EXCEED THE SPACE PROVIDED. Genetic Variation in B-Lymphocyte Ontogeny Whether they lead to cancer, aging, or both, somatic mutations are usually detrimental to the individual. Mutations at the immunoglobulin (Ig) loci are an exception, because they generate high-affinity antibodies, which are important in memory responses to pathogens. Thus, in the segments of immunoglobulin genes that encode the variable regions of antibodies, mutations are beneficial. Since such mutations arise at a rate a million times higher than the normal, spontaneous mutation rate at other loci, the process is called hypermutation. With our experiments we seek to define cis- and trans-acting elements for hypermutation at the immunoglobulin loci. But hypermutation is not the only change mature B lymphocytes undergo. Small, resting B lymphocytes all start out producing IgM antibodies. Upon encountering antigen, the cells become activated and make a switch from IgM to other immunoglobulin classes. This class switch serves to distribute a particular variable (V) region to different Ig constant (C) regions. Each C region mediates a specialized effector function, so an organism can guide its antibodies to various sites through switching. Creating the new heavy chain (H) gene requires loop-out and deletion of DNA between switch regions. Both hypermutation and class switching require transcription, presumably so that necessary factors can gain access to the DNA. The requisite factors include the cytidine deaminase AID and components of general DNA repair. Yet many important factors remain to be discovered, especially those that may guide recombination to a particular subclass. In the proposed work, we want to study the various splice form of AID and assess their physiological functions; study a chromatin remodelling factor that binds to AID; and study the structure of a newly discovered protein and its function in DNA double-strand-break repair. PERFORMANCE SITE ========================================Section End===========================================
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