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Office of Portfolio Analysis and Strategic Initiatives (OPASI) National Institutes of Health  •  U.S. Department of Health and Human Services

Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

July 30–31 and August 1, 2007, Natcher Conference Center Auditorium, Bethesda, Maryland

Session 1

Computational Genetics: Toward Understanding our Drugs and Diseases

Gary Peltz, M.D., Ph.D.
Roche Palo Alto, Palo Alto, CA

Our understanding of genetic factors effecting human disease susceptibility and drug response is advanced by analysis of murine genetic models. However, conventional methods for analysis of mouse genetic models require a significant amount of time and are very costly. A novel computational method was developed to reduce the time and cost required for mouse genetic analysis. This method identifies a causative genetic factor by correlating a pattern of observable physiological or pathological differences among selected strains of mice with the pattern of genetic variation. A haplotypic map of the genome, based upon 250,000 SNPs identified from analysis of 3300 genes across 20 commonly used laboratory mouse strains (http://mouseSNP.roche.comExit Disclaimer), was produced. This computational method correctly predicted the genetic basis for strain-specific differences in multiple biologically important phenotypic traits, including transcriptional regulation, drug metabolism and drug toxicity. Genetic factors affecting narcotic drug withdrawal and susceptibility to fungal infection in transplant patients were also identified by this method.

References

  1. In Silico Mapping of Complex Disease-Related Traits in Mice. Science. 292:1915, 2001.
  2. In silico genetics: identification of a functional element regulating H2-Ea gene expression. Science 306:690, 2004.
  3. From Mouse genetics to human Therapeutics. Current Opinion in Drug Discovery and Development 8:253, 2005.
  4. Computational Genetics: New Tools for Disease Biology. G. Peltz, Ed. Trenton: Humana Press, 2005.
  5. Computational Genetics: From Mouse to Man? Trends in Genetics 21: 526-532, 2005.
  6. In Silico Pharmacogenetics: Warfarin Metabolism. Nature Biotechnology, 24: 531-536, 2006.
  7. Genetic Variants of the P-Glycoprotein Gene Abcb1b Modulate Opioid-Induced Hyperalgesia, Tolerance and Dependence. Pharmacogenetics and Genomics, 16: 825-835, 2006.
  8. Computational In vitro & In silico Pharmacogenetic Analysis in mice. Manuscript submitted, 2007.
  9. Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis. Manuscript submitted, 2007.

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This page last reviewed: March 18, 2008