Dataset Information

Multiple kinases and system robustness: a link between Cdc37 and genome integrity.

ABSTRACT: We identified 38 genes as having a genetic interaction with a mutant form of the kinase specific chaperone, Cdc37, using a genome-wide synthetic screening approach. The identified genes included a sub-network of highly interacting genes enriched for functions in genome integrity and comprising multiple components of several discrete molecular machines. A network analysis approach related these machines to a small group of cell cycle checkpoint kinases.

SUBMITTER: Caplan AJ

PROVIDER: S-EPMC3045565 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Multiple kinases and system robustness: a link between Cdc37 and genome integrity.

Caplan Avrom J AJ Ma'ayan Avi A Willis Ian M IM

Cell cycle (Georgetown, Tex.) 20071003 24

We identified 38 genes as having a genetic interaction with a mutant form of the kinase specific chaperone, Cdc37, using a genome-wide synthetic screening approach. The identified genes included a sub-network of highly interacting genes enriched for functions in genome integrity and comprising multiple components of several discrete molecular machines. A network analysis approach related these machines to a small group of cell cycle checkpoint kinases. ...[more]

PMID: 18075309

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Project description:Deleterious mutations inevitably emerge in any evolutionary process and are speculated to decisively influence the structure of the genome. Meiosis, which is thought to play a major role in handling mutations on the population level, recombines chromosomes via non-randomly distributed hot spots for meiotic recombination. In many genomes, various types of genetic elements are distributed in patterns that are currently not well understood. In particular, important (essential) genes are arranged in clusters, which often cannot be explained by a functional relationship of the involved genes. Here we show by computer simulation that essential gene (EG) clustering provides a fitness benefit in handling deleterious mutations in sexual populations with variable levels of inbreeding and outbreeding. We find that recessive lethal mutations enforce a selective pressure towards clustered genome architectures. Our simulations correctly predict (i) the evolution of non-random distributions of meiotic crossovers, (ii) the genome-wide anti-correlation of meiotic crossovers and EG clustering, (iii) the evolution of EG enrichment in pericentromeric regions and (iv) the associated absence of meiotic crossovers (cold centromeres). Our results furthermore predict optimal crossover rates for yeast chromosomes, which match the experimentally determined rates. Using a Saccharomyces cerevisiae conditional mutator strain, we show that haploid lethal phenotypes result predominantly from mutation of single loci and generally do not impair mating, which leads to an accumulation of mutational load following meiosis and mating. We hypothesize that purging of deleterious mutations in essential genes constitutes an important factor driving meiotic crossover. Therefore, the increased robustness of populations to deleterious mutations, which arises from clustered genome architectures, may provide a significant selective force shaping crossover distribution. Our analysis reveals a new aspect of the evolution of genome architectures that complements insights about molecular constraints, such as the interference of pericentromeric crossovers with chromosome segregation.

Dataset Information

Multiple kinases and system robustness: a link between Cdc37 and genome integrity.

Publications

Multiple kinases and system robustness: a link between Cdc37 and genome integrity.

Similar Datasets

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