Biology subjects

Ohya, Y.

Publications and source records attributed to Ohya, Y..

3 recordsLinked to original sources

bioRxiv2017

Large-scale interpretation of chemical-genetic interaction profiles using a genetic interaction network

Chemical-genetic interactions - observed when the treatment of mutant cells with chemical compounds reveals unexpected phenotypes - contain rich functional information linking compounds to their cellular modes of action. To systematically identify these interactions, an array of mutants is challenged with a compound and monitored for fitness defects, generating a chemical-genetic interaction profile that provides a quantitative, unbiased description of the cellular function(s) perturbed by the compound. Genetic interactions, obtained from genome-wide double-mutant screens, provide a key for interpreting the functional information contained in chemical-genetic interaction profiles. Despite the utility of this approach, integrative analyses of genetic and chemical-genetic interaction networks have not been systematically evaluated. We developed a method, called CG-TARGET (Chemical Genetic Translation via A Reference Genetic nETwork), that integrates large-scale chemical-genetic interaction screening data with a genetic interaction network to predict the biological processes perturbed by compounds. CG-TARGET compared favorably to a baseline enrichment approach across a variety of benchmarks, achieving similar accuracy while substantially improving the ability to control the false discovery rate of biological process predictions. We applied CG-TARGET to a recent screen of nearly 14,000 chemical compounds in Saccharomyces cerevisiae, integrating this dataset with the global S. cerevisiae genetic interaction network to prioritize over 1500 compounds with high-confidence biological process predictions for further study. Upon investigation of the compatibility of chemical-genetic and genetic interaction profiles, we observed that one-third of observed chemical-genetic interactions contributed to the highest-confidence biological process predictions and that negative chemical-genetic interactions overwhelmingly formed the basis of these predictions. We present here a detailed characterization of the CG-TARGET method along with experimental validation of predicted biological process targets, focusing on inhibitors of tubulin polymerization and cell cycle progression. Our approach successfully demonstrates the use of genetic interaction networks in the functional annotation of compounds to biological processes.

systems biology↗

bioRxiv2017

Functional Annotation of Chemical Libraries across Diverse Biological Processes

Chemical-genetic approaches offer the potential for unbiased functional annotation of chemical libraries. Mutations can alter the response of cells to a compound, revealing chemical-genetic interactions that can elucidate a compounds mode of action. We developed a highly parallel and unbiased yeast chemical-genetic screening system involving three key components. First, in a drug-sensitive genetic background, we constructed an optimized, diagnostic mutant collection that is predictive all major yeast biological processes. Second, we implemented a multiplexed (768-plex) barcode sequencing protocol, enabling assembly of thousands of chemical-genetic profiles. Finally, based on comparison of the chemical-genetic profiles with a compendium of genome-wide genetic interaction profiles, we predicted compound functionality. Applying this high-throughput approach, we screened 7 different compound libraries and annotated their functional diversity. We further validated biological process predictions, prioritized a diverse set of compounds, and identified compounds that appear to have dual modes of action.

systems biology↗

bioRxiv2016

Testing the neutral hypothesis of phenotypic evolution

It is generally accepted that a large fraction of genomic sequence variations within and between species are neutral or nearly so1. Whether the same is true for phenotypic variations is a central question in biology2-7. On the one hand, numerous phenotypic adaptations have been documented2,8,9 and even Kimura, the champion of the neutral theory of molecular evolution, believed in widespread adaptive phenotypic evolution1. On the other hand, phenotypic studies are strongly biased toward traits that are likely to be adaptive9, contrasting genomic studies that are typically unbiased. It is thus desirable to test the neutral hypothesis of phenotypic evolution using traits irrespective of their potential involvement in adaptation. Here we present such a test for 210 morphological traits measured in multiple strains of the yeast Saccharomyces cerevisiae and two related species. Our test is based on the premise that, under neutrality, the rate of phenotypic evolution declines as the trait becomes more important to fitness, analogous to the neutral paradigm that functional genes evolve more slowly than functionless pseudogenes10. Neutrality is rejected in favor of adaptation if important traits evolve faster than less important ones, parallel to the demonstration of molecular adaptation when a functional gene evolves faster than pseudogenes. After controlling for the mutational size, we find faster evolution of more important morphological traits within and between species. By contrast, an analysis of 3466 yeast gene expression traits fails to reject neutrality. Thus, yeast morphological evolution is largely adaptive, but the same may not apply to other classes of phenotypes.

evolutionary biology↗