Causes of Substitution Frequency Variation in Pathogenic Bacteria

Detta är en avhandling från Uppsala : Acta Universitatis Upsaliensis

Sammanfattning: Estimating substitution frequencies at sites that influence (Ka) and do not influence (Ks) the amino acid sequence is important for understanding the dynamics of molecular sequence evolution and the selective pressures that have shaped genetic variation. The aim of this work was to gain a deeper understanding of the driving forces of substitution frequency variation in human pathogens. Rickettsia prowazekii, the causative agent of epidemic typhus and Helicobacter pylori, which has been implicated in gastric diseases were used as model systems. A specific focus was on the evolution of orphan genes in Rickettsia. Additionally, adaptive sequence evolution and factors influencing protein evolutionary rates in H. pylori were studied.The comparative sequence analyses of orphan genes using Typhus Group (TG) and Spotted Fever Group (SFG) Rickettsia, indicate that orphan genes in the SFG correspond to pseudogenes in the TG and that pseudogenes in the SFG correspond to extensively degraded gene remnants in the TG. The analysis also showed that ancestral gene sequences could be reconstructed from extant gene remnants of closely related species. The studies of split genes in R. conorii indicate that many of the small fragmented ORFs are probably pseudogenes. Analysis of the H. pylori carbamoyl phosphate synthetase provided an opportunity to understand natural selection acting on a protein undergoing adaptive evolution. Factors such as network properties, protein-protein interactions, gene essentiality and chromosomal position on protein evolutionary rates in H. pylori were studied, of which antigenicity and gene location were identified as the strongest factors. In conclusion, high Ka/Ks ratios in human pathogens may reflect either adaptive sequence evolution or gene deterioration. Distinguishing between the two is an important task in molecular evolution and also of great relevance for medical microbiology and functional genomics research.