GOVERNMENT

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 Lisa Stubbs in LLNL's Biology and Biotechnology Research Program and Susan 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 Andrea 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 Gabriela Loots of LLNL, Marcelo Nobrega of the Genomics Division at LBNL, and Ross Hardison, Webb Miller, 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.