title: An extended set of yeast-based functional assays accurately identifies human disease mutations.
abstract: We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease- and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods.
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden;
authors.forename: Song
authors.initials: S
authors.lastname: Sun
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors.forename: Guihong
authors.initials: G
authors.lastname: Tan
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors.forename: Michael
authors.initials: M
authors.lastname: Costanzo
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA;
authors.forename: Rose
authors.initials: R
authors.lastname: Oughtred
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA;
authors.forename: Jodi
authors.initials: J
authors.lastname: Hirschman
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA;
authors.forename: Chandra L
authors.initials: CL
authors.lastname: Theesfeld
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors.forename: Pritpal
authors.initials: P
authors.lastname: Bansal
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Song
authors.initials: S
authors.lastname: Yi
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors.forename: Analyn
authors.initials: A
authors.lastname: Yu
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors.forename: Tanya
authors.initials: T
authors.lastname: Tyagi
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors.forename: Cathy
authors.initials: C
authors.lastname: Tie
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Andrews
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA;
authors.forename: Kara
authors.initials: K
authors.lastname: Dolinski
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Canadian Institute for Advanced Research, Toronto, Ontario, M5G 1Z8, Canada.
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Roth
mesh_terms: D005816:Genetic Complementation Test / Q000379:methods*; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D006801:Humans; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic