title: The strength of genetic interactions scales weakly with mutational effects.
abstract: BACKGROUND
  Genetic interactions pervade every aspect of biology, from evolutionary theory, where they determine the accessibility of evolutionary paths, to medicine, where they can contribute to complex genetic diseases. Until very recently, studies on epistatic interactions have been based on a handful of mutations, providing at best anecdotal evidence about the frequency and the typical strength of genetic interactions. In this study, we analyze a publicly available dataset that contains the growth rates of over five million double knockout mutants of the yeast Saccharomyces cerevisiae.
  
  
  RESULTS
  We discuss a geometric definition of epistasis that reveals a simple and surprisingly weak scaling law for the characteristic strength of genetic interactions as a function of the effects of the mutations being combined. We then utilized this scaling to quantify the roughness of naturally occurring fitness landscapes. Finally, we show how the observed roughness differs from what is predicted by Fisher's geometric model of epistasis, and discuss the consequences for evolutionary dynamics.
  
  
  CONCLUSIONS
  Although epistatic interactions between specific genes remain largely unpredictable, the statistical properties of an ensemble of interactions can display conspicuous regularities and be described by simple mathematical laws. By exploiting the amount of data produced by modern high-throughput techniques, it is now possible to thoroughly test the predictions of theoretical models of genetic interactions and to build informed computational models of evolution on realistic fitness landscapes.
authors.forename: Andrea
authors.initials: A
authors.lastname: Velenich
authors.forename: Jeff
authors.initials: J
authors.lastname: Gore
mesh_terms: D005075:Biological Evolution; D004843:Epistasis, Genetic; D055786:Gene Knockout Techniques; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D017354:Point Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics*
references.citation: Nat Methods. 2008 Aug;5(8):711-8
references.pmid: 18622397
references.citation: PLoS One. 2008 Jul 16;3(7):e2663
references.pmid: 18648534
references.citation: Nat Rev Genet. 2004 Feb;5(2):101-13
references.pmid: 14735121
references.citation: Theor Popul Biol. 2009 Jun;75(4):286-300
references.pmid: 19285994
references.citation: Nat Rev Genet. 2009 Aug;10(8):565-77
references.pmid: 19584810
references.citation: Nat Genet. 2005 Jan;37(1):77-83
references.pmid: 15592468
references.citation: Evolution. 1998 Aug;52(4):935-949
references.pmid: 28565213
references.citation: Nature. 2007 Jan 25;445(7126):383-6
references.pmid: 17251971
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16653-8
references.pmid: 18931302
references.citation: Science. 2011 Mar 18;331(6023):1433-6
references.pmid: 21415350
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10420-5
references.pmid: 22689976
references.citation: Proc Biol Sci. 2001 Jul 22;268(1475):1469-74
references.pmid: 11454290
references.citation: Nat Genet. 2011 May 29;43(7):656-62
references.pmid: 21623372
references.citation: Science. 2010 Jan 22;327(5964):425-31
references.pmid: 20093466
references.citation: Nature. 2004 Feb 26;427(6977):839-43
references.pmid: 14985762
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12254-9
references.pmid: 22773816
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3461-6
references.pmid: 18305163
references.citation: Nat Methods. 2010 Dec;7(12):1017-24
references.pmid: 21076421
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18638-43
references.pmid: 19858497
references.citation: Nat Rev Genet. 2003 Feb;4(2):145-51
references.pmid: 12560811
references.citation: BMC Evol Biol. 2007 Apr 13;7:60
references.pmid: 17433106
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Science. 2006 Apr 7;312(5770):111-4
references.pmid: 16601193
references.citation: Science. 2011 Jun 3;332(6034):1190-2
references.pmid: 21636771
references.citation: Nat Genet. 2008 Apr;40(4):390-1
references.pmid: 18362882
references.citation: Nat Rev Genet. 2003 Sep;4(9):701-9
references.pmid: 12951571
references.citation: Science. 2011 Jun 3;332(6034):1193-6
references.pmid: 21636772
references.citation: Bioessays. 2005 Feb;27(2):176-88
references.pmid: 15666345
references.citation: Nat Genet. 2010 Mar;42(3):272-6
references.pmid: 20101242
references.citation: Nat Genet. 2005 Oct;37(10):1147-52
references.pmid: 16155567
references.citation: Annu Rev Genet. 2009;43:601-25
references.pmid: 19712041
references.citation: Nature. 2006 Mar 2;440(7080):87-90
references.pmid: 16511495
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2307-12
references.pmid: 17284612
references.citation: Nat Genet. 2007 Apr;39(4):555-60
references.pmid: 17369829
references.citation: Nat Rev Genet. 2005 Feb;6(2):119-27
references.pmid: 15716908
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14402-5
references.pmid: 16983079
references.citation: Nat Rev Genet. 2007 Aug;8(8):610-8
references.pmid: 17637733
references.citation: Curr Opin Chem Biol. 2012 Aug;16(3-4):323-8
references.pmid: 22682889
references.citation: Bioessays. 2008 Apr;30(4):367-73
references.pmid: 18348184
references.citation: Phys Rev Lett. 2011 May 13;106(19):198102
references.pmid: 21668204
references.citation: Evolution. 2012 Oct;66(10):3144-54
references.pmid: 23025604
references.citation: Nature. 2007 May 31;447(7144):585-8
references.pmid: 17538619
references.citation: Evolution. 2005 Jun;59(6):1165-74
references.pmid: 16050094
references.citation: Genetics. 2009 May;182(1):277-93
references.pmid: 19279327
references.citation: Science. 2008 Oct 17;322(5900):405-10
references.pmid: 18818364
references.citation: Nat Rev Genet. 2008 Nov;9(11):855-67
references.pmid: 18852697