title: Genotype to phenotype mapping and the fitness landscape of the E. coli lac promoter.
abstract: Genotype-to-phenotype maps and the related fitness landscapes that include epistatic interactions are difficult to measure because of their high dimensional structure. Here we construct such a map using the recently collected corpora of high-throughput sequence data from the 75 base pairs long mutagenized E. coli lac promoter region, where each sequence is associated with its phenotype, the induced transcriptional activity measured by a fluorescent reporter. We find that the additive (non-epistatic) contributions of individual mutations account for about two-thirds of the explainable phenotype variance, while pairwise epistasis explains about 7% of the variance for the full mutagenized sequence and about 15% for the subsequence associated with protein binding sites. Surprisingly, there is no evidence for third order epistatic contributions, and our inferred fitness landscape is essentially single peaked, with a small amount of antagonistic epistasis. There is a significant selective pressure on the wild type, which we deduce to be multi-objective optimal for gene expression in environments with different nutrient sources. We identify transcription factor (CRP) and RNA polymerase binding sites in the promotor region and their interactions without difficult optimization steps. In particular, we observe evidence for previously unexplored genetic regulatory mechanisms, possibly kinetic in nature. We conclude with a cautionary note that inferred properties of fitness landscapes may be severely influenced by biases in the sequence data.
authors: Department of Physics, Emory University, Atlanta, Georgia, United States of America. jotwinowski@physics.emory.edu
authors: Jakub
authors: J
authors: Otwinowski
authors: Ilya
authors: I
authors: Nemenman
mesh_terms: D000465:Algorithms; D004843:Epistasis, Genetic; D004926:Escherichia coli / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial; D056726:Genetic Association Studies; D056084:Genetic Fitness; D005838:Genotype; D007763:Lac Operon; D008957:Models, Genetic; D011401:Promoter Regions, Genetic
references: J Neurosci. 2008 Jan 9;28(2):505-18
references: 18184793
references: PLoS Comput Biol. 2010 Nov 18;6(11):e1001007
references: 21124945
references: J Mol Biol. 1988 Apr 20;200(4):709-23
references: 3045325
references: Science. 1999 Apr 2;284(5411):87-9
references: 10102823
references: J Hered. 2010 Mar-Apr;101 Suppl 1:S75-84
references: 20194517
references: IET Syst Biol. 2010 Nov;4(6):428-40
references: 21073241
references: Nat Rev Genet. 2008 Nov;9(11):855-67
references: 18852697
references: Evolution. 2010 Sep;64(9):2510-20
references: 20456492
references: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1572-7
references: 15659551
references: Science. 2010 Jan 22;327(5964):425-31
references: 20093466
references: Nature. 2006 Feb 23;439(7079):936-42
references: 16495990
references: J Stat Softw. 2010;33(1):1-22
references: 20808728
references: Cell Rep. 2012 Jul 26;2(1):150-61
references: 22840405
references: Nature. 2010 Jul 29;466(7306):617-21
references: 20601940
references: BMC Bioinformatics. 2006 Mar 20;7 Suppl 1:S7
references: 16723010
references: Nat Genet. 2005 Jan;37(1):13-4
references: 15624016
references: Nat Methods. 2010 Dec;7(12):1017-24
references: 21076421
references: Am Nat. 2001 Mar;157(3):245-61
references: 18707288
references: Science. 2006 Apr 7;312(5770):111-4
references: 16601193
references: Science. 2011 Jun 3;332(6034):1190-2
references: 21636771
references: Nat Biotechnol. 2008 Oct;26(10):1135-45
references: 18846087
references: Nat Genet. 2011 May;43(5):487-9
references: 21441930
references: J Mol Evol. 2002 Oct;55(4):386-400
references: 12355260
references: PLoS Genet. 2011 Jul;7(7):e1002160
references: 21814515
references: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15936-41
references: 16236723
references: PLoS Genet. 2012;8(3):e1002551
references: 22412384
references: Nucleic Acids Res. 1987 Mar 11;15(5):2343-61
references: 3550697
references: J Theor Biol. 2011 Mar 7;272(1):141-4
references: 21167837
references: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6043-8
references: 17376875
references: Science. 2010 Oct 15;330(6002):376-9
references: 20947767
references: Nat Genet. 2005 Jan;37(1):77-83
references: 15592468
references: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5405-10
references: 20212159
references: Genetics. 2010 May;185(1):293-303
references: 20157005
references: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14058-62
references: 19666487
references: Nature. 2006 Apr 20;440(7087):1007-12
references: 16625187
references: Science. 2011 Jun 3;332(6034):1193-6
references: 21636772
references: PLoS Comput Biol. 2009 Dec;5(12):e1000614
references: 20019803
references: Nat Biotechnol. 2009 Sep;27(9):829-39
references: 19741643
references: Science. 2005 Oct 21;310(5747):499-501
references: 16239478
references: Nature. 2007 Jan 25;445(7126):383-6
references: 17251971
references: BMC Evol Biol. 2004 Oct 28;4:42
references: 15511291
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D698-704
references: 21071413
references: Genome Res. 2003 Nov;13(11):2381-90
references: 14597652
references: PLoS Comput Biol. 2011 Aug;7(8):e1002134
references: 21876664
references: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9158-63
references: 20439748
references: Nature. 2005 Jul 28;436(7050):588-92
references: 16049495
references: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12376-81
references: 18723669
references: J Mol Biol. 1987 Feb 20;193(4):723-50
references: 3612791