David G. Schatz, Waldemar Von Zedtwitz Professor of Immunobiology, Professor of Molecular Biophysics and Biochemistry, Chair of Immunobiology, Yale University, will give a talk on "Transposon Molecular Domestication and Evolution of the Adaptive Immune System."

ABSTRACT

Jawed vertebrates have evolved a sophisticated adaptive immune system that relies on assembly of immunoglobulin and T-cell receptor genes by a reaction known as V(D)J recombination.  V(D)J recombination is initiated by the RAG1/RAG2 endonuclease (RAG), proteins that I helped the discovery in the late 1980s.  Ever since then, I have been interested in understanding the evolutionary origins of RAG and of disassembled ("split") antigen receptor genes.  About 20 years ago, we and others discovered that RAG has transposase activity, and it is now believed that RAG1 and RAG2 evolved from the transposase genes of an ancient "RAG transposon".  Furthermore, the ancestral split antigen receptor gene is thought to have been generated when the RAG transposon inserted into a receptor gene.  This theory raises the question:  how did a transposase evolve to become the vital recombinase for adaptive immunity? Using x-ray crystallography and cryo-electron microscopy, we have determined the structures of two of RAG’s evolutionary relatives.  I will discuss how we have used these structures to identify the jawed-vertebrate-specific evolutionary adaptations that potently suppress RAG-mediated transposition, regulate DNA cleavage, and protect the lymphocyte genome.  In addition, I will discuss our growing understanding of the collaboration between RAG1 and RAG2, the forces at work during the evolution of V(D)J recombination, and the mechanisms by which transposases function and evolve.