title: Negative feedback buffers effects of regulatory variants.
abstract: Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a pool of its spores. Allelic differential expression in the hybrid is due to cis-regulatory differences only. Instead, in the pool of spores allelic differential expression is not only due to cis-regulatory differences but also due to local trans effects that include negative feedback. We found that buffering through such local trans regulation is widespread, typically compensating for about 15% of cis-regulatory effects on individual genes. Negative feedback is stronger not only for essential genes, indicating its functional relevance, but also for genes with low to middle levels of expression, for which tight regulation matters most. We suggest that negative feedback is one mechanism of Waddington's canalization, facilitating the accumulation of genetic variants that might give selective advantage in different environments.
authors: Computational Genomics, Gene Center, Ludwig Maximilians University, Munich, Germany.
authors: Daniel M
authors: DM
authors: Bader
authors: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors: Stefan
authors: S
authors: Wilkening
authors: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors: Gen
authors: G
authors: Lin
authors: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors: Manu M
authors: MM
authors: Tekkedil
authors: Computational Genomics, Gene Center, Ludwig Maximilians University, Munich, Germany.
authors: Kim
authors: K
authors: Dietrich
authors: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany Stanford Genome Technology Center, Palo Alto, CA, USA Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors: Lars M
authors: LM
authors: Steinmetz
authors: Computational Genomics, Gene Center, Ludwig Maximilians University, Munich, Germany gagneur@genzentrum.lmu.de.
authors: Julien
authors: J
authors: Gagneur
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D004271:DNA, Fungal / Q000235:genetics; D030541:Databases, Genetic; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D060005:Genotyping Techniques; D008958:Models, Molecular; D058977:Molecular Sequence Annotation; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D013045:Species Specificity
chemical_list: D004271:DNA, Fungal
keywords: buffering; canalization; cis regulation; feedback; trans regulation
references: Nucleic Acids Res. 2012 Jul;40(13):5926-37
references: 22434883
references: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3874-8
references: 22355134
references: Trends Genet. 2011 Aug;27(8):316-22
references: 21763027
references: Genome Res. 2012 Dec;22(12):2376-84
references: 22919075
references: Nucleic Acids Res. 2013 Mar 1;41(5):e65
references: 23295673
references: Science. 2013 Nov 29;342(6162):1100-4
references: 24136357
references: Science. 2013 Nov 29;342(6162):1052-3
references: 24288321
references: PLoS One. 2013;8(12):e83547
references: 24386226
references: Genome Res. 2014 Mar;24(3):411-21
references: 24318729
references: Genome Res. 2014 Mar;24(3):422-30
references: 24318730
references: Genetics. 2014 Mar;196(3):853-65
references: 24374355
references: Genome Res. 2014 Jun;24(6):963-73
references: 24732588
references: PLoS Genet. 2014 Oct;10(10):e1004692
references: 25340754
references: Bioinformatics. 2015 Jan 15;31(2):166-9
references: 25260700
references: Science. 2002 Aug 16;297(5584):1143
references: 12183620
references: Mol Syst Biol. 2012;8:602
references: 22893000
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D700-5
references: 22110037
references: Nature. 1999 Dec 2;402(6761 Suppl):C47-52
references: 10591225
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Science. 2001 Feb 9;291(5506):1001-4
references: 11232561
references: Nat Genet. 2002 Nov;32(3):432-7
references: 12410233
references: Cell. 2003 Mar 7;112(5):697-709
references: 12628189
references: Nat Genet. 2003 Sep;35(1):57-64
references: 12897782
references: J Bacteriol. 1974 Apr;118(1):8-14
references: 4595206
references: Science. 1975 Apr 11;188(4184):107-16
references: 1090005
references: Genetics. 1986 May;113(1):35-43
references: 3519363
references: J Mol Biol. 1990 Oct 5;215(3):403-10
references: 2231712
references: Q Rev Biol. 2005 Sep;80(3):287-316
references: 16250465
references: BMC Bioinformatics. 2006;7:113
references: 16522208
references: PLoS Genet. 2005 Aug;1(2):e25
references: 16121257
references: Nat Rev Genet. 2006 Nov;7(11):862-72
references: 17047685
references: Mol Cell. 2007 Sep 21;27(6):1005-13
references: 17889672
references: Nat Rev Genet. 2009 Feb;10(2):134-40
references: 19119265
references: Nature. 2009 Feb 19;457(7232):1033-7
references: 19169243
references: PLoS Biol. 2009 Mar 3;7(3):e48
references: 19260763
references: Science. 2009 Apr 10;324(5924):218-23
references: 19213877
references: Science. 2009 May 1;324(5927):659-62
references: 19407207
references: Trends Genet. 2009 Sep;25(9):395-403
references: 19717203
references: Nucleic Acids Res. 2009 Oct;37(18):e123
references: 19620212
references: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5058-63
references: 20194736
references: Bioinformatics. 2010 Apr 1;26(7):873-81
references: 20147302
references: Nature. 2010 Apr 15;464(7291):1039-42
references: 20393561
references: Mol Syst Biol. 2010 May 11;6:368
references: 20461075
references: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9546-51
references: 20460310
references: Genome Res. 2010 Jun;20(6):816-25
references: 20354124
references: Genome Res. 2010 Jun;20(6):826-36
references: 20445163
references: PLoS Genet. 2010 Sep;6(9):e1001109
references: 20838597
references: N Engl J Med. 2010 Nov 18;363(21):2076-7; author reply 2077
references: 21083406
references: Proteomics. 2010 Dec;10(23):4209-12
references: 21089048
references: Genome Biol. 2010;11(10):R106
references: 20979621
references: Genome Res. 2011 Jul;21(7):1131-8
references: 21422276