving Escherichia coli cells. PLoS Genet 7:e1002223
Fonville, Natalie C; Vaksman, Zalman; DeNapoli, Jessica et al. (2011) Pathways of resistance to thymineless death in Escherichia coli and the function of UvrD. Genetics 189:23-36
Liu, Pengfei; Erez, Ayelet; Nagamani, Sandesh C Sreenath et al. (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146:889-903
Liu, Pengfei; Lacaria, Melanie; Zhang, Feng et al. (2011) Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over. Am J Hum Genet 89:580-8
Frisch, Ryan L; Su, Yang; Thornton, P C et al. (2010) Separate DNA Pol II- and Pol IV-dependent pathways of stress-induced mutation during double-strand-break repair in Escherichia coli are controlled by RpoS. J Bacteriol 192:4694-700

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