Evolution and function of the AID/APOBEC family of cytidine deaminases in lampreys

Emory University, Atlanta GA

Investigators

Abstract

The immune system of vertebrates uses antibodies to respond to infections. Lampreys are ancient vertebrates that make antibodies differently from mammals, such as humans. This project will analyze the function of a family of enzymes, called cytidine deaminases (CDAs) in generating a diverse repertoire of antibodies in lampreys. The work in lampreys will shed light on the function of human enzymes related to cytidine deaminases, of which little is known. Findings could lead to engineered lamprey antibodies for use in diagnosing and treating human diseases. Graduate and undergraduate students will be trained in modern immunological research methods, developing the next generation of science, technology, engineering and mathematics workforce. Outreach to the Tapestry Public Charter School for Autism Spectrum Disorder is designed to expose students to science and understanding of the natural world. This project will study the assembly and somatic diversification of antigen receptor genes termed Variable Lymphocyte Receptors (VLRs) that encode antibodies in jawless vertebrates. VLR assembly in lampreys is catalyzed by a multi-gene family of cytidine deaminases. In this research, researchers will use genomics to comprehensively characterize lamprey cytidine deaminases. They will examine the expression pattern of newly identified cytidine deaminase 1-like molecules - cytidine deaminase 3-5 and four new splice variants of cytidine deaminase 2 in lamprey tissues and test their function in heterologous systems and cell lines. A deeper understanding of the mechanism and function of different cytidine deaminases family members in lampreys will provide insight into the function of human homologs and advance understanding of the evolution of the adaptive immune systems in vertebrates. Knowledge gained through this research could enable engineering of higher-affinity lamprey VLR antibodies, which have important diagnostic and therapeutic potential in humans. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.