The broad focus of the Alt lab is the elucidation of mechanisms that generate antigen receptor diversity in the Immune system and mechanisms that contribute to genomic instability in mammalian cells. Over the past decade, the lab developed sensitive high throughput approaches to elucidate translocations and DNA breaks genome-wide at nucleotide resolution and help move studies of chromosomal translocations, deletions, and amplifications into the post-genomics era. More recently, the lab further advanced these methods to develop powerful V(D)J recombination and IgH class switch recombination assays that were applied to generate a much more in depth understanding of mechanistic aspects of these processes.  The lab also developed powerful chromatin interaction assay facilitated studies that generated new insights into the role of topological chromatin domains and chromosomal loop domains in influencing DSB generation and joining during V(D)J recombination and IgH class switch recombination. The Alt lab further exploited their discoveries in these basic research areas to generate powerful new mouse models to test vaccination strategies for generating human HIV-1 broadly neutralizing antibodies. They recently further advanced their high throughput V(D)J recombination assays to develop a highly sensitive antibody somatic hypermutation/affinity maturation assay that can determine antibody repertoires and somatic hypermutation in germinal center B cells, including those in intestinal Peyer’s Patches. vFinally, they have extended their new approaches to discover genes that recurrently break in neuronal stem and progenitor cells, potentially providing new insights into mechanisms of cellular diversity in the brain and mechanisms that could contribute various neuropsychiatric diseases and brain cancer.   Alt has trained well over 100 graduate students and postdoctoral fellows. Most have gone on to very productive independent careers in academic research or industry, with a large portion being tenured professors and many holding leadership positions. Dr. Alt received the American Association of Immunologist Excellence in Mentoring Award and the Harvard Medical School William Silen Award for lifetime achievement in Mentoring.