Causes of Substitution Frequency Variation in Pathogenic Bacteria

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…


1 Introduction
1.1 Rickettsia
1.1.1 A historical perspective
1.1.2 The genus Rickettsia
1.2 Comparative genomics of Rickettsia
1.3 Reductive genome evolution
1.4 Deletional bias in Rickettsia
1.5 Sequence evolution in Rickettsia
1.5.1 Evolution of noncoding sequences
1.5.2 Pseudogenes in Rickettsia
1.5.3 Split genes in R. conorii
1.5.4 Evolution of coding sequences
1.5.5 Those mysterious little ORFans in Rickettsia
1.6 Helicobacter pylori
1.6.1 Comparative Genomics of H. pylori
1.7 What determines the rate of protein evolution?
1.7.1 Chromosomal neighbours
1.7.2 Biological networks
1.7.3 Protein essentiality/lethality
1.7.4 Phylogenetic conservation profiles
2 Aims
3 Methodology
3.1 The importance of sequence alignments in biology
3.1.1 Types of sequence alignments
3.1.2 Assessment of sequence alignments
3.2 Gene prediction
3.2.1 Extrinsic approaches to gene prediction
3.2.2 Intrinsic approaches to gene prediction
3.3 Detecting and resolving orthologs
3.3.1 Homologs, paralogs and orthologs
3.3.2 Gene families
3.2.3 Sequence clustering using the TRIBE-MCL algorithm
3.4 Evolutionary substitution rates
3.4.1 What is Ka/Ks?
3.4.2 Methods of estimating Ka/Ks
3.4.3 Applications of Ka/Ks
3.5 Reconstruction of ancestral sequences
3.5.1 Methods of ancestral sequence reconstruction
3.5.2 Uses of ancestral sequences
3.6 Construction of biological interaction networks
3.7 Comparative protein structure modelling
3.7.1 Mapping mutations onto protein structure
4 Results
4.1 Gene degradation in Rickettsia
4.1.1 Small RNAs in Rickettsia- are they functional?
4.2 Birth and death of ORFan genes in Rickettsia
4.2.1 Coding potential of intergenic regions in Rickettsia species
4.2.2 ORFan genes in the SFG correspond pseudogenes in the TG
4.2.3 ORFans as short, internal fragments of deteriorating genes
4.2.4 ORFans as short, fused fragments of deteriorating genes
4.2.5 Deletions and insertions in the TG and SFG Rickettsia
4.2.6 Putative function of reconstructed genes
4.3 Positive selection scanning of H. pylori
4.4 Factors underlying protein evolutionary rates in H.pylori
4.4.1 Evolutionary rates of linked genes
4.4.2 Evolutionary rates of interacting proteins
4.4.3 Evolutionary rates of essential vs nonessential genes
5 Discussion
5.1.1 Transition to intracellular lifestyles is often accompanied by genome size reduction
5.1.2 Acceleration of nucleotide substitution rates following partial loss of function?
5.1.3 Maintenance of nongenic DNA
5.1.4 Gene deletions mediated by repeated sequences
5.2 An evolutionary perspective on ORFan genes
5.2.1 Characteristics of ORFan genes
5.2.2 Origin and formation of new gene families and the acquisition of new functions
5.2.3 On the origin and functions of ORFans
5.2.4 Do ORFans correspond to real genes?
5.2.5 Are ORFans essential proteins?
5.2.6 Prioritising ORFan studies
5.3 Adaptive evolution in H. pylori: Carbamoyl Phosphate synthetase
5.4 Investigating substitution rate variation in pathogenic bacteria
6 Concluding remarks and future prospects
7 Summary in Swedish
8 Acknowledgements
9 References

Author: Davids, Wagied

Source: Uppsala University Library

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