title: Evolution. Systematic humanization of yeast genes reveals conserved functions and genetic modularity.
abstract: To determine whether genes retain ancestral functions over a billion years of evolution and to identify principles of deep evolutionary divergence, we replaced 414 essential yeast genes with their human orthologs, assaying for complementation of lethal growth defects upon loss of the yeast genes. Nearly half (47%) of the yeast genes could be successfully humanized. Sequence similarity and expression only partly predicted replaceability. Instead, replaceability depended strongly on gene modules: Genes in the same process tended to be similarly replaceable (e.g., sterol biosynthesis) or not (e.g., DNA replication initiation). Simulations confirmed that selection for specific function can maintain replaceability despite extensive sequence divergence. Critical ancestral functions of many essential genes are thus retained in a pathway-specific manner, resilient to drift in sequences, splicing, and protein interfaces.
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Aashiq H
authors.initials: AH
authors.lastname: Kachroo
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Laurent
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Yellman
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA. Center for Computational Biology and Bioinformatics, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Meyer
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA. Center for Computational Biology and Bioinformatics, University of Texas at Austin, Austin, TX 78712, USA. Department of Integrative Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Claus O
authors.initials: CO
authors.lastname: Wilke
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA. Center for Computational Biology and Bioinformatics, University of Texas at Austin, Austin, TX 78712, USA. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA. marcotte@icmb.utexas.edu.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Marcotte
mesh_terms: D003198:Computer Simulation; D004261:DNA Replication / Q000235:genetics; D019143:Evolution, Molecular; D020043:Genes, Essential / Q000235:genetics / Q000502:physiology*; D005800:Genes, Fungal / Q000235:genetics / Q000502:physiology*; D006801:Humans; D012326:RNA Splicing / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D012641:Selection, Genetic; D013261:Sterols / Q000096:biosynthesis
chemical_list: D013261:Sterols