Daza Martin Lab

The human genome contains regions rich in repetitive DNA, such as telomeres and centromeres, but repetitive sequences are also dispersed throughout the genome without an apparent function. These sequences must be precisely replicated, transcribed, and repaired when damaged. Studies have shown that repetitive sequences are particularly prone to breakage, can disrupt gene transcription and splicing, and are susceptible to expansion or contraction. These events lead to repeat-induced instability and fragility, which are hallmarks of repeat expansion disorders, a group of neurodegenerative hereditary diseases that includes Huntington’s Disease, Myotonic Dystrophy, and Fragile X Syndrome.

A major challenge in studying repetitive sequences has been the difficulty in accurately mapping novel repeat expansions within a disease-specific context using traditional genomic approaches. However, the advent of long-read sequencing technologies such as PacBio and Nanopore, alongside computational tools like GangSTR and Expansion Hunter, has dramatically improved the detection of novel repeat expansions. For the first time, short tandem repeats have been identified as expanded in a variety of human diseases. Despite these advancements, current studies primarily establish correlations between repeat expansions and disease but lack mechanistic insights into the molecular processes driving these expansions and how they might disrupt gene and cellular function.

Our research seeks to answer critical questions: What are the physiological consequences of repeat expansion? How do these expansions contribute to genomic instability? What cellular factors prevent repeat instability in vitro? How do repeat expansions modulate gene activity? By addressing these questions, we aim to uncover the underlying mechanisms of repeat instability and in the long-term its impact on disease.