Why Are There Still over 1000 Uncharacterized Yeast Genes?

By Hughes, Timothy R. | Genetics, May 2007 | Go to article overview

Why Are There Still over 1000 Uncharacterized Yeast Genes?


Hughes, Timothy R., Genetics


ABSTRACT

The yeast genetics community has embraced genomic biology, and there is a general understanding that obtaining a full encyclopedia of functions of the ~6000 genes is a worthwhile goal. The yeast literature comprises over 40,000 research papers, and the number of yeast researchers exceeds the number of genes. There are mutated and tagged alleles for virtually every gene, and hundreds of high-throughput data sets and computational analyses have been described. Why, then, are there >1000 genes still listed as uncharacterized on the Saccharomyces Genome Database, 10 years after sequencing the genome of this powerful model organism? Examination of the currently uncharacterized gene set suggests that while some are small or newly discovered, the vast majority were evident from the initial genome sequence. Most are present in multiple genomics data sets, which may provide clues to function. In addition, roughly half contain recognizable protein domains, and many of these suggest specific metabolic activities. Notably, the uncharacterized gene set is highly enriched for genes whose only homologs are in other fungi. Achieving a full catalog of yeast gene functions may require a greater focus on the life of yeast outside the laboratory.

SEVERAL years ago we projected that, judging from the steady and predictable increase in database entries, all yeast genes would have "known" functions by mid-2007 (HUGHES et al. 2004). This was an optimistic estimate, since what was known at the time about many of the "known" genes wasunsatisfying (or evenconflicting) in terms of actual understanding of physiological purpose or molecular role. Nonetheless, it seemed reasonable, and still does, that yeast will be the first organismfor which the functions of all the genes are characterized to a degree that would satisfy most molecular biologists.

Characterizing the functions of all of the yeast genes is not a senseless academic pursuit. Yeast is a part of everyday life, being critical to baking and brewing. Yeasts can also be pathogenic. Much of what is known about how all eukaryotic cells work has come from studying yeast. And the possibility that something would be known about virtually all yeast genes only a decade or so after the initial sequencing [at which time only ~1000 genes appeared in the literature, and roughly half could be ascribed some function on the basis of sequence features (GOFFEAU et al. 1996)] could be taken as a harbinger of whatmight eventually be anticipated from similar efforts in more complicated organisms with larger genomes and more genes, such as humans. Examination of the path taken to such an achievement, including any hurdles or missteps, should provide a level of guidance. Although many organisms now have a genome sequence and a set of useful genetic tools, yeast has been the major proving ground for large-scale application of new technologies, and in many respects remains the advance guard of functional genomics, proteomics, and systems biology, as outlined in other recent reviews (BADER et al. 2003; MUSTACCHI et al. 2006; SUTER et al. 2006). Knowing what all the parts do is important if you want to know how a machine works.

It is now mid-2007. Are the functions of all 6000 yeast genes "known"? Given a very liberal definition of known function, this goal has nearly been reached. The commercial database used in our initial time line (HUGHES et al. 2004) is no longer freely available. We therefore examined information present in the Saccharomyces Genome Database (SGD) (NASH et al. 2007), the public database that curates the yeast genes and also compilesGeneOntology(GO)annotations,publications, interactions, and a host of additional information. As of March 20, 2007, there are only 38 genes with no information available whatsoever, and only 566 lack any annotations in any of the three major branches of Gene Ontology (biological process, molecular function, or cellular component), which is a somewhat fluid categorical data structure that incorporates information with a variety of evidence levels (ASHBURNER et al. …

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