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  • Matters Arising
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Insufficient evidence for natural selection associated with the Black Death

Nature volume 638, pages E19–E22 (2025)Cite this article

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Matters Arising to this article was published on 19 February 2025

The Original Article was published on 19 October 2022

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arising from: J. Klunk et al. Nature https://doi.org/10.1038/s41586-022-05349-x (2022).

Klunk et al.1 analysed ancient DNA from before, during and after the Black Death, and claimed that large allele frequency changes at immune genes in aggregate, and at four specific variants, reflected natural selection. These claims are unsupported for four reasons. First, the enrichment in immune genes disappears if an appropriate randomization test is carried out; second, after correcting an error in the estimation of allele frequencies, none of the four reported loci pass the original filtering thresholds; third, these filtering thresholds do not adequately correct for multiple testing, and even the original results were not statistically significant. Finally, we find no evidence of significant change in frequency of the ERAP2 variant rs2549794, either in the data reported by Klunk et al. or in published data for samples spanning 2,000 years.

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Fig. 1: Reported enrichment persists even after permutation to remove any signal that could be due to the Black Death.
Fig. 2: Bias in allele frequency estimates based on genotype likelihoods.
Fig. 3: No evidence of selection at rs2549794.

Data availability

No new data were generated for this publication. The sequence data from Klunk et al.1 were obtained from the authors. Other data sources are described in the Supplementary Methods.

Code availability

Code to replicate the analyses described here is available at https://github.com/arbarton/Klunk_matters_arising/.

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Acknowledgements

P.S. was supported by the European Molecular Biology Organisation, the Vallee Foundation, the European Research Council (grant 852558), the Wellcome Trust (217223/Z/19/Z), and Francis Crick Institute core funding (FC001595) from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. C.G.S. and I. Moltke were funded by a European Research Council starting grant awarded to I. Moltke (ERC-2018-STG-804679). I. Moltke was also supported by a Villum Fonden Young Investigator grant (project VIL19114). A.R.B. and D.R. were supported by the John Templeton Foundation (grant 61220). D.R. was also supported by National Institutes of Health grant HG012287, the Allen Discovery Center programme, a Paul G. Allen Frontiers Group advised programme of the Paul G. Allen Family Foundation, and the Howard Hughes Medical Institute. I. Mathieson was supported by the National Institute of General Medical Sciences (GM133708). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding agencies.

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Author notes

  1. These authors contributed equally: Alison R. Barton, Cindy G. Santander

Authors and Affiliations

  1. Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA

    Alison R. Barton & David Reich

  2. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Cindy G. Santander & Ida Moltke

  3. Ancient Genomics Laboratory, The Francis Crick Institute, London, UK

    Pontus Skoglund

  4. Department of Genetics, Harvard Medical School, Boston, MA, USA

    David Reich

  5. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    David Reich

  6. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    David Reich

  7. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Iain Mathieson

Authors
  1. Alison R. Barton
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  3. Pontus Skoglund
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  4. Ida Moltke
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Contributions

A.R.B., C.G.S., P.S., I. Moltke, D.R. and I. Mathieson conceived and designed the project, analysed data and wrote the manuscript.

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Correspondence to Iain Mathieson.

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Barton, A.R., Santander, C.G., Skoglund, P. et al. Insufficient evidence for natural selection associated with the Black Death. Nature 638, E19–E22 (2025). https://doi.org/10.1038/s41586-024-08496-5

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