More regulatory DNA than previously thought

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More regulatory DNA than previously thought

http://www.news-medical.net/?id=33484

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 Genome Research, Hopkins researchers

have now found that this latter portion, which is known as

regulatory DNA and contributes to inherited diseases like

Parkinson's or mental disorders, may be more abundant than we

realize.

By conducting an exhaustive analysis of the DNA sequence around a

gene required for neuronal development, McCallion, Ph.D., an

assistant professor in the McKusick-s Institute of Genetic

Medicine, and his team found that current computer programs that

scan the genome looking for regulatory DNA can miss more than 60

percent of these important DNA regions.

The current methods find regulatory sequences by comparing DNA from

distantly related species, under the theory that functionally

important regions will appear more similar in sequence than non-

functional regions. " The problem with this approach, we have

discovered, " says McCallion, " is that it's often throwing the baby

out with the bath water. So while we believe sequence conservation

is a good method to begin finding regulatory elements, to fully

understand our genome we need other approaches to find the missing

regulatory elements. "

McCallion had suspected that using sequence conservation would

overlook some regulatory DNA, but to see how much, he set up a small

pilot project looking at the phox2b gene; he chose this gene both

because of its small size and his interest in nerve development

(phox2b is involved in forming part of the brain associated with

stress response as well as nerves that control the digestive system).

The researchers created what they call a " tiled path, " cutting up

the DNA sequence around the phox2b gene into small pieces, then

inserted each piece into zebrafish embryos along with a gene for a

fluorescent protein. If a phox2b fragment was a regulatory element,

then it would cause the protein to glow. By watching the growing

fish embryos - which have the advantage of being transparent - the

researchers could see which pieces were regulators.

They uncovered a total of 17 discrete DNA segments that had the

ability to make fish glow in the right cells. The team then analyzed

the entire region around the phox2b gene using the five commonly

used computer programs that compute sequence conservation; these

established methods picked up only 29 percent to 61 percent of the

phox2b regulators McCallion identified in the zebrafish experiments.

" Our data supports the recent NIH encyclopedia of DNA elements

project, which suggests that many DNA sequences that bind to

regulatory proteins are in fact not conserved, " says McCallion. " I

hope this pilot shows that these types of analyses can be

worthwhile, especially now that they can be done quickly and easily

in zebrafish. "

McCallion is now planning a larger study of other neuronal genes. " I

think we are only starting to realize the importance and abundance

of regulatory elements; by regulating the gene activity in each cell

they help create the diverse range of cell types in our body. "