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 and published in the journal Cellular genomicsreveals 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 alter normal biological functions. These can lead to a variety of health problems, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study delves into how these complex rearrangements are formed and their impact on human health.
Key results
The research team, led by PNRI assistant researcher Cláudia Carvalho, Ph.D., collaborated with their laboratory colleagues, the study’s lead author Christopher Grochowski, Ph.D., of the James R. Lupski Laboratory from Baylor College of Medicine, and other scientists. analyze the DNA of 24 individuals with reverse triplications.
They found that these rearrangements are caused by DNA template segments that change during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to precisely repair damaged DNA. However, sometimes during repair, the repair machinery can inadvertently switch to a different but similar sequence elsewhere in the genome.
These changes 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 an incorrect template, which can disrupt normal gene function and contribute to genetic disorders.
- Structural diversity: The study found that these inverted triplications generate a surprising variety of structural variations in the genome, which can lead to different health outcomes.
- Impact of gene dosage: 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 such as MECP2 Duplication syndrome, a rare neurodevelopmental disorder.
- Breakpoint Mapping: Using advanced DNA sequencing techniques, researchers identified the precise locations where these DNA segments change templates, leading to an altered number of genes, including MECP2.
Dr. Carvalho and Baylor’s scientists first observed this pathogenic genomic structure in 2011 while studying MECP2duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it been possible to investigate in detail how it forms in the genome.
Implications for research and treatment of rare diseases
“This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases,” said Dr. Cláudia Carvalho, lead scientist on the PNRI 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 Davut Pehlivan, MD, of Baylor, investigating how complex genomic structures influence the clinical characteristics of MECP2 Duplication syndrome and its impact on specific therapeutic approaches.