Bacteria evolve during the colonization of human hosts, yet little is known about the selective pressures and evolutionary forces that shape this evolution. Illumination of these processes may inspire new therapeutic directions for combating bacterial infections and promoting healthy bacteria-host interactions. The advent of high-throughput sequencing has enabled the identification of mutations that occur within the human host, and various tools from computational and evolutionary biology can aid in creating biological understanding from these mutations. Chapter 1 describes recent progress in understanding within-patient bacterial adaption, focusing on insights made from genomic studies.
Chapters 2 and 3 investigate how the opportunistic pathogen Burkholderia dolosa evolves during long term infections of people with cystic fibrosis, studying patients infected during the same outbreak in Boston. Chapter 2 reports the genomic sequencing of 112 isolates taken from 14 patients over a period a 16 years. Phylogenetic reconstruction identifies a likely transmission network between patients and reveals multiple lung-to-blood transmissions during disease progression. Seventeen genes underwent parallel evolution in these patients, revealing new genes important to bacterial survival in vivo and highlighting the role of a particular oxygen-dependent gene regulation pathway.
Chapter 3 studies the co-existing B. dolosa diversity within single sputum samples taken from each patient, using both colony re-sequencing and a population deep sequencing approach. The intraspecies diversity within each sample is vast and suggests that the diverging lineages co-exist for many years within patients. Furthermore, these diverging lineages evolve in under the pressure of selection and in parallel, enabling the identification of genes undergoing selection from a single clinical sample.
Chapter 4 describes two ongoing collaborations that extend these approaches to other infections, directly addressing the spatial component of bacterial diversification. Chapter 5 discusses future potential directions and consequences of the further study of bacterial evolution within the human body.
|Commitee:||Fortune, Sarah M., Laub, Michael T., Mitchison, Timothy J., Sabeti, Padis C.|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 75/10(E), Dissertation Abstracts International|
|Subjects:||Microbiology, Evolution and Development|
|Keywords:||Evolution, Genomics, Infectious disease, Microbial evolution, Microbial genomics, Systems biology|
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