Seattle, WA — June 21, 2024 — Researchers at the Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a groundbreaking discovery that could significantly advance our understanding of genomic disorders. Their latest study, funded by the National Institutes of Health [1] and published in the journal Cell Genomics , reveals how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases.
Understanding the Study
Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study delves into how these complex rearrangements form and their impact on human health.
Key Findings
The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D. , collaborated with her lab colleagues, study lead author Christopher Grochowski, Ph.D. , from the James R. Lupski Lab at Baylor College of Medicine , and other scientists to analyze the DNA of 24 individuals with inverted triplications.
They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome.
These switches occur within pairs of inverted repeats—sections of DNA that are mirror images of each other. Inverted repeats can confuse the repair machinery, leading to the use of the wrong template, which can disrupt normal gene function and contribute to genetic disorders.
Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2 duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome.
Implications for Rare Disease Research and Treatment
"This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases," said Dr. Cláudia Carvalho, PNRI’s lead scientist on the study. "By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes."
These findings are being applied in a follow-up study led by Baylor's Davut Pehlivan, M.D. , investigating how complex genomic structures influence the clinical features of MECP2 duplication syndrome and their impact on targeted therapeutic approaches.
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About PNRI:
Pacific Northwest Research Institute (PNRI) is a nonprofit biomedical research institute, where scientists are using innovative approaches in genetics and genomics to tackle some of the most difficult problems in science and medicine. The institute was founded 67 years ago in Seattle, Washington, as a place where scientists were free to pursue discoveries that promised the highest chance of improving human health. The goal was at the beginning, and remains today, to conduct foundational science leading to impactful medical innovations. To learn more, visit pnri.org .
Media contact:
Louise Maxwell
lmaxwell@pnri.org
206-568-1479
[1] Research reported in this press release was supported in part by National Institute of General Medical Sciences of the National Institutes of Health under award number R01132589.
Cell Genomics
Experimental study
Human tissue samples
Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci
21-Jun-2024