title: Intersecting transcription networks constrain gene regulatory evolution.
abstract: Epistasis-the non-additive interactions between different genetic loci-constrains evolutionary pathways, blocking some and permitting others. For biological networks such as transcription circuits, the nature of these constraints and their consequences are largely unknown. Here we describe the evolutionary pathways of a transcription network that controls the response to mating pheromone in yeast. A component of this network, the transcription regulator Ste12, has evolved two different modes of binding to a set of its target genes. In one group of species, Ste12 binds to specific DNA binding sites, while in another lineage it occupies DNA indirectly, relying on a second transcription regulator to recognize DNA. We show, through the construction of various possible evolutionary intermediates, that evolution of the direct mode of DNA binding was not directly accessible to the ancestor. Instead, it was contingent on a lineage-specific change to an overlapping transcription network with a different function, the specification of cell type. These results show that analysing and predicting the evolution of cis-regulatory regions requires an understanding of their positions in overlapping networks, as this placement constrains the available evolutionary pathways.
authors.affiliation: 1] Department of Biochemistry &Biophysics, Department of Microbiology &Immunology, University of California, San Francisco, California 94158, USA [2] Tetrad Graduate Program, University of California, San Francisco, California 94158, USA.
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Sorrells
authors.affiliation: 1] Department of Biochemistry &Biophysics, Department of Microbiology &Immunology, University of California, San Francisco, California 94158, USA [2] Tetrad Graduate Program, University of California, San Francisco, California 94158, USA.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Booth
authors.affiliation: 1] Department of Biochemistry &Biophysics, Department of Microbiology &Immunology, University of California, San Francisco, California 94158, USA [2] Biological and Medical Informatics Graduate Program, University of California, San Francisco, California 94158, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Tuch
authors.affiliation: 1] Department of Biochemistry &Biophysics, Department of Microbiology &Immunology, University of California, San Francisco, California 94158, USA [2] Tetrad Graduate Program, University of California, San Francisco, California 94158, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Johnson
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics*; D005800:Genes, Fungal / Q000235:genetics; D007716:Kluyveromyces / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072235:Mating Factor; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D010675:Pheromones / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D010455:Peptides; D010675:Pheromones; C489241:STE12 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000072235:Mating Factor