There is a genetic feature known as a repeat expansion, in which short sequences are repeated continuously. Some of them naturally get longer as we age, but there are also over 60 diseases that can be caused by changes or abnormalities in these repeat expansions. Some repeat expansions also gradually become more unstable and get longer as people age. A new study has analyzed genetic data from almost one million people and found that there are genetic variants that can accelerate the rate of change in repeat expansions. Some of these expanded sequences have also been associated with diseases such as kidney failure and liver disease.
This work, which was reported in Nature, has shown that repeat expansions are much more common that we knew, and that there are dozens of genes that can influence this process. In this study, the researchers used novel computational tools to find and measure repeat expansions, and the instability they cause, using data from standard sequencing methods. Data from 490,416 volunteers in the UK Biobank and 414,830 volunteers in the All of Us Research Program was included, to analyze over 356,000 locations in the genome where various repeat expansions occur; how their length changes over time; and genetic variants that can affect the rate of increasing expansion.
This study focused on genetic changes in blood cells, and showed that repeat expansions tend to get longer with age. The investigators found 29 variants that could modify DNA repeat expansion rates; some of these variants led to as much as a four-fold difference in carriers compared to people who did not carry those genetic variants.
"We found that most human genomes contain repeat elements that expand as we age," said first study author Margaux L. A. Hujoel, Ph.D., an assistant professor at UCLA.
There were also DNA repair genes that could have opposing effects on some repeats; variants that led to the stabilization of some repeats could have a destabilizing effect on others.
While there are known diseases that are caused by problems with repeat expansions, such as Huntington's disease, myotonic dystrophy, and some type of ALS, this study also looked for new disease links. It identified a new repeat expansion disorder in which certain expansions in a gene called GLS could increase the risk of some liver diseases.
This work can also provide new insights into novel biomarkers for repeat expansion disorders, and aid in the assessment of other biobank data.
"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," added Hujoel.
Sources: University of California, Los Angeles; Nature
