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Cell Rep. 2014 Jun 26;7(6):1789-95. doi: 10.1016/j.celrep.2014.05.018. Epub 2014 Jun 5.

Negative feedback in genetic circuits confers evolutionary resilience and capacitance.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: david.marciano@bcm.edu.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Biology Department, University of St. Thomas, Houston, TX 77006, USA.
4
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.

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.

PMID:
24910431
PMCID:
PMC4103627
DOI:
10.1016/j.celrep.2014.05.018
[Indexed for MEDLINE]
Free PMC Article

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