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Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression

Nature Ecology & Evolution volume 2, pages 152–163 (2018)Cite this article

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Abstract

To gain insight into how mammalian gene expression is controlled by rapidly evolving regulatory elements, we jointly analysed promoter and enhancer activity with downstream transcription levels in liver samples from 15 species. Genes associated with complex regulatory landscapes generally exhibit high expression levels that remain evolutionarily stable. While the number of regulatory elements is the key driver of transcriptional output and resilience, regulatory conservation matters: elements active across mammals most effectively stabilize gene expression. In contrast, recently evolved enhancers typically contribute weakly, consistent with their high evolutionary plasticity. These effects are observed across the entire mammalian clade and are robust to potential confounders, such as the gene expression level. Using liver as a representative somatic tissue, our results illuminate how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.

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Fig. 1: Liver gene expression levels are highly conserved across 25 mammalian species.
Fig. 2: The number of promoters and enhancers corresponds with gene expression stability across evolution.
Fig. 3: Conserved regulatory activity is associated with both high and stable gene expression levels.
Fig. 4: Recently evolved enhancer activities contribute weakly to gene expression levels.
Fig. 5: Recurrent recently evolved regulatory elements contribute to gene expression stability.
Fig. 6: An integrated summary of the evolution of mammalian regulatory complexity.

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Acknowledgements

We thank the Cambridge Institute Biological Resources Unit and Genomics Core for technical support, C. Kutter, C. Feig, M. Roller and T. Rayner for useful comments and discussions, and the systems team at the European Molecular Biology Laboratory’s European Bioinformatics Institute for management of computational resources. This research was supported by Cancer Research UK grant 20412, European Research Council grant 615584, Wellcome Trust grants WT108749/Z/15/Z, WT098051, WT202878/A/16/Z and WT202878/B/16/Z, the Institut National de la Santé et de la Recherche Médicale and the European Molecular Biology Laboratory. Cetacean samples were collected by the UK Cetacean Strandings Investigation Programme, funded by Defra and the governments of Scotland and Wales. This is Duke Lemur Center publication no. 1362.

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  1. Camille Berthelot and Diego Villar contributed equally to this work.

Authors and Affiliations

  1. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK

    Camille Berthelot & Paul Flicek

  2. Institut de Biologie de l’Ecole Normale Supérieure, Centre National de la Recherche Scientifique UMR8197, Institut National de la Santé et de la Recherche Médicale U1024, 46 Rue d’Ulm, 75230, Paris, Cedex 05, France

    Camille Berthelot

  3. University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK

    Diego Villar & Duncan T. Odom

  4. Biological and Biomedical Sciences, North Carolina Central University, Durham, NC, 27707, USA

    Julie E. Horvath

  5. North Carolina Museum of Natural Sciences, Raleigh, NC, 27601, USA

    Julie E. Horvath

  6. Evolutionary Anthropology Department, Duke University, Durham, NC, 27707, USA

    Julie E. Horvath

  7. Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK

    Duncan T. Odom & Paul Flicek

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Contributions

C.B., D.V., P.F. and D.T.O. designed the experiments. D.V. performed the experiments. C.B. and D.V. analysed the data. J.E.H. aided in the selection of primate species and provided the tissue samples. C.B., D.V., P.F. and D.T.O. wrote the paper. P.F. and D.T.O. oversaw the work. All authors read and approved the final paper.

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Correspondence to Duncan T. Odom or Paul Flicek.

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P.F. is a member of the scientific advisory boards of Fabric Genomics and Eagle Genomics.

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Berthelot, C., Villar, D., Horvath, J.E. et al. Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression. Nat Ecol Evol 2, 152–163 (2018). https://doi.org/10.1038/s41559-017-0377-2

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