Abstract: Tiny stretches of repeated DNA known as tandem repeats are far more dynamic than once believed. By analyzing whole-genome sequencing data from over 900,000 participants in the UK Biobank and the All of Us Research Program, researchers uncovered how these repeats expand and contract across a human lifetime. Some repeats showed striking instability in blood as people age, even among healthy individuals, highlighting that most human genomes carry elements that continue mutating long after birth. Importantly, this instability varied widely by genomic location and tissue type, revealing a complex and highly regulated process rather than random genetic noise.
The study also identified 29 genetic loci, many linked to DNA repair pathways, that strongly influence how quickly certain repeats expand. At some sites, individuals with different genetic backgrounds showed up to a four-fold difference in expansion rates. Notably, expansions in a repeat within the GLS gene were associated with significantly higher risks of advanced kidney and liver disease, suggesting previously unrecognized genetic risk mechanisms. Together, these findings show how large-scale biobank sequencing can uncover hidden layers of genetic variation opening new possibilities for biomarkers, disease risk prediction, and future therapies aimed at slowing harmful DNA repeat expansion.
Click here to read more about this study: https://www.nature.com/articles/s41586-025-09886-z
