Researchers Devise New Way to Explore DNA
New Topographical Approach Improves Detection of Functional Regions in the Human Genome
A team that includes researchers from the National Institutes
of Health (NIH) has found a new way of detecting functional regions
in the human genome. The novel approach involves looking at the
three-dimensional shape of the genome’s DNA and not just reading the sequence of
the four-letter alphabet of its DNA bases.
In a paper published in the early online edition of Science, a team led by Elliott
Margulies, Ph.D., of the National Human Genome Research Institute
(NHGRI), and Thomas Tullius, Ph.D., of Boston University, described
an innovative approach for detecting functional genomic regions.
By combining chemical and computer analyses, the researchers are
able to survey the landscape, or topography, of DNA structure for
areas likely to play a key role in biological function.
The method involves identifying all of the grooves, bumps and turns of the DNA
that make up the human genome and then comparing those structural
features to those seen in the genomes of other animal species.
Structural features that have been preserved across many species
are likely to play important roles in how the human body functions,
while those that have changed over the course of evolution may
play a less central role or no role at all.
"This new approach is an exciting advance that will speed our efforts to identify
functional elements in the genome, which is one of the major challenges facing
genomic researchers today," said NHGRI Scientific Director Eric Green, M.D.,
Ph.D. "Coupled with continued innovations in DNA sequencing, this topography-informed
approach will expand our ongoing efforts to use genomic information to improve
human health."
The sequence of the 3 billion DNA base pairs that make up the human genome holds
the answers to many questions pertaining to human development, health and disease.
Consequently, much research aimed at understanding the genome has focused on
establishing the information encoded by the linear order of DNA bases. In the
new study, however, researchers focused on how those bases chemically interact
with each other to coil and fold the DNA molecule into a variety of shapes.
"We often think of DNA as a string of letters on a computer screen and forget
that this string of letters is a three-dimensional molecule. But shape really
matters," said Dr. Margulies, who is an investigator in NHGRI’s Genomic Technology
Branch. "Proteins that influence biological function by binding to DNA recognize
more than just the sequence of bases. These binding proteins also see the surface
of the DNA molecule and are looking for a shape that allows a lock-and-key fit."
In 2003, an international team of researchers finished a reference sequence of
the human genome, an achievement that greatly sped efforts to find genes, which
reflect the approximately 2 percent of the genome that codes for proteins. At
one time, the remaining 98 percent of the genome was referred to as junk DNA.
Researchers now know that this non-coding DNA contains elements that carry out
important biological functions, such as turning genes off or on. However, little
information exists about where these non-coding functional elements are located
and how they work.
The new approach to identifying functional elements in non-coding DNA builds
upon the individual efforts of Dr. Tullius, a chemistry professor who has spent
more than 20 years developing methods to examine the 3-D structure of DNA, and
of Dr. Margulies, a molecular biologist who uses computer methods to compare
the genomes of different species.
"We brought together two diverse fields to think about this problem in a new
way," said Dr. Margulies. "It took the combined expertise of a DNA chemist and
computational biologist to figure out that this chemical technique could advance
our understanding of comparative genomics."
"By considering the three-dimensional structure of DNA, you can better explain
the biology of the genome,” said Dr. Tullius. “For this achievement, Stephen
Parker, a Boston University graduate student, deserves much of the credit for
his development of the algorithm that incorporated DNA structure into evolutionary
analysis."
In their Science paper, the researchers compared the topography of the human
genome with that of 36 other mammalian species, including mouse, rabbit, elephant
and chimpanzee. Using this topographic approach, they found that about 12 percent
of the non-coding DNA in the human genome appears to be functionally important — twice
the amount detected using methods that simply compared DNA sequences.
What accounts for the difference? Researchers say DNA sequence is not always
a good indicator of function. They found that very similar DNA sequences may
assume very different topographical shapes, which can have a major impact on
their function or lack of function. On the other hand, different DNA sequences
may assume very similar topographical shapes and perform very similar functions.
So, in many instances, DNA structure may be a better predictor of function than
DNA sequence.
The researchers went on to mine data organized by the PhenCode Project to see
whether one-base variations in DNA sequence, called single-nucleotide polymorphisms
(SNPs), in non-coding regions can cause structural changes that might lead to
disease. Specifically, they conducted a topographic survey of 734 non-coding
SNPs known to be associated with signs and symptoms of disease. The non-coding
SNPs associated with disease tended to produce larger changes in the shape of
DNA than a set of SNPs not linked to disease.
The entire study made extensive use of data sets generated by the NHGRI-funded
ENCyclopedia of DNA Elements (ENCODE) project, which is a multi-institution effort
to compile a parts list of the biologically functional elements in the human
genome. In addition, some of Dr. Tullius’s work in developing the new technology
was funded through the ENCODE project.
For an artist's depiction of DNA packaging and topography, go to http://www.genome.gov/pressDisplay.cfm?photoID=20150.
NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department
of Health and Human Services. The NHGRI Division of Intramural Research develops
and implements technology to understand, diagnose and treat genomic and genetic
diseases. Additional information about NHGRI can be found at its Web site, www.genome.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov. |