Journal
SCIENCE
Volume 324, Issue 5925, Pages 389-392Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1169050
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Funding
- National Human Genome Research Institute (NHGRI), NIH [R01 HG003541]
- Research Corporation for Science Advancement
- Intramural Research Program of the NHGRI, NIH
- National Academies Ford Foundation Dissertation Fellowship
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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.
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