Researchers develop a structural approach to exploring DNA

Mar 12, 2009
The many topographical levels of a chromosome. Genomic DNA is shown streaming out from a chromosome (left), progressively unfolding as chromatin, the 30-nm filament, nucleosomes, the DNA double helix, and finally the letters representing the nucleotide sequence. Although it is the molecular topography of the DNA helix that is recognized by proteins, current methods of genome analysis mostly focus on the order of nucleotides. Credit: NHGRI

A team led by researchers from Boston University and the National Institutes of Health has developed a new method for 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.

Unlike the well-understood genomic sequences that code for proteins and comprise about two percent of the , the remaining 98 percent is the non-coding portion, which encodes many functions. However, little is known about how this functional non-coding information is specified.

In a study which appears today in the online edition of Science, the researchers focused on examining the non-coding regions of the genome for areas that are likely to play a key role in human biological function.

To do this, the researchers developed a method which incorporates information about the structure of DNA to compare sequences of genomes from humans and 36 mammalian species that included the mouse, chimpanzee, elephant and rabbit.

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's double the six percent detected by simply comparing the linear order of (A, T, G, and C, the familiar letters that make up the genome). The huge increase stems from finding some that differ in the order of nucleotides, but have very similar topographical shapes, and so may perform similar functions.

They went on to show that the topographically-informed constrained regions correlate with functional non-coding elements better than constrained regions identified by alone.

"By considering the three-dimensional structure of DNA, you can better explain the biology of the genome," said Thomas D. Tullius, professor of chemistry who has spent more than 20 years developing ways to map the structure of the human genome. "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."

Bringing a molecular biologist's point of view and expertise in comparing the genomes of different species was Elliott Margulies, an investigator at NHGRI's Genomic Technology Branch. "Proteins that influence biological function by binding to DNA recognize more than just the sequence of bases," he said. "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 their Science paper the researchers also explored how small genetic changes, or variations, 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, noted Tullius, whose work in developing the new technology was funded through the ENCODE project.

Source: Boston University

Explore further: Two-armed control of ATR, a master regulator of the DNA damage checkpoint

add to favorites email to friend print save as pdf

Related Stories

One man's junk may be a genomic treasure

Jul 12, 2007

Scientists have only recently begun to speculate that what’s referred to as “junk” DNA – the 96 percent of the human genome that doesn’t encode for proteins and previously seemed to have no useful purpose – is ...

More 'functional' DNA in genome than previously thought

Dec 11, 2007

Surrounding the small islands of genes within the human genome is a vast sea of mysterious DNA. While most of this non-coding DNA is junk, some of it is used to help genes turn on and off. As reported online this week in ...

Comparing Chimp, Human DNA

Oct 12, 2006

Most of the big differences between human and chimpanzee DNA lie in regions that do not code for genes, according to a new study. Instead, they may contain DNA sequences that control how gene-coding regions are activated ...

Tiny genetic differences have huge consequences

Jan 19, 2008

A study led by McGill University researchers has demonstrated that small differences between individuals at the DNA level can lead to dramatic differences in the way genes produce proteins. These, in turn, are responsible ...

Recommended for you

Japanese scientist resigns over stem cell scandal

Dec 19, 2014

A researcher embroiled in a fabrication scandal that has rocked Japan's scientific establishment said Friday she would resign after failing to reproduce results of what was once billed as a ground-breaking study on ...

'Hairclip' protein mechanism explained

Dec 18, 2014

Research led by the Teichmann group on the Wellcome Genome Campus has identified a fundamental mechanism for controlling protein function. Published in the journal Science, the discovery has wide-ranging implications for bi ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.