Local DNA Topography Correlates with Functional Noncoding Regions of the Human Genome

• Published in: Science (American Association for the Advancement of Science) Vol. 324; no. 5925; pp. 389 - 392
• Main Authors: Parker, Stephen C. J., Hansen, Loren, Abaan, Hatice Ozel, Tullius, Thomas D., Margulies, Elliott H.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 17-04-2009; The American Association for the Advancement of Science
• Subjects: Algorithms; Amino Acid Motifs; Base Sequence; Binding Sites; Biological and medical sciences; Conserved Sequence; Deoxyribonuclease I - metabolism; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - genetics; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Evolution; Evolution, Molecular; Fundamental and applied biological sciences. Psychology; Genetic mutation; Genome, Human; Genomes; Genomics; Human genome; Humans; Molecular structure; Mutant Proteins - metabolism; Nucleic Acid Conformation; Nucleotide sequences; Nucleotides; Phenotype; Polymorphism, Single Nucleotide; Selection, Genetic; Molecular form; Three dimensional structure; Interspecific comparison; DNA; Biological evolution; Genome; Hypothesis; Natural selection
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1169050

The three-dimensional molecular structure of DNA, specifically the shape of the backbone and grooves of genomic DNA, can be dramatically affected by nucleotide changes, which can cause differences in protein-binding affinity and phenotype. We developed an algorithm to measure constraint on the basis of similarity of DNA topography among multiple species, using hydroxyl radical cleavage patterns to interrogate the solvent-accessible surface area of DNA. This algorithm found that 12% of bases in the human genome are evolutionarily constrained--double the number detected by nucleotide sequence-based algorithms. Topography-informed constrained regions correlated with functional noncoding elements, including enhancers, better than did regions identified solely on the basis of nucleotide sequence. These results support the idea that the molecular shape of DNA is under selection and can identify evolutionary history.