With this in mind, we believe that the GSC and the Washington University School of Medicine are uniquely positioned to be at the leading edge in the forthcoming era of "applied genomics". The combination of the GSC's know-how in genomics, coupled with local expertise in human genetics, computational biology, molecular biology and biochemistry, microbiology and immunology, and medicine should provide a powerful environment in which to develop, test and implement new approaches to the study, diagnosis and treatment of human disease. Therefore, a major component of the GSC's current and future research includes new programs aimed at genome sequence analysis and interpretation, functional genomics, and targeted re-sequencing of genes associated with human disease.

• First, while the GSC is clearly among the world leaders in the large-scale production of de novo genome sequence data, we have so far put minimal effort into detailed analysis and interpretation of these data. Since it is our belief that centers who produce the data should be in an excellent position to explore it, we recently have established a new group that will focus on analysis, interpretation and detailed annotation of genome sequence data. In addition to computational approaches, this group will further use laboratory experimentation as a means to both facilitate and verify gene discovery and characterization.
  
  
• Second, using base technologies with which we already have considerable expertise (e.g., robotics, PCR amplification, DNA sequencing), the GSC is launching a foray into additional genome analyses that will provide key information regarding gene (and genome) function. Data from this effort will not only enhance genome sequence annotation, but will facilitate additional relevant discovery of the mechanisms underlying many of the gene products and their respective roles both in normal growth and differentiation as well as in disease. The activities that will be included in this program will include the construction and use of genome microarrays ("gene chips") of our own design for DNA content studies, gene expression microarrays, quantitative RT-PCR, genotyping and single nucleotide polymorphism (SNP) discovery/characterization, and proteomics and protein biochemistry. Further development of these core competencies also will provide potential for collaborations between the GSC and Medical School faculty such as establishing high-throughput methods for genome analysis of patient samples.
  
  
• Third, we have initiated a program to develop and implement the technology and methods necessary to facilitate large-scale re-sequencing of human disease genes. With the current human genome sequence as a reference, it is now possible to investigate the variation present in individual genomes that specifies a progression toward disease. As small sequence differences are correlated with pathogenesis, susceptibility to infection or autoimmune disease, cancer progression, drug efficacy and side effects, we will begin to understand why certain genes underlie certain diseases and, subsequently, how to better diagnose and treat these diseases. At present, the GSC has initiated several re-sequencing projects in collaboration with WU investigators. Each of these projects represents a targeted investigation of a gene or small set of genes associated with a specific disease. However, if we are ever to understand the genetic mechanisms of more complex diseases such as diabetes, Alzheimer's Disease, other types of cancer, etc., it will be necessary to develop DNA sequencing technology and methods that will allow us to analyze thousands of genes from hundreds to thousands of patient samples.

In addition to the research programs described above, the GSC will continue to produce de novo genome sequence data from a number of important organisms. As we finish the remaining regions of human chromosomes 2, 4, 7 and Y, we will turn our attention to the completion of the mouse genome, as well as the genomes of the chimpanzee, chicken and a number of human pathogens. Through these efforts, coupled with our computational and functional genomics efforts described above, we will begin to unlock many of the secrets that are still tucked away in the human genome sequence.

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