Scientists uncover clues to the mystery of 'gene deserts'

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Scientists uncover clues to the mystery of 'gene deserts'

09 Dec 2004

http://www.medicalnewstoday.com/medicalnews.php?newsid=17540

Like the famous living deserts of the Southwest, the so-called " gene deserts " in

our DNA are teeming with activity. The trick is knowing where to look for it.

A new roadmap to the location of DNA segments that are significant in medical,

biological and evolutionary research could emerge from studies published today

(Dec. 9) by scientists at Lawrence Livermore National Laboratory (LLNL) and

their colleagues. The work is reported in the online version of the journal

Genome Research.

Gene deserts are long stretches of DNA between genes that were once thought to

have no biological function, and were dismissed as " junk DNA. " As scientists

probe deeper into the DNA's double helix, however, they are discovering that

many of these " non-coding " segments actually play an important role in

regulating gene activity.

Research last year at the U.S. Department of Energy's Joint Genome Institute

(JGI) and Lawrence Berkeley National Laboratory (LBNL), for example, has shown

that gene deserts contain DNA sequences that can switch genes on and off over

considerable distances along the DNA molecule.

Paradoxically, the same JGI and LBNL scientists were recently able to remove

giant chunks of gene desert DNA - whole chapters in the " book of life " - from

laboratory mice with no apparent effect on the animals. Many of the deleted

sequences are shared by mice and humans, and thus may have no function in humans

as well.

In an effort to resolve the paradox and to help researchers more easily locate

critical segments along the vast stretches of DNA deserts, scientists from LLNL,

LBNL, and the Pennsylvania State University developed computational tools to

decipher gene regulation by comparing the genomes of many different species.

When they used the tools to compare the human genome with the recently sequenced

chicken genome, they discovered that gene deserts actually fall into two

distinct categories: those that remain relatively stable throughout eons of

evolution, and those that undergo significant variation.

Ivan Ovcharenko, a bioinformatics scientist in LLNL's Computation Directorate

who led the study, said that many lines of evidence show that the stable desert

regions, which are able to resist genomic rearrangement and fend off

infringement by repetitive segments of junk DNA, are home to a surprisingly

large fraction of the genome's non-coding regulatory elements.

" There are many indications that stable gene deserts represent treasure boxes of

multiple gene regulatory elements, guarding the proper complex function of the

flanking genes, " he said.

The variable regions, on the other hand - which make up about two-thirds of the

gene deserts and as much as 20 percent of the entire three-billion-base-pair

human genome - " can be devoid of biological function, suggesting that a

significant fraction of the genome may not be essential.

" This information is very important for researchers looking for mutations

leading to diseases, " Ovcharenko said, " because it highlights large areas of the

genome that are not likely to be involved in causing diseases. "

JGI Director Eddy Rubin, a geneticist and physician who led the earlier studies

indicating the presence of both functioning and non-functioning gene deserts,

agreed: " If you're a gene hunter looking for genetic clues to diseases, " he

said, " it might be a good idea to steer clear of regions that are devoid of

critical functions or importance, " such as those that were deleted in the

JGI-LBNL mouse experiments.

The gene desert research is among a number of studies being published today in

Genome Research online and Nature resulting from the public release of the

chicken genome sequence earlier this year. LLNL and JGI researchers, led by

Stubbs in LLNL's Biology and Biotechnology Research Program and Lucas at

JGI, contributed to the Nature paper describing the primary sequence and

comparative analysis of the chicken genome, along with Ovcharenko and Laurie

Gordon of LLNL and Tijana Glavina and Aerts of JGI.

Stubbs and her team joined with JGI to compare human and chicken genomes in 2002

and focused on human chromosome 19, one of three chromosomes sequenced by JGI as

the Department of Energy's contribution to the Human Genome Project. The

LLNL/JGI team's high-quality sequence of parts of the chicken genome related to

chromosome 19 was used in two of the papers published today in Nature.

Participating with Ovcharenko in the gene desert study and in the development of

a new sequence comparison tool called Mulan - shown to be instrumental in

deciphering evolutionary clues by comparing multiple primate, mammalian and fish

species with chicken - were Stubbs and a Loots of LLNL, Marcelo Nobrega

of the Genomics Division at LBNL, and Ross Hardison, Webb , Belinda

Giardine, Minmei Hou and Jian Ma of the Pennsylvania State University. The

papers describing both projects will appear in the January print issue of Genome

Research.

Founded in 1952, Lawrence Livermore National Laboratory (http://www.llnl.gov)

has a mission to ensure national security and to apply science and technology to

the important issues of our time. Lawrence Livermore National Laboratory is

managed by the University of California (UC) for the U.S. Department of Energy's

National Nuclear