DNA Tilts and Stretches Underlie Differences in Mutation Rates Across Genomes
Published:15 Nov.2023    Source:Baylor College of Medicine
Each cell in the body stores its genetic information in DNA in a stable and protected form that is readily accessible for the cell to carry on its activities. Nevertheless, mutations -- changes in genetic information -- occur throughout the human genome and can have powerful influences. Previous studies have shown that the DNA sequences flanking a mutated position -- the sequence context -- play a strong role in the mutation rate. "But this explanation still leaves unanswered questions," Samee said. "We think that a different mechanism could explain how mutation rates vary in the genome."
The genetic code is "written" as a string of bases that is furthermore underwound or overwound and constrained into loops, all of which is known to influence every aspect of DNA activity. Surprisingly, most genome analyses treat DNA merely as a string of bases and ignore the fact that each base has a shape. Surprisingly, the researchers found that although the sequence context may look very different from one mutation to another, the structural properties are remarkably similar. "We found that stretch -- the distance between paired building blocks in the two DNA strings forming the double helix -- is one of the top structural properties that defines whether a location is mutable," Liu said. DNA tilt was the second structural feature that most influenced mutation rate of all types. Researchers confirmed that DNA shape is important in functionally relevant regions of the human genome.
This study supports considering DNA shape when studying mechanisms of mutation rate variations in the human genome. "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.