Pharma Focus Asia
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Model Behaviour

Han-Oh Park, CEO of Bioneer Korea

The use of biological models to study the effects of gene mutations is a cost-effective alternative to an animal model. The yeast Schizosaccharomyces pombe is a particularly useful tool for this process.

After the completion of the human genome project, now the main focus is shifting to the investigation of the relationship between human biology and disease by means of molecular biology, cell biology and genetics. To learn roles of disease-related human genes, it becomes more important to understand not only their corresponding protein's own functions, but also their intricate relationships to other proteins along the physiological pathways. Moreover, it is necessary to carry out systemic analysis on the relationship of a group of proteins with different functions, as well as related proteins, and how a series of events occurring in cells are linked. In this regard, it is desirable to develop model biological systems to order to elucidate biological functions of genes.

Model Biological Systems

An animal model is an ideal system for this purpose. However, it has many drawbacks in terms of feasibility, time and cost. Therefore, it is valuable to develop model biological systems such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster, and Caenorhabditis elegans to study biological function analysis of unknown or target genes, pathway analysis, and disease-causing mechanisms. In particular, S. cerevisiae and S. pombe have clear advantages over other model systems in that they are relatively easy to culture cheaply, genetic manipulations are easy, and experimental tools to analyse their biochemical and physiological functions are well established. Furthermore, with S. cerevisiae and S. pombe, it is easy to analyse biological role of a gene with minimal time and effort, because mutation or over-expression of a specific gene, or treatment by a certain chemical typically result in distinctive phenotypes that are easily observable

S. pombe, along with S. cerevisiae, has been known to be a model system for the study of cell division and signal transduction mechanism. In 2001, genome analysis of S. pombe revealed that it is functionally and structurally more similar to human than S. cerevisiae, which makes S. pombe an ideal alternative system that can be used to study the genes that are difficult to probe their functions with S. cerevisiae. Moreover, since S. pombe genome has an evolutionarily different origin from that of S. cerevisiae, they are complementary.

Gene deletion inside a cell is an essential tool to study the gene function and drug target validation. In particular, a deletion mutant library is useful for large-scale genetic function analysis, and drug target identification and validation. It is also useful to study cells as a single integrated system. In 2001 when the genome sequencing of S. pombe was complete, the Human Genome Laboratory at the Korea Advanced Institute of Bioscience and Biotechnology (KRIBB) decided to launch the genome-wide mutant project. From August 2001, through collaboration with Bioneer ,where oligonucleotides were designed and synthesized, and with funding form the Center for Functional Analysis of Human Genome, along with consultation by Dr Paul Nurse, the construction of genome-wide deletion mutant library for the whole genes of S. pombe began. It is expected that genome-wide deletion mutant library will be used for the functional genomics researches not just on S. pombe but also on mammalian and human, drug development, especially anticancer drug development, and systems biology

S. Pombe Genome Analysis

S. pombe genome project started in 1995 by the Sanger Institute with the funding from Welcome Trust Research Fund. During 1995–96, 66 per cent of chromosome 1 was sequenced. At the end of 1996, the European Commission funded the Welcome Trust Sanger Institute, and researchers from 12 European research teams joined the project and founded the Consortium. By August. 2001, the sequencing of 99.99 per cent of a genome was completed. Today, the whole genome, except the telomere regions of chromosome 1 and 2, has been completely sequenced. The genes were annotated by comparing homology with S. cerevisiae and other species, and the database in European Molecular Biology Laboratory (EMBL) is open through the Sanger Institute to provide S. pombe's genome, DNA sequences, and gene information.

It was reported that in S. pombe genome there are about 4900 ORFs, the smallest among eukaryotes. It is known that the S. pombe genome has small redundancy and structurally large intergenic region, and about 43 per cent of genes have 1-6 introns. When we compare S. pombe with S. cerevisiae genome, these two yeasts have different evolutionary origins. Although they are similar in size, the two genome sequences differ by about 30 per cent. Therefore, by comparing the genomes of the two yeasts, it is possible to obtain useful information provided by the public website at the Welcome Trust Sanger Institute.

Advantages of Using S. Pombe Systematic Deletion Mutant

S. pombe has been an important model system for the study of cell division and signal transduction mechanism. It was reported not only that its genes are highly homologous to human genes, but also that the pathways are similar in two species. Gene deletion inside a cell is an essential tool to study the gene function and drug target validation, and deletion mutant that lacks a specific gene is useful for gene function study through phenotype investigation.

Currently, the genome-wide deletion mutant library contains 4500 deletion mutants out of total 4900 S. pombe genes. By targeted mutagenesis, the entire ORFs of all mutants were completely deleted, which prevents any possible ambiguity in interpreting the experimental results that may be complicated by partial ORF deletion. In addition, because every constructed mutant is tagged by different tag sequence (barcode), it is easy to use a mutant pool to conduct large-scale biological function analysis. Moreover, it can be used for the drug development, especially for anti-cancer drugs, as a tool to investigate the action mode of a drug, and the molecular target identification and validation. It is also expected that it can contribute to the systems biology since it make possible to analyze a cell as a single integrated system.

Author Bio

Han-Oh Park
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