Genetic study reveals how DNA repeats expand with age

An analysis of genetic data from over 900,000 people shows that certain stretches of DNA, made up of short sequences repeated over and over, become longer and more unstable as we age. The study found that common genetic variants can speed up or slow down this process by up to fourfold, and that certain expanded sequences are linked to serious diseases including kidney failure and liver disease.

Why it matters

More than 60 inherited disorders are caused by expanded DNA repeats: repetitive genetic sequences that grow longer over time. These include devastating conditions like Huntington's disease, myotonic dystrophy, and certain forms of ALS. Most people carry DNA repeats that gradually expand throughout their lives, but this instability and what genetic factors control it hadn't been fully analyzed within large biobanks. This study demonstrates that DNA repeat expansion is far more widespread than previously recognized and identifies dozens of genes that regulate this process, opening new avenues for developing treatments that could slow disease progression.

What the study did

Researchers from UCLA, the Broad Institute, and Harvard Medical School analyzed whole-genome sequencing data from 490,416 UK Biobank participants and 414,830 All of Us Research Program participants. They developed new computational methods to detect and measure DNA repeat lengths and instability from standard sequencing data. The team examined 356,131 polymorphic repeat locations across the genome, tracking how repeat lengths changed with age in blood cells and identifying genetic variants that influenced expansion rates. They also searched for links between repeat expansions and thousands of disease outcomes to discover previously unknown disease associations.

What they found

Common DNA repeats in blood cells expand as people age. The researchers identified 29 genetic locations where inherited variants modified DNA repeat expansion rates, with effects varying up to fourfold between individuals with the highest and lowest genetic risk scores. Interestingly, the same DNA repair genes had opposite effects on different repeats: variants that stabilized some repeats destabilized others. The study also discovered that expansions in the GLS gene which have a prevalence around 0.03% were associated with 14-fold higher risk of severe kidney disease and 3-fold higher risk of liver diseases, representing a newly recognized repeat expansion disorder.

What's next

The findings establish blood-based DNA repeat measurements as potential biomarkers for testing future therapies aimed at slowing repeat expansion in diseases like Huntington's. The research team's computational tools can now be applied to other large biobank datasets to discover additional unstable repeats and disease associations. Understanding why the same genetic modifiers have opposite effects on different repeats will require detailed mechanistic studies of how DNA repair processes vary across cell types and genetic contexts. The discovery of GLS repeat-associated kidney and liver disease suggests additional unrecognized repeat expansion disorders may be lurking in biobank data, waiting to be found.

From the experts

"We found that most human genomes contain repeat elements that expand as we age," said Margaux L. A. Hujoel, PhD, lead author of the study and assistant professor in the Departments of Human Genetics and Computational Medicine at the David Geffen School of Medicine at UCLA. "The strong genetic control of this expansion, with some individuals' repeats expanding four times faster than others, points to opportunities for therapeutic intervention. These naturally occurring genetic modifiers show us which molecular pathways could be targeted to slow repeat expansion in disease."