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Dissertation
Sequence based analysis of codon bias and somatic mutational diversity in variable (V) genes of the B cells: models for cross talk between mutation and selection
Doctor of Philosophy (Ph.D.), Drexel University
01 Dec 2014
DOI:
https://doi.org/10.17918/etd-6380
Abstract
Affinity maturation of B cells incorporates somatic hypermutations and competition among B cell mutants to improve repertoire's binding affinity to antigen. This process is of paramount importance to immunity and is observed in all vertebrate species from humans to jawed-fish. The underlying hypothesis for my research thesis is that the non-random patterns of somatic mutation targeting and the codon usage in Immunoglobulin Variable (IgV) genes has evolved in such a way, so as to allow diversification that synergistically enhances selection by skewing mutations. The mutations are targeted to the antigen binding portions, primarily in the complementarity determining regions (CDR), and generally away from the structurally important framework regions (FR), that form the backbone of the receptor. In my thesis, I use an integrated simulation approach to study human germline sequences and quantify the skew in V gene mutation on mutant repertoire formation. I further show how this skew is influenced by the codon bias the V genes express. I validated my germline predictions by analyzing recombined heavy chains associated with the different germline V genes and showed that the codon bias has an enhancing effect on mutational skew towards the CDR. Finally, I related this model to sequence specific models of selection pressure. I designed a sequence-based simulation to study the affinity maturation process, and characterized to what extent mutation is targeted synergistically to aid in selection. Finally, to put my research in a wider biological context and to better understand the background upon which somatic mutation and selection rest in humans, I compared the patterns of mutability and changeability of other genes in the genome and across other species immune repertoires. We observed a strong reverse correlation of GC content and mutability in stable FR and other genes, which was absent in CDR. Mutational skew along with codon bias, was observed across other species repertoires as well. Together these different studies have provided a clearer picture on how somatic mutation and selection at the somatic and species level work in tandem to generate a robust and reliable immune repertoire against antigens.
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Details
- Title
- Sequence based analysis of codon bias and somatic mutational diversity in variable (V) genes of the B cells
- Creators
- Jasmine Saini - DU
- Contributors
- Uri Hershberg (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 6380; 991014632202204721