Don Seto

Areas of Scientific Interest and Specialization:

Genomics: DNA sequencing and analysis of viral genomes; phylogeny and mechanisms of adenovirus evolution.

Bioinformatics: Development of software tools for genome annotation; tools for whole genome comparisons/analysis.

Biodetection: Development and validation of DNA-based molecular diagnostics/microarray pathogen detection (USAF, SG/R: EOS Program) (-ended Oct.31, 2004).

Current Research Interests

I have extensive experience and interests in bioinformatics, genome analysis, genomics and biochemistry. An additional expertise is in nucleic acids core facilities development, operations and management from my diverse opportunities.

Academic labs (my laboratory at GMU and Lee Hood laboratory at Caltech)

Government labs (Molecular Endocrinology Branch at NIDDK/NIH and at USAF/EOS)

Commercial labs (DuPont-Merck Pharm., Digital Genes Tech. and GeneSys Tech.)

As a Scientific Advisor to the Surgeon General and the Director of Molecular Diagnostics for the USAF-EOS program, I have project management experience, dealing with research groups at the USAF Surgeon General’s Office, AFIP, NHRC, NRL and LAFB (see below for an acronym key), as well as arranging, directing and managing contract work with Commonwealth Biotechnologies, Inc. and Virapur, Inc. My lab’s current focus is in software tools development for whole genome data mining and analyses, and in the genomic and bioinformatics analysis of adenovirus genomes, with emphasis on the evolution and natural variation of these genomes.

Software development for whole genome comparisons and analyses
Using virus genome data, e.g., adenoviruses and poxviruses, the Seto Research Group has developed, validated and implemented two net-accessible interactive and “on-the-fly” genome comparison software tools (http://binf.gmu.edu/genometools.html). The first, GeneOrder, compares two genomes to determine synteny and gene order by using a BLAST algorithm. The second, CoreGenes, analyzes up to five genomes in order to catalogue genes that have sequence relationships with each other- e.g., ‘alphabet’ of essential genes within a family. One application of CoreGenes is that it can rapidly predict the function for newly sequenced predicted or hypothetical genes based on other members of the family. Another application is the presentation of unique and common genes, which may be realized as targets for pharmaceutical drug discovery and for molecular diagnostics. Recently these tools have been redeveloped for analyzing small bacterial genomes, up to 2Mb.

Genomics and bioinformatics of human adenoviruses
Several members of the adenoviruses family are important human pathogens. They are agents in acute respiratory disease (ARD). While ARD has a low mortality rate, especially in the military training population, the morbidity rate is high. The Seto Research Group and collaborators have sequenced genomes from sixteen relevant serotypes (1, 4, 6, 7, 14, 16, 21, 34 and 50), and have analyzed and annotated these genomes thoroughly. An algorithm for annotation has been designed and optimized. Bioinformatics analysis shows that serotype 4 arose from a zoonotic event, transmission from a chimpanzee host. Three branches of evolution are suggested, with one branch comprising the majority of the serotypes and species; one branch comprising the species B serotypes; and one ‘relatively recent’ branch comprising the sole member of species E. Species B is subdivided into B1 and B2, with data suggesting B1 is derived from a zoonotic event and B2 diverging from the original human adenovirus branch and converging with the B1 branch. Current epidemic outbreak strains of adenoviruses are being studied to determine epidemiology and evolution of pathogenic strains.

Viral and molecular evolution; Natural variation
Current field strains of HAdV-4 isolated from epidemics appear to contain two genome recombination events allowing this serotype to become now the single agent of adenovirus-caused ARD in the military trainee population (at 99%, NHRC Spring 05). Bioinformatics analyses suggest these recombinations of critical regulatory sites drove the adaptive evolution of this pathogen from a chimpanzee host to a human host. (re-emerging in the absence of vaccines).

Genomic, bioinformatics and molecular analyses of adenoviruses associated with previously vaccinated individuals
During the course of studies, it was noted that archived strains from the US Navy Health Research Center (Global Emerging Infectious Disease Surveillance- GEIS), collected from individuals who were diagnosed with ARD despite vaccinations (‘Breakthrough’ or ‘coinfection’ strains), contained multiple serotypes of adenoviruses. One genome was sequenced and analyzed. This, along with other ARD-relevant adenovirus genomes analyzed earlier, shows that molecular evolution of viral pathogens may be more rapid than earlier thought, and that vaccination with unattenuated viruses may drive recombinations and accelerate the evolution to more problematic substrains. These genomic studies complement molecular and epidemiologic studies with the collection of adenovirus field strains collected by NHRC. Molecular recombination and co-infections may be major forces shaping virus adaptive evolution, particularly of pathogenic strains.

Development of advanced molecular diagnostics platforms for epidemic outbreaks surveillance (May 2002 to November 2004)
As part of a Consortium (Epidemic Outbreak Surveillance- EOS) formed by the US Air Force Surgeon General’s Office to develop molecular diagnostics tools for the identification and surveillance of ARD pathogens in the military, the Seto Research Group has provided unique pathogen genome signatures for populating microarray chips. These set of probes include signatures from several viral and bacterial agents that are identified as pathogens in ARD. Currently, three versions of the Affymetrix-based Respiratory Pathogen Microarray (RPM) have been designed, and are being tested, validated and implemented in a real-world test bed at LAFB. This Consortium includes collaborating groups from the Armed Forces Institute of Pathology at Walter Reed Army Medical Center (AFIP), Naval Research Laboratory (NRL), and Wilford Hall/Lackland USAF base (LAFB). The goal has been to support a rapid response to current epidemic challenges, so methodology has been optimized for sequencing and analyzing viral genomes rapidly, translating this into pathogen signatures for rapid turnaround and for microarray inclusion. Current epidemic field strains of adenoviruses have been sequenced and analyzed rapidly: HAdV-4FS (US Air Force), HAdV-4FS (US Army), HAdV-7FS (US Navy), HAdV-3FS (US Navy) and HAdV-5FS (US Army).

Publications

In review/In transit
Mahadevan, P. and Seto, D. (2006). Comparative genomics using web-based GeneOrder to determine synteny and to function as an annotation tool. BioComp: The 2006 International Conference on Bioinformatics and Computational Biology (Las Vegas, NV. June 26-29, 2006).

Kropinski, A.M., Borodovsky, M., Carver, T.J., Cerdeno-Tarraga, A.M., Darling, A., Mahadevan, P., Stothard, P., Seto, D., van Domselaar, G. and Wishart, D.S. (2006). "In silico genomic analysis of bacteriophage DNA." in Bacteriophages: Methods and Protocols. In press.

Published

Vora, G.J., Lin, B., Gratwick, K., Meador, C., Hansen, C., Tibbetts, C., Stenger, D.A., Irvine, M., Seto, D., Purkayastha, A., Freed, N., Gibson, M.L., Russell K.L. and Metzgar, D. (2006). Coinfections of multiple adenoviral species in previously vaccinated patients. Emerging Infectious Diseases, in press (March 06).

Lin, B., Wang, Z., Vora, G.J., Thornton, J.A., Schnur, J.M., Thach, D.C., Mueller, K.M., Ligler, A.G., Malanoski, A.P., Santiago, J., Walter, E.A., Agan, B.K., Metzgar, D., Seto, D., Daum, L.T., Kruzelock, R., Rowley, R.K., Hanson, E.H., Tibbetts, C. and Stenger, D.A. (2006). Broad spectrum respiratory tract pathogen identification using re-sequencing DNA microarrays. Genome Res. 16: 527-35.

Purkayastha A, Su J, McGraw J, Ditty SE, Carlisle S, Hadfield TL, Seto J, Russell, KL, Tibbetts C and Seto D. (2005). Genomic and bioinformatics analysis of HAdV-4vac and HAdV7vac, two human adenovirus that constituted original prophylaxis against HAdV-related acute respiratory disease, a reemerging epidmeic disease. J Clin Microbiol. 43: 3083-94.

Purkayastha A., Ditty S.E., Su J., McGraw J., Hadfield T.L., Tibbetts C. and Seto D. (2005). Genomic and bioinformatics analysis of HAdV-4, a human adenovirus that causes acute respiratory disease (ARD). Implications for gene therapy and vaccine vector development. J Virol. 79: 2559-72.

Purkayastha A., Su J., Carlisle S., Tibbetts C. and Seto D. (2005). Genomic and bioinformatics analysis of HAdV-7, a human adenovirus of species B1 that causes acute respiratory disease (ARD). Implications for human gene therapy. Virology 332:114-129.

Lauer, K.P., Llorente, I., Blair, E., Seto, J., Krasnov, V., Purkayastha, A., Ditty, S.E., Hadfield, T.L., Buck, C., Tibbetts, C. and Seto, D. (2004). Natural variation among human adenoviruses: Genome sequence and annotation of human adenovirus serotype 1 (HAdV-1). J Gen Virol. 85: 2615-2625.

Celamkoti, S., Kundeti, S., Purkayastha, A, Mazumder, R., Buck, C. and Seto, D. (2004). GeneOrder3.0: Software for comparing the order of genes in pairs of small bacterial genomes. BMC Bioinformatics 5:52.

Purkayastha, A., Celamkoti, S., Kundeti, S., Buck, C. and Seto, D. (2003). Comparative analyses of small bacterial genomes using global computational tools GeneOrder and CoreGenes. Proceedings of the Seventh Joint Conference on Information Sciences (Fifth Conference on Computational Biology and Genome Informatics). Presented in Research Triangle Park, NC. Sept 03. K. Chen, et. al., eds. 863-868.

Zafar, N., Mazumder, R. and Seto, D. (2002). Application of global computational tools GeneOrder and CoreGenes to comparative analyses of chordopoxvirus genomes. Proceedings of the Sixth Joint Conference on Information Sciences (Fourth Conference on Computational Biology and Genome Informatics). Presented in Durham, NC Mar 02. H. J. Caulfield, et. al., eds. 1186-1192. ALSO selected for reprinting @ Information Sciences 146 (1-4): 127-135.

Zafar, N., Mazumder, R. and Seto, D. (2002). CoreGenes: A computational tool for identifying and cataloging Ã¢coreÃ¢ genes in a set of small genomes. BMC Bioinformatics 3:12.

Zafar, N., Mazumder, R. and Seto, D. (2001). Comparisons of gene co-linearity in genomes using GeneOrder2.0. Trends in Biochemical Sciences 26: 514-516.

Mazumder, R., Kolaskar, A. and Seto, D. (2001). GeneOrder: Comparing the order of genes in small genomes. Bioinformatics 17: 162-166.

Pre GMU

Kuo, C. L., Chen, M. L., Wang, K., Chou, C. K., Vernooij, B., Seto, D., Koop, B. F. and Hood, L. (1998). A conserved sequence block in murine and human T-cell receptor (TCR) J alpha region is a composite element that enhances TCR alpha enhancer activity and binds multiple nuclear factors. Proc. Natl. Acad. Sci., USA 95: 3839-3844.

Bunville, J., Krakowski, K. and Seto, D. (1997). Cerium oxide removes background fluorescent contaminants, "Green Smears," from glass plates used for automated fluorescence-based DNA sequencing. BioTechniques 22: 236-238.

Seto, D. and Weintraub, B. (1996). Rapid molecular diagnosis of mutations associated with generalized thyroid hormone resistance by PCR-coupled automated direct sequencing of genomic DNA: Detection of two novel mutations. Human Mutation 8: 247-257.

Boisclair, Y., Seto, D., Hsieh, S., Hurst, K. R. and Ooi. G. (1996). Organization and chromosomal localization of the gene encoding the acid-labile subunit of the insulin-like growth factor binding complex. Proc. Natl. Acad. Sci., USA 93: 10028-10033.

Ooi, G. T., Cohen, F. J., Hsieh, S., Seto, D., Rechler, M. M. and Boisclair, Y. (1995). Structure and regulation of the ALS gene. Progress in Growth Factor Research 6: 151-157.

Krakowski, K., Bunville, J., Seto, J., Baskin, D. and Seto, D. (1995). Rapid purification of fluorescent dye-labeled products in a 96-well format for high-throughput automated DNA sequencing. Nucl. Acids Res. 23: 4930-4931.

Seto, D., Seto, J., Deshpande, P. and Hood, L. (1995). Use of DMSO to resolve banding artifacts in fluorescent DNA sequencing. DNA Sequence 5: 131-140.

Seto, D., Koop, B. F., Deshpande, P., Howard, S., Seto, J., Wilk, E., Wang, K. and Hood, L. (1994). Organization, sequence, and function of 34.5 kilobases of genomic DNA encompassing several murine T-cell receptor a/d variable gene segments. Genomics 20: 258-266.

Koop, B. F., Rowen, L., Wang, K., Kuo, C.-L., Seto, D., Lenstra, J. A., Howard, S., Shan, W., Deshpande, P. and Hood, L. (1994). The human T-cell receptor TCRa/TCRd (Ca/Cd) region: organization, sequence and evolution of 97.6 kb of DNA. Genomics 19: 478-493.

Seto, D., Koop, B. F. and Hood, L. (1993). An experimentally-derived data set constructed for testing large-scale DNA sequence assembly algorithms. Genomics 15: 673-676.

Seto, D., Koop, B. F., Seto, J. and Hood, L. (1992). Complete nucleotide sequence of the cosmid vector pWE15A. Nucl. Acids Res. 20: 3786.

Koop, B. F., Wilson, R. K., Wang, K., Vernooij, B., Zaller, D., Kuo, C. L., Seto, D., Toda, M. and Hood, L. (1992). Organization, structure, and function of 95kb of DNA spanning the murine T-cell receptor Ca/Cd region. Genomics 13: 1209-1230.

Seto, D. and Rohrabacher, C. (1991). Development and application of a nonradioactive phosphorescent autoradiograph marker. BioTechniques 10: 562-572.

Seto, D. (1991). A temperature regulator for microtiter plates. Nucl. Acids Res. 19: 2506.

Seto, D. (1990). An improved method for sequencing double stranded plasmid DNA from minipreps using DMSO and modified template preparation. Nucl. Acids Res. 18: 5905-5906.

Seto, D., Rohrabacher, C., Seto, J. and Hood, L. (1990). Phosphorescent zinc sulfide is a nonradioactive alternative for marking autoradiograms. Analyt. Biochem. 189: 51-53.

Quirk, S., Seto, D., Bhatnagar, S. K., Gauss, P., Gold, L. and Bessman, M. J. (1989). Location and molecular cloning of the structural gene for the deoxyguanosine triphosphate triphosphohydrolase of E. coli. Molec. Microbiol. 3: 1391-1395.

Wiederrecht, G., Seto, D. and Parker, C. S. (1988). Molecular cloning, nucleotide sequencing, and characterization of the Saccharomyces cerevisiae heat-shock transcription factor. Cell 54: 841-853.

Seto, D., Bhatnagar, S. K. and Bessman, M. J. (1988). The purification and properties of deoxyguanosine triphosphate triphosphohydrolase from E. coli. J. Biol. Chem. 263: 1494-1499

Courses taught and resources

Supplemental Lectures

SUMMER 06: Molecular Biotechnology
Syllabus
Lecture 1
Lecture 2
Lecture 3
Lecture 4