| The adaptive immune system provides the body the ability to mount a targeted defense against pathogens. This process depends not on a single cell but rather on the entire "repertoire" of B cells with specific B cell receptors. B cell receptor diversity is generated in two steps: first through V(D)J recombination, where B cells generate an original B cell receptor, and second during an immune response, cells proliferate, mutate, and die, creating a further level of somatic diversity. In my thesis I have studied single sequence position diversity of amino acid usage as well as repertoire wide multiple position motifs. I have used both these scales of sequence analysis to describe how the selection process targets different parts of the B cell receptor to generate the observed somatic patterns of diversity found in the human B cell receptor repertoire through high throughput sequencing experiments.;In particular, I have shown that germline B cell receptor and T cell receptor genes show different patterns of diversity and that B cell receptors in particular show very focused patterns of germline diversity on a background of mostly quite conserved positions (Aim 1, Chapter 2). I then went on to show that this pattern of B cell receptor germline diversity can be used to predict the survival of mutations during the somatic diversification processes and the diversity of amino acids used in these diversification processes (Aim 2, Chapter 3). Finally, I have created a suite of tools that can be used for whole repertoire comparisons between individuals and across immune responses (Aim 3, Chapter 4). These include a spectral clustering based method for identifying amino acid motifs across repertoires and clones, statistical tools to assess sampling sufficiency of clonotypes, and finally a novel metric for assessing the clumpiness of different metadata tags on hierarchical structures, which I used to quantify the relevance of different identified motifs to clone and tissue specific subsets of a given individual immune repertoire. |
