A monumental genetic investigation, encompassing the genomic data of over 900,000 individuals, has illuminated the dynamic nature of specific DNA segments that exhibit increasing instability with the passage of time. These particular genomic regions are characterized by short sequences that are reiterated multiple times, and the study’s findings indicate a tendency for these repetitions to lengthen as individuals advance in age. Furthermore, the research uncovered compelling evidence that common, heritable variations in our genetic makeup can exert a profound influence on the pace of this expansion, potentially accelerating or decelerating the process by as much as a fourfold margin. In certain instances, the observed elongation of these DNA repeats has been correlated with the manifestation of significant health conditions, including but not limited to renal failure and hepatic disease.
The phenomenon of expanded DNA repeats serves as the underlying cause for more than sixty distinct inherited disorders. These complex conditions arise when specific genetic sequences, which are normally present in a particular repeating pattern, extend beyond their established normal lengths. This abnormal elongation can disrupt the intricate mechanisms of healthy cellular function, leading to disease. Prominent examples of such disorders include Huntington’s disease, a neurodegenerative condition; myotonic dystrophy, which affects muscle function; and certain forms of amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease.
While it has been understood that most individuals possess DNA repeats that undergo a gradual expansion throughout their lifespan, comprehensive investigations into the pervasiveness of this inherent instability and the specific genes that govern this process, particularly utilizing large-scale biobank datasets, had been limited. This recent research demonstrably reveals that repeat expansion is a considerably more widespread occurrence than previously acknowledged. Moreover, it pinpoints dozens of genes that play a crucial role in regulating this intricate biological process, thereby forging novel avenues for the development of therapeutic interventions aimed at mitigating disease progression.
The ambitious research initiative, a collaborative effort involving scientists from prestigious institutions such as UCLA, the Broad Institute, and Harvard Medical School, meticulously analyzed whole genome sequencing data derived from an impressive cohort of 490,416 participants enrolled in the UK Biobank and an additional 414,830 participants from the All of Us Research Program. To facilitate this extensive analysis, the research team innovatively developed sophisticated computational methodologies. These new tools were specifically engineered to accurately measure both the length of DNA repeats and their inherent instability, leveraging standard sequencing data that is widely available.
Employing these advanced analytical instruments, the researchers meticulously examined 356,131 distinct sites within the human genome known to harbor variable repeats. Their investigation focused on tracking the alterations in repeat lengths over time, specifically within blood cells, and critically, they identified inherited genetic variants that exerted an influence on the rate at which this expansion occurred. Beyond characterizing the expansion process itself, the scientists also undertook a systematic search for correlations between the observed repeat expansions and thousands of different disease outcomes, with the ultimate goal of uncovering previously unrecognized connections to human illnesses.
A significant finding from the study is the consistent observation that common DNA repeats within blood cells undergo expansion as individuals age. The research team identified a notable 29 regions within the genome where inherited genetic variants demonstrably modulated the rates of repeat expansion. The magnitude of these differences was substantial, with variations reaching up to fourfold between individuals who possessed the highest genetic risk scores for expansion and those with the lowest.
One particularly surprising revelation from the study was the observation that the same genes responsible for DNA repair did not exhibit uniform behavior across all repeat regions. Specifically, genetic variants that contributed to the stabilization of certain repeats were found to simultaneously increase the instability of other, different repeats. Furthermore, the researchers identified a newly recognized disorder associated with repeat expansion, involving the GLS gene. Expansions within this particular gene, which occur in approximately 0.03% of the population, were found to be linked to a striking 14-fold increase in the risk of severe kidney disease and a threefold increase in the risk of developing liver diseases.
These groundbreaking results suggest that the measurement of DNA repeat expansion within blood samples could potentially serve as a valuable biomarker. This biomarker could be instrumental in evaluating the efficacy of future therapeutic strategies designed to decelerate the growth of these repeats in the context of diseases such as Huntington’s. The sophisticated computational tools developed during this study are now poised to be deployed across other large biobank datasets, facilitating the identification of additional unstable DNA repeats and their associated disease risks.
The researchers emphasize that further in-depth mechanistic studies will be essential to fully elucidate why the same genetic modifiers can elicit opposing effects on different repeat sequences. These future research endeavors will concentrate on unraveling the complexities of how DNA repair processes vary across different cell types and within diverse genetic contexts. The newly discovered association between GLS repeat expansion and kidney and liver diseases also strongly implies that other, as-yet-unrecognized repeat expansion disorders may currently lie hidden within existing genetic data.
Dr. Margaux L. A. Hujoel, the lead author of the study and an assistant professor in the Departments of Human Genetics and Computational Medicine at the David Geffen School of Medicine at UCLA, commented on the significance of the findings. "We discovered that the majority of human genomes harbor repeat elements that demonstrably expand as we age," Dr. Hujoel stated. "The substantial genetic control observed over this expansion, with certain individuals’ repeats growing up to four times faster than others, points towards promising opportunities for therapeutic intervention. These naturally occurring genetic modifiers provide crucial insights into the molecular pathways that could be targeted to effectively slow down repeat expansion in the context of disease."
The research team comprised 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), and Po-Ru Loh (Brigham and Women’s Hospital/Harvard Medical School and Broad Institute). Funding for this research was provided by several sources, including US NIH fellowship F32 HL160061 for M.L.A.H.; US NIH grant R01 HG006855 for R.E.H. and S.A.M.; US NIH training grants T32 HG002295 for D.T. and N.K., with N.K. also receiving fellowship F31 DE034283; US NIH grant K25 HL150334 for R.E.M.; a Swiss National Science Foundation Postdoc. Mobility fellowship for S.R.; ERC Starting Grant no. 850869 for P.F.P.; and US NIH grants R56 HG012698, R01 HG013110, and UM1 DA058230, along with a Burroughs Wellcome Fund Career Award, for P.-R.L. The All of Us Research Program is supported by the National Institutes of Health (NIH). The authors have declared no competing interests related to this study.
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