Yeast genome should provide insights to human disease

LONDON — The genome of the fission yeast, Schizosaccharomyces pombe, indicates that it is likely to be unexpectedly useful for research into human diseases. The fully annotated gene sequence published today in Nature suggests that the evolutionary leap from prokaryotic to eukaryotic life forms may have been much greater than the next step, from unicellular to multicellular eukaryotes. Results indicate that the genomes of multicellular eukaryotic organisms, including man, might be more similar to those of unicellular eukaryotes, such as yeasts, than had previously been suspected. The S. pombe genome also revealed that 50 of the nearly 5000 genes have significant similarity to genes associated with a range of human diseases, including cystic fibrosis, hereditary deafness and Type 2 diabetes; 23 of these genes were found to be related to genes involved in human cancers.S. pombe is the sixth eukaryotic organism to be sequenced, following S. cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Arabidopsis thaliana and man. It is a unicellular, free-living archiasmycete fungus first described in the 1950s, which grows on the skins of fruits in the wild. S. pombe is used in East Africa to produce a banana-based beer. Its genome has been decoded by more than 100 researchers working at the Wellcome Trust Sanger Institute and 13 other laboratories that together make up the S. pombe European Sequencing Consortium (EUPOM). A further 100kb of sequence was generated at the Cold Spring Harbor Laboratory.The genome has been completely sequenced to a high level of accuracy. The 13.8 Mb genome is distributed between three chromosomes: I (5.7 Mb), II (4.6 Mb) and III (3.5 Mb), together with a 20 kb mitochondrial genome. The entire sequence of the unique regions of the three chromosomes is now complete, with gaps in the centromeric regions of about 40 kb, and about 260 kb in the telomeric regions. Sequencing showed that S. pombe contains the smallest number of protein-coding genes, 4,824, yet recorded for a eukaryote.Decoding the S. pombe genome — which represents more than seven years of work — provides several important new insights into evolution, control of cell division and the key cellular processes associated with some human diseases. The researchers identified highly conserved genes important for eukaryotic cell organization, including those required for the cytoskeleton, the compartmentation of the cell, and processes within the cell, including cell-cycle control, proteolysis, protein phosphorylation and RNA splicing. They suggested that these genes might have originated with the appearance during evolution of eukaryotic life forms whose cells contain nuclei. Few similarly conserved genes were identified that were important for multicellular organization, suggesting that the transition from prokaryotes to eukaryotes required more new genes than the transition from unicellular to multicellular organization.Paul Nurse, director general of Cancer Research UK and one of the members of the research team, explained: "The highly conserved genes specific to eukaryotes may be necessary for eukaryotic cell organization to be generated. In contrast, the transition from unicellularity to multicellularity may not have required many new genes. Instead, it may have used genes already present in unicellular eukaryotes, perhaps by the shuffling of functional domains, to give rise to new combinations, which allowed the development of pathways required for the evolution of multicellularity." If these speculations are correct, they imply that the evolutionary transition from unicellular prokaryotic to unicellular eukaryotic life may have been more complex than the transition to multicellular life. This might provide some explanation as to why it took around 2300 million years to evolve from the first prokaryote to the first eukaryote (thought to have arisen around 3800 million and 1500 million years ago, respectively) but only 500 million years for the evolution of the first multicellular organisms, which appeared around 1000 million years ago.Because the team has achieved almost complete sequencing of the centromeres — the regions of the chromosomes ensuring correct separation during cell division — this provides the potential for clarifying how centromeres operate. One important finding was that a central element of nearly two kilobases in the centromere is 97% conserved. The genome was also found to have many introns: nearly 5000, in 43% of its genes versus only 5% of genes in S. cerevisiae. This makes the yeast a good model for exploring the role of introns.Not surprisingly, the 23 genes in the S. pombe genome that were found to be similar to human cancer genes are involved in DNA damage and repair, checkpoint controls and the cell cycle. Nurse pointed out: "Genomic stability is very important in cancer, so these genes are likely to be useful for studying cancer disease pathways." The genome also contains 12 genes similar to human genes involved in metabolic diseases, 13 genes similar to those found in neurological diseases, one similar to a cardiac disease gene and one similar to a renal disease gene.Nurse outlined the potential significance of the findings: "Many steps in yeast cell division use genes that are closely related to genes implicated in many human cancers. This small organism could prove vital in helping to better understand and treat cancer and other diseases." S. pombe is also useful because it can be manipulated particularly easily. "It grows rapidly and it is possible to change its genes easily. These are then accurately replicated, which makes it a very efficient model to work with."

Yeast genome should provide insights to human disease

The fission yeast genome contains 50 genes with similarity to genes involved in human diseases.

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