"Our hope is that this new computational approach will increase the utility of the vast amount of DNA sequence information available today and help researchers more fully leverage mouse models of human disease to identify genes contributing to disease risk and drug response," said Gary Peltz, M.D., Ph.D., head of Genetics and Genomics at Roche Palo Alto. "It will help researchers understand the relationship between trait differences and variations in the mouse genome, which will move us a long way toward understanding the impact of human genetic differences. As that happens, we should be able to translate genetic data more effectively and efficiently into the development of both novel diagnostic tools and new medicines to treat human diseases."
In this regard, Roche Palo Alto is engaged in research with several leading universities and government institutions to leverage the power of the new computational technique. The studies are directed toward better understanding the genetic causes of a range of human diseases and toward pharmacogenetic analysis of how various drugs that are used commonly to treat disease work in humans.
The paper, entitled "In Silico Genetics: Identification of a Novel Functional Element Regulating H2-Ea Gene Expression," reports that the new computational algorithm correctly identified the genetic basis for strain-specific differences in several biologically important traits, including differences in drug metabolism. The examples presented in the paper demonstrate the ability of the methodology to identify causative genetic factors accurately for a wide range of trait data. The technique also has the potential to uncover currently unknown genetic factors contributing to a host of different diseases.
Roche scientists first published a computational method for mouse genome analysis in the June 8, 2001 issue of Science. That method predicted regions of a mouse chromosome responsible for a trait difference. The predicted regions contained hundreds of genes and the results were assessed by relative (percentile ranking) statistical criteria. The new method offers the same analytic speed, but is much more exact, linking a single gene to a trait difference. This method eliminates the need for follow-up studies to mine large chromosomal regions, saving researchers from months to years of experimentation. In addition, the results are assessed by absolute (p-value) statistical criteria, which give researchers greater confidence in their analyses.
The pattern of genetic variation analyzed by this new computational method was created by mining a database of common genetic markers, called single nucleotide polymorphisms (SNPs), covering 1,900 genes across 16 commonly used inbred mouse strains. That database was created by Roche scientists in Palo Alto and Alameda, Calif., and Basel, Switzerland, and was partially sponsored by a National Human Genome Research Institute Grant. It was recently selected as the top SNP database by respondents to a survey of scientists conducted by Genome Technology and GenomeWeb Daily News. The genetic pattern maps are now available to the public for the first time as part of the Roche SNP database web site (http://mouseSNP.Roche.com). The web site delivers a wealth of genetic information about many mouse strains that are commonly used to model human disease.
The mouse genome is similar to that of humans and mice can be genetically manipulated. Because of this, the mouse is the most commonly used experimental model for studying human disease, and the "mouse to man" approach is widely used. Since analyses of mouse genetic models by traditional methods are very time-consuming and costly, this novel computational approach represents a major advance for this entire field of research.
Study participants from Roche included Guochun Liao, Jianmei Wang, Jingshu Guo, John Allard, Janet Cheng, Anh Nguyen, Gary Peltz, and Jonathan Usuka from the Roche Palo Alto campus, and Dorothee Foernzler from the Roche Center for Medical Genomics in Basel, Switzerland. Other study participants included: Steve Shafer from Stanford University, Stanford, California; Anne Peuch from the Centre National de Génotypage, France and John D. McPherson from the Washington University School of Medicine, St. Louis, Missouri.
About Roche (www.roche.com)
Headquartered in Basel, Switzerland, Roche is one of the world's leading research-intensive healthcare groups. Its core businesses are pharmaceuticals and diagnostics. As a supplier of innovative products and services for the prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is number one in the global diagnostics market, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2003, the Pharmaceuticals Division generated 19.8 billion Swiss francs in prescription drug sales, while the Diagnostics Division posted sales of 7.4 billion Swiss francs. Roche employs roughly 65,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai.
About Roche Palo Alto (http://paloalto.roche.com)
Roche has 1,000 people on its Palo Alto campus, which is located adjacent to Stanford University in California's Silicon Valley. It is one of five global Roche research centers. Scientists at Roche Palo Alto are focused on the discovery of new medicines to treat central nervous system, genitourinary, viral, inflammatory and autoimmune diseases and to support organ transplantation. Medicines discovered on the Roche Palo Alto campus include CellCept® (mycophenolate mofetil) for the prevention of renal, cardiac and hepatic organ transplant rejection, Valcyte® (valganciclovir) for the treatment of cytomegalovirus (CMV) in patients with AIDS and prevention of CMV disease in kidney, heart and kidney-pancreas transplant in high risk patients and Aleve®, a naproxen-sodium based over-the-counter pain reliever.
Full prescribing information can be accessed at www.rocheusa.com.
Journal
Science