Letter | Published:

The diversity-generating benefits of a prokaryotic adaptive immune system

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

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

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.

References

  1. 1.

    , , & Unravelling the structural and mechanistic basis of CRISPR-Cas systems. Nature Rev. Microbiol. 12, 479–492 (2014)

  2. 2.

    et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709–1712 (2007)

  3. 3.

    & Virus population dynamics and acquired virus resistance in natural microbial communities. Science 320, 1047–1050 (2008)

  4. 4.

    et al. Strong bias in bacterial CRISPR elements that confer immunity to phage. Nature Commun . 4, 1430 (2013)

  5. 5.

    et al. CRISPR immunity drives rapid phage genome evolution in Streptococcus thermophilus. MBio 6, e00262–e15 (2015)

  6. 6.

    et al. Parasite exposure drives selective evolution of constitutive versus inducible defense. Curr. Biol. 25, 1043–1049 (2015)

  7. 7.

    , , & Bacteriophage genes that inactivate the CRISPR/Cas bacterial immune system. Nature 493, 429–432 (2013)

  8. 8.

    et al. Phage response to CRISPR-encoded resistance in Streptococcus thermophilus. J. Bacteriol. 190, 1390–1400 (2008)

  9. 9.

    et al. Interference by clustered regularly interspaced short palindromic repeats (CRISPR) RNA is governed by a seed sequence. Proc. Natl Acad. Sci. USA 108, 10098–10103 (2011)

  10. 10.

    , , , & CRISPR-induced distributed immunity in microbial populations. PLoS ONE 9, e101710 (2014)

  11. 11.

    The effect of host genetic diversity on disease spread. Am. Nat. 175, E149–E152 (2010)

  12. 12.

    & Does genetic diversity limit disease spread in natural populations? Heredity 109, 199–203 (2012)

  13. 13.

    & The costs and benefits of genetic heterogeneity in resistance against parasites in social insects. Am. Nat. 167, 568–577 (2006)

  14. 14.

    & Genetic diversity of Daphnia magna populations enhances resistance to parasites. Ecol. Lett. 11, 918–928 (2008)

  15. 15.

    & Polygyny versus polyandry versus parasites. Phil. Trans. R. Soc. Lond. B 354, 507–515 (1999)

  16. 16.

    , , & The population and evolutionary dynamics of phage and bacteria with CRISPR immunity. PLoS Genet. 9, e1003312 (2013)

  17. 17.

    , , & Evolutionary dynamics of the prokaryotic adaptive immune system CRISPR-Cas in an explicit ecological context. J. Bacteriol. 195, 3834–3844 (2013)

  18. 18.

    et al. Impacts of biodiversity on the emergence and transmission of infectious diseases. Nature 468, 647–652 (2010)

  19. 19.

    Analyzing tables of statistical tests. Evolution 43, 223–225 (1989)

  20. 20.

    et al. Molecular memory of prior infections activates the CRISPR/Cas adaptive bacterial immunity system. Nature Commun . 3, 945 (2012)

  21. 21.

    , van Passel, M. W. & Brouns, S. J. CRISPR interference directs strand specific spacer acquisition. PLoS ONE 7, e35888 (2012)

  22. 22.

    et al. Degenerate target sites mediate rapid primed CRISPR adaptation. Proc. Natl Acad. Sci. USA 111, E1629–E1638 (2014)

  23. 23.

    , & Sexual reproduction as an adaptation to resist parasites (a review). Proc. Natl Acad. Sci. USA 87, 3566–3573 (1990)

  24. 24.

    , , , & Coevolution with viruses drives the evolution of bacterial mutation rates. Nature 450, 1079–1081 (2007)

  25. 25.

    , , , & Running with the red queen: host-parasite coevolution selects for biparental sex. Science 333, 216–218 (2011)

  26. 26.

    & Diversity and the maintenance of sex by parasites. J. Evol. Biol. 28, 511–520 (2015)

  27. 27.

    An epidemiological model of host–parasite coevolution and sex. J. Evol. Biol. 23, 1490–1497 (2010)

  28. 28.

    & The Red Queen and fluctuating epistasis: a population genetic analysis of antagonistic coevolution. Am. Nat. 154, 393–405 (1999)

  29. 29.

    et al. Costs of CRISPR-Cas-mediated resistance in Streptococcus thermophilus. Proc. R. Soc. B 282, 20151270 (2015)

  30. 30.

    & Capturing the superorganism: a formal theory of group adaptation. J. Evol. Biol. 22, 659–671 (2009)

Download references

Acknowledgements

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

Affiliations

  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

Authors

  1. Search for Stineke van Houte in:

  2. Search for Alice K. E. Ekroth in:

  3. Search for Jenny M. Broniewski in:

  4. Search for Hélène Chabas in:

  5. Search for Ben Ashby in:

  6. Search for Joseph Bondy-Denomy in:

  7. Search for Sylvain Gandon in:

  8. Search for Mike Boots in:

  9. Search for Steve Paterson in:

  10. Search for Angus Buckling in:

  11. Search for Edze R. Westra in:

Contributions

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.

Extended data

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature17436

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing