Mapping and understanding Somatic Hypermutation Mechanism

Somatic hypermutation (SHM) has a critical contibution in the creation of immunoglobulin diversity. Folowing antigen recognition and B-cell stimulation, SHM ensures higher antigen-affinity mainly through nucleotide substitutions and, less frequently, insertions or deletions, that can occur throughout the immunoglobulin variable domain.These nucleotide substitutions may or may not result to amino acid substitutions (replacement and silent mutations respectively).

Studies on SHM have been instrumental in unraveling the dynamics of immune processes in health and disease, including malignancies of B cells where relevant research work has been instrumental in understanding their pathophysiology. Such studies provided strong evidence for the implication of antigens in disease ontogeny and evolution, revealing patterns of somatic hypermutation typical of antigen receptors selected by antigen. Furthermore, certain types of B-cell lymphomas were found to display intraclonal diversification of the clonotypic immunoglobulin genes due to ongoing somatic hypermutation in the context of continuous interaction with antigen.

Study objectives

In depth analysis of somatic hypermutation (SHM) aiming to (i) identifymutational patterns across different immune-mediated conditions, disease entities and/or disease subgroups and (ii) subcategorize mutations based on their specific features, thus leading to a better understanding of normal and pathological immune responses.

Methodology

  • Development of purpose-built bioinformatics tools enabling:
  • comparison and mapping of nucleotides, amino acids and, also, amino acid properties in different positions across the germline sequences.
  • acquisition of information concerning each mutational position, namely conservation, V-gene region, hotpots, the type of substitution (both for nucleotides and amino acids) etc.
  • identification of mutations that result in nucleotides and/or amino acids never identified in the germline in those particular positions.
  • pairwisequalitative and quantitative comparisons of amino acid composition between disease subgroups or diseases of related ontogeny (e.g.lymphoid malignancies of marginal zone origin) aiming at defining the similarity/disparity of the aforementioned subgroups.
  • patternidentification across different entities regarding amino acids and amino-acid properties composition