Genomics

Edited by: Steve Bunk A. Goffeau, B.G. Barrell, H. Bussey, R.W. Davis, B. Dujon, H. Feldmann, F. Galibert, J.D. Hoheisel, C. Jacq, M. Johnston, E.J. Louis, H.W. Mewes, Y. Murakami, P. Philippsen, H. Tettelin, S.G. Oliver, "Life with 6000 genes," Science, 274:546-67, 1996. (Cited in more than 250 papers since publication) Comments by Steve Oliver , professor, Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, United Kingdom, and Andre Goffeau , professor of biochemistry, Unite de Biochimie Physiologique, Universite Catholique de Louvain, Belgium Steve Oliver In genetics, reverse engineering has just about had its day. The rise of whole-genome sequen- cing means that researchers no longer are forced to trace back a change in biological function to a specific gene or genes. Instead, studying the form of the complete genome can reveal the functions of individual genes. This paper had good reason to predict such a reversal in the traditional path of genetic research. It gave the scientific community a platform for analyzing the functions of eukaryotes, organisms with membrane-bound nuclei and cellular organelles, including all plants and animals. The platform these researchers provided was the first complete genome sequencing of a eukaryote, the yeast Saccharomyces cerevisiae, in which they found 5,885 potential protein-encoding genes. It isn't surprising that many scientists worldwide--and not just yeast geneticists--now examine S. cerevisiae's whole genome almost daily in their work, given the extensive similarities in the amino acid sequences of yeast proteins and those of higher organisms, including humans. What did surprise senior author Steve Oliver was the extent of redundancy within the yeast genome, the existence of sets of two or more genes encoding proteins with identical or very similar sequences. It appears likely that the origin of this redundancy was a complete duplication of the genome at some time in the yeast's evolutionary history after the divergence of the genus Saccharomyce from that of Kluyveromyces.1 The paper suggests that redundancy "may be more apparent than real," based on a long-standing theory that genetic duplication could be a major source of innovation in evolution.2 "One of a duplicated pair of genes is freed from the constraints of selection and may evolve new, and selectively advantageous, functions," Oliver explains. "As the functional analysis of the yeast genome proceeds, we see many examples of this, and also of genes drifting into a nonfunctional state." Lead author Andre Goffeau adds that one of the most intriguing redundancies of genes in yeast concerns the ABC transporters, involved in functions related to drug resistance. "As many as 16 homologous transporters can be identified in yeast," he notes. "The evolutionary history of this family is not clear but this particular redundancy has important practical consequences for the development of new fungicides, which are badly needed today." Oliver is now leading detailed functional analysis of 814 novel yeast genes through a large European network of laboratories. In Phase II of that project, the European labs will collaborate with others in the United States and Canada to produce, within two years, a functional map that shows the direct and indirect interactions of all the yeast's genes. This will be a major step toward achieving functional mapping of the genomes of higher organisms onto that of yeast. Oliver is no stranger to such large-scale collaborations. He initiated the sequencing of the S. cerevisiae genome, a project led by Goffeau that eventually involved about 600 scientists in Europe, North America, and Japan, working over a six-year period. At the end, the two cowrote this paper. The immediate goals of Oliver's own lab are to study yeasts within the genus Saccharomyces or closely related to it, to shed further light on yeast genome evolution, and "to discover something about the molecular basis of speciation." He says pharmaceutical companies interested in developing antifungal drugs are keeping a close eye on the emerging functional data from S. cerevisiae, particularly the identification of essential genes. K.H. Wolfe, D.C. Shields, "Molecular evidence for an ancient duplication of the entire yeast genome," Nature, 387:708-13, 1997. S. Ohno, Evolution Through Gene Duplication, London, Allen and Unwin, 1970.

Genomics

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