Letter | Published:

The diversity-generating benefits of a prokaryotic adaptive immune system

Nature volume 532, pages 385388 (21 April 2016) | Download Citation


Prokaryotic CRISPR-Cas adaptive immune systems insert spacers derived from viruses and other parasitic DNA elements into CRISPR loci to provide sequence-specific immunity1,2. This frequently results in high within-population spacer diversity3,4,5,6, but it is unclear if and why this is important. Here we show that, as a result of this spacer diversity, viruses can no longer evolve to overcome CRISPR-Cas by point mutation, which results in rapid virus extinction. This effect arises from synergy between spacer diversity and the high specificity of infection, which greatly increases overall population resistance. We propose that the resulting short-lived nature of CRISPR-dependent bacteria–virus coevolution has provided strong selection for the evolution of sophisticated virus-encoded anti-CRISPR mechanisms7.

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Primary accessions

European Nucleotide Archive

Data deposits

Sequence data are available from the European Nucleotide Archive under accession number PRJEB12001 and analysis scripts are available from https://github.com/scottishwormboy/vanHoute.


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We thank D. Morley and S. Kay for experimental contributions and A. Gardner for comments on the manuscript. S.v.H. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 660039. E.R.W. received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under Research Executive Agency grant agreement number 327606. E.R.W., A.B. and M.B. also acknowledge the Natural Environment Research Council, the Biotechnology and Biological Sciences Research Council, the Royal Society, the Leverhulme Trust, the Wellcome Trust and the AXA research fund for funding. J.M.B.-D. was supported by the University of California San Francisco Program for Breakthrough in Biomedical Research, the Sandler Foundation, and a National Institutes of Health Director’s Early Independence Award (DP5-OD021344). H.C. was funded by the Erasmus+ programme (European Union), the Explora’Sup programme (Région Rhône-Alpes) and the Centre Régional des Œuvres Universitaires et Scolaires (CROUS; French State).

Author information


  1. ESI and CEC, Biosciences, University of Exeter, Cornwall Campus, Penryn TR10 9EZ, UK

    • Stineke van Houte
    • , Alice K. E. Ekroth
    • , Jenny M. Broniewski
    • , Hélène Chabas
    • , Angus Buckling
    •  & Edze R. Westra
  2. CEFE UMR 5175, CNRS-Université de Montpellier, Université Paul-Valéry Montpellier, EPHE, 1919, route de Mende 34293, Montpellier Cedex 5, France

    • Hélène Chabas
    •  & Sylvain Gandon
  3. Department of Integrative Biology, University of California, Berkeley, California 94720, USA

    • Ben Ashby
    •  & Mike Boots
  4. CEC, Biosciences, University of Exeter, Cornwall Campus, Penryn TR10 9EZ, UK

    • Ben Ashby
    •  & Mike Boots
  5. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94158, USA

    • Joseph Bondy-Denomy
  6. Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK

    • Steve Paterson


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E.R.W., A.B. and S.v.H. conceived and designed the experiments. H.C. performed coevolution experiments. S.v.H., E.R.W., A.K.E.E. and J.M.B. performed all competition experiments and associated analysis of virus persistence and host and virus evolution. S.P. performed and analysed deep sequencing of virus genomes. J.B.-D. supplied virus with anti-CRISPR gene. B.A. and M.B. contributed to discussions and provided feedback throughout the project. S.G. and H.C. helped to set up the experiments with S. thermophilus. S.v.H., E.R.W. and A.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stineke van Houte or Angus Buckling or Edze R. Westra.

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