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  • DNA Shape Plays a Pivotal Role in Mutation Rates Across Genomes

    New research conducted at Baylor College of Medicine has illuminated previously unexplored aspects of DNA's three-dimensional shape and its influence on mutation rates within genomes. This groundbreaking study, led by Dr. Md. Abul Hassan Samee, assistant professor of integrative physiology, offers insights into the underlying mechanisms that cause mutations, crucial for understanding both human health and evolution.

    While mutations, or changes in genetic information, have a powerful impact on human health, the reasons for variations in mutation rates at different DNA locations have remained largely elusive. Although previous studies have identified the sequence context around a mutated position as significant, this explanation has been incomplete.

    The research team at Baylor sought to understand these variations by examining the role of DNA's 3D chemical shape. The genetic code is traditionally viewed as a linear sequence of bases, but this view overlooks the complexity of the DNA's physical form, including its underwound or overwound structure and constrained loops.

    "We built a statistical model using only DNA structural information, otherwise ignoring the sequence data,” said first author Zian Liu, a graduate student in the Samee lab. “We used the model to pinpoint which DNA shape features, such as stretches, twists or tilts, underlie variations of mutation rates in the human genome. Surprisingly, we found that although the sequence context may look very different from one mutation to another, the structural properties are remarkably similar.”

    Remarkably, the study revealed that the "stretch"—the distance between paired building blocks in the DNA's double helix—plays a crucial role in determining mutation rates. The researchers discovered that this stretch feature, along with DNA tilt, most influenced mutation rates, regardless of the mutation type.

    This novel insight not only challenges the conventional linear view of DNA but also suggests that DNA shape is significant in functionally relevant regions of the human genome, such as protein-DNA binding sites. Additionally, this structural mechanism appears to be conserved across various species.

    The DNA-shape models developed showed similar or improved performance when compared to sequence-based models. This study supports considering DNA shape when studying mechanisms of mutation rate variations.

    “For the last 20 years, the human genome has been seen as a linear sequence of building blocks. But studies like ours and others show that DNA is much more than that; it has a 3D structure that carries important meaning,” Samee said. “A meaning that is very consistent when it comes to explaining the variation of mutation rates and is likely conserved among species.”

    The implications of this research are far-reaching, potentially leading to improved genomic analysis tools and further understanding of genetic diseases and evolution. By recognizing the structural properties of DNA, the scientific community is poised to enhance the comprehension of the genomic forces that shape human life.

    The full details of the study are available in the journal Nucleic Acids Research.

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