DNA Structure Holds Key to Varying Mutation Rates in Human Genome
Scientists at Baylor College of Medicine have discovered that the 3D structure of DNA plays a crucial role in determining varying mutation rates within the human genome. While previous research has focused on the DNA sequence context surrounding mutations, this study delves deeper into the shape of the DNA molecule itself.
Dr. Md. Abul Hassan Samee, assistant professor of integrative physiology at Baylor College of Medicine, explained that although the sequence context does influence mutation rates, there are still unanswered questions. By considering the structural properties of DNA, the team sought to uncover why mutation rates can differ significantly within the same sequence context.
The genetic code is a string of bases that can be underwound or overwound and constrained into loops, all of which impact DNA activity. However, traditional genome analyses tend to treat DNA merely as a string of bases, overlooking the distinct shape of each base.
The researchers built a statistical model that solely utilized DNA structural information, disregarding sequence data. By doing so, they were able to identify specific DNA shape features, such as stretches, twists, and tilts, that correlate with variations in mutation rates across the human genome. Surprisingly, they found that despite the different sequence contexts, the structural properties remained remarkably consistent.
One of the key structural properties that affects mutability is the stretch—the distance between paired building blocks in the DNA double helix. The second most influential structural feature was the tilt of the DNA. The team confirmed that DNA shape plays a crucial role in functionally important regions of the human genome, including protein-DNA binding sites that regulate gene expression. Furthermore, this structural mechanism appears to be conserved across various species.
The DNA-shape models developed by the researchers showcased comparable or improved performance when compared to sequence-based models. They accurately identified mutation hotspots and supported the notion that DNA shape should be considered in studying variations in mutation rates.
Dr. Lynn Zechiedrich, professor of molecular virology and microbiology at Baylor College of Medicine, emphasized the importance of understanding DNA’s 3D structure and the limitations of treating it as a mere linear sequence. DNA possesses a complex 3D structure that carries significant meaning, consistently explaining the variation of mutation rates and likely being conserved across species.
This study sheds light on the crucial role of DNA structure in understanding mutation rates within the human genome. By considering the shape of DNA along with its sequence context, researchers can gain deeper insights into the mechanisms governing genetic mutations. The findings highlight the need to extend genomic analysis beyond the linear sequence and explore the intricate 3D nature of the DNA molecule.
