title: Translation of Genotype to Phenotype by a Hierarchy of Cell Subsystems.
abstract: Accurately translating genotype to phenotype requires accounting for the functional impact of genetic variation at many biological scales. Here we present a strategy for genotype-phenotype reasoning based on existing knowledge of cellular subsystems. These subsystems and their hierarchical organization are defined by the Gene Ontology or a complementary ontology inferred directly from previously published datasets. Guided by the ontology's hierarchical structure, we organize genotype data into an "ontotype," that is, a hierarchy of perturbations representing the effects of genetic variation at multiple cellular scales. The ontotype is then interpreted using logical rules generated by machine learning to predict phenotype. This approach substantially outperforms previous, non-hierarchical methods for translating yeast genotype to cell growth phenotype, and it accurately predicts the growth outcomes of two new screens of 2,503 double gene knockouts impacting DNA repair or nuclear lumen. Ontotypes also generalize to larger knockout combinations, setting the stage for interpreting the complex genetics of disease.
authors.affiliation: Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla CA 92093, USA; Department of Medicine, University of California San Diego, La Jolla CA 92093, USA.
authors.forename: Michael Ku
authors.initials: MK
authors.lastname: Yu
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla CA 92093, USA; Biomedical Sciences Program, University of California San Diego, La Jolla CA 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla CA 92093, USA; Data4Cure, La Jolla, CA 92037, USA.
authors.forename: Janusz
authors.initials: J
authors.lastname: Dutkowski
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla CA 92093, USA; Department of Bioengineering, University of California San Diego, La Jolla CA 92093, USA.
authors.forename: Rohith
authors.initials: R
authors.lastname: Srivas
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla CA 92093, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Licon
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla CA 92093, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kreisberg
authors.affiliation: aTyr Pharmaceuticals, San Diego, CA 92121, USA.
authors.forename: Cherie T
authors.initials: CT
authors.lastname: Ng
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco 94143, USA.
authors.forename: Nevan
authors.initials: N
authors.lastname: Krogan
authors.affiliation: Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv 69978, Israel.
authors.forename: Roded
authors.initials: R
authors.lastname: Sharan
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla CA 92093, USA.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker