Researchers Discover Hidden DNA Mechanisms of Rare Genetic Diseases

Rare Daily Staff

Researchers said they have made a groundbreaking discovery that could significantly advance the understanding of genomic disorders by showing how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases.

Researchers at the Pacific Northwest Research Institute and collaborating institutions reported their findings in the journal Cell Genomics.

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). The study shows how these complex rearrangements form and their impact on human health.

“This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases,” said Cláudia Carvalho, PNRI assistant investigator, who led the research. “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.”

The researchers analyzed 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.

The study found that these inverted triplications generate a variety of structural variations in the genome, which can lead to different health outcomes. They can also alter the number of copies of certain genes, which can affect development and function.

Researchers at Baylor College of Medicine, who participated in the study, first observed this pathogenic genomic structure in 2011 while studying MECP2 duplication syndrome. The advent of long-read sequencing technology has made it possible to now investigate in detail how it forms in the genome.

“By unraveling these complex DNA structures,” said Carvalho, “we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes.”