New Insight Into Junk DNA With Tool To Find Critical Gene Control Regions

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New Insight Into " Junk DNA " With Tool To Find Critical Gene Control

Regions

http://www.medicalnewstoday.com/medicalnews.php?newsid=40226

Researchers at the McKusick-s Institute of Genetic Medicine at

s Hopkins have invented a cost-effective and highly efficient way

of analyzing what many have termed " junk " DNA and identified regions

critical for controlling gene function. And they have found that

these control regions from different species don't have to look alike

to work alike.

The study was published online at Science Express.

The researchers developed a new system that uses zebrafish to test

mammalian DNA and identify DNA sequences, known as enhancers,

involved in turning on a gene. In studying RET, the major gene

implicated in Hirschsprung disease and multiple endocrine neoplasia

(MEN2), the team identified DNA sequences that can control RET but

had not been identified using standard methods. Hirschsprung disease,

also known as congenital megacolon, is a relatively common birth

defect marked by bowel obstruction. MEN2 is an inherited

predisposition to neuroendocrine cancers.

The notion that mutations in enhancers play a role in human disease

progression has been difficult to confirm because usually enhancers

are located in the 98 percent of the human genome that does not code

for protein, termed non-coding DNA. Unlike DNA sequences that code

for protein, non-coding DNA, sometimes referred to as " junk " DNA,

follows few rules for organization and sequence patterns and

therefore is more difficult to study.

" The difficulty with human genetic approaches to common disease is

that we lack the power to precisely localize DNA sequences that are

associated with disease, often leaving us immense stretches of DNA to

look at, " says one of the study's corresponding authors, Andy

McCallion, Ph.D., an assistant professor in the McKusick-s

Institute. Most often one is limited to looking in the most obvious

places, which may not yield the best results. " Until now, " he

says, " we've only been able to look under the lamplights for the car

keys. "

Traditionally, DNA sequences are thought to have to look similar to

function similarly; this is how scientists identify genes in other

species, a strategy best used for studying similar species. From an

evolutionary standpoint, the last common ancestor of human and

zebrafish lived more than 300 million years ago. Because DNA

sequences in each species have changed over time, traditional methods

of comparing DNA sequences between humans and zebrafish have failed

to identify any potential enhancers around the RET gene because the

DNA sequences differ too much.

That drove the Hopkins researchers to seek and develop this new

system, by which virtually any DNA sequence can be tested for its

ability to turn on a marker gene in zebrafish embryos. The system is

a significant advance over current methods in this model species,

allowing researchers to study more sequences in a shorter period of

time. Using this, they identified several human enhancers able to

control expression consistent with the zebrafish ret gene.

Zebrafish have become the ideal system for doing these types of large

scale studies. They are small - only about a half inch in length -

they grow quickly, and are relatively inexpensive to maintain

compared to mice or rats. " Zebrafish are the only vertebrate embryo

you can even think about doing this type of work in, " says

Fisher, M.D., Ph.D., the study's first author and an assistant

professor in cell biology in s Hopkins' Institute for Basic

Biomedical Sciences.

The researchers' next steps are further study of the RET enhancers

they found to identify other mutations that might contribute to

Hirschsprung disease and MEN2, and to entice other investigators to

collectively build a database of human enhancers. " If there's one

thing we've learned here, it's that we are not very good at

recognizing enhancers. We just don't know what they look like, " says

Fisher. " We are anxious for others to use this technology on their

favorite genes. "