PNRI's Landmark Study Reveals DNA Rearrangement's Role in
Genetic Disorders, Paving Way for New Treatments
SEATTLE, June 21, 2024 /PRNewswire/ -- 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
Health1 and published in 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 examines 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 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—mirror-image DNA sections that confuse the repair
machinery. This can lead to using the wrong template, disrupting
gene function and contributing to genetic disorders.
- Structural Diversity: The study found that inverted
triplications generate a surprising variety of structural
variations in the genome, which can lead to different health
outcomes.
- Gene Dosage Impact: These rearrangements can alter the
number of copies of certain genes, known as gene dosage. The
correct number of gene copies is crucial for normal human
development and function. Changes in gene dosage can cause diseases
like MECP2 duplication syndrome, a rare
neurodevelopmental disorder.
- Mapping Breakpoints: By using advanced DNA sequencing
techniques, the researchers identified the precise locations where
these DNA segments switch templates leading to an altered number of
genes including MECP2.
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 Medical 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."
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.
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.
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SOURCE Pacific Northwest Research Institute