The genetic material in our cells undergoes rearrangements during healthy, everyday processes. Yet sometimes a cell’s repair system malfunctions and it becomes unable to defend itself against errors in gene replication processes or chromosome breakage. With such genomic instability, vulnerability to cancer is increased. Dr. Alt’s lab is interested in understanding the interplay between these phenomena—in understanding both how healthy genomic rearrangements occur and what goes wrong when there is genomic instability. This research has significant implications for neuroscience in addition to genetics and immunology.

One famous example of genomic rearrangements in healthy cellular processes is the way diversity is generated in the immune system. Dr. Alt has made seminal discoveries in uncovering how immune cells are generated to recognize and respond to an infinite number of invaders. In a process called “VDJ recombination,” T cells and B cells randomly arrange different segments of variable (V), diversity (D) and joining (J) genes in order to produce a vast number of unique antigen receptors. Yet many fundamental questions about antigen receptor diversity remain unanswered, and Dr. Alt’s lab uses a mix of biochemical, molecular, genomic, computational and mouse modeling approaches to pursue these questions.

Recently the lab has designed high throughput methods to study double strand DNA breaks and chromosomal translocations and used these methods to learn about chromosomal rearrangements within the 3D genome of developing lymphocytes and cancer cells or their progenitors. The lab also has used their new approaches to identify a set of genes that recurrently break in neuronal stem and progenitor cells and, thereby, which may contribute to brain diversification and neuropsychiatric diseases, as well as cancer.