Computational Methods to Study Diversification in Pathogens, and Invertebrate and Vertebrate Immune Systems
Pathogens and host immune systems use strikingly similar methods of diversification. Mechanisms such as point mutations and recombination help pathogens escape the host immune system and similar mechanisms help the host immune system attack rapidly evolving pathogens. Understanding the interplay between pathogen and immune system evolution is crucial to effective drug and vaccine development. In this thesis we employ various computational methods to study diversification in a pathogen, an invertebrate and a vertebrate immune system.
First, we develop a technique for phylogenetic inference in the presence of recombination based on the principle of minimum description length, which assigns a cost-the description length-to each network topology given the observed sequence data. We show that the method performs well on simulated data and demonstrate its application on HIV <italic>env</italic> gene sequence data from 8 human subjects.
Next, we demonstrate via phylogenetic analysis that the evolution of repeats in an immune-related gene family in <italic>Strongylocentrotus purpuratus</italic> is the result of recombination and duplication and/or deletion. These results support the evidence suggesting that invertebrate immune systems are highly complex and may employ similar mechanisms for diversification as higher vertebrates.
Third, we develop a probabilistic model of the immunoglobulin (Ig) rearrangement process and a Bayesian method for estimating posterior probabilities for the comparison of multiple plausible rearrangements. We validate the software using various datasets and in all tests, SoDA2 performed better than other available software.
Finally, we characterize the somatic population genetics of the nucleotide sequences of >1000 recombinant Ig pairs derived from the blood of 5 acute HIV-1 infected (AHI) subjects. We found that the Ig genes from the 20 day AHI PC showed extraordinary clonal relatedness among themselves; a single clone comprised of 52 members, with observed and inferred precursor antibodies specific for HIV-1 Env gp41. Antibodies from AHI patients show a decreased CDR3H length and an increased mutation frequency when compared to influenza vaccinated individuals. The high mutation frequency is coupled with a comparatively low synonymous to non-synonymous mutation ratio in the heavy chain. Our results may suggest presence of positive antigenic selection in previously triggered non-HIV-1 memory B cells in AHI.
Taken together, the studies presented in this thesis provide methods to study diversification in pathogens, and invertebrate and vertebrate immune systems.
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