TULLIUS Group results published in Science

Tom Tullius
Professor Tom Tullius

TULLIUS Group reports in Science that evolutionary selection works on DNA shape

Professor Tom Tullius, his graduate student, Steve Parker, and their collaborator at the National Institutes of Health, Dr. Elliott Margulies, have developed a new methodfor uncovering functional areas of the human genome by studying DNA’s three-dimensional structure — a topographical approach that extends the more familiar analysis of the sequence of the four-letter alphabet of the DNA bases and which will better explain the biology of the genome. Their study was reported in Science (see citation below).

Research Team: Tullius and Parker (Boston University) and Margulies (NIH)

By examining the shapes, grooves, turns, and bumps of the DNA that comprises the human genome, the team discovered that 12 percent of the human genome appears to be constrained by evolution. That is double the six percent detected by simply comparing the linear order of DNA nucleotides (A, T, G, and C, the familiar letters that make up the genome). The huge increase stems from finding some DNA sequences that differ in the order of nucleotides, but have very similar topographical shapes, and so may perform similar functions. The study shows that the topographically-informed constrained regions correlate with functional non-coding elements better than constrained regions identified by nucleotide sequence alone.

In their Science paper, the researchers also explored how small genetic changes, known as SNPs (Single Nucleotide Polymorphisms), could prompt structural changes that might lead to disease. In studying these mutations from a database of 734 non-coding SNPs associated with diseases such as cystic fibrosis, Alzheimer’s disease, and heart disease, they found that disease-associated SNPs produced larger changes in the shape of DNA than SNPs not associated with a disease.

The new research findings on evolutionary conservation of DNA structure stem from recent progress in analyzing the functional elements in a representative fraction of the human genome. That study, known as ENCODE (ENCyclopedia of DNA Elements), organized by the National Human Genome Research Institute (NHGRI), challenged the traditional view of the human genetic blueprint as a collection of independent genes. Instead, researchers found a complex network of genes, regulatory elements, and other DNA sequences that do not code for proteins. The study determined, for the first time, where many types of functional elements are located, how they are organized, and how the genome is pervasively made into RNA. The current research on genome structure and function is based on some of the ENCODE findings.

In addition to Tullius, Margulies, and Parker, the other authors of the Science paper are Loren Hansen, a BU graduate student in bioinformatics, and Hatice Ozel Abaan, a technician in Margulies’ laboratory.

  • “Local DNA Topography Correlates with Functional Noncoding Regions of the Human Genome,” Stephen C. J. Parker, Loren Hansen, Hatice Ozel Abaan,Thomas D. Tullius, Elliott H. Margulies. Originally published in Science Express on 12 March 2009.
    Science, 17 April 2009, Vol. 324. no. 5925, pp. 389 – 392, DOI: 10.1126/science.1169050
  • “There’s more to life than sequences: The shape of DNA can play a crucial role in genetics,” Philip Ball, Nature News, 12 March 2009.
  • “Shapely DNA: DNA conformations, often overshadowed by sequence studies, determine biological fuction,” Ivan Amato, C&EN, Volume 87, Number 20, May 18, 2009, 47-49.
    The new topographical approach reveals that DNA shape is constrained by evolution and enhances detection of functional regions in the human genome,” BU News Release, March 13, 2009
    Contact: Ronald Rosenberg, 617-358-1240, ronrosen@bu.edu
  • “Genomes Have Bumps: BU scientists find that shape is part of DNA’s code” by Chris Berdik, BU Today, March 25, 2009.

For further information about this work, please contact Tom Tullius at tullius@bu.edu
May 2009