title: Gene Essentiality Is a Quantitative Property Linked to Cellular Evolvability.
abstract: Gene essentiality is typically determined by assessing the viability of the corresponding mutant cells, but this definition fails to account for the ability of cells to adaptively evolve to genetic perturbations. Here, we performed a stringent screen to assess the degree to which Saccharomyces cerevisiae cells can survive the deletion of ~1,000 individual "essential" genes and found that ~9% of these genetic perturbations could in fact be overcome by adaptive evolution. Our analyses uncovered a genome-wide gradient of gene essentiality, with certain essential cellular functions being more "evolvable" than others. Ploidy changes were prevalent among the evolved mutant strains, and aneuploidy of a specific chromosome was adaptive for a class of evolvable nucleoporin mutants. These data justify a quantitative redefinition of gene essentiality that incorporates both viability and evolvability of the corresponding mutant cells and will enable selection of therapeutic targets associated with lower risk of emergence of drug resistance.
authors.affiliation: Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Gaowen
authors.initials: G
authors.lastname: Liu
authors.affiliation: Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore.
authors.forename: Mei Yun Jacy
authors.initials: MY
authors.lastname: Yong
authors.affiliation: Singapore Immunology Network (SIgN), A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Marina
authors.initials: M
authors.lastname: Yurieva
authors.affiliation: Singapore Immunology Network (SIgN), A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Kandhadayar Gopalan
authors.initials: KG
authors.lastname: Srinivasan
authors.affiliation: Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore.
authors.forename: Jaron
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore.
authors.forename: John Soon Yew
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Singapore Immunology Network (SIgN), A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore.
authors.forename: Graham Daniel
authors.initials: GD
authors.lastname: Wright
authors.affiliation: Singapore Immunology Network (SIgN), A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zolezzi
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore (NUS) and National University Health System, Singapore 117549, Singapore.
authors.forename: Hyungwon
authors.initials: H
authors.lastname: Choi
authors.affiliation: Singapore Immunology Network (SIgN), A(∗)STAR, Singapore 138648, Singapore. Electronic address: norman_pavelka@immunol.a-star.edu.sg.
authors.forename: Norman
authors.initials: N
authors.lastname: Pavelka
authors.affiliation: Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138648, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore. Electronic address: giulia.rancati@imb.a-star.edu.sg.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rancati
mesh_terms: D005075:Biological Evolution; D017353:Gene Deletion; D020043:Genes, Essential; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000145:classification / Q000166:cytology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013172:Spores, Fungal / Q000378:metabolism
chemical_list: C435210:Brr6 protein, S cerevisiae; D008565:Membrane Proteins; C091559:NUP57 protein, S cerevisiae; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins