News and Publications

Systems Biology of Yeast and Protozoa

Systems biology is a relatively new discipline in which the complete set of proteins or genes or other molecules produced by an organism is studied by using computational methods that integrate data from genome sequencing projects, global gene expression monitoring experiments, or full genome proteomics experiments to make new observations that would not be possible if only a single cellular process or entity were studied. We use the yeast Saccharomyces cerevisiae as a model organism, but we are beginning to investigate organisms with important medical relevance, such as Plasmodium falciparum, the parasite that causes malaria. Our goal is to use a systems biology approach to find new treatments for malaria.

We have 2 basic areas of malaria research. First, we are interested in finding new antigens for vaccine development. Discovery of antigens in malaria has traditionally relied on the biochemical purification of proteins expressed on the cell surfaces of P falciparum or infected erythrocytes. However, this approach has produced no effective licensed malaria vaccine, in part because of variation in the expressed antigens within and across isolates of the parasite. We are using genome-wide analysis methods to discover genes that appear to be under selective pressure from the host's immune system. Our goal is to find the complete set of proteins that elicit the immunogenic response that provides adults from malarious regions some immunity to the disease.

In addition, in order to find new targets for drug development, we are interested in understanding how the malaria parasite functions at the molecular level. For example, only 15% of the proteins identified in the P falciparum genome sequencing project have direct experimental evidence supporting their functional assignment. Because P falciparum is an intracellular parasite and determining its gene function via traditional genetic methods is difficult, these numbers are unlikely to change significantly soon. However, functional information about malaria genes and the genomes of other parasites whose genome sequences have been determined can be added cost-effectively by using new high-throughput technologies, such as large-scale proteomic experiments, comprehensive 2-hybrid studies, global gene expression monitoring, and sequencing of comparative species. We examined gene expression profiles from a large number of P falciparum stages and found that genes expressed at the same time and at the same place often participate in the same biological processes. These experiments provided new groups of genes that most likely are involved in processes such as hemoglobin degradation and host-parasite interactions.

Publications

Borevitz, J.O., Liang, D., Plouffe, D., Chang, H.-S., Zhu, T., Weigel, D., Berry, C.C., Winzeler, E., Chory, J. Large-scale identification of single feature polymorphisms in complex genomes. Genome Res. 13:513, 2003.

Giaever, G., Chu, A.M., Ni, L., Connelly, C., Riles, L., Veronneau, S., Dow, S., Lucau-Danila, A., Anderson, K., Andre, B., Arkin, A.P., Astromoff, A., El-Bakkoury, M., Bangham, R., Benito, R., Brachat, S., Campanaro, S., Curtiss, M., Davis, K., Deutschbauer, A., Entian, K.-D., Flaherty, P., Foury, F., Garfinkel, D.J., Gerstein, M., Gotte, D., Guldener, U., Hegemann, J.H., Hempel, S., Herman, Z., Jaramillo, D.F., Kelly, D.E., Kelly, S.L., Kotter, P., LaBonte, D., Lamb, D.C., Lan, N., Liang, H., Liao, H., Liu, L., Luo, C., Lussier, M., Mao, R., Menard, P., Ooi, S.L., Revuelta, J.L., Roberts, C.J., Rose, M., Ross-Macdonald, P., Scherens, B., Schimmack, G., Shafer, B., Shoemaker, D.D., Sookhai-Mahadeo, S., Storms, R.K., Strathern, J.N., Valle, G., Voet, M., Volckaert, G., Wang, C., Ward, T.R., Wilhelmy, J., Winzeler, E.A., Yang, Y.C., Yen, G., Youngman, E., Yu, K., Bussey, H., Boeke, J.D., Snyder, M., Philippsen, P., Davis, R.W., Johnston, M. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418:387, 2002.

Grunenfelder, B., Winzeler, E.A. Treasures and traps in genome-wide data sets: case examples from yeast. Nat. Rev. Genet. 3:653, 2002.

Hanway, D., Chin, J.K., Xia, G., Oshiro, G., Winzeler, E.A., Romesberg, F.E. Previously uncharacterized genes in the UV- and MMS-induced DNA damage response in yeast. Proc. Natl. Acad. Sci. U. S. A. 99:10605, 2002.

Hartl, D.L., Volkman, S.K., Neilsen, K.M., Barry, A.E., Day, K.P., Wirth, D.F., Winzeler, E.A. The paradoxical population genetics of Plasmodium falciparum. Trends Parasitol. 18:266, 2002.

Karlyshev, A.V., Dorrell, N., Winzeler, E., Wren, B.W. Further strategies for signature-tagged mutagenesis and the application of oligonucleotide microarrays for the quantitation of DNA-tagged strains. In: Functional Microbial Genomics. Wren, B., Dorrell, N. (Eds.). Academic Press, San Diego, 2002, p. 167. Methods in Microbiology, Vol. 33.

Le Roch, K.G., Zhou, Y., Batalov, S., Winzeler, E.A. Monitoring the chromosome 2 intraerythrocytic transcriptome of Plasmodium falciparum using oligonucleotide arrays. Am. J. Trop. Med. Hyg. 67:233, 2002.

Oshiro, G., Wodicka, L.M., Washburn, M.P., Yates, J.R. III, Lockhart, D.J., Winzeler, E.A. Parallel identification of new genes in Saccharomyces cerevisiae. Genome Res. 12:1210, 2002.

Que, Q.Q., Winzeler, E.A. Large-scale mutagenesis and functional genomics in yeast. Funct. Integr. Genomics 2:193, 2002.

Volkman, S.K., Hartl, D.L., Wirth, D.F., Nielsen, K.M., Choi, M., Batalov, S., Zhou, Y., Plouffe, D., Le Roch, K.G., Abagyan, R., Winzeler, E.A. Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum. Science 298:216, 2002.

Washburn, M.P., Koller, A., Oshiro, G., Ulaszek, R.R., Plouffe, D., Deciu, C., Winzeler, E., Yates, J.R. III. Protein pathway and complex clustering of correlated mRNA and protein expression analyses in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. U. S. A. 100:3107, 2003.

Williams, R.M., Primig, M., Washburn, B.K., Winzeler, E.A., Bellis, M., Sarrauste de Menthiere, C., Davis, R.W., Esposito, R.E. The Ume6 regulon coordinates metabolic and meiotic gene expression in yeast. Proc. Natl. Acad. Sci. U. S. A. 99:13431, 2002.

Winzeler, E.A., Castillo-Davis, C.I., Oshiro, G., Liang, D., Richards, D.R., Zhou, Y., Hartl, D.L. Genetic diversity in yeast assessed with whole-genome oligonucleotide arrays. Genetics 163:79, 2003.