title: Chromosome-Specific and Global Effects of Aneuploidy in Saccharomyces cerevisiae.
abstract: Aneuploidy, an unbalanced karyotype in which one or more chromosomes are present in excess or reduced copy number, causes an array of known phenotypes including proteotoxicity, genomic instability, and slowed proliferation. However, the molecular consequences of aneuploidy are poorly understood and an unbiased investigation into aneuploid cell biology is lacking. We performed high-throughput screens for genes the deletion of which has a synthetic fitness cost in aneuploidy Saccharomyces cerevisiae cells containing single extra chromosomes. This analysis identified genes that, when deleted, decrease the fitness of specific disomic strains as well as those that impair the proliferation of a broad range of aneuploidies. In one case, a chromosome-specific synthetic growth defect could be explained fully by the specific duplication of a single gene on the aneuploid chromosome, highlighting the ability of individual dosage imbalances to cause chromosome-specific phenotypes in aneuploid cells. Deletion of other genes, particularly those involved in protein transport, however, confers synthetic sickness on a broad array of aneuploid strains. Indeed, aneuploid cells, regardless of karyotype, exhibit protein secretion and cell-wall integrity defects. Thus, we were able to use this screen to identify novel cellular consequences of aneuploidy, dependent on both specific chromosome imbalances and caused by many different aneuploid karyotypes. Interestingly, the vast majority of cancer cells are highly aneuploid, so this approach could be of further use in identifying both karyotype-specific and nonspecific stresses exhibited by cancer cells as potential targets for the development of novel cancer therapeutics.
authors.affiliation: Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
authors.forename: Stacie E
authors.identifier: http://orcid.org/0000-0002-3129-8853
authors.initials: SE
authors.lastname: Dodgson
authors.affiliation: Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
authors.forename: Sharon
authors.initials: S
authors.lastname: Kim
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario M5S3E1, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S3E1, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Costanzo
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, New Jersey 08544-1014.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Baryshnikova
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
authors.forename: Darcy L
authors.initials: DL
authors.lastname: Morse
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Kaiser
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario M5S3E1, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S3E1, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.affiliation: Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142 angelika@mit.edu.
authors.forename: Angelika
authors.initials: A
authors.lastname: Amon
mesh_terms: D000782:Aneuploidy; D015825:Chromosomes, Fungal; D017353:Gene Deletion; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D056084:Genetic Fitness; D059785:Karyotype; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D000072020:Synthetic Lethal Mutations / Q000235:genetics
chemical_list: D029701:Saccharomyces cerevisiae Proteins
keywords: aneuploidy; dosage imbalance; protein transport; synthetic lethality
references.citation: Nat Genet. 2000 Jul;25(3):333-7
references.pmid: 10888885
references.citation: Mol Cell. 1998 Apr;1(5):639-48
references.pmid: 9660948
references.citation: Genes Dev. 2015 May 1;29(9):898-903
references.pmid: 25934502
references.citation: Clin Neuropathol. 2005 Sep-Oct;24(5):209-18
references.pmid: 16167544
references.citation: Exp Cell Res. 2010 Dec 10;316(20):3351-7
references.pmid: 20846524
references.citation: Methods Enzymol. 1991;194:697-710
references.pmid: 2005817
references.citation: Elife. 2014 Jul 29;3:e03023
references.pmid: 25073701
references.citation: Genes Dev. 2012 Dec 15;26(24):2696-708
references.pmid: 23222101
references.citation: Int J Clin Exp Pathol. 2013 Jun 15;6(7):1230-44
references.pmid: 23826405
references.citation: Nature. 2012 Jan 29;482(7384):246-50
references.pmid: 22286062
references.citation: Annu Rev Biochem. 1999;68:89-125
references.pmid: 10872445
references.citation: Genes Dev. 1999 Mar 1;13(5):532-44
references.pmid: 10072382
references.citation: Cell. 2015 Feb 12;160(4):771-84
references.pmid: 25679766
references.citation: Science. 2001 Dec 14;294(5550):2364-8
references.pmid: 11743205
references.citation: Genetics. 2014 Jun;197(2):451-65
references.pmid: 24939991
references.citation: G3 (Bethesda). 2013 Oct 03;3(10):1741-51
references.pmid: 23979930
references.citation: FEMS Yeast Res. 2005 Jun;5(9):823-8
references.pmid: 15925310
references.citation: J Biol Chem. 2005 Jul 29;280(30):27613-23
references.pmid: 15932880
references.citation: Cell. 2010 Oct 1;143(1):71-83
references.pmid: 20850176
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8542-7
references.pmid: 11447286
references.citation: J Biol Chem. 1993 Mar 15;268(8):5345-8
references.pmid: 8449896
references.citation: Traffic. 2012 Feb;13(2):317-28
references.pmid: 22082017
references.citation: Int J Biochem Cell Biol. 2005 Jan;37(1):48-53
references.pmid: 15381149
references.citation: Science. 2010 Jan 22;327(5964):425-31
references.pmid: 20093466
references.citation: Histochem Cell Biol. 1998 May-Jun;109(5-6):571-90
references.pmid: 9681636
references.citation: Nat Cell Biol. 2003 Jul;5(7):661-7
references.pmid: 12778054
references.citation: Genome Res. 2013 Feb;23(2):300-11
references.pmid: 23275495
references.citation: Eur J Biochem. 1992 Nov 1;209(3):951-9
references.pmid: 1425702
references.citation: Nature. 2010 Nov 11;468(7321):321-5
references.pmid: 20962780
references.citation: Nat Methods. 2012 Feb 05;9(4):373-8
references.pmid: 22306811
references.citation: Mol Cell. 2006 Feb 3;21(3):319-30
references.pmid: 16455487
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D502-7
references.pmid: 19880385
references.citation: Genetics. 2002 Nov;162(3):1091-9
references.pmid: 12454058
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Mol Biol Cell. 2013 May;24(9):1274-89
references.pmid: 23468524
references.citation: Nat Methods. 2010 Dec;7(12):1017-24
references.pmid: 21076421
references.citation: Nucleic Acids Res. 2013 Jul;41(Web Server issue):W591-6
references.pmid: 23677617
references.citation: Trends Cell Biol. 2006 Feb;16(2):113-20
references.pmid: 16406524
references.citation: Mol Biol Cell. 2010 Sep 1;21(17):3054-69
references.pmid: 20610658
references.citation: J Cell Sci. 2000 Sep;113 ( Pt 18):3309-19
references.pmid: 10954428
references.citation: Genetics. 1993 Nov;135(3):677-91
references.pmid: 8293973
references.citation: J Antimicrob Chemother. 2000 Aug;46(2):191-7
references.pmid: 10933640
references.citation: Nature. 2002 Jul 25;418(6896):387-91
references.pmid: 12140549
references.citation: Biochemistry. 2009 Sep 15;48(36):8494-504
references.pmid: 19670905
references.citation: Science. 2008 Oct 31;322(5902):703-9
references.pmid: 18974345
references.citation: Cell Oncol. 2006;28(3):71-84
references.pmid: 16823176
references.citation: J Cell Biol. 2002 May 13;157(4):631-43
references.pmid: 12011112
references.citation: Science. 2007 Aug 17;317(5840):916-24
references.pmid: 17702937
references.citation: Nat Protoc. 2006;1(5):2253-6
references.pmid: 17406464
references.citation: Science. 2011 Aug 19;333(6045):1026-30
references.pmid: 21852501
references.citation: Cell. 2011 Feb 18;144(4):499-512
references.pmid: 21315436
references.citation: Mol Biol Cell. 2002 May;13(5):1484-500
references.pmid: 12006647
references.citation: Mol Biol Cell. 2015 Apr 15;26(8):1440-51
references.pmid: 25694455
references.citation: Cancer Genet Cytogenet. 1998 Jan 15;100(2):106-10
references.pmid: 9428352
references.citation: Methods Mol Biol. 2006;313:171-92
references.pmid: 16118434
references.citation: Eukaryot Cell. 2006 Mar;5(3):507-17
references.pmid: 16524906
references.citation: Dev Cell. 2001 Oct;1(4):527-37
references.pmid: 11703943
references.citation: Nat Methods. 2012 Mar 27;9(4):341, 343
references.pmid: 22453910
references.citation: J Bacteriol. 1997 Apr;179(7):2154-62
references.pmid: 9079899
references.citation: J Bacteriol. 1999 May;181(10 ):3076-86
references.pmid: 10322008
references.citation: Genetics. 2015 Feb;199(2):315-58
references.pmid: 25657349
references.citation: Yeast. 1998 Jul;14(10):953-61
references.pmid: 9717241
references.citation: Nat Rev Genet. 2012 Jan 24;13(3):189-203
references.pmid: 22269907
references.citation: Genes Dev. 2015 Oct 1;29(19):2010-21
references.pmid: 26404941
references.citation: Mol Syst Biol. 2012;8:608
references.pmid: 22968442
references.citation: J Biol Chem. 1999 Mar 5;274(10):6579-85
references.pmid: 10037752
references.citation: Nat Rev Genet. 2012 Jun 18;13(7):493-504
references.pmid: 22705668
references.citation: Carbohydr Res. 2008 Aug 11;343(12):2024-31
references.pmid: 18353293
references.citation: J Cell Biol. 1999 Jan 11;144(1):71-82
references.pmid: 9885245
references.citation: Curr Opin Cell Biol. 2006 Dec;18(6):658-67
references.pmid: 17046232
references.citation: Curr Genet. 1998 Jun;33(6):412-9
references.pmid: 9644204
references.citation: Histochem Cell Biol. 2013 Sep;140(3):271-83
references.pmid: 23839779
references.citation: Nat Cell Biol. 2001 Jul;3(7):687-90
references.pmid: 11433303