Somatic hypermutation is the targetted process of mutagenesis which introduces single base changes into the rearranged variable regions encoding immunoglobulin heavy and light chains. Mutations are localized to the V regions of the rearranged heavy and light chain loci; promoter, leader, and constant regions do not display mutations, nor do unrearranged germ line V regions. The rate of mutation, 10-3 per base per generation, is about one million-fold higher that the typical rate of mutation in a mammalian cell. Somatic hypermutation results in the production of some B cell clones with increased affinity for antigen, thus enhancing the efficiency of the immune response. We have exciting recent results showing that gene conversion is the mechanism of somatic hypermutation of mammalian immunoglobulin genes. Our long-term goal is to understand in detail the molecular mechanism and regulation of the process of immunoglobulin gene hypermutation. Our specific experimental goals are (1) to expand the database demonstrating that gene conversion mediates somatic hypermutation: (2) to determine the molecular parameters of this process; and (3) to analyze the regulation of somatic hypermutation, asking in particular whether germinal centers are the site of hypermutation, and whether hypermutation and heavy chain class switch recombination are coordinately regulated. These experiments address the mechanism of a fundamental process in the immune response. Furthermore, since the somatic events that diversity the cellular genome during B lymphocyte development probably occur by directed use of mechanisms common to all cells, understanding the mechanism of somatic hypermutation at the immunoglobulin loci is likely to provide insight into analogous mutation events that are central to genomic evolution, genetic disease, and oncogenesis.
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