title: Negative feedback in genetic circuits confers evolutionary resilience and capacitance.
abstract: Natural selection for specific functions places limits upon the amino acid substitutions a protein can accept. Mechanisms that expand the range of tolerable amino acid substitutions include chaperones that can rescue destabilized proteins and additional stability-enhancing substitutions. Here, we present an alternative mechanism that is simple and uses a frequently encountered network motif. Computational and experimental evidence shows that the self-correcting, negative-feedback gene regulation motif increases repressor expression in response to deleterious mutations and thereby precisely restores repression of a target gene. Furthermore, this ability to rescue repressor function is observable across the Eubacteria kingdom through the greater accumulation of amino acid substitutions in negative-feedback transcription factors compared to genes they control. We propose that negative feedback represents a self-contained genetic canalization mechanism that preserves phenotype while permitting access to a wider range of functional genotypes.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: david.marciano@bcm.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Marciano
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rhonald C
authors.initials: RC
authors.lastname: Lua
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Katsonis
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Biology Department, University of St. Thomas, Houston, TX 77006, USA.
authors.forename: Shivas R
authors.initials: SR
authors.lastname: Amin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Herman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Computational and Integrative Biomedical Research Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: lichtarge@bcm.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
mesh_terms: D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000235:genetics; D005075:Biological Evolution; D005246:Feedback; D005786:Gene Expression Regulation; D008957:Models, Genetic; D012641:Selection, Genetic; D012697:Serine Endopeptidases / Q000235:genetics; D000099160:LexA Repressor Protein
chemical_list: D001426:Bacterial Proteins; D012697:Serine Endopeptidases; D000099160:LexA Repressor Protein