A large scale genetic analysis of more than 900,000 people has revealed that specific regions of DNA become increasingly unstable over time. These regions are made up of very short sequences that repeat again and again, and the study shows that they tend to grow longer as people age. Researchers also found that common inherited genetic differences can strongly influence how quickly this expansion occurs, speeding it up or slowing it down by as much as fourfold. In some cases, expanded DNA repeats were linked to serious health conditions, including kidney failure and liver disease.
Expanded DNA repeats are responsible for more than 60 inherited disorders. These conditions develop when repeating genetic sequences lengthen beyond normal limits and interfere with healthy cell function. Examples include Huntington's disease, myotonic dystrophy, and certain forms of ALS.
Although most people carry DNA repeats that slowly expand throughout life, scientists had not previously examined how widespread this instability is or which genes control it using large biobank datasets. This research shows that repeat expansion is far more common than previously recognized. It also identifies dozens of genes involved in regulating the process, creating new opportunities to develop treatments that could slow disease progression.
How Researchers Studied Nearly a Million Genomes
The research team, which included scientists from UCLA, the Broad Institute, and Harvard Medical School, analyzed whole genome sequencing data from 490,416 participants in the UK Biobank and 414,830 participants in the All of Us Research Program. To carry out the analysis, they developed new computational approaches capable of measuring DNA repeat length and instability using standard sequencing data.
Using these tools, the team examined 356,131 variable repeat sites across the human genome. They tracked how repeat lengths changed with age in blood cells and identified inherited genetic variants that affected the speed of expansion. The researchers also searched for associations between repeat expansion and thousands of disease outcomes in order to uncover previously unknown links to human illness.
Key Findings on DNA Repeat Instability
The study found that common DNA repeats in blood cells consistently expand as people get older. Researchers identified 29 regions of the genome where inherited genetic variants altered repeat expansion rates, with differences of up to fourfold between individuals with the highest and lowest genetic risk scores.
One surprising result was that the
same DNA repair genes did not behave uniformly. Genetic variants that
helped stabilize some repeats made other repeats more unstable. The
researchers also identified a newly recognized repeat expansion disorder
involving the GLS gene. Expansions in this gene, which occur in about
0.03% of people, were linked to a 14-fold increase in the risk of severe
kidney disease and a 3-fold increase in the risk of liver diseases.
What the Findings Mean for Future Research
The results suggest that measuring DNA repeat expansion in blood could serve as a useful biomarker for evaluating future treatments designed to slow repeat growth in diseases such as Huntington's. The computational tools developed for this study can now be applied to other large biobank datasets to identify additional unstable DNA repeats and related disease risks.
Researchers note that further mechanistic studies will be needed to understand why the same genetic modifiers can have opposite effects on different repeats. These efforts will focus on how DNA repair processes differ across cell types and genetic contexts. The discovery of kidney and liver disease linked to GLS repeat expansion also suggests that additional, previously unrecognized repeat expansion disorders may be hidden within existing genetic data.
Expert Perspective on the Findings
"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."
Margaux L. A. Hujoel (UCLA and Brigham and Women's Hospital/Harvard Medical School), Robert E. Handsaker (Broad Institute and Harvard Medical School), David Tang (Brigham and Women's Hospital/Harvard Medical School), Nolan Kamitaki (Brigham and Women's Hospital/Harvard Medical School), Ronen E. Mukamel (Brigham and Women's Hospital/Harvard Medical School), Simone Rubinacci (Brigham and Women's Hospital/Harvard Medical School and Institute for Molecular Medicine Finland), Pier Francesco Palamara (University of Oxford), Steven A. McCarroll (Broad Institute and Harvard Medical School), Po-Ru Loh (Brigham and Women's Hospital/Harvard Medical School and Broad Institute).
What the Findings Mean for Future Research
The results suggest that measuring DNA repeat expansion in blood could serve as a useful biomarker for evaluating future treatments designed to slow repeat growth in diseases such as Huntington's. The computational tools developed for this study can now be applied to other large biobank datasets to identify additional unstable DNA repeats and related disease risks.
Researchers note that further mechanistic studies will be needed to understand why the same genetic modifiers can have opposite effects on different repeats. These efforts will focus on how DNA repair processes differ across cell types and genetic contexts. The discovery of kidney and liver disease linked to GLS repeat expansion also suggests that additional, previously unrecognized repeat expansion disorders may be hidden within existing genetic data.
Expert Perspective on the Findings
"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."
Margaux L. A. Hujoel (UCLA and Brigham and Women's Hospital/Harvard Medical School), Robert E. Handsaker (Broad Institute and Harvard Medical School), David Tang (Brigham and Women's Hospital/Harvard Medical School), Nolan Kamitaki (Brigham and Women's Hospital/Harvard Medical School), Ronen E. Mukamel (Brigham and Women's Hospital/Harvard Medical School), Simone Rubinacci (Brigham and Women's Hospital/Harvard Medical School and Institute for Molecular Medicine Finland), Pier Francesco Palamara (University of Oxford), Steven A. McCarroll (Broad Institute and Harvard Medical School), Po-Ru Loh (Brigham and Women's Hospital/Harvard Medical School and Broad Institute)
Story Source:
Materials provided by University of California - Los Angeles Health Sciences. Note: Content may be edited for style and length.
