Modeling synthetic lethality.
BACKGROUND
Synthetic lethality defines a genetic interaction where the combination of mutations in two or more genes leads to cell death. The implications of synthetic lethal screens have been discussed in the context of drug development as synthetic lethal pairs could be used to selectively kill cancer cells, but leave normal cells relatively unharmed. A challenge is to assess genome-wide experimental data and integrate the results to better understand the underlying biological processes. We propose statistical and computational tools that can be used to find relationships between synthetic lethality and cellular organizational units.


RESULTS
In Saccharomyces cerevisiae, we identified multi-protein complexes and pairs of multi-protein complexes that share an unusually high number of synthetic genetic interactions. As previously predicted, we found that synthetic lethality can arise from subunits of an essential multi-protein complex or between pairs of multi-protein complexes. Finally, using multi-protein complexes allowed us to take into account the pleiotropic nature of the gene products.


CONCLUSIONS
Modeling synthetic lethality using current estimates of the yeast interactome is an efficient approach to disentangle some of the complex molecular interactions that drive a cell. Our model in conjunction with applied statistical methods and computational methods provides new tools to better characterize synthetic genetic interactions.
Le Meur
Nolwenn
N
Division of Public Health Sciences, Fred Hutchinson Cancer Center Research, Program in Computational Biology, Seattle, WA 98109, USA. nlemeur@fhcrc.org
Gentleman
Robert
R
D019295:Computational Biology / Q000379:methods; D004843:Epistasis, Genetic; D005804:Genes, Lethal; D008957:Models, Genetic; D018832:Molecular Chaperones / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; C112806:prefoldin
Genome Biol. 2007;8(9):R186
17845715
Biochem J. 2005 Feb 15;386(Pt 1):1-13
15521820
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D41-4
14681354
Nat Genet. 2000 May;25(1):25-9
10802651
Mol Cell. 2004 Nov 5;16(3):487-96
15525520
Genes Cells. 2006 Feb;11(2):99-110
16436047
Nucleic Acids Res. 2002 Jan 1;30(1):303-5
11752321
Nature. 2002 Jul 25;418(6896):387-91
12140549
Science. 2004 Feb 6;303(5659):808-13
14764870
Nat Rev Cancer. 2005 Sep;5(9):689-98
16110319
BMC Bioinformatics. 2005 Nov 09;6:270
16283923
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
10592173
Genetics. 2006 Jun;173(2):635-46
16582437
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9
16381927
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D452-5
14681455
Nat Biotechnol. 2005 May;23(5):561-6
15877074
Cell. 2006 Mar 10;124(5):1069-81
16487579
Bioinformatics. 2005 Sep 1;21(17):3548-57
15998662
Annu Rev Biochem. 2001;70:603-47
11395418
Science. 2001 Feb 9;291(5506):1001-4
11232561
Cell. 1998 May 29;93(5):863-73
9630229
Bioinformatics. 2005 Mar;21(6):832-4
15531608
Mol Syst Biol. 2007;3:104
17437029
Nature. 2007 Apr 12;446(7137):806-10
17314980