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. Why do mutation rates in the genome vary so tremendously from one DNA location to another? 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. “For example, one type of mutation occurs frequently in a specific sequence context while a different type of mutation occurs infrequently in that same sequence context.” 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. The team 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.

 

DNA tilt was the second structural feature that most influenced mutation rate of all types. We confirmed that DNA shape is important in functionally relevant regions of the human genome, such as protein-DNA binding sites that regulate gene expression, and that this structural mechanism is conserved across many species. The DNA-shape models of mutation rates developed by Liu and Samee showed similar or improved performance when compared to sequence-based models and accurately characterized mutation hotspots. This study supports considering DNA shape when studying mechanisms of mutation rate variations in the human genome.