Finding DNA gold in a genetic desert
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October 27, 2003--Vast regions of the human genome thought to be genetic "deserts" harboring DNA sequences of no value may actually contain heretofore hidden nuggets of DNA gold. A team of researchers at the Office of Science's Lawrence Berkeley National Laboratory and the Joint Genome Institute (JGI) compared DNA sequences from gene deserts in the genomes of humans, mice, frogs, and fish and discovered sequences that regulate the "expression" or activation of genes over surprisingly long distances.
"The distance from which these long-range enhancers can reach out across the genome to regulate a gene is a hundredfold greater than anyone thought," says Edward Rubin, M.D., who led this research. "Gene deserts may not be home to any genes but they can host DNA sequences that act as long-distance switches to activate far away genes. This suggests that the idea that all gene deserts could be eliminated with no consequences to the organism is wrong."
Rubin is director of the JGI and Berkeley Lab's Genomics Division. As a research geneticist, he has been a pioneer in the study of the evolutionary conservation of non-coding DNA sequences that play an important role in regulating gene expression. The results of his latest finding are reported in the October 17, 2003, issue of the journal Science.
Co-authoring the Science paper with Rubin were Marcelo Nobrega and Veena Afzal, with Berkeley Lab and JGI, and Ivan Ovcharenko, who is now with Lawrence Livermore National Laboratory.
Earlier work led by Rubin established that comparative analysis techniques used to identify genes--sequences of DNA bases that code for proteins--in humans and other vertebrates can also be used to identify DNA sequences that regulate genes.
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He explains the principle as this: "If evolution conserved a sequence over the millions of years since humans and other vertebrates diverged, it likely has a function. Whether this function is to code for a protein or to regulate gene expression, we should be able to identify these sequences through genomic comparisons."
In this latest research, Rubin and his Science co-authors applied the principle of conserved non-coding sequences to gene deserts. Genes are distributed in clumps throughout the 3 billion DNA bases that make up the human genome. It is estimated that as a result of this uneven distribution, approximately 25 percent of the genome is a genetic wasteland made up of gene deserts that stretch out more than 500,000 bases in length. Because gene deserts were thought to contain nothing of importance, they have gone largely unexplored.
"We went into one of these deserts looking for a gene regulatory element that could regulate from far away, something that has been conserved by evolution since humans and fish shared a common ancestor," Rubin says.
He and his co-authors focused on a human gene called DACH1, which is involved in the development of the brain, limbs, and sensory organs and resides between two large gene deserts. Because there have been few regulatory elements found near the DACH1 gene, Rubin speculated that such elements might be located in the surrounding gene deserts.
To identify evolutionarily conserved "footprints" that might correspond to possible DACH1 enhancers, Rubin and his co-authors compared more than 2.5 million DNA bases from the human DACH1 gene and its desert neighbors to the bases in their mouse genome counterparts. They identified more than a thousand conserved non-coding sequences, meaning sequences at least 70 percent identical in both species over at least 100 bases. They then determined which of these sequences had also been conserved in the genomes of the frog, the zebra fish, and two types of Fugu or puffer fish. This reduced the number of conserved non-coding sequences to 32. A series of in vivo testing was then used to identify seven long-range gene enhancers buried in the deserts on either side of the human DACH1 gene.
The findings in this Science paper indicate that future studies aimed at understanding the way genes are expressed in the human genome and how they function may have to expand the DNA sequence territory taken into consideration. The findings also hold implications for the treatment of diseases.
Explains Rubin, "Regulatory elements that are very far away from a gene can cause serious problems. You can think of these long-range enhancers like the root system of a tree. Previously we thought that roots only extended a short distance from the tree. Our new study suggests that some roots can extend far away from the tree's trunk and branches, cutting those distant roots can still do harm to the tree."
--by Lynn Yarris
Media contact: Lynn Yarris, LBNL media coordinator, (510) 486-5375, lcyarris@lbl.gov
Technical contact: Eddy Rubin, director of the JGI and LBNL's Genomics Division, 510-486-5072, EMRubin@lbl.gov
Related Web Links
"Scanning Human Gene Deserts for Long-Range Enhancers." Nobrega, MA, I Ovcharenko, V Afzal, and EM Rubin. October 17, 2003 Science 302(5644):413-414. (subscription may be required)
"Phylogenetic Shadowing: Apes and Monkeys Are Helping Scientists to Understand the Human Genome," L Yarris, DOE Science News, April 28, 2003.
Funding: This research was supported by the DOE Office of Science's Biological and Environmental Research program.
Lawrence Berkeley National Laboratory was founded by Ernest Orlando Lawrence founded this Lab in 1931, making it the oldest of the national laboratories. Lawrence invented the cyclotron, which led to a Golden Age of particle physics and revolutionary discoveries about the nature of the universe. Of our nine Nobel Prizes awarded to LBNL scientists, five are in physics and four in chemistry. Today, LBNL is a multiprogram lab where research in advanced materials, life sciences, energy efficiency, detectors and accelerators serves America's needs in technology and the environment. LBNL is managed by the University of California for DOE.
The Joint Genome Institute (JGI), established in 1997, is one of the largest and most productive publicly funded human genome sequencing institutes in the world. The JGI was founded by three DOE national laboratories managed by the University of California: Lawrence Berkeley National Laboratory, Lawrence Livermore National Laboratory in California, and Los Alamos National Laboratory in New Mexico. The JGI has whole genome sequencing programs that include vertebrates, fungi, plants, and bacteria and other single-celled microbes.
Author: Lynn Yarris is the senior science writer and the media coordinator for Lawrence Berkeley National Laboratory. He heads the Lab's efforts to assist science and technical news media in reporting on research news at Berkeley Lab. For more late-breaking research news, see Berkeley Lab's Science Beat.