Search

Background In the model eukaryote, Saccharomyces cerevisiae, previous experiments have identified those genes that exert the most significant control over cell growth rate. These genes are termed HFC for high flux control. Such genes are overrepresented within pathways controlling the mitotic cell cycle. Results We postulated that the increase/decrease in growth rate is due to a change in the rate of progression through specific cell cycle steps. We extended and further developed an existing logical model of the yeast cell cycle in order elucidate how the HFC genes modulated progress through the cycle. This model can simulate gene dosage-variation and calculate the cycle time, determine the order and relative speed at which events occur, and predict arrests and failures to correctly execute a step. To experimentally test our model's predictions, we constructed a tetraploid series of deletion mutants for a set of eight genes that control the G2/M transition. This system allowed us to vary gene copy number through more intermediate levels than previous studies and examine the impact of copy-number variation on growth, cell-cycle phenotype, and response to different cellular stresses. Conclusions For the majority of strains, the predictions agreed with experimental observations, validating our model and its use for further predictions. Where simulation and experiment diverged, we uncovered both novel tetraploid-specific phenotypes and a switch in the determinative execution point of a key cell-cycle regulator, the Cdc28 kinase, from the G1/S to the S/G2 boundaries. [ABSTRACT FROM AUTHOR]

Background: Copy-number variation (CNV), rather than complete loss of gene function, is increasingly implicated in human disease. Moreover, gene dosage is recognised as important in tumourigenesis, and there is an increasing realisation that CNVs may not be just symptomatic of the cancerous state but may, in fact, be causative. However, the identification of CNV-related phenotypes for mammalian genes is a slow process, due to the technical difficulty of constructing deletion mutants. Using the genome-wide deletion library for the model eukaryote, Saccharomyces cerevisiae, we have identified genes (termed haploproficient, HP) which, when one copy is deleted from a diploid cell, result in an increased rate of proliferation. Since haploproficiency under nutrient-sufficient conditions is a novel phenotype, we sought here to characterise a subset of the yeast haploproficient genes which seem particularly relevant to human cancers. Results: We show that, for a subset of HP genes, heterozygous deletion is sufficient to cause aberrant cell cycling and altered rates of apoptosis, phenotypes associated with cancer in mammalian cells. A majority of these yeast genes are the orthologs of mammalian cancer genes, and hence our studies suggest that CNV of these oncogenic orthologs may be sufficient to lead to tumourigenesis in human cells. Moreover, where not already implicated, this cluster of cancer-like phenotypes in this model eukaryote may be predictive of the involvement in cancer of the mammalian orthologs of these yeast HP genes. Using the yeast set as a model, we show that the response to a range of anti-cancer drugs is strongly dependent on gene dosage, such that intermediate concentrations of the drugs can actually increase a mutant's growth rate. Conclusions: The exploitation of data on the phenotypic impact of heterozygosis in Saccharomyces cerevisiae has permitted the prediction of CNVs affecting tumourigenesis in humans. Our yeast data also suggest that the identification of CNVs in tumour cells may assist both the selection of anti-cancer drugs and the dosages at which they should be administered if they are to be a beneficial, rather than a deleterious, therapy. [ABSTRACT FROM AUTHOR]

Background: Haploinsufficient (HI) genes are those for which a reduction in copy number in a diploid from two to one results in significantly reduced fitness. Haploinsufficiency is increasingly implicated in human disease, and so predicting this phenotype could provide insights into the genetic mechanisms behind many human diseases, including some cancers. Results: In the present work we show that orthologues of Saccharomyces cerevisiae HI genes are preferentially retained across the kingdom Fungi, and that the HI genes of S. cerevisiae can be used to predict haploinsufficiency in humans. Our HI gene predictions confirm known associations between haploinsufficiency and genetic disease, and predict several further disorders in which the phenotype may be relevant. Haploinsufficiency is also clearly relevant to the gene-dosage imbalances inherent in eukaryotic sex-determination systems. In S. cerevisiae, HI genes are over-represented on chromosome III, the chromosome that determines yeast's mating type. This may be a device to select against the loss of one copy of chromosome III from a diploid. We found that orthologues of S. cerevisiae HI genes are also over-represented on the mating-type chromosomes of other yeasts and filamentous fungi. In animals with heterogametic sex determination, accumulation of HI genes on the sex chromosomes would compromise fitness in both sexes, given X chromosome inactivation in females. We found that orthologues of S. cerevisiae HI genes are significantly under-represented on the X chromosomes of mammals and of Caenorhabditis elegans. There is no X inactivation in Drosophila melanogaster (increased expression of X in the male is used instead) and, in this species, we found no depletion of orthologues to yeast HI genes on the sex chromosomes. Conclusion: A special relationship between HI genes and the sex/mating-type chromosome extends from S. cerevisiae to Homo sapiens, with the microbe being a useful model for species throughout the evolutionary range. Furthermore, haploinsufficiency in yeast can predict the phenotype in higher organisms. [ABSTRACT FROM AUTHOR]