Genetic diversity is created by mutations in the genome of all living organisms. When combined with natural selection, this diversity underpins evolution and adaptation to the environment. The Laboratory of Mechanisms of Genetic Diversity aims to understand systems in which mutations are actively generated and fixed in particular regions of the genome of a cell.

In particular, we are studying immunoglobulin (Ig) gene diversification, a set of processes that allow the affinity maturation of antibodies that is important for immunological memory and change the isotype of the antibodies from IgM to IgG, IgE or IgA that confers new biological properties. We are focusing in the interplay between the initiating enzyme Activation Induced Deaminase (AID), a mutator that converts deoxycytidine into deoxyuridine by enzymatic deamination acting specifically in the variable regions of the Ig genes, and the repair pathways that normally remove uracil from DNA. Of major importance and central to our research is the enzyme uracil-DNA glycosylase UNG, required for many of the mutagenic outcomes of Ig diversification despite being usually an antimutagenic enzyme.

A combination of genetic, molecular and biochemical techniques are applied to study Ig diversification in cellular systems as well as whole organisms. We use especially the DT40 chicken B cell line, with powerful genetics thanks to its high efficiency for gene targeting by homologous recombination, and we are developing genetically engineered mice to study these enzymes in vivo.

We want to understand how the action of AID is regulated and coordinated with UNG in order to favour mutation over repair. By understanding the mechanistic details of the process and identifying new factors involved we could understand the molecular basis of human diseases resulting from the inaccurate action of, or deficiency in, AID and UNG like immunodeficiency syndromes and B cell lymphomas.