title: Allele-specific behavior of molecular networks: understanding small-molecule drug response in yeast.
abstract: The study of systems genetics is changing the way the genetic and molecular basis of phenotypic variation, such as disease susceptibility and drug response, is being analyzed. Moreover, systems genetics aids in the translation of insights from systems biology into genetics. The use of systems genetics enables greater attention to be focused on the potential impact of genetic perturbations on the molecular states of networks that in turn affects complex traits. In this study, we developed models to detect allele-specific perturbations on interactions, in which a genetic locus with alternative alleles exerted a differing influence on an interaction. We utilized the models to investigate the dynamic behavior of an integrated molecular network undergoing genetic perturbations in yeast. Our results revealed the complexity of regulatory relationships between genetic loci and networks, in which different genetic loci perturb specific network modules. In addition, significant within-module functional coherence was found. We then used the network perturbation model to elucidate the underlying molecular mechanisms of individual differences in response to 100 diverse small molecule drugs. As a result, we identified sub-networks in the integrated network that responded to variations in DNA associated with response to diverse compounds and were significantly enriched for known drug targets. Literature mining results provided strong independent evidence for the effectiveness of these genetic perturbing networks in the elucidation of small-molecule responses in yeast.
authors: College of Bioinformatics Science and Technology and The Second Affiliated Hospital, Harbin Medical University, Harbin, PR China.
authors: Fan
authors: F
authors: Zhang
authors: Bo
authors: B
authors: Gao
authors: Liangde
authors: L
authors: Xu
authors: Chunquan
authors: C
authors: Li
authors: Dapeng
authors: D
authors: Hao
authors: Shaojun
authors: S
authors: Zhang
authors: Meng
authors: M
authors: Zhou
authors: Fei
authors: F
authors: Su
authors: Xi
authors: X
authors: Chen
authors: Hui
authors: H
authors: Zhi
authors: Xia
authors: X
authors: Li
mesh_terms: D000483:Alleles; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D004843:Epistasis, Genetic / Q000187:drug effects; D053263:Gene Regulatory Networks; D006861:Hydrogen Peroxide / Q000494:pharmacology; D046228:Microarray Analysis; D008957:Models, Genetic; D010597:Pharmacogenetics; D010641:Phenotype; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D049490:Systems Biology
chemical_list: D054316:Biomarkers, Pharmacological; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D006861:Hydrogen Peroxide