The Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a groundbreaking discovery that DNA rearrangements known as inverted triplications play a crucial role in the development of various genetic disorders. Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions, leading to a range of health issues. This study delves into the complex nature of DNA mutations involving duplication-triplication/inversion-duplication structures and their impact on human health.
Lead by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., the research team collaborated with colleagues from Baylor College of Medicine to analyze the DNA of 24 individuals with inverted triplications. They found that these rearrangements are caused by segments of DNA switching templates during the repair process. This switch occurs within pairs of inverted repeats, confusing the repair machinery and leading to the use of the wrong template, disrupting normal gene function, and contributing to genetic disorders.
The study found that inverted triplications generate a variety of structural variations in the genome, leading to different health outcomes. These rearrangements can alter the number of copies of certain genes, known as gene dosage, which is crucial for normal human development and function. Changes in gene dosage can result in diseases like MECP2 duplication syndrome, a rare neurodevelopmental disorder. By mapping breakpoints using advanced DNA sequencing techniques, the researchers identified the precise locations where these DNA segments switch templates, resulting in altered gene numbers, including MECP2.
Dr. Carvalho and Baylor scientists first observed the pathogenic genomic structure in 2011 while studying MECP2 duplication syndrome. With the advancement of long-read sequencing technology it has become possible to investigate in detail how these structures form in the genome. This study sheds light on the intricate mechanisms behind genetic rearrangements and their impact on rare diseases, opening new avenues for understanding the genetic causes of rare disorders 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. The insights gained from the study have far-reaching implications for rare disease research and treatment, providing a deeper understanding of how DNA rearrangements contribute to the development of genetic disorders and offering potential avenues for targeted therapies to improve patient outcomes.