Abstract
AbstractEukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug–gene and gene–gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background.
Publisher
Springer Science and Business Media LLC
Subject
Applied Mathematics,Computer Science Applications,Drug Discovery,General Biochemistry, Genetics and Molecular Biology,Modeling and Simulation
Reference87 articles.
1. Falconer, D. S. & MacKay, T. F. C. Introduction to Quantitative Genetics. (Longmans Green, Harlow, Essex, UK, 1996).
2. Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010).
3. Chari, S. & Dworkin, I. The conditional nature of genetic interactions: the consequences of wild-type backgrounds on mutational interactions in a genome-wide modifier screen. PLoS Genet. 9, e1003661 (2013).
4. Dowell, R. D. et al. Genotype to phenotype: a complex problem. Science 328, 469 (2010).
5. Forsberg, S. K. G., Bloom, J. S., Sadhu, M. J., Kruglyak, L. & Carlborg, Ö. Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast. Nat. Genet. 49, 497–503 (2017).
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