Combining classical Mendelian genetics with state-of-the-art "DNA chip" technology, researchers from The David Geffen School of Medicine at UCLA, in collaboration with several other institutions, have developed a clever and powerful tool for dissecting the molecular roots of such diseases as obesity, heart disease, Alzheimer's, diabetes and cancer. The findings, reported in the March 20 issue of Nature, will likely speed up the drug discovery process for these and many other common disorders.
"Basically, we've created a new approach for understanding the complex molecular relationships that underlie living systems and pathological processes," says A. Jake Lusis, Ph.D., Professor of Microbiology, Medicine and Human Genetics at UCLA's David Geffen School of Medicine and a co-author of the report.
By uniting genetics with genomics - two already compelling strategies for studying genes - the researchers were able to identify DNA "hotspots" that control the activity of many genes. Hotspots can accelerate the rate at which scientists uncover the genes and biochemical pathways that contribute to disease.
This advantage is beautifully demonstrated in the Nature paper for the case of obesity. Using the new technology, UCLA researchers managed to rapidly pinpoint a few mouse genes that may play a role in the formation of fat.
Other contributors to this study include scientists from Rosetta Inpharmatics, LLC; University of Washington, Seattle; Monsanto Company and Merck Research Laboratories. The first author of the study is Eric E. Schadt, Ph.D., Director of Research Genetics at Rosetta Inpharmatics and a former graduate student at UCLA.
Typically, to hunt down the gene or genes behind a given disease, researchers rely on classical Mendelian or "single gene" genetics. In this technique, the inheritance of a trait, such as a disease, is correlated with the inheritance of different parts of the genome, to eventually identify the DNA that gives rise to the trait. Mapping Mendelian traits in human families or experimental genetic crosses is now routine. But, when it comes to "complex" diseases - diseases caused by a mix of genetic and environmental factors, such as obesity, heart disease and cancer to name a few -- this traditional approach can at best locate only some of the culprit genes.
In the new Nature study, the researchers overcame this limitation by combining classical genetics with "DNA chip" technology. DNA chips or microarrays are commonly used to gather large amounts of gene activity or "gene expression" data across entire genomes. (Gene expression is measured in levels of corresponding messenger RNA.) Thus, instead of disease traits, the collaborators attempted to link gene expression to specific patches of DNA - a feat at that time accomplished only in yeast.
What they discovered was more powerful than they had originally hoped for. Surveying the genomes of maize, mice and man, the scientists were able to link the expression of approximately one-third of the genes they tested to the DNA that controls their expression. In addition, many of these genes mapped to a select few DNA regions, better known as "hotspots." These hotspots, when used in combination with classical genetics data, can lead scientists almost directly to the genes and biochemical pathways that underlie complex diseases.
"One advantage to this combined strategy lies with its ability to narrow the search for novel disease genes more rapidly than is possible with classical methods," says Thomas Drake, M.D., Professor of Pathology and Laboratory Medicine at UCLA's David Geffen School of Medicine and a contributor to the study. "This translates to fewer mice and quicker results."
Dr. Drake showed the release to the first author and he would like to make a change to his title before it goes up on the Web, if possible.
To further demonstrate the power of this novel approach, the UCLA researchers chose to study obesity in mice. They mapped gene expression in obese mice to specific DNA regions, and again identified several hotspots. As predicted, the hotspots led the scientists to putative obesity genes in less time than would be expected with classical genetics alone. Further studies into the possible roles these obesity genes play in the formation of fat are underway at UCLA.
The obesity hotspots also allowed the scientists to pull out subgroups of obese mice that differ from each other at the genetic level. Such stratification of diseased populations may ultimately lead to tailor-made medical treatments for humans.
"We were able to see genetic patterns of disease that otherwise would have gone undetected," says Lusis. "By combining this new kind of gene expression data with DNA sequence variability data, doctors may eventually be able to treat patients according to their precise genetic needs. You might call it pharmacogenomics." Pharmacogenetics refers to the practice of tailoring treatments to individuals based on DNA sequence data alone.
In the end, Drake says that the real beauty of this novel approach lies in its potential to discover new molecular networks and relationships. When it comes to the vast complexity of human beings, this kind of scientific tool is of utmost importance.
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